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Table of Contents
Efficacy of Allogeneic HSCT in Intermediate Risk
Evidence Based Nutritional Guidelines for Pediatric
Novel Immunotherapeutic Approaches...treatment of Acute Leukemia
The biology and therapy of Adult Acute Lymphoblastic Leukemia
Update on Diagnosis, Risk, Mngt. of Acute Myeloid Leukemia
RESEARCH ARTICLE
Efficacy of Allogeneic Hematopoietic Stem
Cell Transplantation in Intermediate-Risk
Acute Myeloid Leukemia Adult Patients in
First Complete Remission: A Meta-Analysis of
Prospective Studies
Dandan Li1,2☯, Li Wang1,2☯, Honghu Zhu3, Liping Dou1, Daihong Liu1, Lin Fu4, Cong Ma5,
Xuebin Ma6, Yushi Yao1, Lei Zhou1,7, Qian Wang1, Lijun Wang1, Yu Zhao1, Yu Jing1,
Lili Wang1, Yonghui Li1*, Li Yu1*
1 Department of Hematology, Chinese PLA General Hospital, Beijing, China, 2 Medical College of Chinese
PLA, Beijing, China, 3 Department of Hematology, Peking University People’s Hospital, Peking University
Institute of Hematology, Beijing, China, 4 Department of Hematology, Peking University Third Hospital,
Beijing, China, 5 Department of clinical laboratory, PLA Navy General Hospital, Beijing, China, 6 Tumor
diagnosis and treatment center, PLA Navy General Hospital, Beijing, China, 7 Department of Hematology,
No. 202 Hospital of PLA, Shenyang, China
OPEN ACCESS
Citation: Li D, Wang L, Zhu H, Dou L, Liu D, Fu L, et
al. (2015) Efficacy of Allogeneic Hematopoietic Stem
Cell Transplantation in Intermediate-Risk Acute
Myeloid Leukemia Adult Patients in First Complete
Remission: A Meta-Analysis of Prospective Studies.
PLoS ONE 10(7): e0132620. doi:10.1371/journal.
pone.0132620
Editor: Antonio Perez-Martinez, Hospital Infantil
Universitario Niño Jesús, SPAIN
Received: January 19, 2015
Accepted: June 16, 2015
Published: July 21, 2015
Copyright: © 2015 Li et al. This is an open access
article distributed under the terms of the Creative
Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information files.
Funding: This work was supported by grants from
the Doctor Scientific research innovation projects,
National Natural Science Foundation of China
(81370635, 81170518, 81270611, and 81470010),
Capital Medical Development Scientific Research
Fund (SF2001-5001-07), Beijing Natural Science
Foundation (7151009), National Public Health Grant
Research Foundation (No. 201202017), and the
☯ These authors contributed equally to this work.
* chunhuiliyu@yahoo.com (LY); yonghuililab@163.com (YL)
Abstract
Hematopoietic stem cell transplantation (HSCT) and consolidation chemotherapy have
been used to treat intermediate-risk acute myeloid leukemia (AML) patients in first complete
remission (CR1). However, it is still unclear which treatments are most effective for these
patients. The aim of our study was to analyze the relapse-free survival (RFS) and overall
survival (OS) benefit of allogeneic HSCT (alloHSCT) for intermediate-risk AML patients in
CR1. A meta-analysis of prospective trials comparing alloHSCT to non-alloHSCT (autologous HSCT [autoHSCT] and/or chemotherapy) was undertaken. We systematically
searched PubMed, Embase, and the Cochrane Library though October 2014, using keywords and relative MeSH or Emtree terms, ‘allogeneic’; ‘acut*’ and ‘leukem*/aml/leukaem*/leucem*/leucaem*’; and ‘nonlympho*’ or ‘myelo*’. A total of 7053 articles were
accessed. The primary outcomes were RFS and OS, while the secondary outcomes were
treatment-related mortality (TRM) and relapse rate (RR). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated for each outcome. The primary outcomes were RFS
and OS, while the secondary outcomes were TRM and RR. We included 9 prospective controlled studies including 1950 adult patients. Patients with intermediate-risk AML in CR1
who received either alloHSCT or non-alloHSCT were considered eligible. AlloHSCT was
found to be associated with significantly better RFS, OS, and RR than non-alloHSCT (HR,
0.684 [95% CI: 0.48, 0.95]; HR, 0.76 [95% CI: 0.61, 0.95]; and HR, 0.58 [95% CI: 0.45,
0.75], respectively). TRM was significantly higher following alloHSCT than non-alloHSCT
(HR, 3.09 [95% CI: 1.38, 6.92]). However, subgroup analysis showed no OS benefit for
PLOS ONE | DOI:10.1371/journal.pone.0132620 July 21, 2015
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Meta-Analysis of AlloHSCT in Intermediate-Risk AML
capital of the public health project
(Z111107067311070).
Competing Interests: The authors have declared
that no competing interests exist.
alloHSCT over autoHSCT (HR, 0.99 [95% CI: 0.70, 1.39]). In conclusion, alloHSCT is associated with more favorable RFS, OS, and RR benefits (but not TRM outcomes) than nonalloHSCT generally, but does not have an OS advantage over autoHSCT specifically, in
patients with intermediate-risk AML in CR1.
Introduction
Acute myeloid leukemia (AML) is a heterogeneous disease. An important prognostic factor
for AML patients is the presence of cytogenetic abnormalities at diagnosis. The categories of
AML (good-, intermediate-, and poor-risk), based on cytogenetic features have each been
assigned a risk-adapted treatment regimen after post-remission therapy [1]. According to the
AML guidelines of the National Comprehensive Cancer Network (NCCN; AML, Version
1.2014; www.nccn.org) [2], high-dose cytarabine (HiAra-C)-based chemotherapy is most beneficial for patients with core-binding factor AML[3,4]. Allogeneic hematopoietic stem cell
transplantation (alloHSCT) has been established as the preferred post-remission therapy for
AML patients with defined adverse risk cytogenetic features [5–7]. However, the best postremission treatment (whether alloHSCT, or non-alloHSCT [autologous stem cell transplantation (autoHSCT), chemotherapy]) for intermediate-risk AML patients remains to be determined [8–10].
Over the past four decades, there has been evidence demonstrating the efficacy of HSCT
in patients with intermediate-risk AML. According to donor versus no-donor studies,
alloHSCT is the best treatment option for younger patients with intermediate-risk AML in
first complete remission (CR1) [9,11], as it confers a significant relapse-free survival (RFS)
and overall survival (OS) benefit in these patients [12]. In contrast, another study showed that
there was no RFS or OS benefit [5]. Moreover, numerous prospective trials have demonstrated
that alloHSCT increases treatment-related mortality (TRM) [5,11,12], and can lead to graftversus-host disease (GVHD), which has substantial adverse effects on the quality of life.
With advances in determining the cytogenetic and molecular lesions underlying the pathogenesis of AML, risk-stratified treatment has become possible. There is evidence that cytogenetic analysis can identify biologically distinct subsets of AML, allowing tailored therapeutic
approaches [13,14]. Moreover, higher resolution and key loci tested for HLA matching [15],
the increase in unrelated-donor pool sizes, and the use of haplo-identical HSCT technology
[16,17] have improved donor HLA matching and selection. There have also been improvements in conditioning regimens, supportive relative therapy (including carbapenem and antifungal agents to treat bacterial and fungal infections), and new immune suppressant drugs
such as tacrolimus and mycophenolate mofetil for GVHD prophylaxis [18,19]. Technological
improvements have been aided by an increase in the number of alloHSCT clinical trials that
have been carried out to determine the optimal post-remission treatment for intermediate-risk
AML. Hence, we asked whether using alloHSCT to treat intermediate-risk AML patients in
CR1 was comparable to using autoHSCT. If autoHSCT has similar RFS and OS benefits to
alloHSCT in these patients, it would be highly valuable information because the autograft
source is easier to obtain and is associated with fewer less post-transplant complications, especially GVHD.
Koreth et al. [9] carried out a meta-analysis to analyze alloHSCT for AML patients, and
included good-, intermediate-, and poor-risk subgroup analysis. As they only analyzed RFS
and OS, there were no overall robust data on TRM and relapse rate (RR). For intermediate-risk
PLOS ONE | DOI:10.1371/journal.pone.0132620 July 21, 2015
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Meta-Analysis of AlloHSCT in Intermediate-Risk AML
AML patients in CR1, the doctor should balance disease-related and transplant-related risks
before their decision make. Unfortunately, there are currently no uniform guidelines. In our
study, we pooled the primary outcomes (OS and RFS) and the secondary outcomes (TRM and
RR) of available prospective clinical trial data.
Methods
We searched PubMed, Embase and the Cochrane Library Registry of Controlled Trials
(updated October 2014), using the following terms and related MeSH terms: ‘allogeneic’;
‘acut ’ and ‘leukem / aml/ leukaem / leucem / leucaem ’; and ‘nonlympho ’ or ‘myelo ’,
which is the search strategy used by Koreth et al. [9]. We limited our search to adults, humans,
and English and Chinese language articles. The titles and abstracts were screened, and nonrelevant articles were excluded. Cross-references from selected articles, recent reviews, and
meta-analysis were also accessed to identify other potentially eligible studies [9,20,21]. Full text
articles were assessed to extract the data for this meta-analysis.
Potential studies for inclusion were prospective trials of adults (wholly or largely) with intermediate-risk AML in CR1 that were assigned to receive alloHSCT or non-alloHSCT. The intermediate-risk classification was defined by cytogenetics and molecular abnormalities. The
outcomes were OS, RFS, RR, and TRM. If more than one publication reported a trial, the most
up-to-date data were analyzed. Unadjusted hazard ratios (HR) were recorded in our analysis,
as adjusted HR values may have been modified according to different variables in different
studies. The baseline characteristics were assessed to equalize related covariates between the
alloHSCT and non-alloHSCT groups. Furthermore, we utilized the Newcastle-Ottawa Scale to
determine the quality of the included articles [22].
Two reviewers independently extracted the data. Data were recorded included the following:
first author, publication year, total patient numbers, number of patients assigned to each treatment category, median follow-up duration (months), number of events (death and relapse) in
each arm, assessment criteria for intermediate-risk AML, induction treatment, conditioning
regimen, study endpoints for OS, and/or RFS benefit and so on. We recorded OS and RFS (also
reported as disease free survival, failure-free survival, or leukemia-free survival) according to
the individual studies. Data on RR and TRM (also reported as non-relapse mortality) were also
collected. If important information was not provided in the paper, we attempted to contact the
corresponding author to obtain it.
We used Stata (version 12.0) software (StataCorp, College Station, TX) to analyze the data.
Publication bias was estimated using a funnel plot and P values from the Egger’s test. The Q
statistic and I2 were used to assess heterogeneity. Some of the HRs for RFS and OS were calculated using the spreadsheet [23]. A forest plot with pooled HRs and 95% confidence intervals
(CI) for the RFS, OS, TRM, and RR benefit of alloHSCT versus non-alloHSCT was used in random effects analysis, regardless of the heterogeneity between groups. Further subgroup analysis
of OS was conducted. P < 0.05 was considered statistically significant. To evaluate the impact
of missing RFS or OS data, we conducted sensitivity analyses. We also analyzed the impact of
trials that stratified treatment options according to subgroup, such as alloHSCT versus
autoHSCT and alloHSCT versus chemotherapy.
Results
Study Selection and Characteristics
Our initial online search yielded 7053 articles (Fig 1). A total of 6908 non-relevant articles were
excluded after screening the titles and abstracts. Two reviewers carefully read 145 full text articles in a structured format. A total of 41 articles relevant to autoHSCT versus non-alloHSCT
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Meta-Analysis of AlloHSCT in Intermediate-Risk AML
Fig 1. The flowchart of search strategy.
doi:10.1371/journal.pone.0132620.g001
treatment for AML in CR1, including 9 articles that referred to intermediate-risk AML in CR1,
were selected. We recorded 41 articles relevant to alloHSCT versus non-alloHSCT treatment
for AML patients in CR1 that provided prospective data on RFS and/or OS [7,24–54], as
detailed in S1 Table. Of these, 9 articles were related to intermediate-risk AML [5,6,11,12,55–
59]; therefore, we extracted these data in detail (Tables 1, 2, 3 and 4). When estimating and
extracting the data, there were no significant discrepancies between the analyses of the two
reviewers. It is noted that the “intermediate-risk” acute myeloid leukemia is not a general consensus group, it is a dynamic changing concept and the included articles involved different
“intermediate-risk” definition. However, the majority of “intermediate-risk” AML is identical
and the risk stratification based on cytogenetics and molecular abnormalities is same, that is
“intermediate-risk” includes normal cytogenetics, +8, and all other abnormal cytogenetics.
Thus, we think it is feasible to pool these articles. To better show the concept of “intermediaterisk” AML evolves, we summarized the change of intermediate-risk (Table 3). Based on the
cytogenetics and molecular abnormalities of intermediate-risk changes recently, we classified
the 9 included articles into two subgroups: earlier criteria group and updated criteria group,
and conducted a subgroup meta-analysis based on this clinical heterogeneity.
Qualitative Assessment
The articles included in our review were regarded as high quality, as the main inclusion criteria
were that the trial had to be prospective and controlled to avoid confounding errors of bias that
occur with retrospective analyses. The clinical trials enrolled patients, ranging from 32 to 713
in number, from 1987 to 2011. The trial that included only 32 patients was not excluded from
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Meta-Analysis of AlloHSCT in Intermediate-Risk AML
Table 1. Summary of trials characteristic.
Author
Publication y
Trial Name
N
Enrollment
ys
AlloHSCT Arm
Median age y
(range)
Non-alloHSCT arm
Median age y (range)
Int-risk group
Median age y
(range)
Median followup Mon (range)
Harousseau
1997a[55]
GOELAM
94
1987–1994
NA
NA
NA
62 (23–103)
Slovak 2000[6]
E3489/S9034
128
1990–1995
34 (18–54)
39 (16–55)
40 (16–55)
57.6 (8–90)
Suciu 2003[5]
EORTC/
GIMEMA-AML10
165
1993–1999
35 (15–45)
33 (15–45)
NA
48 (NA)
Tsimberidou2003
[56]
AML8
49
1996–2000
mean: 28 ~b
Mean: Auto 44
(NA)bMean: Chemo 46
(NA)b
NA
43 (18–64)
Brunett 2006
[12,64]
MRC AML10
713
1988–1995
NA (0–45+)
NA (0–45+)
NA
142 (26–193)
Cornelissen 2007
[11]
HOVON/SAKK
AML4/29/42
511
1987–2003
39 (15–55)
39 (16–55)
NA
63 (NA)
Pfirrmann 2012[57]
AML96-1
190
1996–2003
41 (15–60)
Auto 47 (17–60)Chemo
50 (18–60)
48 (42–56)
98.4 (3.6–162)
Zhu 2013[58]
AML05
32
2005–2011
38 (15–53)b
28 (14–59)b
36.5 (14–59)
36 (6–83)
Stelljes 2014[59]
AMLCG 99
68
1999–2011
45 (16–59)
46 (17–59)
NA
94.8 (NA-144)
y indicates year; Int-risk, intermediate-risk; NA, not applicable; Auto, autogenetic group; and Chemo, chemotherapy.
a
This study only reported 4y-RFS and 4y-OS.
data from int-risk AML CR1 group.
b
doi:10.1371/journal.pone.0132620.t001
the study because it was based on the new cytogenetic criteria [58]. The inclusion criteria for
patients were as follows: de-novo adult AML, no severe metabolic disease, and no cardiac, pulmonary, or other diseases (Table 2). One of the 9 articles included some pediatric patients [12],
another included a minority population with myelodysplasia syndrome [59], and a third
included patients with secondary AML [57]. Different studies had varying cytogenetic criteria,
such as those of the Southwest Oncology Group (SWOG), International System for Cytogenetic Nomenclature (ISCN), the Medical Research Council (MRC United Kingdom), and the
NCCN 2014 (Table 3). We summarized the details according to the main cooperative group
cytogenetic risk categories mentioned in our inclusion studies. In the trial conducted by
Table 2. Therapies utilized of trials.
Author Publication y
Induction Therapy (optional)
Consolidation Chemotherapy
Conditioning Regimen
Harousseau 1997[55]
Ara-C+IDR/RBZ
Amsa+Ara-C
Bu+Cy; TBI
Slovak 2000[6]
IDA+Ara-C×1–2
HiAra-C
Bu+Cy
Suciu 2003[5]
DNR/IDA/Mito+Ara-C+VP×1–2
DNR/IDA/Mito+Ara-C+VP×1–2
Cy+TBI (12Gy); Bu+Cy
Tsimberidou 2003[56]
Ara-C+IDA×2
HiAra-C
Bu+Cy
Brunett 2006[12,64]
DNR+Ara-C+Tg/VP×2
CTX
Cy+TBI (7.5-14Gy); Bu+Cy
Cornelissen 2007[11]
DNR/IDA+Ara-C-> Amsa+midAra-C
CTX+Mito+etoposide (only 65%)
Bu+Cy
Pfirrmann 2012[57]
MidAra-C; Mito, etoposide and Amsa×2
HiAra-C
TBI (12Gy); Bu+Cy
Zhu 2013[58]
DNR+IDA×1–2
MidAra-C±DNR/Mito
Ara-C+Bu+Cy+Me-CCNU±ATG
Stelljes 2014[59]
Tg+Ara-C+DNR or HiAra-C+Mito×2
Tg+Ara-C+DNR or none
Bu+Cy
y indicates year; NA, not applicable; Cy, cyclophosphamide; TBI, total body irradiation; Bu, busulfan; Ara-C, cytarabine; IDR, idarubicin; RBZ, rubidazone;
Amsa, amsacrine; IDA, idarubicin; HiAra-C: high-dose Ara-C; DNR, daunorubicin; Mito, mitoxantrone; VP, etoposide; Tg, thioguanine; CTX,
cyclophosphamide; MidAra-C, intermediate-dose AraC; Mel, melphalan; Flud, fludarabine; BUS, busulfan; and ATG, Anti-thymocyte globulin.
doi:10.1371/journal.pone.0132620.t002
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Meta-Analysis of AlloHSCT in Intermediate-Risk AML
Table 3. Eligibility, intermediate-risk criteria and other characteristic of trials.
Author
Publication y
Multicenter
Eligibility for Study
Standard
criteria
Intermediate-risk inclusion
Stem
cellsource
Donor category
Harousseau
1997[55]
Yes
de novo AML; 15–50y
NA
All other abns excluding: t(8;21), t
(15;17) or inv (16), -5, 5q-, -7, or
multiple abns
BM
MSD
Slovak 2000
[6,9]
Yes
AML; 16–55y; no prior treatment;
no infection/renal/hepatic/cardiac
diagnosis
SWOG
+8,-Y, +6, del(12p), or NK
BM
MSD or HLAsingle
mismatched
family donor
Suciu 2003
[5,9]
Yes
AML; 15–46y; no prior Rx/MDS/
APL; no renal/hepatic/cardiac/
pulmonary/neurologic diagnosis
ISCN
NK,-Y
BM (some
TCD)
MSD
Tsimberidou
2003[56]
Yes
de novo AML; 60y; no APL or
M3v; performance status
score2; no hepatic/cardiac/
infection diagnosis
NA
NK (+8 or <3 abns), excluding those
involving chromosomes 5 or 7
BM
MSD
Brunett 2006
[9,12,64]
Yes
AML; 55y includes pediatric;
few "good-risk cytogenetics"
NA
NK, all other abns excluding: t(15;17), t
(8;21), inv(16); -7, -5, del 5q, abn(3q)
and CK
BM
MSD
Cornelissen
2007[11]
Yes
de-novo AML; 15–50 or 55y; no
APL; no severe metabolism/
cardiac/pulmonary/neurologic
diagnosis
NA
All other abns excluding: t(8;21)(q22;
q22), inv(16), t(16;16)(p13; q22), nor
CK, -5q, -7q, abn(3q), t(6;9)(q23;q34),
abn(11q23), t(9;22)(q34;q11)
BM
MSD
Pfirrmann
2012[57]
Yes
15–60y; de-novo or secondary
AML; CR; excluding t(8;21)AML
NA
Except the following karyotypes: CK, -5/
del(5q), -7/del(7q), hypodiploid
karyotypes (other than-X and-Y),
abn3q, abn11q, abn12p, t(6;9), t(9;22), t
(9;11), +11, +13, +21, or +22. Including
inv(16)/t(16;16)
BM/PB
MSD
Zhu 2013[58]
Yes
14–60y; de-novo AML with t
(8;21); received CR with one or
two induction cycles; no
contraindications
NCCN14
t(8;21)AML with c-KIT mutation
BM+PB
MSD, MUD, HRD
Stelljes 2014
[59]
Yes
de-novo AML, 16 ys, MDS with
more than 10% BM blasts
ELN-2010
Cytogenetic abns not classified as
favorable or adverse
BM/PB
MSD, MUD
y indicates year; NA, not applicable; BM, bone marrow; MSD, HLA-matched sibling donor; abns, abnormality; NK, normal karyotype; TCD, T-cell depleted;
CK, complex karyotype; PB, peripheral blood; MUD, HLA-matched unrelated donor; and HRD, haploidentical related donor.
doi:10.1371/journal.pone.0132620.t003
Pfirrmann et al. [57], there were three points of relevance to consider. First, they included
some intermediate-risk and inv(16)/t(16;16) patients because they had used their own criteria
to categorize the patient group. Second, the intermediate-risk group in this study was based on
an estimate. According to the cytogenetic risk profile at diagnosis, there were 469 intermediate-risk, and 91 high-risk AML patients, but in the final analysis, the author included 452 cases
with complete data. Therefore we assumed that the majority of patients had intermediate-risk
AML. Third, when extracting the data related to intermediate-risk, we chose the favorable
score groups (AML96). We did not include AML2003 trials, because the population studied in
this trial was not equivalent to that of AML96; it included good-, intermediate-, and poor-risk
patients, not just intermediate- and poor-risk patients. We used the Newcastle-Ottawa Scale to
comprehensively assess each of the 9 studies included (Tables 5 and 6) [22]. These scale tables,
includes the most important factors to be compared, as well as the other factors. However, we
did not strictly abide by the important or the other factors that needed to compare; instead, we
only described the baseline characteristics (Table 6).
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Meta-Analysis of AlloHSCT in Intermediate-Risk AML
Table 4. The comparison and outcome of alloHSCT benefit in intermediate-risk AML-CR1?
Author Publication y
AlloHSCT v Non-HSCT Arms
Overall
conclusion
in AML
RFS
OS
Overall conclusion in int-risk
AML
RFS
a
Harousseau 1997[55]
Allo v CC
No
Slovak 2000[6]
Allo v Auto v CC
No
No
No
Suciu 2003[5]
Allo v Auto
Yes
No
OS
TRM
RR
RFS
RFS
OS
Yes
No
No
No
No
No
No
Yes
Yes
No
No
No
No
No
Allo v Auto v CC
No
No
Brunett 2006[12,64]
Allo v Auto v Obs
Yes
No
Yes
Yes
Yes
Yes
Cornelissen 2007[11]
Allo v Auto v Obs
Yes
No
Yes
No
Yes
Yes
Pfirrmann 2012[57]
Allo v Auto v CC
Zhu 2013[58]
Allo v Auto/CC
No
No
Stelljes 2014[59]
Allo v CC
Yes
Yes
OS
Allo v CC in
int-risk AML
a
Tsimberidou 2003[56]
Yes
Allo v Auto
in int-risk
AML
No
No
Yes
Yes
No
Yes
Yes
y indicates year; Int-risk, intermediate-risk; Allo, allogeneic stem cell transplantation; Auto, autologous stem cell transplantation; and CC, consolidation
chemotherapy.
a
The studies data were not analyzed in this meta-analysis, for there were no available data for HR and 95% CI, only reported outcome.
The empty tables show there were not applicable data.
doi:10.1371/journal.pone.0132620.t004
Because our aim was to analyze outcomes following alloHSCT and non-alloHSCT, we
included all prospective controlled studies, including donor versus no-donor trials and other
forms of trials. We could not assess the potential bias produced by patient selection and the
exclusion of patients with no HLA-matched siblings.
To ensure relative comparability, the 9 studies included in our meta-analysis had similar
induction, consolidation chemotherapy, and conditioning regimens (Table 2). The induction
regimens in most cases were daunorubicin and cytarabine (the DA regimen) or different doses
of cytarabine, while the consolidation regimen was mainly cytarabine with or without other
Table 5. The selection of Newcastle-Ottawa Scale.
Author
Publication y
Representativeness of the exposed
cohort (a or b = 1, c or d = 0)
Selection of the not
exposed cohort
(a = 1)
Ascertainment of
exposure (a or b = 1)
Demonstration that outcome of interest
was not present at start of study (a = 1,
b = 0)
Harousseau
1997[55]
b
a
a
a
Slovak 2000[6]
b
a
a
a
Suciu 2003[5]
b
a
a
a
Tsimberidou
2003[56]
a
a
a
a
Brunett 2006
[12,64]
a
a
a
a
Cornelissen
2007[11]
a
a
a
a
Pfirrmann 2012
[57]
b
a
a
a
Zhu 2013[58]
b
a
a
a
Stelljes 2014
[59]
a
a
a
a
y indicates year.
doi:10.1371/journal.pone.0132620.t005
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Meta-Analysis of AlloHSCT in Intermediate-Risk AML
Table 6. The comparison and outcome of Newcastle-Ottawa Scale.
Author
Publication y
Comparability of cohorts on the basis of the design or
analysisa
Assessment of
outcome (a or b = 1)
follow-up long
enough (a = 1,
b = 0)
Adequacy of follow
up of cohorts (a = 1,
b = 0)
Harousseau
1997[55]
NA
b
a
b
Slovak 2000[6]
NA
b
a
a
Suciu 2003[5]
Age, WBC count at diagnosis, FAB subtype, and the CR rate
after the first induction coursec
b
a
a
Tsimberidou
2003[56]
Ageb
b
a
a
Brunett 2006
[12,64]
Age, Sex, Type of AML, WBC count, FAB type,Risk group,
Status after course 1, Intermediate-risk, Adverse-risk,
UnknowncFavorable-riskb
b
a
a
Cornelissen
2007[11]
Age, FAB type, WBC count, Number of cycles to achieve
remission, Cytogenetic risk distributions prognostic risk scoreb
b
a
a
Pfirrmann 2012
[57]
only described: age, sex, WBC count, disease status,
cytogenetic risk profile at diagnosis, combined cytogenetic risk,
disease status variable, FLT3-ITD mutant-to-wild-type ratio,
NPM1 mutation status, CEBPA mutation status, peroxidasepositive blasts, CD34-positive blasts, Blasts in bone marrow
after first cycle of induction
b
a
b
Zhu 2013d[58]
Age, WBC count, BM blastc
b
a
a
Stelljes 2014
[59]
Age, cytogenetic risk classification, sex, FAB type, WBC count,
LDH, induction treatmentc
b
a
a
y indicates year; NA, not applicable; and WBC, white blood cell.
a
For most of the intermediate-risk are subgroup of the AML patients, there are no direct comparison between intermediate-risk group, so this item we just
referred, not literally to the criteria
P < 0.05
b
P > 0.05
d
comparison of group among intermediate-risk AML patients, other comparison of AML patients.
c
doi:10.1371/journal.pone.0132620.t006
drugs. The myeloablative regimen included busulfan (Bu) and cyclophosphamide (Cy) or total
body irradiation (TBI), followed by graft infusions (bone marrow and/or peripheral blood
Fig 2. Forest plot of the RFS benefit of alloHSCT in intermediate-risk AML-CR1.
doi:10.1371/journal.pone.0132620.g002
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Meta-Analysis of AlloHSCT in Intermediate-Risk AML
stem cells). When extracting the data, the essential requirement was that any heterogeneity
within the study not be significant. There was one study where the patients who underwent
alloHSCT were younger than those who underwent non-alloHSCT (autoHSCT or HiAra-C)
[56]. It is important to note that the aim of this meta-analysis was to study intermediate-risk
AML. Indeed, some studies did not have clinical characteristics of subgroup comparing
alloHSCT with non-alloHSCT arms. Table 4 listed the outcome of alloHSCT benefit or not in
intermediate-risk AML-CR1.
RFS benefit
The overall RFS was analyzed via a random-effects forest plot of the HRs from all of the studies.
A total of 7 articles reported intermediate-risk AML data for RFS, while only 1 article reported
4-year RFS. The overall HR was 0.68 [95% CI: 0.48, 0.95] (P = 0.024). For the 6 articles,
adjusted HRs and non-adjusted HRs were pooled, and I2 was 67.9% (P = 0.008; Fig 2).
AlloHSCT-treated intermediate-risk AML patients in CR1 had a significant decrease in the
incidence of death or AML relapse. The recent two articles [58,59] included “intermediaterisk” AML patients had a minor difference definition with the others. Then, we conducted a
subgroup meta-analysis based on this clinical heterogeneity. The result showed both RFS benefit of alloHSCT in earlier criteria group and updated criteria group (HR: 0.79, 95% CI: 0.66 to
0.94; HR: 0.33, 95% CI: 0.13 to 0.87; respectively, Fig 2).
OS benefit
The OS was analyzed via a random-effects forest plot of the HRs from all of the studies. A total
of 9 articles reported intermediate-risk AML data for OS, including some articles that reported
the adjusted OS. However, only 1 article reported 4-year OS, so this article was not included in
the final analysis. The overall HR was 0.76 [95% CI: 0.61, 0.95] (P = 0.016), and the overall I2
was 32.9% (P = 0.166; Fig 3A). Data were available to compare alloHSCT and autoHSCT subgroups as well as alloHSCT and chemotherapy subgroups. The former included 4 articles with
183 and 234 patients, respectively, while the latter included 4 articles assessing 156 and 149
patients, respectively. Interestingly, we found that the HR of OS for alloHSCT versus
autoHSCT was 0.99 [95% CI: 0.70, 1.39] (P = 0.944) (I2 = 35.9%, P = 0.197, Fig 3), while that
for alloHSCT versus chemotherapy was 0.52 [95% CI: 0.35, 0.78] (P = 0.001) (I2 = 0.0%,
P = 0.679, Fig 3B). This indicated that alloHSCT did not confer an OS benefit over autoHSCT;
however, an OS benefit with alloHSCT compared to chemotherapy was noted. Subgroup metaanalysis based on previous mentioned clinical heterogeneity showed the differences between
alloHSCT and non-alloHSCT were not significant in earlier criteria group (HR: 0.80, 95% CI:
0.65 to 1.00, Fig 3A), however, alloHSCT has OS benefits compared to non-alloHSCT in
updated criteria group (HR: 0.43, 95% CI: 0.22 to 0.84, Fig 3A). It is consisted with overall
conclusion.
TRM benefit
The overall TRM was analyzed via a random-effects forest plot of HRs from all of the studies.
A total of 4 articles reported intermediate-risk AML data for TRM. The overall HR was 3.09
[95% CI: 1.38, 6.92] (P = 0.006). The overall I2 was 75.4% (P = 0.017; Fig 4). This outcome indicated that the alloHSCT group had higher non-relapse mortality than the non-alloHSCT
group.
PLOS ONE | DOI:10.1371/journal.pone.0132620 July 21, 2015
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Meta-Analysis of AlloHSCT in Intermediate-Risk AML
Fig 3. Forest plot of the OS benefit of alloHSCT in intermediate-risk AML-CR1. (A) Forest plot of the
overall OS benefit and the subgroup OS benefit (earlier criteria group versus updated criteria group) in
intermediate-risk AML-CR1. (B) Forest plot of the subgroup OS benefit (alloHSCT versus autoHSCT,
alloHSCT versus chemotherapy) in intermediate-risk AML-CR1. The study of Tsimberidou 2003 has a wide
95% CI, we speculated it may influence by the small size of number.
doi:10.1371/journal.pone.0132620.g003
RR benefit
The RR was analyzed via a random-effects forest plot of the HR from all of the studies. A total
of 4 articles reported intermediate-risk AML data for RR. The overall HR was 0.58 [95% CI:
Fig 4. Forest plot of TRM benefit of alloHSCT in intermediate-risk AML-CR1.
doi:10.1371/journal.pone.0132620.g004
PLOS ONE | DOI:10.1371/journal.pone.0132620 July 21, 2015
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Meta-Analysis of AlloHSCT in Intermediate-Risk AML
Fig 5. Forest plot of RR benefit of alloHSCT in intermediate-risk AML-CR1.
doi:10.1371/journal.pone.0132620.g005
0.45, 0.75] (P = 0.000). The overall I2 was 45.4% (P = 0.16; Fig 5). There was a significant difference between the outcomes of alloHSCT and non-alloHSCT, with fewer patients relapsing following alloHSCT treatment.
Publication Bias
Publication bias was analyzed used Egger’s funnel test. The plots included 6 articles for determination of the RFS benefit, and 8 articles for the OS benefit. There was no significant difference in publication bias for either of these primary outcomes (P = 0.919 and P = 0.523,
respectively).
Discussion
Cytogenetic risk profiling is important for stratifying AML treatment. Several clinical trials and
meta-analysis have verified that there is no OS or RFS benefit with alloHSCT compared to
non-alloHSCT in good-risk AML patients in CR1 [9,60]. While alloHSCT is a curative treatment for AML patients in CR1, it is the first choice for poor-risk AML patients in CR1 [9].
Although Koreth et al. [9] reported that alloHSCT had significant RFS and OS benefit for intermediate-risk AML patients in CR1. As there are limits to the number of patients included in
trials and the resulting data, large-scale studies and robust data are urgently needed. To clearly
determine whether alloHSCT has RFS and OS benefits for intermediate-risk AML patients in
CR1 compared to autoHSCT.
According to the NCCN AML 2014 edition 1 (V1.2014: www.nccn.org) [2], patients with
intermediate-risk AML who are age < 60 years of age after post-remission treatment should be
enrolled in a clinical trial, receive matched-sibling or alternative donor HSCT, or receive
HiAra-C 1–3 g/m2 over 3 h every 12 h, on days 1, 3, and 5 × 3–4 cycles. Further clinical trials
that compare of alloHSCT versus chemotherapy, especially HiAra-C, are urgently needed.
To address this, we undertook a comprehensive literature search to further and analyze
update information on alloHSCT treatment for intermediate-risk AML patients in CR1. The
main inclusion criteria of this meta-analysis were that the trials be prospective and controlled.
We concluded that alloHSCT produces OS or RFS benefits, which was consistent with the findings of previous studies [9,61]. In comparison with non-alloHSCT, alloHSCT reduced relapse
in patients with intermediate-risk AML. Interestingly, further subgroup analysis of alloHSCT
versus autoHSCT showed an equal OS benefit. AutoHSCT is considered an alternative treatment to alloHSCT, especially when an HLA-matched related adult donor is not available. Furthermore, alloHSCT has OS benefits compared to chemotherapy, in intermediate-risk AML
CR1 patients. The earlier criteria group analysis of OS did not show alloHSCT was superior to
non-alloHSCT, however, alloHSCT has OS benefits compared to non-alloHSCT in updated
PLOS ONE | DOI:10.1371/journal.pone.0132620 July 21, 2015
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Meta-Analysis of AlloHSCT in Intermediate-Risk AML
criteria group. It may be related to the inclusive studies are over 25 year times, and there have
been some changes in patient population and the clinical management. Notably, the conclusion
of RFS was not influenced by the time changes. Limit to the conclusions between two studies
in updated criteria group are significant different, the heterogeneity is significant in this group
(I2 = 57.8%). Large-scale clinical trials are needed.
We considered treatment toxicity by quantifying the results of TRM. While alloHSCT
patients benefit from fewer relapses, they may suffer from greater treatment-related toxicity. In
our study, that included 3 articles, the I2 was 75.4 (P = 0.017). The I2 was above 50% towing to
the fewer studies available to analyze. The high TRM in the alloHSCT group is largely attributable to early mortality. Despite advances in supportive care, and the procedure of alloHSCT
improved, the high rate of early mortality is still an important limitation for alloHSCT[62].
Apart from the major variables mentioned above regarding allo-HSCT, There is a consensus
on the variables relevant to the success of the procedure, such as the type of transplant performed (myeloablative versus reduced conditioning). Table 2 shows myeloablative conditioning as the only type of conditioning regimens; this may be because patients were adults and the
earlier period of clinical trials carried out. Wahid et al. [63] published a meta-analysis showing
that there is no OS benefit with myeloablative conditioning regimens over reduced-intensity
regimens. Based on the data presented, both myeloablative and reduced conditioning regimens
have the same efficacy in intermediate-risk AML adult patients in CR1.
The limitations of this meta-analysis are as follows. First, the majority of the clinical trials
included AML patients in CR1, and intermediate-risk AML patients in CR1 comprise but one
subgroup this population. Therefore, the original articles only described and compared the
characteristics of two groups of AML patients and did not report the specific characteristics of
intermediate-risk AML patients in CR1. Second, the various definitions of the intermediaterisk category, including the differing criteria set by SWOG, ISCN, and MRC, included the
FLT3-ITD mutation. However, according to the NCCN-AML 2014 version 1 [2], this mutation
has been classified under poor-risk.
A meta-analysis is not a discovery tool, but it can help pool evidence and may assist indecision-making when there are no large-scale prospective controlled studies available. Our findings have identified the most appropriate post-remission treatment for intermediate-risk AML
based on high quality evidence, and useful for determining the course of future trials. As for
TRM, non-alloHSCT provides the greater benefit. These data may help guide decision-making
and planning of future trials that compare alloHSCT to either autoHSCT or chemotherapy. It
would also be informative to study alloHSCT using a less intensive conditioning regimen in the
present era.
Supporting Information
S1 PRISMA Checklist. PRISMA preferred reporting items for meta-analyses checklist.
(DOC)
S1 Table. Summary of study relating alloHSCT benefit for AML in CR1.
(DOCX)
Author Contributions
Conceived and designed the experiments: LY YL. Performed the experiments: D. Li Li. Wang.
Analyzed the data: D. Li Li Wang HZ LD D. Liu LF CM XM YY LZ QW Lijun Wang YZ YJ Lili
Wang. Contributed reagents/materials/analysis tools: HZ D. Liu XM. Wrote the paper: D. Li.
PLOS ONE | DOI:10.1371/journal.pone.0132620 July 21, 2015
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Meta-Analysis of AlloHSCT in Intermediate-Risk AML
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PLOS ONE | DOI:10.1371/journal.pone.0132620 July 21, 2015
16 / 16
Nutrients 2013, 5, 4333-4346; doi:10.3390/nu5114333
OPEN ACCESS
nutrients
ISSN 2072-6643
www.mdpi.com/journal/nutrients
Review
The Need for Evidence Based Nutritional Guidelines for
Pediatric Acute Lymphoblastic Leukemia Patients: Acute and
Long-Term Following Treatment
Joyce L. Owens *, Sheila J. Hanson, Jennifer A. McArthur and Theresa A. Mikhailov
Division of Critical Care, Department of Pediatrics, Medical College of Wisconsin/Children’s Hospital
of Wisconsin, 9000 W. Wisconsin Avenue, M/S #681, Milwaukee, WI 53226, USA;
E-Mails: shanson@mcw.edu (S.J.H.); jmcarthu@mcw.edu (J.A.M.); tmikhail@mcw.edu (T.A.M.)
* Author to whom correspondence should be addressed; E-Mail: jowens@mcw.edu;
Tel.: +1-414-266-3360; Fax: +1-414-266-3563.
Received: 24 July 2013; in revised form: 16 September 2013 / Accepted: 18 October 2013 /
Published: 31 October 2013
Abstract: High survival rates for pediatric leukemia are very promising. With regard to
treatment, children tend to be able to withstand a more aggressive treatment protocol than
adults. The differences in both treatment modalities and outcomes between children and
adults make extrapolation of adult studies to children inappropriate. The higher success is
associated with a significant number of children experiencing nutrition-related adverse
effects both in the short and long term after treatment. Specific treatment protocols have
been shown to deplete nutrient levels, in particular antioxidants. The optimal nutrition
prescription during, after and long-term following cancer treatment is unknown. This
review article will provide an overview of the known physiologic processes of pediatric
leukemia and how they contribute to the complexity of performing nutritional assessment
in this population. It will also discuss known nutrition-related consequences, both short and
long term in pediatric leukemia patients. Since specific antioxidants have been shown to be
depleted as a consequence of therapy, the role of oxidative stress in the pediatric leukemia
population will also be explored. More pediatric studies are needed to develop evidence
based therapeutic interventions for nutritional complications of leukemia and its treatment.
Keywords: antioxidants and cancer; childhood leukemia; leukemia; nutrition; antioxidant
supplementation in leukemia; childhood cancer
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1. Introduction
Pediatric acute lymphoblastic leukemia (ALL) is the most frequently occurring cancer in children
and adolescents. An overview of the physiologic processes by which leukemia develops and potential
nutritional implications will be reviewed. The treatment protocols used in pediatric oncology patients
are more aggressive than those used in adults, with resulting differences in nutrition-related
complications of leukemia and its treatment.
Current pediatric treatment protocols yield a cure rate approaching 90% [1]. This excellent cure rate
means that there are and will be more childhood cancer survivors reaching adulthood. The higher cure
rate obtained in children has not been duplicated in adolescents or older adults [2]. The ALL cure rate
declines in adults to approximately 40%. In the United States (U.S.) sixty percent of children under the
age of fifteen participate in clinical trials compared to less than 5% of adolescents and young adults.
Improvement in pediatric survival rates has been attributed to early detection, enhanced treatment
involving the use of multiple treatment modalities, management of infections and improvement in
supportive care [3]. These advancements in care may be facilitated by the high rates of pediatric
participation in study trials.
The substantial gains in pediatric oncology treatment have caused an array of adverse treatment
related effects leading to an increase in the complexity of assessing acute and long-term nutritional
status as well as nutritional needs. These adverse effects may have an acute or delayed onset [3]. One
of the more commonly described nutrition-related adverse effects from chemotherapy is depletion of
antioxidants. This is especially problematic during the conditioning phase as this is the most intense
phase of treatment. During conditioning, patients receive high doses of chemotherapy without much
break in between in order to place the patient into remission from their cancer. Many chemotherapeutic
agents produce oxygen free radicals and deplete the body’s stores of antioxidants while attempting to
neutralize them. In addition, patients typically feel quite ill during this phase and often are not able to
tolerate and/or consume adequate nutritional intake, which makes it difficult to replenish their
antioxidants. Other adverse effects of treatment include malnutrition, an increase in total body fat or
obesity (especially in female ALL patients treated with cranial irradiation), and heightened protein
turnover in children treated with high dose intravenous methotrexate and glucocorticoids [4]. An
increased body mass index (BMI ≥ 25 kg/m2) has been exhibited in childhood survivors of ALL,
whose age at the time of diagnosis was less than 4 years, [3,5–7]. Other adverse effects include several
chronic conditions: endocrine disorders, hypothyroidism, disorders of growth and pubertal
development, cardiovascular disease, pulmonary disease, neurological and neurosensory disorders,
osteonecrosis, secondary cancers, fatigue, and chronic pain.
Currently, no uniform evidence based nutritional guidelines have been established addressing the
optimal nutritional prescription regarding energy, physical activity, nutrients, and the use of dietary
supplements during and after treatment [4]. This article will review and discuss the recent literature
and highlight areas in which further research is needed.
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2. Overview of Leukemia
Cancer is a disorder of cell growth and regulation, leading to abnormal cell division and
production [8]. This dysregulation results in unlimited, dysfunctional cell production [9]. These
unregulated cells may form cancer cells that then can spread throughout the body [8].
Leukemia is a form of cancer that originates in the bone marrow and is released into the blood
stream [10]. The bone marrow is responsible for producing stem cells that will eventually mature into
the different types of blood cells: red blood cells (RBC), white blood cells (WBC) and platelets. White
blood cells are comprised of granulocytes (eosinophils, basophils, and neutrophils), monocytes
(macrophages) and lymphocytes (B-cells and T-cells) [10]. Stem cells mature into two different
myeloproginator cell lines, lymphoblasts and myeloblasts. Lymphoblasts mature into the type of WBC
called lymphocytes. Myeloblasts differentiate into RBC, non-lymphoid WBC or platelets. Cancer cells
produced from the myeloid or lymphoid cell lines by the bone marrow are termed leukemia cells.
Leukemia is categorized as an acute (rapid onset and progression) or chronic (slow onset and
progression) production of malignant blood cells. It is further sub-categorized according to the type of
WBC affected [11]. White blood cells that are affected include lymphoid (lymphocytic or
lymphoblastic) or myeloid cells (myeloid). The four most common types of leukemia include chronic
lymphocytic leukemia, chronic myeloid leukemia, ALL, and acute myeloid leukemia [11]. Both ALL
and acute myeloid leukemia commonly occur in children. The annual incidence of leukemia in the
U.S. is 30 to 40 per one million. In children and adolescents under the age of 20, the annual incidence
of ALL amounts to 2900 new cases per year in the U.S. The highest incidence of leukemia in children
occurs between the ages of 2–3 years in the U.S. [12].
The development and function of WBC and their cellular differentiation requires nutritional factors.
These nutritional factors include vitamins and minerals such as vitamin A, zinc, and iron. In particular,
the B-vitamins (folate, cobalamin, niacin and pyridoxine) are critical for cellular deoxyribonucleic acid
synthesis [10].
No one causative factor has been linked to cancer development. Childhood cancer most often
involves transformation of stem cells and is the result of a spontaneous mutation in the area of the
genes that control the growth and life cycle of the cells involved [1,13]. These mutations can develop
at any of the numerous stages of normal lymphoid differentiation [14]. Genetic mutations can be
detected in 75% to 80% of all childhood ALL. Signs and symptoms of leukemia are related to the
quantity and location of leukemia cells in the body. Leukemia cells can affect many different body
systems and organs such as the brain, kidneys, heart, lung, and gastrointestinal tract. Common signs
and symptoms of pediatric acute and chronic leukemia include general malaise, gums that bruise or
bleed readily, recurrent infections, enlarged lymph nodes, bone or joint pain, fevers, pallor and
abdominal discomfort or swelling.
The diagnosis of leukemia involves a physical examination to assess for enlarged lymph nodes,
liver, or spleen. A simple blood test, the complete blood count, is used to evaluate the number of blood
cells (WBC, RBC and platelets). In leukemia there is an enhanced production of immature blast cells,
but they are not capable of maturing into functional cells. The overproduction of one cell line in the
bone marrow leads to an increased number of blast cells, crowding out the production of other normal
cells such as RBC and platelets, often causing the patient to be anemic and thrombocytopenic. To
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confirm the presence of leukemic cells in the bone marrow, a bone marrow aspirate or biopsy is
performed. Other tests are usually performed to determine the specific type of leukemia present
through assessment of chromosome abnormalities (cytogenetics) and lumbar puncture to assess for the
presence of leukemic cells in the cerebrospinal fluid [9].
There are several treatment options available for leukemia based on the individual’s age, leukemia
type, and the location of leukemic cells. Major treatment options involve chemotherapy using a
combination of drugs, radiation therapy (high-energy rays used to destroy cancer cells), biological
therapy (drugs to enhance the body’s own defense against cancer) and hematopoietic stem cell
transplantation (HSCT). The latter enables high doses of chemotherapy, radiation therapy, or both to
be used. High dose therapy destroys both normal and leukemic cells. Once the high dose chemotherapy
is completed, normal stem cells are administered as replacement for the blood cells destroyed by the
treatment. Stem cells are acquired by self (patient) donation (autologous), family member or matched
unrelated donor (allogeneic), or identical twin (syngeneic). This topic and other treatment modalities
result in important nutritional consequences of cancer and will be further discussed.
3. Nutrition Considerations
Malnutrition is a general phrase that serves to define an inadequate nutritional state. Malnutrition
ensues from an imbalance in consumption (insufficient or excessive), and utilization of energy,
nutrients and/or both [15,16]. Malnutrition may be a consequence of the cancer itself and/or its
treatment. The occurrence of malnutrition in pediatric oncology patients cited in the literature varies
extensively, largely due to a lack of a consensus in identifying and classifying malnutrition. The World
Health Organization defines malnutrition as a BMI less than the 5th percentile, a criterion, which most
pediatric oncology patients do not meet [3]. There is also no consensus regarding the identification of
nutritionally at risk children with cancer. A diminished nutritional status is a potential risk factor for
reduced immune function, altered drug metabolism, leading to drug toxicities, and prolonged wound
healing. Thus malnutrition has the potential to cause appreciable adverse clinical outcomes [3,10,16]
and reduced quality of life and overall well-being [16].
Standard parameters used in assessing nutritional status are often altered in pediatric oncology
patients. Corticosteroid-induced edema can mask undernutrition (weight gain as a result of fluid
retention) thereby negating weight as an accurate nutritional marker of nutritional status. Weight may
further be altered by hydration status during chemotherapy [3]. Lack of clear definitive guidelines for
assessing or identifying children and young adult oncology patients with malnutrition or at risk for
malnutrition, makes it difficult to obtain an accurate prevalence rate of malnutrition in this
population [3,17], though the rate is approximated at 46% [3].
Serum protein markers have limited use in identification of malnutrition as their concentrations are
affected by the liver’s rate of synthesis, degradation, and seepage from the circulatory system [15].
During inflammation or infections the synthesis of acute-phase proteins by the liver such as
ceruloplasmin, C-reactive protein and ferritin is up-regulated while the synthesis of negative acute-phase
proteins such as albumin, prealbumin, retinol-binding protein and transferrin is down-regulated [15] as
a consequence of the stress response. Furthermore, chemotherapy and recurrent episodes of infection
and sepsis may further diminish body nutrients (zinc in particular) as a result of altered metabolism
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leading to sub-optimal growth. An unrecognized depletion of micronutrients may also result as a
consequence of decreased food consumption, significant gastrointestinal losses or increased nutrient
requirements, further adding to the complexity of malnutrition in this population [3,10]. Weight is also
not a precise representation of long-term alteration in body cell mass [3] related to several factors.
Weight may be appropriate or excessive, yet loss of lean body mass has occurred. Fat mass may
decrease or remain stable, even though wasting of skeletal muscle has occurred. The loss of cell mass
(skeletal muscle) is associated with impaired immune and pulmonary function, increased disability and
mortality [3,15].
A standardized definition and description of malnutrition and the predominant factors associated
with pediatric malnutrition in the developed world has been proposed [18]. The proposed
standardization classifies the cause of malnutrition into two broad categories, illness and non-illness
related. Illness related causes are associated with disease (i.e., cancer), trauma/injury, surgery and/or
chronic conditions. Non-illness related causes are associated with behavioral and/or environmental
causes leading to undernutrition. Illness related and non-illness causes are further divided into acute
(onset less than 3 months ago) or chronic (onset 3 months ago or more) [18]. A homogeneous method
of defining and classifying malnutrition criteria will allow for a more accurate identification and
documentation of the incidence of malnutrition [18]. Establishment of malnutrition criteria may also
facilitate the development of nutritional guidelines and rapid enactment of appropriate
nutritional interventions.
4. Pathophysiology of Malnutrition in Children with Leukemia
Several pathophysiological processes lead to the development of growth failure and malnutrition in
this population. These processes include inflammation, skeletal muscle breakdown, loss of body
proteins, and lipid oxidation. Aggressive multimodal cancer therapy and its induced toxicities can
result in altered gastrointestinal function, absorption, metabolism, and utilization as a consequence of
altered hormonal response and metabolic demands. Pain (i.e., mucositis) and disorders of appetite,
dysgeusia and xerostomia can further increase the risk for inadequate nutritional intake leading to
increased risk of malnutrition [3]. Body composition changes also affect the absorption, distribution,
metabolism, and elimination of cytostatic medications. Opiate pain medications such as morphine
decrease oral intake due to their propensity to cause nausea, constipation, and anorexia [10].
Other treatment complications related to nutrition involve nutrient-medication interactions. For
example, methotrexate inhibits folate metabolism. Cyclosporine alters potassium and magnesium
homeostasis, which can lead to depleted serum levels requiring nutritional replenishment.
Glucocorticoid steroids induce hyperglycemia, fluid retention, weight gain (fat mass) resulting in
altered body composition, electrolyte abnormalities, and increases requirements for calcium, zinc, and
vitamins D and C with long term use [10,19]. A significant increase in long-term fat mass (altered
body composition) has been reported in pediatric leukemia patients prescribed glucocorticoid steroids
in conjunction with methotrexate [4].
The hormone leptin is the chief regulator of appetite and satiety. Elevated levels of leptin
down-regulate appetite and enhance energy utilization [20]. Human studies in cancer patients have
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shown that leptin levels are not elevated during weight loss demonstrating that the hormone leptin is
not involved in the initiation of anorexia in this population [3].
A significant number of children who receive radiation or chemotherapy develop oral mucositis.
Mucositis is the inflammation of mucosa as a result of ionizing radiation or chemotherapeutic
drugs [21]. Lesions caused by mucositis can result in increased risk for systemic infection, significant
pain and oral hemorrhage decreasing or inhibiting oral intake and increasing the risk for malnutrition
(undernutrition). Frequent oral care is paramount to treatment. The medication palifermin
(Kepivance®) was approved by the U.S. Food and Drug Administration for use in a subset of adult
patients. Palifermin, the recombinant human keratinocyte growth factor is approved for adults with
hematologic malignancies [22] to prevent or treat severe oral mucositis in those undergoing high dose
chemotherapy, (with or without radiation) followed by HCST [22].
Hepatic veno-occlusive disease, also known as sinusoidal obstructive syndrome occurs with certain
types of chemotherapy or after HSCT. It is a disease in which the blood vessels that flow within the
liver and other surrounding organs supported by portal circulation are blocked. Veno-occlusive disease
is the result of endothelial cell injury in the blood vessels adjacent to the liver and its ancillary organs
induced by an increase in oxidative stress. The deficiency of the AOX glutathione (GSH) is believed to
have a substantial role in the pathogenesis of this complication. A diet rich in AOX and adequate
protein and energy may help reduce the frequency of this complication [10].
5. Dietary Supplements in Cancer
Complementary and Alternative Medicine, also known as CAM, is a group of diverse medical and
health care products and practices that are not deemed part of conventional medicine [21,23]. CAM
therapies are commonly used by the general public and consist of an enormous array of heterogeneous
therapies that are for the most part not well understood by conventional healthcare providers [21].
CAM is challenging to define because of its range of therapies and the fact that its constituents are
continuously being expanded. For example, a dietary supplement may consist of one or more dietary
ingredients which include vitamins, minerals, herbs, amino acids, and other botanicals that are taken
by mouth in the form of a capsules, liquids, pills or tablets [24]. The most frequently identified reasons
for taking dietary supplements by individuals with cancer are to help cope with the adverse side effects
of conventional treatment, to augment conventional anticancer therapy, and to prevent secondary
malignancies [3,21,23]. It is estimated that between 35 and 50% of children with cancer in the U.S.
take dietary supplements [21,23] and 6% to 91% use CAM [21,23].
Several supplements have been researched regarding their ability to modulate the progression of
mucositis. Adverse effects of mucositis are associated with oral pain and difficulty swallowing,
thereby increasing the risk of dehydration and/or malnutrition [21,25–27]. Traummel S®
(Heel Incorporated) is one such product. It is a homeopathic remedy made up of highly diluted
botanical extracts and minerals. In a randomized controlled, double-blinded clinical trial involving
32 pediatric patients at multi-institutional sites it was shown to be effective in the reduction of
stomatitis and mucositis in pediatric patients undergoing HSCT [21]. A subsequent international
multi-center double-blinded, randomized study involving 181 patients with a much larger age range
(3–25 years) undergoing HSCT did not confirm Traummel S® as an effective treatment for mucositis.
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The latter study did find a trend toward less narcotic use for mouth pain [26] with the use of
Traummel S®. Another supplement that is used to prevent and/or reduce the severity and/or duration of
mucositis is glutamine (GLN) in children undergoing HSCT [21]. Glutamine is the most abundant
amino acid in the plasma and muscles of humans [27]. Glutamine has several roles and is a precursor
of glutamate, which is required for synthesis of the major AOX GSH [27]. One possible drawback to
parenteral GLN use is that it requires a substantial amount of fluid administration [21], which may be
contraindicated in children undergoing HSCT requiring fluid restriction [27].
6. Antioxidant Supplements in Cancer
Patients in the conditioning phase of treatment have been found to have reduced or depleted levels
of AOX especially vitamin C [3,10], selenium, and vitamin E [28]. Several cancer treatments cause
oxidative stress (an imbalance of the body’s pro-oxidants and AOX) as a part of their method of action
to destroy cancer cells. The opposing states (low AOX level in conditioning versus oxidative stress
mechanism of therapy) have prompted controversy regarding the benefit or harm of supplemental
AOX at levels well beyond the recommended daily intake during cancer therapy [3,11,29]. These
therapies exert a portion of their anticancer effects through the formation of free radicals also termed
reactive oxygen species (ROS) [11,21,30]. Current U.S. Food and Drug Administration approved
anticancer therapies that generate ROS include anthracyclines, arsenic trioxide, cytarabine, and
vincristine [11]. The concern is that AOX could impair the action of particular types of anticancer
therapy. The impairment of anticancer therapy with AOX use has not been confirmed by clinical
trials [21]. Not all anticancer agents are involved in the formation of ROS as part of the anticancer
effects. Thus, there is the potential benefit for AOX supplementation to improve the patient’s
nutritional status and reduce toxicities related to chemotherapy in a subset of patients, though study
results have been inconsistent [4,30].
The production of ROS is a normal aerobic physiological process that results from both endogenous
and exogenous sources [31]. Examples of endogenous sources include activation of inflammatory
cells, mitochondria metabolism, and peroxisomes, while exogenous sources include chemicals
(industrial), environmental and pharmaceutical agents [30,31]. ROS have both a positive and negative
function in cell proliferation and cell survival [11].
Antioxidants can also be broadly classified as enzymatic and non-enzymatic [30]. Examples of
enzymatic AOX include superoxide dismutase, catalase dismutase, and glutathione peroxidase [32].
Non-enzymatic AOX are classified as metabolic or nutrient. Glutathione is a metabolic non-enzymatic
AOX and vitamin C and E, carotenoids, selenium and thiol are classified as non-enzymatic nutrient
AOX [32–34].
The normal balance between the production of ROS and AOX activity is maintained by the body in
equilibrium. The loss of this balance is particularly important in leukemia cells. Leukemia cells
inherently contain moderately elevated levels of ROS [11,31] as a consequence of alterations that
occur in pro-oxidant and AOX pathways [11]. Pro-oxidant and AOX pathways potentially contribute
to the susceptibility to cancer treatment in leukemia. Once ROS levels exceed that manageable
by cells, oxidative damage ensues leading to lipid peroxidation and deoxyribonucleic acid
damage [11,31]. The sustainment of higher ROS levels occurs in all four forms of leukemia.
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The higher ROS levels promote leukemogenesis and ultimately promote growth and survival of cancer
cells even with insults from traditional cancer treatment. Leukemic cells frequently are dysregulated in
both the expression and activity of diverse AOX pathways. In leukemia, the alteration in the oxidative
balance plays a significant role in the survival, growth, progress and resistance to therapy. The oxidant
balance in leukemia has an advantage toward ROS production. Reactive oxygen species producing
complexes have the potential for significant clinical application; either by causing direct damage to
cancer cells or through inhibition of growth and survival of potential cancer cells. For the most part,
AOX are down-regulated in leukemia cells and thereby promote ROS signaling and genomic
instability. However, upon treatment with ROS-producing agents, many AOX enzymes have the
potential to be up-regulated and potentially promote resistance to anticancer treatment. Enhanced
understanding of the oxidative balance in leukemia will lead to further advancement in the treatment of
leukemia and reduction in the associated toxicities [11] and lead to evidence based nutritional
guidelines for the use or non-use of AOX supplementation during and after anticancer therapy for
pediatric leukemia.
7. Methods of Review
References were obtained using the search engine PubMed. Review of research articles and
textbook references were limited to the years of publication from 2000 to present. The primary search
criteria focused on pediatric leukemia, AOX assessment and/or measurement in this population. The
search target was acute and long-term nutritional implications of pediatric ALL and its primary
treatment modalities.
Pediatric patients are inherently different than adult patients. Pediatrics is categorized into several
different age groups (neonates, infants, young children, and adolescents). Each group is at a different
developmental and growth stage with different nutritional and energy needs [15]; thus children are not
just small adults. Pediatric studies related to nutrition are generally small and somewhat sparse. Since
the treatment modalities for pediatric ALL are more aggressive than in adults, and children have a
higher survival rate, extrapolations of study results from adults to children are not appropriate. The
available pediatric literature at this time shows a lack of consensus in criteria to identify malnutrition,
and highlights the overall complexity of nutrition assessments in the pediatric leukemia population.
A wide range of AOX levels were measured and/or evaluated as potential adjunct therapies in
leukemic patients. Two studies specifically focused on mucositis therapy following anticancer
treatment. An overview of research studies is listed by category and publication date in Tables 1–3.
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Table 1. Overview of nutrition-related pediatric oncology studies—mucositis and nutrition
care practices.
Author
Overview
Results
Srinivason, A. et al.
Phase I cohort study
No evidence of toxicity with dosing 90 μg/kg/day
2012 [22]
Involved 12 children (median age 9.2 years), five males,
based on pharmacokinetics:
seven females with ALL, and AML
•
Most frequent side effect: macular rash
Assessment of tolerance to Palifermin in dose progression •
Drug elimination occurred within 24–48 h of
levels of 40, 60 and 90 μg/kg/day to assess toxicity risk
administration
Sencer, S.F. et al.
International multi-institutional, double-blinded,
Lack of confirmation of Traumeel S®:
2012 [26]
randomized trial
•
A total of 181 participants between the ages of
3–25 years; evaluation of the effectiveness of Traumeel
As an effective treatment for CT-induced
mucositis
•
Found trend toward reduced narcotic used
®
S in the treatment of mucositis
Ladas, E.J. et al.
A total of 223 COG institutions were invited to complete
A total of 120 COG facilities responded and it was
2006 [35]
a survey as a means to ascertain the degree of consensus
found that nutritional assessments were performed
practices utilized in assessment of nutritional status; either using numerous different indices to:
a MD, RD or RN completed the survey
•
Identify nutritional status
•
Classify malnutrition and its severity
Thornley, I. et al.
Pilot Study, 37 participants
The most distinct benefits were found in high risk
2004 [36]
Assessment of the benefit of the AOX:
patients assessed by:
ursodexycholic acid, vitamin E, and folinic acid in
•
Shorter time period to engraftment
children receiving PN undergoing HSCT
•
Reduced severity and incidence of mucositis
•
Decreased severity of liver toxicity
Oberbaum, M. et al.
A randomized, controlled clinical trial, 32 participants,
TRAUMEEL S® may have significantly lowered:
2001 [25]
ages 3–25 years, evaluation of TRAUMMEL S® in the
•
treatment of mucositis
WHO grading score used to assess the severity
Severity and duration of oral mucositis induced
by SCT
•
of mucositis
Mean mucositis days for placebo group 24.3;
10.4 for treatment group
®
HEEL Corporation SCT/HSCT: stem cell transplantation/hematopoietic stem cell transplant; CT: chemotherapy; ALL:
acute lymphoblastic leukemia; AML: acute myeloid leukemia; PN: parenteral nutrition; WHO: World Health Organization.
Table 2. Overview of nutrition-related pediatric oncology—studies of body composition.
Author
Overview
Results
Karaman, S. et al.
A total of 93 survivors of childhood ALL, 74 previously
Leptin and BMI levels:
2010 [37]
received CRT as part of ALL treatment as a child
•
Fifty healthy adults similar in age served as controls
The purpose of the study was to evaluate obesity risk
Levels for females who received CRT were
significantly higher compared to the controls
•
ALL treatment can lead to obesity
factors (BMI and serum leptin levels) in adults treated
with CRT for childhood ALL
Garmey, E.G. et al.
Retrospective cohort study
2008 [38]
evaluating body composition (BMI) of 1451 survivors of •
A higher BMI in children that receive CRT
childhood ALL over a 16-year period
during their first 10 years of life, particularly
ALL is associated with:
females
ALL: acute lymphoblastic leukemia; CRT: cranial radiotherapy; BMI: body mass index.
Nutrients 2013, 5
4342
Table 3. Overview of nutrition related pediatric oncology studies—antioxidants.
Author
Overview
Results
Radhakrishnan, N. Case control study, 45 newly diagnosed children
Patients with lower serum levels of selenium and tocopherol
et al.
with ALL serum fasting levels of zinc, selenium,
at diagnosis were found to be at greater risk for:
2012 [28]
retinol and tocopherol were compared to an
•
Febrile neutropenia
age-matched control group of 20
•
Sepsis during the first 8 weeks of therapy
Al-Tonbary, Y.
Prospective observational study involving
Compared to the controls, children with ALL at diagnosis and
et al.
Fifty newly diagnosed children with ALL between
completion of induction had:
2011 [39]
the ages of 1.5–12 years, median age
•
Higher oxidative stress levels
6.84 ± (SD) 3.73 years
•
Low AOX levels
Oxidative stress (MDA, TAC) evaluated at
•
diagnosis and completion of induction phase of CT
Significantly elevated levels of apoptosis 1 week post
induction phase compared to levels at diagnosis
Apoptosis evaluated at diagnosis and 1 week post
treatment by fluoremetric TUNEL
Healthy age and gender matched children served
as controls
Al-Tonbary, Y.
Cohort study, 40 participants
The vitamin E and NAC group were associated with a
et al.
NAC and vitamin E prescribed as adjuvant AOX
decrease in:
2009 [40]
therapy in pediatric ALL
•
Radiation and CT toxicities
Twenty participants received vitamin E and NAC
•
Blood and platelet transfusions
supplementation and 20 did not
•
Hepatic toxicities
Levels of Glu.Px, MDA and TNF-α were obtained
to evaluate AOX therapy
Mazor, D. et al.
Observational study, 13 children between the ages
•
Both groups had lower AOX and thiol levels
2008 [41]
of 4–18 years with ALL or solid tumors evaluated
•
The ALL group had substantially lower thiol levels
AOX status and oxidative stress levels
•
There was a potentially higher oxidative stress level in the
ALL group
Papageorgiou, M.
Observational study, 80 participants receiving CT,
During CT:
et al.
TAC and cTAC levels were evaluated
•
TAC and cTAC levels progressively declined
•
TAC and cTAC levels remained low for 6 months
2005 [42]
post treatment
Aquino, V.M. et al. Double-blinded randomized placebo-controlled
2005 [43]
•
study,120 children
Twenty-eight days following HSCT or hospital
The GLN group was found to havea reduction in the
number of days requiring narcotics for mucositis
•
discharge in which 50% received oral-glycine and
GLN appears to be both safe and effective in decreasing
the severity of mucositis
50% received oral-GLN
Kennedy, E. et al.
Multi-centered, prospective, observational study of •
2004 [29]
103 children diagnosed with ALL
•
The AOX levels of vitamin A, E, ascorbate,
β-carotene, total carotenoid were evaluated
AOX intake was low for all except vitamin C
Higher dietary intake of vitamin E at 3 months correlated
with a lower infection rate
•
Higher dietary intake of vitamin C and β-carotene at
Dietary intake of AOX: calculated based on 24 h
6 months correlated with decreased toxicity related to
Food recall and food frequency questionnaire
therapy
obtained at three separate intervals
ALL: acute lymphocytic leukemia; MDA: malondialdehyde; TAC: total AOX capacity; CT: chemotherapy;
TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; AOX: antioxidants; GLN: glutamine;
cTAC: corrected total; AOX capacity; NAC: N-acetylcysteine; Glu.Px: glutathione peroxidase; TNF-α: tumor necrosis
factor alpha; HSCT: hematopoietic stem cell transplantation.
Nutrients 2013, 5
4343
8. Future Directions
Research has shown that AOX levels are depleted in pediatric oncology patients receiving
chemotherapy and/or radiation therapy. Antioxidants and ROS have dual biological functions in both
the body’s normal physiological processes and in cancer development. Reactive oxygen species are
generated as a byproduct of metabolism and in specific cancer treatments as a part of their anticancer
mechanism, though not all anticancer treatments use ROS as a method to destroy cancer cells. Based
on the few pediatric studies reviewed here, intake of AOX in this population is sub-optimal except for
vitamin C. This population was associated with higher oxidative stress and low AOX levels. Specific
AOX supplementation demonstrated a trend toward decreased therapeutic toxicity and severity of
mucositis. The pediatric studies reviewed here have used an array of supplemental vitamin and mineral
(AOX) cocktails in addition to diverse methods to evaluate both oxidative stress and study endpoints.
Large randomized, double-blind trials are needed to ascertain the ideal dosage and optimal vitamin and
mineral combinations of AOX to assess the benefit or harm in pediatric ALL patients.
9. Conclusions
It is well documented that the survival rate for pediatric ALL patients has approached 90%.
However, current treatment modalities are associated with toxicities and an increased complexity in
performing both nutrition assessments and interventions acutely and chronically. A unified criterion
for identification of malnutrition or nutritional at risk pediatric oncology patients is greatly needed.
Awareness of these complications has increased and evolving knowledge regarding oxidative stress
and its impact on cancer development at the cellular and molecular level is in progress. This
knowledge can be translated to the development of adjuvant therapeutic interventions to treat toxicities
of cancer treatment or as cancer treatment modalities. Treatments of this nature should be given high
priority in an effort to provide more effective cancer treatment with less toxicity and adverse
nutritional related outcomes.
Conflict of Interest
The authors declare no conflict of interest.
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616544
research-article2015
TAH0010.1177/2040620715616544Therapeutic Advances in HematologyK. Ishii and A.J. Barrett
Therapeutic Advances in Hematology
Review
Novel immunotherapeutic approaches for
the treatment of acute leukemia (myeloid
and lymphoblastic)
Ther Adv Hematol
2016, Vol. 7(1) 17­–39
DOI: 10.1177/
2040620715616544
© The Author(s), 2015.
Reprints and permissions:
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Kazusa Ishii and Austin J. Barrett
Abstract: There have been major advances in our understanding of the multiple interactions
between malignant cells and the innate and adaptive immune system. While the attention of
immunologists has hitherto focused on solid tumors, the specific immunobiology of acute
leukemias is now becoming defined. These discoveries have pointed the way to immune
interventions building on the established graft-versus-leukemia (GVL) effect from hematopoietic
stem-cell transplant (HSCT) and extending immunotherapy beyond HSCT to individuals with acute
leukemia with a diversity of immune manipulations early in the course of the leukemia. At present,
clinical results are in their infancy. In the coming years larger studies will better define the place
of immunotherapy in the management of acute leukemias and lead to treatment approaches that
combine conventional chemotherapy, immunotherapy and HSCT to achieve durable cures.
Keywords: immune-editing, leukemia, immunotherapy
Introduction
One of the major obstacles to the cure of
acute leukemia (AL) is its propensity to relapse
after chemotherapy or hematopoietic stem-cell
transplantation (HSCT). Treatments exploiting
immune responses against malignant disease and
more recently leukemia have advanced in recent
years. The rationale for immunotherapy in AL is
supported by evidence for immune surveillance in
the development of leukemia. Notably, solid
organ transplant recipients on lifelong immunosuppression have an increased risk of developing
AL [Adami et al. 2003; Vajdic et al. 2006;
Villeneuve et al. 2007; Gale and Opelz, 2012].
Furthermore, swift lymphocyte reconstitution
after chemotherapy is associated with improved
relapse-free survival [Ohnishi et al. 1998; Behl
et al. 2006; De Angulo et al. 2008]. In addition to
these indirect observations, the efficacy of allogeneic HSCT provides clear evidence that donorderived immune system can attack the recipient’s
leukemic cells. This graft-versus-leukemia (GVL)
effect is mediated by donor T cells recognizing
alloantigens and leukemia-associated antigens
presented by the leukemia and by natural killer
(NK) cells through killer immunoglobulin-like
receptor (KIR) and KIR–ligand interaction
[Barrett, 2008]. Escape of leukemia in the form of
relapse after either allogeneic HSCT or from
some form of autologous immune control following induction chemotherapy control is, however,
all too frequent. Some of the immune evasion
mechanisms discovered in solid tumors are shared
by AL, but the field is less well explored in hematological malignancies. Better understanding of
these mechanisms is essential for the design of
rational and effective immunotherapy for AL.
The first section of this review addresses the
mechanisms by which AL evades immune control. In the second section, current developments
and recent clinical experience with immunotherapy, designed both to overcome immune evasion
and to deliver lethal damage to the leukemia cell,
are examined. Finally, we discuss how immunotherapy can be incorporated into transplant and
nontransplant treatment approaches for AL.
Correspondence to:
Austin J. Barrett, MD
FRCP, FRCPath
Stem Cell
Allotransplantation
Section, Hematology
Branch, National Heart,
Lung and Blood Institute,
National Institutes of
Health, Bethesda, MD,
USA
barrettjj@mail.nih.gov
Kazusa Ishii , MD MPH
Hematology Branch,
National Heart, Lung,
and Blood Institute, US
National Institutes of
Health, Bethesda, MD,
USA
How leukemia evades the immune system
Recent studies have revealed a broad range of
strategies employed by leukemia to block cytotoxicity of T cells and NK cells against leukemia.
Most research has involved myeloid malignancies
and less is known about acute lymphoblastic leukemia (ALL). In the process of disabling immune
http://tah.sagepub.com17
Therapeutic Advances in Hematology 7(1)
Figure 1. Immune evasion mechanisms seen in acute leukemia.
Multiple immune pathways and functions are targeted by acute leukemia. Leukemic blasts directly and indirectly inhibit
the host’s immune response by inducing phenotypic changes in T cells and NK cells by: modifying milieu toward hostile
environment for immune system to function; inducing suppressor cells; and promoting immune checkpoint and coinhibitory
pathways. The magnitude to which each pathway contributes to leukemia’s immune escape ability remains to be elucidated.
Studies are mostly done in AML and immune evasion mechanisms applicable to ALL are less well understood.
ALL, acute lymphoblastic leukemia; AML, acute myeloblastic leukemia; CD4/8, costim, costimulatory; GITR, glucocorticoidinduced tumor necrosis factor-related protein; IDO, indolamine 2,3-dioxygenase; KIR, killer immunoglobulin-like receptor;
LAG3, lymphocyte-activation gene 3; MDSC, myeloid-derived suppressor cells; MHC, major histocompatibility complex; MIC,
major immunogene complex; NK, natural killer; NKG2D, natural killer group 2, member D; NOS, nitric oxide synthase; PD1,
programmed death 1; PD-L1, programmed death–ligand 1; STAT3, signal transducer and activator of transcription 3; TIM3,
T-cell immunoglobulin domain and mucin domain 3; Treg, regulatory T cell.
attack, leukemia causes many changes in T and
NK cell phenotype and function. This process is
termed immune editing. Interactions of leukemia
with the innate and adaptive immune system are
diverse. They are described below and summarized in Figure 1.
Lymphocyte phenotype changes
due to immune editing
T cells in acute myeloblastic leukemia (AML)
show many abnormalities. The spectrum of circulating T cells from the most recent thymic emigrants (RTE) to the end effector cells is perturbed
with a reduction of RTE [Li et al. 2009] and an
excess of CD57+ CD45RO + end effectors
[A.J.B. personal observation]. There is a general
increase in the expression of ‘exhaustion markers’
such as programmed death 1 (PD1) and T-cell
immunoglobulin domain and mucin domain 3
(TIM3) in T cells in AML [Zhou et al. 2011].
These markers characterize the end effector stage
of T-cell evolution following antigen stimulation
and expansion and can imply T-cell senescence.
T cells from AML patients have aberrant T-cell
activation patterns based on gene expression profiling and they fail to synapse normally with their
leukemic targets [Le Dieu et al. 2009]. There is
an increased proportion of regulatory T cells
(Tregs) in both AML and ALL [Szczepanski et al.
2009; Kanakry et al. 2011; Shenghui et al. 2011]
which persists into remission. Thus leukemiainduced T-cell tolerance coupled with a preponderance of Tregs reduces the ability of cytotoxic
T cells to target leukemia.
NK cells also show significant phenotypic changes
with a tendency for overexpression of surface
molecules that reduce NK cytotoxicity (i.e. inhibitory receptors) such as NK group 2, member 2A
(NKG2A) which recognizes human leukocyte
antigen (HLA) E expressed by the leukemia and
18http://tah.sagepub.com
K Ishii and AJ Barrett
downregulation of activating receptors such as
NKG2D [Davies et al. 2014]. Overnight co-incubation of NK cells from healthy donors with
AML blasts induces NKG2A and inhibits their
cytotoxic capacity, demonstrating that AML
blasts directly impair innate immune function
[Stringaris et al. 2014].
Tregs
Tregs, characterized by expression of the transcription factor FoxP3 [Sakaguchi et al. 2010],
suppress effector T cells. Tregs can diminish anticancer T-cell immunity [Zou, 2006] and are
increased in both murine and human AML
[Wang et al. 2005; Szczepanski et al. 2009; Zhou
et al. 2009; Shenghui et al. 2011]. Treg numbers
at presentation of leukemia are associated with
poor response to chemotherapy [Szczepanski
et al. 2009; Shenghui et al. 2011]. Presence of
Tregs can limit effective immunotherapy, leading
to attempts to block Tregs prior to, or in conjunction with, various other immunotherapeutic
modalities (discussed in detail below).
Myeloid-derived suppressor cells (MDSC)
A heterogeneous population of immature myeloid-derived cells expands in pathological conditions including cancer [Gabrilovich and Nagaraj,
2009]. Granulocytic MDSC (CD11b + CD33 +
CD14-) and monocytic MDSC (CD11b+
CD33+ CD14+) are the two major subtypes
described in leukemia [Abu Alex et al. 2012;
Christiansson et al. 2013; Jitschin et al. 2014].
MDSCs suppress T-cell responses through various mechanisms including l-arginine catabolism
by arginase 1 and inducible nitric oxide synthetase
(iNOS) (discussed below) [Bronte and Zanovello,
2005; Rodriguez and Ochoa, 2008], increased
production of reactive oxygen species [Kusmartsev
et al. 2004], indolamine 2,3-dioxygenase (IDO)
expression (discussed below) and induction of
Tregs [Huang et al. 2006; Ustun et al. 2011].
The role of MDSCs in suppressing the proliferation and function of leukemia antigen-specific T
cells is insufficiently understood. However, their
contribution is suggested by recent studies where
we found that both CD34+ and CD33+ AML
blasts suppress T-cell proliferation in an MDSClike manner [Ito et al. 2013]. Furthermore, dendritic cells (DCs) grown from AML blasts are
functionally impaired and induce T-cell anergy
[Mohty et al. 2001; Narita et al. 2001].
Establishment of a milieu hostile
to immune cells
Various defects observed in T cell and NK cell
function can be caused by soluble factors secreted
by leukemic cells [Orleans-Lindsay et al. 2001].
Some leukemic cells have abnormal enzymatic
activities, causing depletion of substrates or excess
of metabolites, both of which can lead to immunosuppression. A key transcription factors
involved in tumorigenesis, also constitutively
expressed in myeloid leukemia is signal transducer and activator of transcription 3 (STAT3)
[Yu et al. 2009]. STAT3 targets genes that stimulate cell proliferation, prevent apoptosis, promote
angiogenesis and facilitate tumor immune evasion. It plays a significant role in subversion of
host immune responses, causing accumulation
and activation of immunosuppressive cells [Tregs,
T helper 17 (Th17) cells and MDSC] while
reducing DC function [Rebe et al. 2013]. In a
murine model of AML, STAT3 blockade was
shown to rescue the immune response to AML,
leading to remission by upregulation of major histocompatibility complex (MHC) class II, costimulatory and proinflammatory mediators, while
coinhibitory PD-L1, programmed death–ligand 1
(PD-L1) molecule was downregulated [Hossain
et al. 2014].
IDO. IDO is a rate-limiting enzyme in tryptophan
degradation into kynurenine [Taylor and Feng,
1991; Mellor and Munn, 1999]. It is constitutively expressed in many human tumors and contributes to cancer immune evasion [Uyttenhove
et al. 2003]. In AML, IDO expression is described
in about half of patients at diagnosis [Curti et al.
2007a] and IDO enzymatic activity is elevated
[Corm et al. 2009]. IDO depletes tryptophan,
which leads to inhibition of T cell and NK cell
proliferation [Mellor and Munn, 1999; Frumento
et al. 2002]. Furthermore, IDO-expressing AML
cells induce Tregs [Curti et al. 2007b, 2010] and
patients with IDO-expressing AML have higher
circulating Treg frequencies [Curti et al. 2007b].
Importantly, IDO expression level and activity in
AML is associated with poor clinical outcomes
[Chamuleau et al. 2008; Corm et al. 2009].
l-Arginine,
nitric oxide synthase (NOS) and arginase. l-Arginine, a conditionally essential amino
acid, is metabolized by arginase and iNOS [Rodriguez and Ochoa, 2008]. Increased expression of
arginase and iNOS causes l-arginine depletion in
the microenvironment leading to impaired T-cell
responses [Bronte and Zanovello, 2005]. Patients
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Therapeutic Advances in Hematology 7(1)
with AML have high plasma concentration of arginase II secreted by AML blasts [Mussai et al.
2013]. AML blasts exert arginase-dependent
T-cell suppression and polarize monocytes toward
an MDSC-like immunosuppressive phenotype
[Gabrilovich and Nagaraj, 2009; Mussai et al.
2013]. iNOS uses l-arginine as a substrate to generate l-citrulline and nitric oxide (NO) [Bronte
and Zanovello, 2005]. In turn, NO suppresses
T-cell function by inhibiting signaling proteins in
the interleukin (IL) 2 receptor pathway, including
Janus kinase (JAK) 3 and STAT5 [Bingisser et al.
1998]. NO has an anti-apoptotic effect on tumor
growth [Rivoltini et al. 2002], while promoting
T-cell apoptosis [Allione et al. 1999]. It reduces
tumor antigenicity by inhibiting MHC class II
gene transcription [Harari and Liao, 2004].
Leukemia evasion from immune attack
It is well described that loss or downregulation of
MHC class I molecules by cancer cells make them
invisible to cytotoxic T cells [Khong and Restifo,
2002]. After haploidentical HSCT for AML, loss
of mismatched HLA haplotype due to uniparental
disomy of chromosome 6p was reported as one of
the mechanisms of post-transplant relapse [Vago
et al. 2009; Crucitti et al. 2015]. Subsequently,
partial loss of HLA was demonstrated and implicated as the cause of post-transplant leukemic
relapse in matched related [Stolzel et al. 2012] and
unrelated donor HSCT [Toffalori et al. 2012].
Factors that affect the ability of HLA molecules to
present antigen to T lymphocytes also matter:
class II associated invariant chain peptide (CLIP)
occupies the HLA–class II antigen groove and
must be released before antigenic peptides can
bind to the groove [Romagnoli and Germain,
1994; Sloan et al. 1995]. High expression of CLIP
associated with failure of the leukemia antigen to
occupy the antigen presentation groove is associated with worse clinical outcome in AML, implying a failure of antigen presentation by the
leukemia [van Luijn et al. 2010]. Loss of costimulation molecules on leukemia blasts can cause
T-cell anergy. Leukemia blasts commonly lack
CD80 expression while CD86 expression level
can be heterogeneous [Whiteway et al. 2003; Graf
et al. 2005; Mansour et al. 2014]. Diminished
expression of costimulatory molecules on AML
blasts [Vollmer et al. 2003] may be associated with
worse clinical outcome [Whiteway et al. 2003].
Abnormal cells, such as virus infected cells and
malignant cells, lack MHC class I expression,
allowing NK cells to exert their cytotoxic function
by recognition of ‘missing-self’ (by lack of interaction between cognate HLA molecule and KIR).
In the HLA mismatched transplant setting, donor
NK cells and their KIRs recognize disparity in the
MHC class molecules expressed on leukemic
blasts and exert a GVL effect [Ruggeri et al.
1999]. Underexpression of MHC class I molecules in mismatched HSCT setting should render
the leukemia susceptible to allogeneic NK-cell
cytotoxicity. However, leukemias also escape
NK-cell mediated lysis by various mechanisms.
The activating NK cell receptor, NKG2D, recognizes the major immunogene complex (MIC) A/B
expressed on leukemia blasts [Bauer et al. 1999].
MIC A/B is overexpressed by myeloid leukemias
but is also shed, blocking NK cell engagement
with the target [Sconocchia et al. 2005]. AML
blasts with high expression of inhibitory KIR
ligands, HLA-Bw4 and C, are less susceptible to
NK-cell mediated lysis [Demanet et al. 2004;
Verheyden et al. 2009]. HLA-G, one of ligands
for KIR2DL4 [Hofmeister and Weiss, 2003], is
also expressed by AML blasts and is implicated in
the inhibition of NK-cell function [Yan et al.
2008]. NK cell function is also blocked through
interaction
between
glucocorticoid-induced
tumor necrosis factor-related protein (GITR) on
the NK cell and its ligand, GITRL, expressed or
secreted by AML cells [Baessler et al. 2009].
Promotion of immune checkpoints
Immune checkpoint pathways are important for
control of T-cell activation and maintenance of
selftolerance [Fife and Bluestone, 2008]. Various
cancers use immune checkpoints to their survival
advantage
[Pardoll,
2012].
Cytotoxic
T-lymphocyte associated antigen 4 (CTLA-4) is
expressed on T cells and shares the same ligands,
CD80 and CD86, with CD28. Ligation of CD28
to these ligands elicits costimulatory signaling and
T-cell activation. However, when CTLA-4 binds
to CD80 or CD86, early T-cell activation is
inhibited [Schwartz, 1992; Fife and Bluestone,
2008; Pardoll, 2012]. Furthermore, CTLA-4
increases inhibitory cytokine production by
CD4+ T cells [Chen et al. 1998]. CTLA-4 is
expressed in up to 85% of leukemia blasts [Pistillo
et al. 2003] and its blockade may have therapeutic
benefit by increasing the activity and numbers of
AML-reactive T cells [Zhong et al. 2006].
PD-1 is expressed on antigen-experienced and
activated T cells, B cells and NK cells [Fife and
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K Ishii and AJ Barrett
Bluestone, 2008]. There are two known ligands
of PD-1, PD-L1 and PD-L2: PD-L1 is broadly
expressed on peripheral tissues while PDL2 is
expressed in a more limited manner on DCs and
monocytes [Fife and Bluestone, 2008]. The PD-1
pathway induces peripheral T-cell tolerance by
directly inhibiting activated T cells and by
enhancing Treg-mediated immune suppression
[Francisco et al. 2010]. PD-L1 is upregulated on
various cancers [Dong et al. 2002; Pardoll, 2012].
Between a fifth to a half of AL express PD-L1
[Salih et al. 2006; Chen et al. 2008; Berthon et al.
2010]. Enhanced PD-1 expression on tumorinfiltrating lymphocytes (TILs) or circulating
peripheral blood T cells is a well-described phenomenon in various human cancers, and PD-1
expression on T cells may be increased in patients
with AL [Ahmadzadeh et al. 2009; Sfanos et al.
2009; Christiansson et al. 2013; Yang et al. 2014].
In murine leukemia models, PD-1 expression on
cytotoxic T cells increased with AML progression
[Zhou et al. 2010; Zhou et al. 2011] and in the
post-transplant setting, causing T-cell exhaustion
[Asakura et al. 2010; Flutter et al. 2010].
Advances in the field of immunotherapy
for AL
The goals for immunotherapy (excluding antibody treatment which is not discussed in this
review) in the treatment and cure of AL are threefold: (1) to boost cytotoxicity of lymphocytes targeting the leukemia; (2) to block the process of
immune editing and recreate a permissive environment for T cell and NK cell function; and (3)
to integrate immunotherapy with conventional
existing approaches of chemotherapy and HSCT.
Various immunotherapeutic approaches for AL
are summarized in Figure 2.
Allogeneic HSCT
Immunotherapy for AL involves two distinct therapeutic domains: allogeneic HSCT and nontransplant treatments. Immunotherapy approaches are
often first explored in patients who have received
allogeneic HSCT either to prevent or treat relapsing leukemia. While many immunotherapy strategies apply in or outside the context of HSCT, the
alloimmune GVL effect is both unique and powerful, and is discussed separately here.
Allogeneic HSCT is still the only undisputed
immune-based approach to curing leukemias
resistant to chemotherapy alone. The GVL effect
is mediated by both T cells and NK cells [Bleakley
and Riddell, 2004; Barrett, 2008; Warren and
Deeg, 2013]. While the stem-cell source (bone
marrow, peripheral blood or cord blood), degree
of compatibility (identical twin, matched related,
matched unrelated and haplotype matched
related donors) and transplant approach [conditioning regimen and method of graft-versus-host
disease (GVHD) prevention] can all influence
outcome, the major factor determining the survival and cure of AL is the status of the leukemia
at the time of transplant.
Patients of standard risk with AL transplanted in
first remission have a relapse rate of 20% or less;
those in second or subsequent remission have an
intermediate relapse risk of around 40%, while
patients transplanted with overt disease either
because of refractoriness to induction treatment
or uncontrolled relapse had a relapse risk around
60% [Barrett, 2008). Despite numerous strategies manipulating the transplant schedule to
decrease relapse rates, these statistics have not
changed significantly for over 40 years. This is in
part due to the fact that approaches that boost
the GVL effect are constrained by the increase in
morbidity and mortality from GVHD, and
increased ablation of leukemia by radiation and
chemotherapy is limited by increased mortality
from nonrelapse causes. In addition, despite
many innovative attempts to control relapsed
disease by boosting GVL, relapse of AL after
HSCT is largely incurable and still carries a dismal prognosis. Palliative treatment aside, the
standard treatment of relapsed AL is chemotherapy followed by donor lymphocytes infusion
(DLI). While up to 20% of patients may enjoy
prolonged survival, few are cured and relapse
occurring within 6 months of transplant is almost
universally incurable [Treleaven and Barrett,
2009].
DLI. The full realization that GVL was a major
contributor to the curative effect of allogeneic
HSCT in the 1980s led logically to the use of
DLI to prevent or treat relapse after transplant.
Unfortunately, the first demonstrations that DLI
could achieve durable remissions in relapsed
CML were not borne out in AL and myelodysplastic syndromes (MDS) where the therapeutic
benefit of DLI is at best modest. The failure of
DLI to fulfill its promising results with AL stimulated a number of approaches to improve DLI
as detailed in Table 1. Treg-depleted DLI has
been used to augment GVL [ClinicalTrials.gov
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Therapeutic Advances in Hematology 7(1)
Figure 2. Exploiting therapeutic effects by targeting leukemia’s immune evasion mechanisms.
The immune evasion mechanisms described in Figure 1 can be targeted for therapeutic effects. Some therapeutic modalities
have more than one mechanism of action and overlap with other types of immunotherapy: for instance, improvement of
hostile milieu by IDO inhibitor works partly by blocking Treg pathways. Combination of different immunotherapies may
augment the effect of one another: examples include providing cell therapy in combination with Treg blockade to augment
the effect of adoptively transferred cell products.
ALL, acute lymphoblastic leukemia; AML, acute myeloblastic leukemia; BiTE, bispecific T-cell engagers; CAR, chimeric
antigen receptor; CIK, cytokine induced killer; CTLA-4, cytotoxic T lymphocyte antigen-4; DC, dendritic cell; IDO, indolamine
2,3-dioxygenase; IMiDs, immunomodulatory drugs; NK, natural killer; PD1, programmed death 1; PD-L1, PDL1, programmed
death–ligand 1; STAT3, signal transducer and activator of transcription 3; TCR, T-cell receptor; Treg, regulatory T cell.
Table 1. Strategies used to improve therapeutic efficacies of DLI.
Approach
Comment
Immunostimulation [Barrett, 2008]
• Cytokines: IL-2, IFN-γ, GM-CSF
Modest improvement in response rates
• Lenalidomide
• Induction of lymphopenia
Increased responses with GVHD
Checkpoint inhibitors
• CTLA-4 blockade
Limited trials with anti-CTLA-4 and anti• PD-1/PDL-1 blockade
PD-L1 suggest GVHD is not provoked Selective reduction of GVHD while preserving GVL
• CD8+ T-cell depletion [Giralt et al. 1995;
Alyea et al. 1998; Alyea et al. 2004]
• Treg depletion [Maury et al. 2010]
DLI with low tumor burden [Kumar et al. 2013; Liga et al. 2013; Eefting et al. 2014]
• Chemotherapy followed by DLI
Improves the outcome for AML and MDS
• DLI given for residual disease management
Reduced relapse in a nonrandomized study
AML, acute myeloblastic leukemia; CTLA-4, cytotoxic T lymphocyte antigen-4; DLI, donor lymphocytes infusion; GM-CSF,
granulocyte-macrophage colony-stimulating factor; GVHD, graft-versus-host disease; IFN, interferon; IL, interleukin;
MDS, myelodysplastic syndromes; PD1, programmed death 1; PD-L1, PDL1, programmed death–ligand 1; Treg, T-cell
regulator
22http://tah.sagepub.com
K Ishii and AJ Barrett
identifier: NCT00675831, NCT00987987].
Manipulation of Tregs in the context of HSCT
(both in the graft and in the host after transplantation) has two implications: depletion of Tregs
may enhance GVL, but enrichment of Tregs is
efficacious for prevention and treatment of
GVHD [Martelli et al. 2014]. Further studies
are required to identify the optimal therapeutic
approach involving Treg-mediated pathways to
achieve a fine balance between GVL and GVHD.
Unfortunately there is insufficient data from any
strategy to determine a definitive role for ‘augmented’ DLI. Only the prophylactic application
of DLI has any clear advantage.
Immunotherapy beyond HSCT
New developments in immunological understanding and ability to manipulate immune cells
are beginning to break the impasse of GVL linked
to GVHD and improve the curative potential of
allogeneic HSCT. Relapse after HSCT with its
extremely poor prognosis has become a proving
ground for the most innovative and experimental
immunotherapy, appropriate for such desperate
circumstances. Thus many of the strategies
described below were initially developed or have
only been applied in the context of HSCT.
However, the application of novel immunotherapy outside the context of HSCT is now gaining
momentum. These new strategies can be categorized as: (1) lymphocyte products to deliver
enhanced and specific anti-leukemic cytotoxic
(cell therapy); (2) vaccines; and (3) treatments to
boost immunity and enhance leukemia’s susceptibility to immune system.
Cell therapy. Chimeric antigen receptor modified
T cells (CAR-T). The remarkable therapeutic successes using CAR-modified T cells to treat leukemia have attracted wide enthusiasm for CAR cell
therapy and T-cell therapy in general. The principle is to insert a T-cell receptor (TCR)/costimulatory molecule/linker/antigen binding domain
derived from the fusion of the variable regions of
the heavy and light chains of immunoglobulins
specific for a leukemia surface antigen (e.g. anti
CD19) construct into T cells. The antibody binds
surface molecules on the leukemia, triggers TCR
activation and directs T-cell cytotoxicity to the
leukemia.
Initial reports of remissions achieved in ALL and
chronic lymphocytic leukemia (CLL) by Porter
and colleagues [Porter et al. 2011; Grupp et al.
2013] have led many investigators to adopt and
further refine this technology. Key developments
have been the improvement of the construct with
substitution of 41BB for CD28 as the costimulatory molecule, and use of long-lived viral specific
T cells rather than CD3/CD28 bead stimulated T
cells as the vehicle for TCR transduction generating CAR cells to improve persistence. Other
approaches under investigation employ virus-free
transduction systems (sleeping beauty transposons) and the development of NK CAR cells as
an alternative to T cells. The most advanced clinical trials with CAR cells in AL have been in
patients with ALL. Maude and colleagues
described the treatment of 30 adults and children
with relapsed or refractory ALL with autologous
T cells transduced with a CD19-directed CAR
(CTL019) [Maude et al. 2014]. All the patients
had a cytokine-release syndrome which was severe
and required anti-IL-6 treatment in about a quarter of the recipients. A total of 27 achieved a complete remission, with a 6 month event-free survival
and overall survival rate of 67% and 78%, respectively. The CAR cells persisted and were associated with a prolonged B-cell aplasia. These results
were all the more remarkable because durable
remissions were seen in patients failing blinatumomab and HSCT.
There has been considerable interest in using
CAR technology to target myeloid leukemias.
CD123 is overexpressed by AML but it is also
well-expressed on normal myeloid cells, although
expression on hematopoietic stem and progenitor
cells is weaker. Nevertheless the risk of marrow
ablation limits the application of antimyeloid leukemia CAR cells to pretransplant conditioning
where healthy stem cells can be infused after ablation of the CAR cells.
While CAR cells have alerted the oncology community to the potency of T-cell-based therapy
and stimulated considerable interest of pharmaceutical companies in developing cell therapy,
they have some important limitations. Firstly
their use in leukemia is restricted by the lack of
antigens that are uniquely expressed by the leukemic cell and not the normal counterpart. A further problem is the ability of the leukemia to
downregulate surface expression of molecules
such as CD19 – a common form of immune evasion in B-cell malignancies. It may, in future, be
possible to target the much larger population of
intracellular tumor specific antigens recognized
by T cells when presented as peptide fragments
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Therapeutic Advances in Hematology 7(1)
through the tumor MHC, by developing antibodies specific for the antigenic-peptide MHC complex. Such antibodies have been developed for
WT1 and PR1, but their application would be
restricted to the specific HLA molecule expressing the tumor peptide (usually HLA A2) [Alatrash
et al. 2012; Veomett et al. 2014].
TCR transduction. Several investigators have used
T cells genetically modified to express a TCR
specific for a single MHC class I or II expressed
antigen. Preclinical studies suggest efficacy and
clinical trials are in progress [Xue et al. 2010;
Katsuhara et al. 2015]
Bispecific T-cell engagers (BiTEs). Bispecific antibodies target both a tumor antigen and CD3.
When the molecule targets the tumor, the CD3
binds and activates circulating T cells at the site
of the tumor [Huehls et al. 2015]. Blinatumomab,
a BiTE which targets CD19 and CD3, shows
important antitumor activity in patients with
B-cell malignancies. The US Food and Drug
Administration (FDA) gave accelerated approval
for blinatumomab to be used in treatment of
ALL. Early experience with blinatumomab in
ALL is promising [Topp et al. 2011]. The agent
eliminated minimal residual disease in 16/20
patients with adult ALL and prolonged remission
[Topp et al. 2012]. Blinatumomab is also active
for primary refractory or relapsed pre-B ALL with
response [complete remission (CR) or complete
response with partial hematologic recovery
(CRh)] rate of over 40% [Topp et al. 2015].
However, similar to CAR cells, the lack of a specific myeloid leukemia surface antigen specific for
AML currently limits the BiTE strategy to B-cell
ALL.
Antigen specific T cells. ALs express a variety of
leukemia-associated antigens (LAA), including
classical tumor antigens, via their MHC class I
and II molecules, rendering them susceptible to
attack by tumor antigen-specific T cells [Goswami
et al. 2014]. It is important to note that such CTL
can target leukemia progenitors, which increases
their likelihood of therapeutic efficiency
[Quintarelli et al. 2011; Schneider et al. 2015].
ALs commonly express multiple LAA, making it
possible to target them with T cells recognizing
more than one antigen, thereby reducing the risk
of tumor escape by antigenic downregulation. We
have shown that multi-LAA-specific cytotoxic
CD4 and CD8 T cells can be generated against
peptide mixtures of tumor antigens in 2–3 week
expansion cultures using T cells from healthy
donors or leukemia patients in remission [Weber
et al. 2013a, 2013b]. WT1 specific LAA specific
T cells generated using peptide antigens have
been shown to have efficacy in AML [Weber et al.
2013b]. In HSCT, the opportunity to target
minor histocompatibility and LAA antigens with
donor T cells has been developed in several centers and early clinical trials show promise in
patients relapsing after HSCT with AL. In a study
from Seattle, 11 high risk patients after HSCT
received donor-derived HLA-A2 restricted
CD8+ T-cell clones specific for the WT1126–134
peptide [Chapuis et al. 2013]. No GVHD
occurred. The study highlighted the need to
expand T cells in vitro in the presence of IL-21:
patients who received T cells expanded with
IL-21 were alive and achieved durable remission
after infusion of CTL, while most patients receiving CTL without IL-21 expansion had short CTL
persistence and relapsed quickly [Chapuis et al.
2013].
A phase I clinical trial at the Memorial Sloan
Kettering Cancer Institute gave WT-1 specific T
cells to allogeneic HSCT recipients with AML,
ALL or MDS. WT-1 specific T cells were generated by DCs pulsed with pools of overlapping
peptides spanning the WT1 protein. Minimal
residual disease was transiently reduced after
T-cell infusion without causing GVHD [O’Reilly
et al. 2010]. Other investigators have exploited
minor histocompatibility antigen (mHA) differences between donor and patient to generate
mHA-specific T cells to target leukemia following
HSCT [Bleakley and Riddell, 2011].
NK cell therapy. It is now feasible to expand NK
cells ex vivo for cell therapy. NK cells can be
selected with magnetic beads coated with CD56
from an apheresis collection and can be expanded
with Epstein–Barr virus (EBV) transformed B
cell lines or K562 cell lines expressing costimulatory molecules and membrane-bound IL-15 or
IL-21 [Denman et al. 2012; Shah et al. 2013].
Early trials show that NK cell infusions are without the risk of GVHD. Two recent uncontrolled
studies suggest that NK cells may be efficacious
in preventing relapse or treating refractory AML
[Miller et al. 2005; Rubnitz et al. 2010]. After
lymphodepleting treatment with cyclophosphamide and fludarabine, haploidentical NK cells
were administered to children with AML in first
complete remission. The 2 year event-free survival was 100% [Rubnitz et al. 2010]. A similar
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K Ishii and AJ Barrett
lymphodepletion/haploidentical NK cell infusion study in 19 adults with refractory AML
achieved 5 complete remissions [Miller et al.
2005]. These results are preliminary and need
further validation.
Cytokine induced killer (CIK) cells. CIK cells represent a population of T cells and NK cells with
cytotoxic capacity induced by IL-2 and other
cytokines. While numerous studies have explored
these cells manufactured in a variety of ways,
their overall impact on control of AL has been
disappointing. Studies with CIK cells are well
reviewed by Pittari and colleagues [Pittari et al.
2015].
Vaccines. Immunotherapy of AL experienced a
brief period of enthusiasm in the 1970s when several groups explored vaccination of AL patients in
remission with irradiated leukemia cells and Bacille Calmette Guerin (BCG) vaccine given either
together or separately. These studies were inconclusive and were soon bypassed by the development of HSCT as a curative approach. More
recently, with better knowledge of antigen presentation and leukemia antigens, and the ability to
monitor residual disease and immune responses,
there is renewed enthusiasm for vaccination to
prevent relapse after remission induction or after
HSCT. Vaccination approaches are diverse. They
may target specific leukemia antigens such as
WT1 and BCR-ABL, or undefined antigens
derived from entire leukemia cells lysed or fused
with antigen-presenting cells (APC), or leukemia
lines engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF)
[Zeng et al. 2003; Rosenblatt and Avigan, 2006;
Ho et al. 2009]. Vaccines can be delivered as APC
(DCs or leukemia cells) [Palucka and Banchereau,
2013; Schurch et al. 2013] or as proteins, peptides
or DNA [Rice et al. 2008; Tabarkiewicz and Giannopoulos, 2010; Rezvani, 2011].
Recent developments on leukemia vaccines in AL.
Single epitopes of WT1 and PR1 peptides were
given with adjuvant to patients with AML and
MDS in a phase I/II study. Although there were
impressive falls in minimal residual disease
(MRD) in association with a rise in PR1 or WT1
specific T cells, the responses were not sustained
and overall clinical responses were modest. Nine
clinical trials using WT1 peptides in patients with
MDS and/or AML, published between 2004 and
2012, were recently reviewed [Di Stasi et al.
2015]. A total of 51 patients received vaccine.
Vaccination was safe and associated with clinical
responses with a few patients achieving long-term
disease-free survival sustained up to 8 years.
Responses correlated with the detection of WT1specific T cells and normalization/reduction of
WT1 mRNA levels. Controlled clinical trials are
needed before these promising results can be
properly assessed.
DC vaccines. Anguille and colleagues have
reviewed the strategy of using DCs as antigen
presenting cells transduced with tumor antigen
DNA [Anguille et al. 2014]. This group described
encouraging results with a WT1-transduced DC
in patients with AML: five of 10 patients achieved
complete remissions including two patients refractory to chemotherapy [van Tendeloo et al. 2010].
These results are encouraging but have not been
reproduced in a larger patient series. A major limitation of vaccination approaches is the fact that
most defined leukemia antigens are products
of normal genes overexpressed or selectively
expressed in leukemia cells. The immune system
is finely balanced to distinguish foreign antigens
from self antigens. In effect, cancer vaccination
aims to break tolerance to self and elicit an ‘autoimmune’ response. Thus one of the major hurdles
for effective vaccination is overcoming the central
and peripheral tolerance to self antigens.
Vaccines after HSCT. The opportunity provided
by HSCT to combine vaccines with the immune
cells from a nontolerized donor has led to studies
exploring vaccination after HSCT. The association of vaccines with HSCT has some unique
advantages. Firstly, the lower tumor burden early
after HSCT phase, which is an ideal setting for
anti-tumor immune responses to operate.
Secondly, the unique immune milieu around the
time of the transplantation characterized by lymphopenia, Treg depletion, and the release of
growth factors such as IL-7, IL-15, and IL-21, is
permissive to the generation of antileukemia
immune responses. Thirdly, HSCT provides the
opportunity to associate vaccination with administration of leukemia specific cells, either by donor
vaccination or vaccinating the patient post cell
infusion [Rezvani and Barrett, 2008; Barrett and
Rezvani, 2009]. Alternatively vaccine-primed
lymphocytes can be collected by apheresis and
reinfused after transplant with further vaccination
to boost the response. There are also limitations
to the efficacy of vaccine given after allogeneic
HSCT: antigen-specific CD8+ T cells during
this time may be at risk for rapid induction of
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Therapeutic Advances in Hematology 7(1)
senescence [Rezvani and Barrett, 2008; Barrett
and Rezvani, 2009].
In summary, vaccination approaches have shown
promise but, frustratingly in the absence of substantial well-controlled trials in AL, the field
remains in its infancy.
Treatments to boost immunity and enhance leukemia’s susceptibility to immune system. Immune
checkpoint blockade. PD-L1 blockade on the tumor
cell or PD1 blockade targeting the T cell is emerging as one of the most powerful strategies to
enhance T-cell effectiveness against cancer [Pardoll, 2012]. Antibodies or blocking molecules have
been developed targeting the key checkpoint inhibitors illustrated in Figure 1. Most experience with
these agents comes from the field of solid tumor
immunotherapy [Brahmer et al. 2012; Prieto et al.
2012;Topalian et al. 2012]. However, anti-CTLA-4
has been used in a preclinical AML model [LaBelle
et al. 2002; Zhong et al. 2006] and also for treatment of patients with post-HSCT relapse [Bashey
et al. 2009]. This study demonstrated that CTLA-4
inhibition with ipilimumab does not increase the
risk of GVHD, even in patients who received DLI
in conjunction [Bashey et al. 2009]. While promising responses were achieved, the study was too
small to clearly identify efficacy of the agent in AL.
Ongoing trials are testing the safety and efficacy of
CTLA-4 blockade in both post-transplant relapse
settings and nontransplant settings [ClinicalTrials.
gov identifier: NCT00060372, NCT01757639,
NCT01822509]. Similarly, preclinical data for PD-1/
PD-L1 blockade have shown that the target has therapeutic potential in leukemia [Zhang et al. 2009].
PD-1/PD-L1 blockade has been tested and actively
investigated in various hematologic malignancies
[Armand, 2015] [ClinicalTrials.gov identifier:
NCT02117219, NCT01953692, NCT02332980],
but clinical experiences in AL remain limited. In a
phase I study of anti-PD-1 antibody for hematologic malignancies that enrolled total of 17 patients,
8 patients had AML [Berger et al. 2008]. None of
the patients experienced toxicity attributable to the
agent. Majority of them did not show any response,
except for one patient who demonstrated marked
reduction in peripheral blood blasts burden. The
result suggests that PD-1/PD-L1 blockade can be
effective in a selected setting. Anti-PD-1 antibody
along with DC vaccine for AML [ClinicalTrials.gov
identifier: NCT01096602] is being tested. While
checkpoint inhibition is a promising novel treatment, further studies are required to understand
the most efficacious methods of administration to
exploit the possible clinical benefit.
Enhancing leukemia’s susceptibility to immune
attack. In addition to immune checkpoint inhibition, there are other agents that aim to restore
leukemia’s susceptibility to immune surveillance.
The mechanisms by which these agents potentially exert therapeutic effect are not completely
understood. Many of these agents have been
proven to have some efficacy in other hematologic malignancies, such as myelodysplastic syndrome, but clinical data for AL is still limited.
Immunomodulatory drugs (IMiDs). IMiDs include
prototypical thalidomide and its structural analogs lenalidomide and pomalidomide [Zeidner
and Foster, 2015]. IMiDs have protean immunomodulatory functions that work in concert to
reverse various immune evasion mechanisms
described in Figure 1.
(1)
They modulate cytokine levels, such as
suppressing tumour necrosis factor-α
(TNF-α) [Moreira et al. 1993; Corral et al.
1999] and augmenting other pro-inflammatory cytokines including IL-2 and interferon (IFN) γ and promote type 1 T cell
(Th1) responses [Haslett et al. 1998;
Dredge et al. 2002].
(2)They upregulate costimulatory molecules
(such as CD80 and CD86) [Aue et al.
2009] and tumor-associated antigens,
making malignant cells more readily recognizable to effector T cells [Henry et al.
2013].
(3)They downregulate coinhibitory molecules
and overcome immune checkpoint pathway-related immune evasion mechanisms
[LeBlanc et al. 2004; Luptakova et al.
2013].
(4)
They allow cytotoxic T lymphocytes to
form normal immunological synapse with
leukemic blasts [Ramsay et al. 2008;
Shanafelt et al. 2013].
(5)They inhibit Tregs [Galustian et al. 2009].
(6)They restore NK cell-mediated tumor lysis
[Davies et al. 2001; Krieg and Ullrich,
2012; Lagrue et al. 2015].
Epigenetic agents. Another therapeutic approach for
AL is to restore normal gene expression by modifying epigenetic changes and remodeling chromatin
structure by DNA methyltransferase (DNMT)
inhibitors or histone deacetylase (HDAC) inhibitors. AL cells frequently have gene mutations that
26http://tah.sagepub.com
K Ishii and AJ Barrett
affect DNA methylation and/or histone post-translational modifications, such as DNA methyltransferase-3A (DNMT3A) [Marcucci et al. 2012], Tet
methylcytosine dioxygenase 2 (TET2) [Metzeler
et al. 2011; Weissmann et al. 2012], additional sex
combs-like 1 (ASXL-1) [Pratcorona et al. 2012],
and isocitrate dehydrogenase (IDH) 1 and 2
[Figueroa et al. 2010; Janin et al. 2014].
In addition to restoring normal gene expression
pattern and inducing leukemic blasts differentiation (or phenotypic modifications toward maturation), epigenetic agents may have various
immunomodulatory functions by either downregulating or upregulating various genes involved
in regulation of T-cell proliferation, activity and
plasticity [Leoni et al. 2002; Reddy et al. 2004;
Tao et al. 2007; Choi et al. 2010; SanchezAbarca et al. 2010]. When DNMT inhibitors are
used as a single agent (either azacitidine or decitabine) for AML, they confer modest overall
response rates of about 20% [Silverman et al.
2006; Cashen et al. 2010; Fenaux et al. 2010;
Kantarjian et al. 2012; Lubbert et al. 2012]. Data
for single agent efficacy of HDAC inhibitors
(such as vorinostat, romidepsin, valproic acid
and entinostat) in AML is further limited and
less promising, with reported response rates of 0
to <20% in phase I and II trials [Bug et al. 2005;
Kuendgen et al. 2005; Raffoux et al. 2005; Gojo
et al. 2007; Garcia-Manero et al. 2008; Odenike
et al. 2008; Schaefer et al. 2009]. However, combination of DNMT inhibitors and HDAC inhibitors seem to have much better efficacy in AML
[Garcia-Manero et al. 2006; Blum et al. 2007;
Soriano et al. 2007; Prebet et al. 2014; Issa et al.
2015]. DNMT inhibitors and HDAC inhibitors
have been tried in conjunction with IMiDs and
combinations are reported to have synergistic
effects [Raza et al. 2008; Platzbecker et al. 2013;
Pollyea et al. 2013; Ramsingh et al. 2013].
Furthermore, epigenetic therapy in the transplant setting seems to preferentially suppress
GVHD while preserving GVL effects [Reddy
et al. 2004; Choi et al. 2010], suggesting the
potential for improving transplant outcome if
used appropriately.
IMiDs and epigenetic drugs are not curative at
this time, but leave an important treatment option
for those who cannot tolerate conventional chemotherapy. It is natural to consider designing clinical trials combining one immunotherapy to the
other, but the possibility of added toxicity should
be monitored closely. IMiDs and epigenetic drugs
have been shown to have effects on both side of
immune regulation, activation and suppression,
so it is important to find the dosage, timing and
combination that allows their beneficial effects to
prevail rather than immunosuppressive effects.
Strategies that block suppressor cells and hostile immune
milieu against immune cells. Cyclophosphamide and
5-fluorouracil (5-FU) selectively suppress Tregs
and MDSCs [Ghiringhelli et al. 2007; Vincent et al.
2010; Le and Jaffee, 2012], suggesting that these
classical chemotherapeutic agents may have some
effects via blockade of suppressor cell functions. As
shown in the Figure 1, there are multiple immune
evasion pathways that involve Tregs, for example,
immune checkpoint engagement, and blockade of
such pathways may be efficacious partly by indirectly abrogating the immunosuppressive capacity
of Tregs. In murine AML models, Treg depletion
by denileukin diftitox, a conjugated protein of IL-2
and diphtheria toxin, improved proliferation and
the antileukemic effect of adoptively transferred
cytotoxic T lymphocytes [Zhou et al. 2009] and
denileukin diftitox prior to vaccination enhanced
antileukemic T-cell response [Litzinger et al. 2007].
Treg depletion using daclizumab (an anti-CD25
antibody) has been demonstrated to improve vaccination potency in patients with solid malignancies
[Jacobs et al. 2010; Sampson et al. 2012], but such
data do not exist for AL. However, host Treg depletion by denileukin diftitox improved the efficacy of
haploidentical NK cell infusions in AML patients,
and translated into improved clinical outcome
including better disease-free survival at 6 months
[Bachanova et al. 2014].
MDSCs have also been investigated as a promising target for therapy. There are no agents that
selectively deplete MDSCs, but numerous agents
affect MDSC function [De Veirman et al. 2014].
For example, phosphodiesterase (PDE5) inhibitors augment antitumor response by MDSC suppression [Serafini et al. 2006]. An early clinical
study of tadalafil in multiple myeloma suggested
possible clinical benefit [Noonan et al. 2014] and
there is an ongoing phase II trial testing tadalafil
in conjunction with lenalidomide for the treatment of multiple myeloma [ClinicalTrials.gov
identifier: NCT01858558]. Similar studies have
not been performed for AL patients, but may be
considered in conjunction with IMiDs or other
immunotherapeutic modalities.
As discussed earlier, some of the immune evasion
mechanisms mediated by IDO and arginine
http://tah.sagepub.com27
Therapeutic Advances in Hematology 7(1)
metabolites are intertwined with proliferation and
function of MDSCs. In a preclinical model, a
competitive inhibitor of IDO, 1-methyltryptopha
(1-MT), and an oral small molecule that selectively inhibits IDO1, INCB024360, were shown
to enhance antitumor response by T and NK
cells, and prevent phenotypic conversion of T
cells to Treg-like cells [Hou et al. 2007; Liu et al.
2010]. In the phase II study for patients with
MDS, the agent was well tolerated but there was
no significant changes in associated laboratory
makers (such as intracellular IDO expression in
mononuclear bone marrow cells and bone marrow MDSC percentage) or in clinical outcome
[Komrokji et al. 2014].
The l-arginine metabolism pathway has also been
tested in preclinical models [Rodriguez et al.
2004]. Recently, Mussai and colleagues reported
single-agent activity of BCT-100, a pegylated
human recombinant arginase that depletes arginine concentration, in blocking AML blasts
growth [Mussai et al. 2015]. Therapeutic targeting of immune milieu disadvantageous of antileukemic response is still in its infancy, but
improvement in the metabolites balance and
milieu promise to enhance the effect of other
immunotherapies.
Putting it all together – the role and timing
of immunotherapy for AL
As a general principle, early phase studies with
experimental agents can be justified only in the
setting where there are no other better standard
treatment options. As a result, immunotherapy
for AL has been explored first in desperate settings such as post-transplant relapse and relapsed
or refractory leukemia with high blasts burden.
However, these are not the best situations in
which immunotherapy can exert its role and the
next step must be to define the best time to deliver
immunotherapy. The timeline for intervention
with immunotherapy in AL can be divided into
four periods: prevention; remission induction;
consolidation (maintenance of remission) including the option of HSCT; and the management of
refractory or relapsed cases. Scheme of an example of how immunotherapy can be incorporated
into the treatment course is depicted in Figure 3.
Prevention
Unfortunately, although the increased risk of
AML after prolonged immunosuppression in
organ transplant recipients is evidence of immune
control in preventing occurrence of leukemia
[Adami et al. 2003; Vajdic et al. 2006; Villeneuve
et al. 2007; Gale and Opelz, 2012], primary prevention of AL is unlikely to become the target of
immunotherapy development considering the low
disease incidence rate.
Immunotherapy at presentation and remission
induction
At least in the near future, novel immunotherapeutic strategies will not be routinely incorporated as a part of induction therapy for newly
diagnosed AL patients who can tolerate standardof-care cytoreductive chemotherapy. In the setting of high leukemic blasts burden and a
perturbed immune system, therapy exploiting the
immune function is likely inadequate to control
leukemia. However, this may not always be the
case: CD19-CAR T cells directly target blasts
and can eliminate high disease-burden B-ALL.
The combination of immunomodulatory agents
and intensive chemotherapy has been tested in
limited numbers of studies for relapsed or refractory AL, and even less so in treatment-naïve AL.
According to these limited data, concurrent usage
of either lenalidomide or thalidomide with induction chemotherapy regimen does not improve the
outcome but potentially increases toxicity [Cortes
et al. 2003; Barr et al. 2007; Dennis et al. 2013].
The HDAC inhibitor, vorinostat, in conjunction
with induction chemotherapy, has been shown to
be tolerated and is active even in high-risk AML
in phase I and II trials [Kadia et al. 2010; GarciaManero et al. 2012], although a long-term clinical
impact of the combination remains to be demonstrated. Further incorporating cell-based therapy
and other immune interventions in induction will
require establishment of safety, efficacy and the
pipeline to allow the cell products to be readily
available for immediate clinical usage.
Immunotherapy for AL in remission or low
disease burden
This may be advantageous in conjunction with
consolidation chemotherapy or as a maintenance
therapy after allogeneic HSCT to prevent relapse.
For the control of any MRD that may be undetectable with current laboratory techniques, immune
checkpoint inhibitors, IMiDs or hypomethylating
agents could be helpful by boosting immune surveillance mechanisms. Numerous ongoing clinical
trials are testing the concept of maintenance
28http://tah.sagepub.com
K Ishii and AJ Barrett
Figure 3. Timing of immunotherapy application in the course of leukemia progression.
It is important to identify the most efficacious timing for each immunotherapeutic strategy. The immune environment is not
static, and is actively modified by the status of the leukemia and the host, most dramatically in the context of HSCT. Thus the
same treatment may not have the same effect depending on the environment in which it was administered. Novel therapies
have been frequently tested first in relapsed or refractory disease in phase I studies. Accumulating evidences provide some
rationale to choose the timing and combination of multiple therapeutic modalities for better effect.
CAR, chimeric antigen receptor; CR1, complement receptor 1; DLI, donor lymphocytes infusion; HSCT, hematopoietic
stem-cell transplant; IMiDs, immunomodulatory drugs; NK, natural killer.
immunotherapy, augmenting immune surveillance
during remission; anti-PD-1 [ClinicalTrials.gov
identifier: NCT02275533], anti-PD-1 in combination with DC-AML vaccine [ClinicalTrials.gov
identifier: NCT01096602], lenalidomide [Clinical
Trials.gov identifier: NCT01578954, NCT
02126553] and azacitidine [ClinicalTrials.gov
identifier: NCT01757535, NCT01700673]. The
bispecific antibody, blinatumomab, for B-ALL
with persistent or recurrent MRD achieves durable
complete remissions [Topp et al. 2011; Topp et al.
2012]. Cell-based therapies may also become a
consolidation modality in the future.
Bridge to transplant
Various immunotherapies can be used as a bridge
to transplant or as a part of the transplant preparative regimen. Most clinical experiences of
cell-based therapy so far has been in refractory
and/or relapsed cases without an HSCT option.
In cases with HSCT options, cell-based therapy
may achieve remission or at least MRD (as
opposed to overt hematologic relapse) prior to
transplantation, thereby improving the transplant
outcome. Some cell-based therapies logistically
require HSCT as a platform: CAR T-cell therapy
for myeloid leukemia leads to marrow ablation as
discussed above. It could only be used with transplant backup, unless reliable ways to control the
in vivo persistence of adoptively transferred cells
can be developed.
Post-transplant prevention of relapse. With
improvement in transplant-related mortality over
the past decades, the prevention of post-transplant
relapse becomes important. The early post-transplant setting is uniquely advantageous for immunotherapy to work, where the leukemic burden is
small and anti-leukemia lymphocytes have the
chance to expand in the post-transplant immune
milieu and lymphodepleted environment [Muranski et al. 2006]. Furthermore, it is possible to
adoptively transfer donor cells that are not
exhausted or tolerized as a part of transplant
course. As described in the vaccine therapy section, post-transplant vaccines in conjunction with
vaccine-primed lymphocytes to promote GVL are
under investigation. Azacitidine for the treatment
of MRD post-HSCT has been reported to either
prevent or delay hematological relapse [Sockel
et al. 2011; Platzbecker et al. 2012]. Prophylactic
usage of low-dose azacitidine for patients with
high-risk MDS/AML post-transplant is safe and
may improve event-free survival and overall survival [de Lima et al. 2010]. IMiDs and immune
http://tah.sagepub.com29
Therapeutic Advances in Hematology 7(1)
checkpoint inhibitors are also being tested as a
maintenance therapy post-transplant [ClinicalTrials.gov identifier: NCT01433965, NCT01254578]
and CTLA-4 post-HSCT relapse [ClinicalTrials.
gov identifier: NCT01822509].
Relapsed and refractory AL
Treatment of refractory/relapsed leukemia, especially post-transplant relapse, is challenging. This
is the setting for experimental phase I immunotherapy studies and many examples of such trials
are alluded to in this review. Breakthroughs
achieved in immunotherapy treatment of such
patients, notably with CAR cells, nevertheless
support offering the opportunity for experimental
treatments to even very poor prognosis patients.
Funding
The author(s) received no financial support for
the research, authorship, and/or publication of
this article.
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Conflict of interest statement
The author(s) declared no potential conflicts of
interest with respect to the research, authorship,
and/or publication of this article.
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1337
The Biology and Therapy of Adult Acute
Lymphoblastic Leukemia
Stefan Faderl, M.D.
Sima Jeha, M.D.
Hagop M. Kantarjian,
BACKGROUND. Much progress has been made in understanding the biology of
M.D.
Department of Leukemia, The University of Texas
M. D. Anderson Cancer Center, Houston, Texas.
acute lymphoblastic leukemia (ALL). This has translated into the recognition of
several subgroups of ALL and the institution of risk-adapted therapies. New therapies are emerging based on the definition of specific cytogenetic-molecular
abnormalities.
METHODS. A review from the English literature, including original articles and
related reviews from Medline (Pubmed) and abstracts based on publication of
meeting material, was performed.
RESULTS. Changes in the pathologic classification of ALL have led to therapeutic
consequences. Adaptation of successful treatment strategies in children with ALL
has resulted in similar complete response rates in adults. Prognosis has especially
improved in mature–B-cell and T-lineage ALL. The role of tyrosine kinase inhibitors in Philadelphia chromosome–positive ALL was evaluated in the current study.
However, regardless of the ALL subgroup, long-term survival of adults is still
inferior to that in children.
CONCLUSIONS. Intense clinical and laboratory research is attempting to close the
gap in outcome between children and adults with ALL. Investigations are focusing
on 1) refinement of the basic treatment stratagem of induction, consolidation, and
maintenance; 2) expansion of risk-based, subgroup-oriented therapies; 3) assessment of minimal residual disease, its impact on disease recurrence, and its practical implications in clinical practice; 4) salvage strategies; 5) the role of stem cell
transplantation in ALL; and 6) the development of new drugs based on a better
understanding of disease biology. Cancer 2003;98:1337–54.
© 2003 American Cancer Society.
KEYWORDS: acute lymphoblastic leukemia, adult acute leukemias, Philadelphia
chromosome, risk-adapted therapies.
M
Address for reprints: Stefan Faderl, M.D., Department of Leukemia, The University of Texas M. D.
Anderson Cancer Center, P.O. Box 428, 1515 Holcombe Blvd., Houston, TX 77030; Fax: (713) 7944297; E-mail: sfaderl@mdanderson.org
Received April 3, 2003; revision received June 11,
2003; accepted June 30, 2003.
© 2003 American Cancer Society
DOI 10.1002/cncr.11664
uch progress has been made in understanding the biology of
acute lymphoblastic leukemia (ALL), which is now recognized as
an expanding group of heterogeneous entities. Recognition of distinct
gene expression patterns may identify patient subgroups with unique
responses to therapy and prognosis. Accurate definition of prognostic
subgroups based on cytogenetic-molecular markers has allowed institution of risk-oriented therapies. Adaptation of successful pediatric
ALL treatment strategies into the therapeutic algorithms of adult ALL
has resulted in complete response (CR) rates similar to those achieved
in children. Improvement is particularly evident in subgroups such as
mature–B-cell or T-lineage ALL. However, whereas almost 80% of
children are cured from ALL, only about 30 – 40% of adults achieve
long-term disease-free survival (DFS). With further molecular dissection of ALL subtypes, and with the development of new and targeted
drugs, significant progress will hopefully occur soon in adult ALL.
1338
CANCER October 1, 2003 / Volume 98 / Number 7
EPIDEMIOLOGY
About 5000 patients with ALL are diagnosed annually
in the United States.1,2 ALL is the most frequently
diagnosed childhood acute leukemia, constituting
25% of childhood malignancies. It represents only 20%
of adult acute leukemias. ALL has a bimodal distribution. The incidence is 4 –5 per 100,000 population between the ages of 2– 4, which decreases during later
childhood, adolescence, and young adulthood before
a second, smaller peak occurs in patients older than 50
years (incidence 1 per 100,000 population).3
Among children, white children are affected more
frequently than African-American children. There is
little difference in incidence rates by gender among
children, but in older age groups, ALL is more predominant in males. The incidence of ALL has remained stable worldwide for decades. An unexplained
small increase in the number of cases has been observed recently.4
ETIOLOGY
Associations with environmental, socioeconomic, infectious, and genetic events are being studied extensively. Few causal links have been established and the
etiology of ALL remains obscure in most cases.5 The
strongest associations to date exist with genetic factors
and the role of Epstein-Barr virus (EBV) and human
immunodeficiency virus (HIV) in patients with mature–B-cell ALL.
The role of genetic factors is suggested by several
observations. ALL in a monozygotic twin has a 20 –25%
likelihood of developing in the second twin within 1
year.6 Among dizygotic siblings, there is a fourfold
higher risk of leukemia compared with the general
population.7,8 Patients with trisomy 21 (Down syndrome) have a 20-fold higher risk of developing ALL
compared with the general population.9 –12 Klinefelter
syndrome and inherited diseases with excessive chromosomal fragility (Fanconi anemia, Bloom syndrome,
ataxia-telangiectasia) also have been associated with
the development of ALL.13, 14 –16
An increased number of ALL cases have been recorded after the atomic bomb explosions,17 other nuclear exposures such as the Chernobyl accident,18 exposure to therapeutic radiotherapy,19 and in utero
exposure.20 Increased incidence of ALL also has been
associated with residence close to industrial sites; exposure to gasoline, diesel and motor exhausts, smoking, and hair dyes;21–24 parental use of amphetamines,
diet pills, and mind-altering drugs before and during
the pregnancy;25 and exposure to electromagnetic
fields.26
An increased incidence of ALL has been described
with higher socioeconomic status, which may relate to
better hygiene, less social contact in early infancy, and
thus a differing exposure to infectious agents.27
EBV, a DNA virus causing infectious mononucleosis, is associated with Burkitt lymphoma and mature–B-cell ALL including many HIV-related lymphoproliferative disorders.28 A link between the onset of
ALL and seasonality has been described and also may
be related to infectious etiologies.29,30
Few cases of ALL after chemotherapy exposure
have been described. Translocation t(4;11)(q21;q23)
has been demonstrated in ALL up to 2 years after
treatment with topoisomerase II inhibitors.31
CLINICAL PRESENTATION
Symptoms arise from expansion of leukemic cells in
the bone marrow, peripheral blood, and extramedullary sites. Fatigue, lack of energy, dyspnea, dizziness,
bleeding, easy bruising, and infections are common.
Extremity and joint pain may be the presenting symptom in children. Physical examination may reveal pallor, ecchymoses, or petechiae. Lymphadenopathy and
hepatosplenomegaly are infrequent and rarely symptomatic.32 Involvement of skin, testicles, kidneys,
joints, and bones is uncommon in adults.33,34 Central
nervous system (CNS) involvement is uncommon at
diagnosis, except in patients with mature–B-cell ALL.
These patients may present with cranial nerve deficiencies (especially cranial nerves VI, III, IV, and VII),
leading to double vision, abnormal ocular movements, facial dysesthesia, and facial droop.35 Chin
numbness due to mental nerve involvement may be
subtle and can be overlooked easily. Patients with
T-lineage ALL present with a mediastinal mass on
chest X-ray. If the mass is sufficiently large, it results in
stridor, wheezing, pericardial effusions, and superior
vena cava syndrome.36,37 B-cell ALL is a rapidly proliferating tumor. Patients present with signs and
symptoms of metabolic hyperactivity, including profound constitutional symptoms, weight loss, and often
large abdominal and (especially in children) testicular
masses that can lead to obstructive hydronephrosis
with renal insufficiency.38,39 Involvement of the gastrointestinal tract is frequent and may cause bleeding
or rupture.
CLASSIFICATION
French–American–British Classification
Morphology and cytochemical stains are essential in
the initial workup. The bone marrow is usually hypercellular and replaced with a homogenous population
of leukemic blasts. Bone marrow hypocellularity with
increased numbers of lymphoblasts or a necrotic bone
marrow at presentation is rare.40 – 43
Adult ALL/Faderl et al.
1339
TABLE 1
French–American–British Classification of Acute Lymphoblastic Leukemia
Morphology
Size
N/C ratio
Nucleoli
Vacuolization
Basophilia
Cytochemistry
MPO
NSE
PAS
AP
Frequency (%)
Adults
Children
FAB L1
FAB L2
FAB L3 (Burkitt lymphoma)
Small and homogenous
Higher in ⬎ 75% of cells
Inconspicuous, 0–1
Not prominent
Moderate
Larger and pleomorphic
Lower in ⬎ 25% of cells
Prominent, ⱖ 1
Not prominent
Moderate
Medium and homogenous
Variable
Multiple and prominent
Sharply defined
Deep
⫺
⫾
⫹
⫹
⫺
⫾
⫹
⫹
⫺
⫺
⫺
⫺
30
85
60
14
10
1
FAB: French–American–British classification; N/C: nuclear-to-cytoplasmic; MPO: myeloperoxidase; NSE: nonspecific esterase; PAS: periodic acid-Schiff; AP: acid phosphatase.
The French–American–British (FAB) Group described three types of ALL (L1, L2, and L3), which are
distinguished by cell size, amount of cytoplasm,
prominence of nucleoli, degree of cytoplasmic basophilia, and vacuolation (Table 1).44 – 46 By definition,
ALL blasts are negative for myeloperoxidase (MPO).
Low-level MPO positivity (3–5%) has been described
in rare cases that otherwise lack expression of myeloid
markers by flow cytometry.47,48
The World Health Organization (WHO) proposed
new diagnostic guidelines for neoplastic diseases of
hematopoietic and lymphoid tissues or lymphomas.49
The WHO classification suggested that 20% or a
greater amount of blasts are sufficient for the diagnosis of ALL. The WHO classification also suggested that
the distinction of L1, L2, and L3 morphologies be
abandoned because L1 and L2 morphologies do not
predict immunophenotype, genetic aberrations, or
clinical behavior.
Immunophenotype
Immunophenotyping has contributed to a prognostically relevant view of the leukemic blasts in ALL. Due
to the ease of application, accuracy in diagnosis, and
quantifiability of results, flow cytometry has become
the preferred method for lineage assignment.50 A distinct lineage determination is possible in greater than
98% of the leukemic blasts (Fig. 1). ALL blasts are
divided into precursor–B-cell types, mature–B-cell
ALL, and T-lineage ALL (Table 2).51,52
Precursor–B-cell ALL includes pre–pre-B ALL
(pro-B ALL), common ALL (cALL), and pre-B ALL.
Pro-B ALL blasts express CD19, CD79a, or CD22, but
no other B-cell differentiation antigens. CD19-posi-
FIGURE 1. Diagnostic approach to patients with acute lymphoblastic leukemia (ALL). EST: Esterase stain; PAS: periodic acid–Schiff stain; AML: acute
myelogenous leukemia; Ph: Philadelphia chromosome; TdT: terminal deoxynucleotidyl transferase; NK: natural killer; cALL; common ALL; cyIg: cytoplasmic
immunoglobulin; sIg: surface immunoglobulin; MPO: myeloperoxidase.
tive, CD10-negative, cytoplasmic immunoglobulinnegative B-lineage ALL with myeloid marker coexpression is common among infants with ALL and
translocation t(4;11) and MLL gene rearrangements.53
cALL (early pre-B ALL), the most common immunophenotype in adults and children, is positive for CD10
(common ALL antigen). It is found frequently in Philadelphia chromosome (Ph)-positive ALL (i.e., in 50%
of cases), accounting for the worse prognosis of CD10-
1340
CANCER October 1, 2003 / Volume 98 / Number 7
TABLE 2
Immunophenotype of Adult Acute Lymphoblastic Leukemia
Lineage
Precursor–B-cell ALL
Pro-B ALL
cALL
Pre-B ALL
Transitional
precursor–B-cell ALL
Mature–B-cell ALL
T-lineage ALL
Pro-T ALL
Pre-T ALL
Cortical-T ALL
Mature-T ALL
Frequency
(%)
TdT
HLA-DR
CD34
CD19
CD22
CD79a
CD10
cy␮
cy␬/␭
slgH/L
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫺
⫺
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫺
⫺
⫺
⫹
⫾
⫺
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫺
5–10
40–50
10
1
⫾
⫺
⫹
⫹
⫺
⫺
⫹
⫹
⫹
⫾
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫹a
⫹
1
5
⫹
⫹
⫹
⫹
⫾
⫾
⫺
⫺
⫾
⫾
⫺
⫺
cyCD3
⫹
⫹
⫹
⫹
CD7
⫹
⫹
⫹
⫹
CD1a
⫺
⫺
⫹
⫺
CD2
⫺
⫹
⫹
⫹
CD5
⫺
⫹
⫹
⫹
sCD3
⫺
⫺
⫺
⫹
5
10–15
5–10
TdT: terminal deoxynucleotidyl transferase; cy: cytoplasmic; s: surface; IgH: immunoglobulin heavy chain; IgL: immunoglobulin light chain; ALL: acute lymphoblastic leukemia; cALL: common acute lymphoblastic
leukemia.
a
Usually no surface light chain (L) expression.
positive ALL in adults versus children. Finally, pre-B
ALL blasts express cytoplasmic immunoglobulins (Ig).
The blasts are more differentiated than in early pre-B
ALL and more cases have translocation t(1;19).54,55 In
children, but not in adults, identification of this cytogenetic abnormality has been linked to a worse prognosis in pre-B ALL than in early pre-B ALL.56
Mature–B-cell ALL is distinguished by the expression of surface Ig, usually IgM, and by the absence of
staining for the enzyme terminal deoxynucleotidyl
transferase (TdT). Mature–B-cell ALL is associated
with the FAB L3 subtype. In some cases, L1 or L2
morphology has been described.57 Translocations between the c-myc locus on chromosome 8q24 and one
of the loci for the Ig heavy (IgH) or light chain genes
(14q32, 2p12, and 22q11) are characteristic.58
The T ALL subtypes are distinguished according to
the stage of normal thymocyte development.59 Cytoplasmic CD3 (cCD3) is the most T-lineage–specific
marker. Although early subtypes do not express surface CD3 (sCD3), they are positive for cCD3. CD4 and
CD8 are either double-positive or double-negative.
CD2 is negative. The more mature subtypes of T ALL
are positive for both sCD3 and cCD3, CD2, and either
CD4 or CD8 but not both.60 Although it is the most
sensitive T-cell marker, CD7 lacks specificity, as cases
of acute myelogenous leukemia (AML) or natural killer
(NK) cell leukemia can express CD7 too.61
ALL blasts coexpress myeloid markers in 15–50%
of adults and in 5–35% of children.51,62– 65 The most
frequently coexpressed myeloid markers are CD13
and CD33.66 –– 68 No association exists between myeloid marker expression and FAB group or karyotype,
except for a higher incidence with translocations t(9;
FIGURE 2. Cytogenetic abnormalities in adult acute lymphoblastic leukemia.
22) and t(4;11).69 Although earlier studies had shown a
worse outcome with coexpression of myeloid markers,
recent studies did not show any prognostic significance.63,70 –75
Cytogenetic-Molecular Markers
Recurrent cytogenetic-molecular abnormalities occur
in about 80% of children and 60 –70% of adults (Fig.
2).76 Distinct subsets of ALL can now be identified
based on molecular abnormalities with implications
on prognosis and on the choice of therapy.77
The Philadelphia chromosome
Ph results from a reciprocal translocation between
chromosomes 9 and 22, t(9;22)(q34;q11). With a frequency of 15–30%, it is the most common cytogenetic
abnormality in adult ALL.76 A segment of the ABL gene
Adult ALL/Faderl et al.
(9q34) is moved into one of several breakpoint cluster
regions of the BCR gene (22q11). The chimeric BCRABL gene is translated into BCR-ABL oncoproteins of
different molecular weights, depending on the location of the breakpoint in the BCR gene.78 Whereas
p210BCR-ABL is characteristic for chronic myeloid leukemia, a shorter version, p190BCR-ABL, predominates in
Ph-positive ALL. The abnormal fusion proteins have
deregulated and abnormally increased tyrosine kinase
activity, leading to the involvement of downstream
signaling pathways. Patients with t(9;22) typically are
older and frequently have higher leukocyte and blast
counts at diagnosis than patients with normal karyotypes.79 A pre–B-cell immunophenotype and expression of CD10 and myeloid markers typically are associated with Ph.
Chromosome 9p21 abnormalities
Chromosome 9p21 abnormalities occur in about 15%
of patients.80 The cyclin-dependent kinase inhibitors
(CDKI), p16INK4a/p14ARF and p15INK4b, are localized on
chromosome 9p21 and deletions of these genes, more
so than silencing of gene expression by hypermethylation, are their major mode of inactivation.81 Using
fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR), deletions of p16INK4a are
present in 80% of children with T-ALL and 20% of
children with pre-B ALL. Patients with 9p21 abnormalities are prognostically heterogeneous. Deletions of 9p
are an adverse risk factor in B-lineage, but not T-cell,
ALL, although homozygous deletions are associated
with a significantly poorer survival in T-ALL as well.82
Prognostic associations are stronger in children than
in adults with ALL.83– 85
11q23 rearrangements
The common denominator among 11q23 abnormalities is the involvement of the mixed lineage leukemia
gene, MLL (previously ALL-1, HRX, or HTRX1). More
than 20 chromosomal loci participate in reciprocal
rearrangements with 11q23, including 4q21, 9p22,
19p13, and 1p32.86,87 The most common translocation
is t(4;11)(q21;23). It is specifically associated with ALL
in infants (85% of the cases) and it is found in 3– 8% of
adults.77,86 Adults with this translocation tend to be
older and more frequently have higher leukocyte
counts, organomegaly, and CNS involvement. The
pro-B ALL immunophenotype is positive for TdT,
HLA-DR, and CD19 and is variably negative for CD10.
Myeloid antigen coexpression is common. Prognosis
with 11q23 rearrangements is poor. Allogeneic stem
cell transplantation (SCT) for patients with their first
disease remission is currently the treatment of
choice.88
1341
Chromosome 19p13
The two known translocations involving 19p13 are
t(1;19)(q23;p13) and its rare variant, t(17;19)(q21;p13).
Translocation t(1;19) has a strong association with
cytoplasmic Ig-positive pre-B ALL.89 Its overall frequency in childhood ALL and pre-B ALL is 5% and
25%, respectively. The translocation juxtaposes the
E2A gene on chromosome 19 with the homeoboxcontaining gene, PBX1, to generate the E2A-PBX1 fusion gene. It functions as a potent transcriptional activator and transforms in vitro several cell types
including fibroblasts, myeloid progenitors, and lymphoblasts.90 Patients with E2A-PBX1– expressing ALL
do poorly with standard therapy, but have a better
prognosis with more aggressive approaches. In contrast to the unfavorable prognosis of patients with
pre-B ALL and t(1;19), patients with pro-B ALL and
t(1;19) do better.91
Translocation t(12;21)
Using PCR, this otherwise cryptic translocation now
can be identified in up to 30% of children with ALL,
making it the most frequent recurring cytogeneticmolecular abnormality in pediatric ALL. It is rare in
adults (i.e., it occurs in 1–3% of adults).92,93 The translocation involves TEL (ETV6), a transcription-regulating gene of the Ets family of transcription factors on
12p11, and AML1 on 21q22.94 The outcome of patients
with a TEL-AML1 fusion is favorable in children with
pre-B ALL, independent of age or leukocyte count at
presentation. One study suggested that the favorable
outcome was from exclusion of patients with other
poor-risk cytogenetic abnormalities and the younger
age of these patients compared with patients with
normal karyotypes.78 Translocation t(12;21) may be
associated with late disease recurrences.95,96 Its prognostic significance is undetermined in adults.
Translocation t(8;14) and its variants
Translocation t(8;14)(q24;q32), and its less common
variants, t(8;22)(q24;q11) and t(2;8)(p12;q24), are
characteristic of mature–B-cell ALL. All three translocations result in deregulation, increased transcription,
and overexpression of c-MYC. In 80% of patients, 8q24
is juxtaposed to the IgH gene locus on 14q32, whereas
the Ig lamba gene locus on 22q11 is involved in 15% of
patients and the Ig kappa gene locus on 2p12 is involved in 5% of patients.97 Mature–B-cell ALL and
Burkitt lymphoma typically are associated with 8q24
rearrangements.
T-cell receptor gene rearrangements
T-cell receptor (TCR) gene rearrangements are the
most common genetic abnormalities in T-ALL.76 Al-
1342
CANCER October 1, 2003 / Volume 98 / Number 7
because within the same recurrent translocation (e.g.,
Ph abnormality), adults fare much worse than children. New therapies targeting newly identified specific
molecular abnormalities may increase the effectiveness of current therapies.
PROGNOSIS
FIGURE 3.
Comparison of the incidence of prognostically relevant cytogenetic abnormalities between adults and children.
though no specific cytogenetic abnormality can be
linked to a specific clinical subtype of T-ALL, a number of distinct chromosomal translocations have been
identified (Fig. 3).
Gene Expression Profiling
Success in ALL therapy is achieved partly from recognizing ALL as heterogeneous and using risk-adapted
therapies.98 Assignment of risk is based on a number
of clinical and laboratory parameters in ALL, but cytogenetic-molecular alterations are emerging as the
defining prognostic features.99 Oligonucleotide microarray technology simultaneously quantifies the expression of thousands of individual genes and therefore establishes gene expression profiles for well
defined ALL subgroups. The goals of gene expression
profiling are 1) definition of lineage affiliation and
distinct molecular subtypes that may defy current
classification schemes; 2) association of gene expression with chromosomal abnormalities including the
possibility to identify cases with cryptic translocations; 3) identification of genetic alterations that underlie the pathogenesis of individual leukemia subtypes; 4) detection of gene expression clusters that
characterize patients with distinct responses to therapy, providing prognostic information; and 5) establishment of gene expression clusters in disease recurrence.
Oligonucleotide or cDNA microarray technology
is being established as an alternative and extension to
conventional karyotyping and FISH in the diagnosis of
leukemia subtypes and as a method to define previously unrecognized molecular subtypes of ALL.98 –101
Further applications will include comparisons of gene
expression profiles of adults versus children with ALL
Advances in ALL therapy have changed the risk assignment of some subgroups such as T-lineage ALL and
mature–B-cell ALL. Some believed to be previously
useful prognostic, clinical, laboratory, or biologic predictors have now little value as the treatment has improved dramatically over the last two decades.102–104
Other prognostic factors can be explained by superceding genetic-molecular abnormalities that are being
recognized increasingly as powerful predictors of outcome.76
Persistent adverse prognostic features include
older age, leukocytosis, delayed response to therapy,
specific cytogenetic abnormalities, and immunophenotype, with some limitations (Table 3).105–112 Up to
75% of adults with ALL are considered to be poor-risk
patients, with an expected DFS rate of 25%. Only 25%
of adults with ALL constitute standard-risk patients,
with a projected DFS rate of greater than 50%. Recently, other factors were identified to predict prognosis. The dynamics of blast clearance in response to
steroids, assessed within 1–2 weeks, have prognostic
value in adults.113 Markers of drug resistance, such as
expression of MDR-1, were reported to be prognostic
factors by the Italian GIMEMA group.114 Finally, assessment of minimal residual disease (MRD) is emerging as important for determining the risk of disease
recurrence.
PRIMARY THERAPY
Chemotherapy
Treatment programs incorporate multiple drugs into
regimen-specific sequences of dose intensity and time
intensity (Table 4).104,113,115–125 The goal is rapid restoration of normal hematopoiesis, prevention of the
emergence of resistant subclones, adequate prophylaxis of sanctuary sites such as the CNS, and elimination of MRD through postremission consolidation.
Therefore, therapy is divided into several phases: induction, consolidation and intensification, and maintenance. CNS prophylaxis is essential in ALL and is
usually delivered during induction and consolidation.
Induction
Vincristine plus corticosteroids achieve CR rates of
40 – 65%, but the median duration of disease remission
is only 3–7 months. Adding anthracyclines has increased the CR rate to 72–92% and the median dura-
Adult ALL/Faderl et al.
1343
TABLE 3
Prognostic Factors in Adult Acute Lymphoblastic Leukemia
Characteristic
Patient-related
Age
Performance status
Gender
Race
Plasma albumin levels
Treatment-related
Late response
Response to steroids
Dose intensity
Pharmacodynamics
Disease-related
Leukocytosis
Cytogenetics
Immunophenotype
Other characteristics
P-glcyoprotein
p53
p15INK4b
Glutathione
Caspase 2 and 3
High-risk factor(s)
Standard-risk factor(s)
⬎ 50 yrs
Poor
Male
Black
Low
⬍ 35 yrs
Good
Time to CR ⬎ 4 weeks
Persistence of blasts in PB at Day 7 and BM at Day 14
Delayed, incomplete
Decreased
Nontherapeutic levels of 6-MP, MTX
Time to CR ⬍ 4 weeks
Timely clearance of blasts
Fast, complete
Normal
⬎ 30 ⫻ 109/L (B-lineage)
⬎ 100 ⫻ 109/L (T-lineage)
t(9;22), t(4;11)
Early- and mature-T ALL, pro-B ALL (null type)
Therapeutic levels of drugs
⬍ 30 ⫻ 109/L
t(12;21), hyperdiploid
Cortical-T ALL
Greater expression
Aberrant expression
Greater methylation
High levels
High levels
ALL: acute lymphoblastic leukemia; CR: complete response; PB: peripheral blood; BM: bone marrow; 6-MP: 6-mercaptopurine; MTX: methotrexate.
tion of disease remission to approximately 18
months.125–127 Dexamethasone has been substituted
for prednisone because of better in vitro antileukemic
activity and achievement of higher drug levels in the
cerebrospinal fluid (CSF).128 –130 It has been difficult to
demonstrate further improvement of CR rates with the
addition of asparaginase, cyclophosphamide, cytarabine, and other agents. Intensification of induction
may, however, positively influence the duration of
disease remission and survival (e.g. in T-lineage ALL
with cytarabine [ara-C] and cyclophosphamide and in
mature–B-cell ALL with fractionated doses of cyclophosphamide and high doses of methotrexate).104,113,118,131–133
Other approaches to induction therapy include
high-dose ara-C and mitoxantrone without vincristine-steroids,134 high doses of daunorubicin (total of
270 mg/m2) and ara-C during induction-consolidation,124 and high doses of liposomal daunorubicin
during induction.
The use of growth factors during induction may
alleviate profound myelosuppression and its complications and allow timely administration of dose-intensive treatment regimens.135–137 In a double-blind, randomized trial (Cancer and Leukemia Group B [CALGB]
9111), granulocyte– colony-stimulating factor (G-CSF)
during induction was associated with faster recovery
of neutrophils to greater than 1 ⫻ 109/L (P ⬍ 0.0001),
platelet recovery, and reduction of the duration of the
hospital stay (P ⫽ 0.02).137 The CR rate was higher with
G-CSF (90% vs. 81%; P ⫽ 0.10), which was more pronounced in elderly patients. A higher rate of induction
deaths was observed in the placebo group compared
with the G-CSF–treated group (11% vs. 4%, P ⫽ 0.04)
and in patients age 60 years or older (25% vs. 10%, P
⫽ 0.24).
Consolidation
Consolidation may include a modified induction
treatment, rotational consolidation programs, and
SCT. It is difficult to assess the value of individual
components of the treatment because the number,
schedule, and combination of cytostatic drugs vary
considerably among studies. Current strategies address the subtype and risk-oriented approaches of
consolidation programs.
Hyper-CVAD is a dose-intensive regimen with alternating hyperfractionated cyclophosphamide and
high doses of ara-C and methotrexate.118 Compared
with the earlier and less intensive regimen of vincristine, doxorubicin, and dexamethasone (VAD), CR rates
(91% vs. 75%, P ⬍ 0.01) and survival (P ⬍ 0.01) were
superior with hyper-CVAD.
In the CALGB 8811 study, patients underwent
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CANCER October 1, 2003 / Volume 98 / Number 7
TABLE 4
Results of Chemotherapy Studies in Adult Acute Lymphoblastic Leukemia
Study
n
Median age
(range) (yrs)
CR (%)
Induction
mortality (%)
LTS (%) (yrs)
Annino et al., 2002113
Linker et al., 2002122
Goekbuget et al., 2001138
Bassan R et al., 2001196
Dekker et al., 2001197
Rowe et al., 2001161
Kantarjian et al., 2000118
Thiebaut et al., 2000160
Hallbook et al., 1999198
Todeschini et al., 1998124
Ribera et al., 1998139
Larson et al., 1998137
Durrant et al., 1997123
Larson et al., 1995104
Gökbuget et al., 2000115
Hussein et al., 1989120
GIMEMA, 1989121
794
84
1200
121
193
871
203
572
120
60
108
198
618
197
569
168
358
27.5 (12–59.9)
27 (18–59)
35 (15–65)
35 (NA)
33 (15–60)
30 (14–60)
39.5 (16–79)
33 (15–60)
44 (16–82)
34 (14–71)
28 (15–74)
35 (16–83)
⬎ 15
32 (16–80)
27 (15–65)
28 (15–85)
31 (15–64)
82
93
86
84
82
89
91
76
85
93
86
82
88
85
75
68
79
7
NI
5
NI
NI
5
6
9
5
5
5
8
9
9
⬍ 10
17
7
NI
48 (5)
47 (5)
49 (3)
35 (5)
34 (5)
39 (5)
27 (10)
36 (3)
55 (6)
41 (5)
23 mosa
28 (5)
36 mosa
39 (7)
17.7 mosa
21.7 mosa
CR: complete response; LTS: long-term survival; NI: no information; GIMENA: Grupo Italiano Malattie Ematologische dell’Adulto.
a
Median survival.
early and late intensification courses with eight drugs
following a five-drug induction regimen.104 Maintenance therapy was given for 2 years after diagnosis.
The median duration of disease remission was 29
months, and the median survival period was 36
months; these results were considerably better than
those from earlier, less intensive trials.
In the Medical Research Council (MRC) UKALL
XA, patients were randomized to receive early intensification at 5 weeks, late intensification at 20 weeks,
both, or neither.123 The early block of intensive treatment prevented disease recurrence although the DFS
at 5 years was increased only slightly.
The German multicenter trial 05/93 intensified
the consolidation in a subtype-specific manner.138 In
that study, patients received high-dose methotrexate
for standard-risk B-lineage ALL, cyclophosphamide
and ara-C for T-lineage ALL, and high-dose methotrexate and high-dose ara-C for high-risk B-lineage
ALL. Induction was intensified with high-dose ara-C (4
doses of 3 g/m2) and mitoxantrone instead of the
Phase II induction in high-risk patients. The CR rate
was 87% for standard-risk patients, with a median
duration of disease remission of 57 months and a
5-year survival rate of 55%. Intensified induction/consolidation did not improve the CR rate and DFS in
high-risk patients, with the exception of pro-B ALL.
Patients with pro-B ALL achieved a continuous CR
rate of 41% compared with 19% in other high-risk
patients.
The GIMEMA ALL 0288 study randomized patients to receive an early post-CR intensification versus maintenance therapy.113 Of 388 patients, 201 had
maintenance alone whereas 187 received consolidation followed by maintenance. Intensification of postCR treatment did not influence the continuous CR
rate. At 8 years, 36% of patients who received consolidation-maintenance and 37% of patients who received maintenance remained in CR. Only 35% of
patients randomized to the intensified consolidation
completed their treatment in the expected time frame
because of toxicities and compliance problems. In the
PETHEMA ALL-89 trial, patients in disease remission
at the end of the first year were randomized to receive
1 6-week cycle of late intensification therapy.139 There
was no difference in survival and DFS between patients who did or did not receive late intensification.
Maintenance
The maintenance regimen consists of daily doses of
6-mercaptopurine, weekly doses of methotrexate, and
monthly pulses of vincristine and prednisone given
over 2–3 years. Extension of the maintenance regimen
beyond 3 years has not shown additional benefits.
Omission of maintenance therapy has been associated
with shorter DFS rates.140 –142 No clear advantage has
been demonstrated with intensified versus conventional maintenance doses,143 leading some investigators to revisit shorter maintenance strategies. In T-cell
ALL, the benefit of maintenance chemotherapy has
Adult ALL/Faderl et al.
been questioned. No maintenance therapy is given to
patients with mature–B-cell ALL. These patients respond well to short-term dose-intensive regimens and
disease recurrences beyond the first year in remission
are rare.
1345
remains to be determined whether any particular
group of patients may benefit from this approach.
CNS prophylaxis remains essential. Omission of craniospinal XRT in favor of IT therapy, possibly combined with high-dose systemic therapy, may be possible, particulary in adult patients.
Central nervous system prophylaxis
CNS disease is rare at diagnosis (i.e., in ⬍ 10% of
patients), but may be diagnosed in 50 –75% of patients
at 1 year in the absence of CNS-directed therapy.108,118,144 –146 The diagnosis of CNS leukemia requires the presence of more than five leukocytes per
microliter in the CSF and the identification of lymphoblasts in the CSF differential.147 The presence of blasts
in a CSF sample with less than five leukocytes per
microliter may still signify CNS disease.148 False-negative CSF results may occur in patients with predominantly cranial nerve involvement.
CNS prophylaxis clearly reduced the incidence of
CNS disease.149 Measures of CNS prophylaxis include
intrathecal (IT) chemotherapy (methotrexate, ara-C,
steroids), high-dose systemic chemotherapy (methotrexate, ara-C, L-asparaginase), and craniospinal irradiation (XRT).35 The role of cranial XRT has become
controversial. It can result in neurologic adverse
events including seizures, dementia, intellectual dysfunction, growth retardation in children, and other
complications. Risk factors for CNS leukemia in children include an age of 1 year or younger, excessive
leukocytosis, T-lineage and mature–B-cell ALL,
lymphadenopathy, thrombocytopenia, hepatomegaly,
and splenomegaly.150,151 Mature–B-cell ALL, serum
lactate dehydrogenase levels, and a high proportion of
bone marrow cells in a proliferative state (⬎ 14% of
cells in the S⫹G2M phase of the cell cycle) have been
associated with a higher risk of CNS disease in adults
compared with adults without these risk factors.152
Recent studies suggested that effective CNS prophylaxis can be achieved with a combination of IT and
high-dose systemic chemotherapy without cranial
XRT, even in patients at high risk for developing CNS
disease.146,152 Based on the experience with hyperCVAD, CNS prophylaxis consists of 4 IT treatments in
the low-risk category, 8 IT treatments with high-risk
disease, and 16 IT treatments for mature–B-cell ALL or
Burkitt disease. Patients with cranial nerve root involvement may benefit from selective XRT to the base
of the skull.
The backbone of chemotherapy for ALL remains
the sequence of induction, consolidation, and a prolonged maintenance of at least 2 years. Attempts to
intensify treatment during the consolidation phase
have been met with mixed results. Whereas the compliance rate has been questioned in some trials, it
Stem Cell Transplantation
Allogeneic sibling stem cell transplantation
The survival rate for adult patients with ALL with
matched related allogeneic SCT in first CR is about
50% (range, 20 – 81%).153–155 Several studies have tried
to compare the outcome of SCT versus chemotherapy
in ALL in first CR. As 70% of adults with ALL cannot be
allocated to SCT because of a lack of a matched related
sibling, comorbidities, or severe infections, an objective and unbiased comparison among treatments is
difficult.156
The International Bone Marrow Transplant Registry compared 251 patients who received intensive
postremission chemotherapy with 484 patients who
received matched related sibling allogeneic SCT. After
adjustments for differences in disease characteristics
and time to treatment, the 9-year DFS rates were 32%
for chemotherapy and 34% for allogeneic SCT.157 The
causes of treatment failure were different, i.e., the
actuarial disease recurrence rates at 9 years were 66%
with chemotherapy and 30% with transplantation.
Treatment-related mortality was the main cause of
failure in patients who received transplants.158
A large French multicenter trial (LALA 87) compared allogeneic SCT with chemotherapy or autologous SCT in first CR.159 Of 257 randomized patients,
116 were allocated to receive allogeneic SCT and 114
were allocated to the control group (chemotherapy
and autologous SCT). The 5-year survival rates were
not significantly different (48% and 35%, respectively;
P ⫽ 0.08). Among patients with high-risk ALL, the
5-year overall survival rate (44% vs. 20%, P ⫽ 0.03) and
the 5-year DFS rate (39% vs. 14%, P ⫽ 0.01) were more
favorable with allogeneic SCT. An update of the LALA
87 study presented the long-term comparative data of
allogeneic SCT versus the control arm of these patients.160 Based on an intent-to-treat analysis, the
overall survival rate was 46% with SCT versus 31% with
chemotherapy (P ⫽ 0.04). In the high-risk group, survival rates at 10 years were 44% with SCT and only 11%
in the control arm (P ⫽ 0.009). In the standard-risk
group, the corresponding numbers were 49% and
39%, respectively (P ⫽ 0.6). These results support the
value of allogeneic SCT in first CR in patients with
high-risk ALL.
In the international ALL trial (MRC UKALL XII/
Eastern Cooperative Oncology Group E2993), all pa-
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CANCER October 1, 2003 / Volume 98 / Number 7
tients received two phases of induction therapy and
were assigned in CR to receive allogeneic SCT if they
had a histocompatible donor.161 The remaining patients received either standard consolidation/maintenance therapy for another 2.5 years or autologous
SCT. Early results have been presented for 170 patients receiving allogeneic SCT and 264 patients eligible for randomization. The reported data focus on
Ph-negative patients and are based on an intent-totreat analysis from the time of their intended therapy.
The 5-year event-free survival (EFS) rate was 54% in
the allogeneic group and 34% in the randomized
group (P ⫽ 0.04). In the standard-risk group, the
5-year EFS rates were 66% with allogeneic SCT and
45% for the randomized group (P ⫽ 0.06). The rates
were 44% and 26%, respectively, for high-risk patients.
Contrary to the findings of other studies, these data
suggested that allogeneic SCT was beneficial in first
CR, regardless of the risk group.
Autologous stem cell transplantation
In most studies, autologous SCT is inferior to allogeneic SCT.156 No advantage in DFS has been demonstrated with autologous SCT compared with chemotherapy alone.162,163 In the LALA 87 trial, the results
were still not significant, even when comparing highrisk and standard-risk patients.160 Investigators at The
University of Texas M. D. Anderson Cancer Center
(Houston, TX) found no significant difference between
the 3-year DFS and overall survival rates with autologous SCT in first CR versus continued postremission
chemotherapy (60% vs. 49% and 58% vs. 62%, respectively).164
Powles et al.165 combined conventional ALL therapy with autologous SCT. Seventy-seven patients in
first remission received autografts followed by posttransplantation maintenance chemotherapy with
methotrexate, 6-mercaptopurine, vincristine, and
prednisone. The cumulative incidence of disease recurrence at 10 years was 42%. The 10-year DFS and
overall survival rates were 50% and 53%, respectively.
The study performed by Powles et al. highlighted two
important points: 1) patients who received at least two
maintenance chemotherapy agents fared better than
those who received one or none; and 2) there was no
benefit from autologous SCT in high-risk ALL.
Whereas autologous SCT has not provided any
benefit compared with chemotherapy in first CR, recent data on the role of allogeneic transplant for patients in first CR are more intriguing. If the data from
the international ALL trial are confirmed, then allogeneic SCT appears to be superior to chemotherapy
even in standard-risk patients with ALL, challenging
the current approach of restricting allogeneic SCT to
high-risk ALL patients in first CR only.
Minimal Residual Disease (MRD)
MRD can be measured with flow cytometry and PCR
techniques using either fusion transcripts resulting
from chromosome abnormalities or patient-specific
junctional regions of rearranged Ig and TCR genes.166
To determine residual disease at various time points
during the first 6 months after disease remission, Cavé
et al.167 used quantitative PCR for junctional sequences of TCR or Ig gene rearrangements in 246
children with ALL. There was a significant correlation
between detection of MRD and risk of early disease
recurrence at each of the time points studied, particularly in patients with ⱖ 10⫺2 residual blasts per 2
⫻ 105 mononuclear bone marrow cells immediately
after disease remission or with ⱖ 10⫺3 at later time
points.
Less data are available on MRD in adult ALL and
differences in pattern and dynamics of clearance of
residual disease exist between adult and childhood
ALL. Foroni et al.168 analyzed bone marrow samples
from 33 adults and 21 children by PCR for IgH gene
rearrangements at specific time points after diagnosis.
Among patients who remained in CR, a decrease in
MRD positivity occurred during the first 12 months.
The proportion of positive tests decreased more
quickly in children than in adults, suggesting more
rapid resolution of MRD, particularly in the first 6
months of CR.
Using quantitative PCR in 27 adults with ALL,
Brisco et al.169 found a significantly higher rate of
disease recurrence (89%) if residual disease persisted
above a level of 10⫺3 leukemic cells per bone marrow
cell. However, even in patients with lower levels of
residual disease, the risk of disease recurrence was still
high (46%). In addition to reservations about the predictive threshold of residual disease, the optimal time
point to measure residual disease is not clear. In a
study of 85 adult patients with B-lineage ALL, residual
disease was assessed by semiquantitative IgH gene
analysis during 4 time points in the first 24 months of
treatment.170 MRD positivity was associated with increased disease recurrence rates at all times, but the
association was most significant 3–5 months after induction and beyond. The association between residual
disease and DFS was independent of and greater than
other standard predictors of outcome.
Although data from analysis of MRD are increasingly applied in protocols and are integrated into clinical decision-making, important issues remain to be
resolved by future studies. Even if early detection of
residual disease by sensitive techniques predicts dis-
Adult ALL/Faderl et al.
ease recurrence, how can early detection of molecular
disease recurrence guide therapy?, and does treatment
of molecular disease recurrence improve survival? Finally, it may not be necessary to completely eliminate
residual disease to achieve cure. Other homeostatic
mechanisms may modulate growth of the leukemic
clones that are currently not identifiable with the assays applied to residual disease.166
SALVAGE THERAPY
The outcome of salvage therapy remains unsatisfactory. CR rates range from 10% to 50% and long-term
DFS is poor. Salvage regimens are patterned according
to promising leads from frontline therapy. Regimens
are divided into combinations of vincristine, steroids,
and anthracyclines, combinations of asparaginase and
methotrexate, programs that integrate high-dose
ara-C, and, finally, SCT.171 New agents are assessed
continually and incorporated into salvage strategies.
Chemotherapy
The VAD regimen in 64 patients with recurrent or
refractory ALL achieved a CR rate of 39%, with a median CR duration and survival of 7 and 6 months,
respectively.128 The DFS rate at 2 years and the overall
survival rate were 20% and 8%, respectively. Koller et
al.172 compared hyper-CVAD with high-dose ara-C–
based treatments (mitoxantrone, high-dose ara-C, and
granulocyte-macrophage– colony-stimulating factor).172
The CR rates were similar with both regimens (44%
and 38%), but survival was better with hyper-CVAD.
L-asparaginase was administered in combination
with methotrexate, anthracyclines, vinca alkaloids,
and prednisone. Response rates ranged from 33% to
79% and the median DFS period ranged from 3 to 6
months.173–175 Remission rates of 17–70% have been
reported with high-dose ara-C– based regimens.176 –178
Stem Cell Transplantation
Although SCT is superior to chemotherapy with longterm DFS rates of 20 – 40% in salvage therapy,179 only
30 – 40% of patients who achieved a second CR were
eligible for SCT and fewer than one-half had enough
time before disease recurrence to undergo SCT. Considering a DFS rate of about 25%, only a fraction of the
total population at risk would benefit from a transplant.180,181
In the absence of a matched related sibling donor,
identifying an unrelated donor in a timely fashion can
be difficult. Davies et al.182 studied the outcome of 115
consecutive patients with recurrent ALL over a 2-year
period to determine the success rate of identifying a
matched related or unrelated donor, as well as the
feasibility of SCT.182 A matched related donor was
1347
identified in 35%, and 75% of these patients underwent SCT. Of 58 patients for whom an unrelated donor
search was initiated, a donor was identified for 22
patients and 15 patients proceeded to an SCT from a
matched unrelated donor.
PHILADELPHIA CHROMOSOME–POSITIVE ACUTE
LYMPHOBLASTIC LEUKEMIA
Patients with Ph-positive ALL have long-term DFS
rates of less than 10%.183 In a CALGB study, the CR
rate in Ph-positive ALL was 79% and the 5-year continuous CR rate was 8% (vs. 38% with diploid ALL).184
Currently, SCT is recommended for all patients
with Ph-positive ALL who achieve a CR. The international ALL trial group compared the outcome of 167
patients with Ph-positive ALL who received a matched
related SCT (n ⫽ 49), a matched unrelated donor
transplant (n ⫽ 23), autologous SCT (n ⫽ 7), or continued chemotherapy (n ⫽ 77).185 The treatment-related mortality rate was higher with SCT (37% for
matched sibling transplants, 43% for matched unrelated donor transplants, 14% with autologous SCT,
and 8% with chemotherapy). The 5-year risk of disease
recurrence was lower with allogeneic SCT (29%) than
with autologous SCT/chemotherapy (81%). The 5-year
survival rates were 43% with allogeneic SCT and 19%
with autologous SCT or chemotherapy.
Imatinib mesylate (STI571, Gleevec; Novartis, East
Hanover, NJ) is a potent and selective inhibitor of the
BCR-ABL tyrosine kinase.186 The M.D. Anderson Cancer Center studies combined imatinib with hyperCVAD for newly diagnosed patients with Ph-positive
ALL.187 Eight induction/consolidation courses (hyperCVAD alternating with high-dose methotrexate and
ara-C), during which imatinib is given for 14 days of
each treament cycle, is followed by a 1-year maintenance with imatinib at a dose of 600 mg orally daily.
Preliminary results showed that this combination is
safe and that disease remission rates are high. The
effect on long-term DFS remains unclear. In a study of
56 patients with recurrent and refractory Ph-positive
ALL, imatinib 400 mg or 600 mg was given once daily.188
The CR rate was 29%. Responses were sustained for at
least 4 weeks in only 6% of patients. The median time
to progression and overall survival were 2.2 and 4.9
months, respectively. Limited experience exists with
imatinib in Ph-positive ALL transplant failures.189 In a
study of 20 consecutive Ph-positive patients with ALL
who had disease recurrence after allogeneic SCT, imatinib induced a CR in 11 patients (55%).
BURKITT ACUTE LYMPHOBLASTIC LEUKEMIA
Outcome with conventional ALL therapy for mature–
B-cell ALL was poor, with long-term DFS rates of less
1348
CANCER October 1, 2003 / Volume 98 / Number 7
TABLE 5
Outcome of Therapy for Mature–B-Cell Acute Lymphoblastic
Leukemia
Study
Conventional (VAD)
Kantarjian et al., 1990164
Short-time, dose-intensive
Thomas et al., 1999151
Age ⬍ 60 yrs
Age ⱖ 60 yrs
Soussain et al., 1995194
Hoelzer et al., 2002199
Todeschini et al., 1997200
Fenaux et al., 1989201
n
CR (%)
TABLE 6
New Therapeutic Agents for Acute Lymphoblastic Leukemia
Agent type
Agent
Monoclonal antibody
Anti-CD20 (rituximab)
Anti-CD19 ⫹ ricin/genistein
Anti-CD52 (alemtuzumab)
Anti-CD33
Anti-CD7 ⫹ ricin
Imatinib mesylate
Farnesyltransferase inhibitors (R115777,
Sch66336)
Nelarabine (compound 506U)
Clofarabine
BCX1777
Liposomal vincristine
Pegylated asparaginase
Liposomal ara-C (DepoCyt; Skye Pharma,
London, United Kingdom)
% DFS (yrs)
86
44–65
0–15
26
14
12
65
89
21
18
81
92
67
89
75
100
56
49 (3)
74 (3)
16
74 (3)
38 (4)
75a
57b
CR: complete response; DFS: disease-free survival; VAD: vincristine, doxorubicin, and dexametnasone.
a
Event-free survival, with a median follow-up of 28 months.
b
Survival plateau at 7 months, with no late disease recurrences.
than 10%.37 Hyperfractionation of the alkylating agent
cyclophosphamide, and use of different non– crossresistant agents in tandem, formed the basis of many
dose-intensive programs (Table 5).190 –193 Complete
disease remission was attained in 89 –92% of patiemnts and 2-year DFS rates increased to 60 – 80%.
Disease recurrence was rare after the first year in
remission. Intensive early prophylactic IT therapy
(with or without cranial XRT), in addition to intensive
systemic methotrexate and ara-C, significantly reduced the rate of disease recurrence in the CNS.
Hyper-CVAD, modeled after the total therapy B
designed by Murphy et al. for childhood mature–B-cell
ALL,142 was given to 26 patients. The overall CR rate
was 81%.102,194 The long-term DFS rate was 83% for
patients younger than 60 years of age, but only 16% for
patients 60 years of age or younger. The less favorable
outcome in older patients was accounted for by both
higher induction mortality and higher disease recurrence rates. Rituximab (anti-CD20 monoclonal antibody) is now incorporated into hyper-CVAD to further
improve the prognosis of mature–B-cell ALL.
Cortes et al.195 studied hyper-CVAD for newly diagnosed patients with HIV-related mature–B-cell ALL,
adding highly active antiretroviral treatment (HAART).
The CR rate in 13 patients was 92%, the median survival period was 12 months, and about 50% of the
patients were alive more than 2 years after diagnosis.
The outcome was better in the group receiving HAART
early in the course of therapy (Cortes J. Personal communication).
The role of autologous or allogeneic SCT in mature–B-cell ALL is less clear. With short-term, doseintensive chemotherapy programs, most patients either achieve disease remission or experience rapidly
Tyrosine kinase inhibitor
Nucleoside analog
Purine nucleoside phosphorylase
inhibitor
Other
progressive disease not amenable to successful tumor
reduction to allow consolidation with SCT.
CONCLUSIONS
Improvements in chemotherapy programs for adult
ALL have achieved CR rates of about 90% and longterm DFS rates of 30 – 40%. Prognosis has improved
remarkably in subsets of T-lineage ALL and mature–
B-cell ALL; about 50% of patients achieve disease remission. Conversely, patients with Ph-positive ALL
and other high-risk cytogenetic abnormalities continue to do poorly. Improving the outcomes of these
subsets of patients is a major future challenge.
How can prognosis in these patients be improved?
Better knowledge of the biologic subtleties of leukemic
blasts and the pathophysiology of ALL will facilitate
therapy-oriented discoveries (e.g., imatinib mesylate
in Ph-positive ALL). The ultimate goal in ALL therapy
will be to devise risk-group and disease-specific directed therapies.
Many investigational approaches are promising
(Table 6). Novel chemotherapy agents (e.g., compound 506U, liposomal vincristine, and clofarabine),
use of monoclonal antibodies (e.g., rituximab in
CD20-positive ALL, alemtuzumab, anti-CD19, and anti-CD22 monoclonal antibodies), reduced intensity
SCT, or immunomodulatory strategies are being explored. Even though progress in adult ALL lags behind
that achieved in childhood programs, the gap finally is
starting to narrow.
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Continuing medical education activity
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Article Title: Acute Myeloid Leukemia: 2012 Update
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AJH Educational Material
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES: A CONTINUING
MEDICAL EDUCATION SERIES
Acute myeloid leukemia: 2012 update on diagnosis,
risk stratification, and management
Elihu H. Estey1,2
Disease Overview: Acute myeloid leukemia (AML) results from accumulation of abnormal immature cells in
the marrow. These cells interfere with normal hematopoiesis can escape into the blood and infiltrate lung
and CNS. The most common cause of death is bone marrow failure. It is likely that many different mutations
and/or epigenetic aberrations can produce the same disease, with these differences responsible for the
very variable response to therapy, which is AML’s principal clinical feature.
Diagnosis: This rests on demonstration that the marrow or blood has >20% blasts of myeloid lineage. Blast
lineage is assessed by multiparameter flow cytometry with CD33 and CD13 being surface markers typically
expressed by myeloid blasts. It should be realized that clinical/prognostic considerations, not the blast %
per se, should be the main factor determining how a patient is treated.
Risk stratification: Two features determine risk: the probability of treatment-related mortality (TRM) and, more
important, even in patients aged >75 with Zubrod performance status 1, the probability of resistance to standard therapy despite not incurring TRM. The chief predictor of resistance is cytogenetics with a monosomal
karyotype (MK) denoting the disease is essentially incurable with standard therapy even if followed by a standard allogeneic transplant (HCT). The most common cytogenetic finding is a normal karyotype (NK) and those
of such patients with an NPM1 mutation but no FLT3 internal tandem duplication (ITD), or with a CEBPA mutation, have a prognosis similar to that of patients with the most favorable cytogenetics [inv(16) or t(8;21)]
(60–70% cure rate). In contrast, NK patients with a FLT3 ITD have only a 30–40% chance of cure even after
HCT. Accordingly analyses of NPM1, FLT3, and CEBPA should be part of routine evaluation, much as is cytogenetics. Risk is best assessed considering several variables simultaneously rather than, for example, only age.
Risk-adapted therapy: Patients with inv(16) or t(8;21) or who are NPM11/FLT3ITD2 can receive standard
therapy (daunorubicin 1 cytarabine) and should not receive HCT in first CR. It seems likely that use of a
daily daunorubicin dose of 90 mg/m2 will further improve outcome in these patients. There appears no reason to use doses of cytarabine > 1 g/m2 (for example, bid 3 6 days), as opposed to the more commonly
used 3 g/m2. Patients with an unfavorable karyotype (particularly MK) are unlikely to benefit from standard
therapy (even with dose escalation) and are thus prime candidates for clinical trials of new drugs or new
approaches to HCT; the latter should be done in first CR. Patients with intermediate prognoses (for example, NK and NPM and FLT3ITD negative) should also receive HCT in first CR and can plausibly receive either investigational or standard induction therapy, with the same prognostic information about standard
therapy leading one patient to choose the standard and another an investigational option. Am. J. Hematol.
C 2011 Wiley Periodicals, Inc.
87:90–99, 2012. V
Disease Overview
Acute myeloid leukemia (AML) is a disease of aging with
a median age of 67 years at diagnosis [1]. The most commonly recognized antecedent is cytotoxic therapy for a solid
tumor [therapy-related—(t-)AML]. Older patients with seemingly spontaneously arising (de novo) AML are more likely
than younger de novo patients to have cytogenetic abnormalities identical to those seen in t-AML suggesting that cumulative exposure to environmental analogues of cytotoxic
therapies predisposes to ‘‘de novo’’ AML in many older
patients [2]; indeed the incidence of the AML characterized
by other cytogenetic findings, such as t(15;17), t(8;21), or
inv(16), is not age dependent. AML is also commonly associated with an antecedent hematologic disorder (AHD),
most frequently myelodysplasia (MDS), less commonly a
myeloproliferative, or plasma cell, neoplasm [3]. AML developing after an AHD is also associated with the cytogenetic
abnormalities seen in t-AML, such as a ‘‘monosomal karyotype’’ (MK). Although older patients have poorer outcomes
than younger patients, the age effect is largely explained by
the associations between older age and (a) poor performance status, (b) comorbidities, (c) t-AML and/or AHD (col-
lectively known as ‘‘secondary AML’’), and most importantly,
(d) specific cytogenetic abnormalities [4–5].
AML is thought to commonly arise in a very small population of quiescent stem cells recognized by their expression of CD34 and CD123, but not CD38 [6]. Most such
cells lose their stem cell properties and proceed to proliferate, differentiate, and ultimately die. However, those
remaining act as a reservoir maintaining the great bulk of
the AML population. While remissions reflect reduction
in this bulk population, cure of AML probably requires
1
DIVISION of Hematology, University of Washington; 2Clinical Research Division, Fred Hutchinson Cancer Research Center
Conflict of interest: Nothing to report
*Correspondence to: Elihu H. Estey, c/o Seattle Cancer Care Alliance, 825
Eastlake Ave E, MS G3-200, Seattle, WA 98109-1023.
E-mail: eestey@u.washington.edu
Received for publication 31 October 2011; Accepted 2 November 2011
Am. J. Hematol. 87:90–99, 2012.
Published online in Wiley Online Library (wileyonlinelibrary.com).
DOI: 10.1002/ajh.22246
C 2011 Wiley Periodicals, Inc.
V
American Journal of Hematology
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annual clinical updates in hematological malignancies: a continuing medical education series
management of the stem cell compartment; the high frequency of relapse reflects a failure to accomplish this. AML
stem cells are less sensitive than the bulk population to
therapeutic agents, such as cytarabine (ara-C), and the
larger the stem cell compartment the worse the prognosis
[7]. However, some AMLs, for example, those associated
with t(15;17), t(8;21), or inv(16), probably arise in relatively
more differentiated normal hematopoietic cells possibly
explaining why they are more curable than AMLs of stem
cell origin, which are often characterized by a MK [8].
These observations indicate that AML comes in several
(probably many) forms, with management dependent on
the specific type of AML.
Diagnosis
Patients typically present with symptoms of anemia. If
bleeding is prominent, it is crucial to immediately rule in/
rule out acute promyelocytic leukemia (APL), particularly if
the WBC is > 10,000/ll. Morphologic examination, using
blood if it contains >1,000 blasts/ll), can be employed for
this purpose and in particular to justify immediate institution
of arsenic trioxide (ATO) 1 all-transretinoic acid (ATRA).
The diagnosis of APL must however be confirmed by demonstrating the pathognomonic PML-RARa rearrangement
and the resultant 15:17 translocation; this is typically done
using fluorescent in situ hybridization (FISH) [9].
The diagnosis of non-APL AML requires >20% blasts of
myeloid lineage in marrow or blood [World Health Organization (WHO) criteria] [10]. Multicolor flow cytometry (MFC)
has largely replaced histochemical staining for establishment of blast lineage. Myeloid lineage antigens include
CD33, CD13, CD117 (CKIT), CD14, CD64 CD41, and glycophorin A. If there are >1,000–2,000 blasts/ll blood specimens suffice for diagnostic and stratification purposes and
obtaining a marrow only delays treatment [11].
The 20% blast criterion contrasts with the previous 30%
[12], suggesting the arbitrary nature of any cutoff. Indeed,
although patients with 10–19% blasts (‘‘MDS’’ by WHO criteria) are often ineligible for ‘‘AML protocols,’’ the natural
histories of AML and MDS with 10–20% blasts are very
similar and therapeutic outcome may depend more on
covariates such as cytogenetics, de novo vs. secondary
AML, and age than on the distinction between ‘‘MDS’’ and
‘‘AML,’’ with prognostically unfavorable characteristics more
common in MDS [13]. Thus, the 20% cut-off should serve
only as an approximate guide to clinical decisions, with
specific treatment resting on benefit/risk considerations. For
example, the WHO regards patients with <20% blasts but
with t(8;21) or inv(16) as AML because they respond so
well to AML therapy. In contrast, frail patients who present
with low WBC counts might appropriately be treated as
MDS even if the blast count is >20%.
Risk Stratification
After the diagnosis is made, the first consideration is the
need for emergency treatment, as based on high (>10,000
in APL, >50,000 in other types), or rapidly rising WBC, or
symptoms suggestive of pulmonary of CNS infiltration.
Although leukapheresis likely reduces the risk of leukostasis, or of tumor lysis once definitive therapy begins, it is of
unclear benefit in removing blasts from organs, not obviously associated with improved outcomes [14], and often
delays administration of chemotherapy. Although frequently
given to reduce WBC, hydroxyurea has much less activity
than ara-C [15] and is less likely to enter lung or CNS than
high doses (1–3 g/m2) of the latter. Although investigational
treatment protocols typically exclude patients given ara-C,
rather than hydroxyurea to reduce a high WBC, ara-C
should be used if there are CNS or pulmonary symptoms
and if protocol treatment cannot be administered promptly.
American Journal of Hematology
Figure 1. Survival in newly diagnosed AML according to pre-treatment cytogenetics [19].
If emergency treatment is unnecessary, information
should be gathered to assess prognosis with standard therapy, most commonly 3 days of an anthracycline and 7 of
ara-C (3 1 7) [16]. If prognosis is unsatisfactory, investigational treatment should be advised. It is tempting to begin
all patients on 3 1 7 before prognostic information
becomes available, while relying on an allogeneic transplant (HCT) once patients found to have a poor prognosis
after induction therapy begins achieve CR. However,
patients, who although in CR by conventional criteria, have
minimal residual disease (MRD) at time of HCT are much
more likely to subsequently relapse [17]. Since MRD at
HCT reflects inadequacy of pre HCT chemotherapy, consideration should be given to investigational induction therapy
in poor prognosis patients. In cooperative group studies,
rates of treatment-related mortality (TRM) are <15–20% in
patients, even those aged >75, with performance status 1
[4], and hence the major cause of failure to enter CR is resistance to therapy (similarly the risk of relapse far outweighs that of death in CR even in patients in their 70s
[18]). Nonetheless the risk of TRM, not to mention morbidity, does not appear to justify use of 3 1 7 to patients with
high probabilities of resistance (no CR) to it.
Predictors of Sensitivity/Resistance to Standard
Therapy
Cytogenetics: These can be classified as follows
(Fig. 1):
Best. Collectively known as core-binding factor (CBF)
abnormalities, inversion 16 [inv(16)] or t(8;21) are associated with CR rates >90% and 3-year event-free survival
rates of 60%, with relapse rates falling precipitously past 3
years for all types of AML [20]. Nonetheless, inv(16) and
t(8;21) differ in that subsequent CRs after relapse are more
common in the former [21]. However in patients age > 65
[22], inv(16) patients age > 35–40 [23], or t(8;21) patients
with initial WBC >5,000–10,000 [24], 3-year success rates
are closer to 20–30%. The presence of CKIT mutations
also seems to affect outcome in CBF AML as noted below.
Worst. Multiple cooperative groups have identified
monosomies of chromosomes 5 or 7, deletions of the long
arm of chromosome 5, abnormalities of the long arm of
chromosome 3, and ‘‘complex abnormalities’’ involving at
least three distinct aberrations as comprising a high-risk
group in younger and older patients [25]. However more
recent findings strongly suggest that ‘‘monosomal karyoype’’ (MK) should be the primary criterion for ‘‘worst
prognosis cytogenetics’’ [19,26]. The deleterious effect of
91
annual clinical updates in hematological malignancies: a continuing medical education series
Figure 3. Relapse-free, and overall, survival according to genotype and whether
patients had donors for myeloablative HCT [28]. [Color figure can be viewed in the
online issue, which is available at wileyonlinelibrary.com.]
Figure 2. Relapse-free, and overall, survival in newly diagnosed AML according
to genotype [28]. [Color figure can be viewed in the online issue, which is available
at wileyonlinelibrary.com.]
complex karyotypes largely reflects associations with MK,
defined as at least two autosomal monosomies, or one
autosomal monosomy in conjunction with a structural abnormality; indeed noncomplex MK does as poorly as complex MK. In various SWOG studies CR rates following 3 1
7 in patients with MK were: age 31–40 (27%) (13 patients),
age 41–50 (14%) (23 patients), age 51–60 (24%) (43
patients), and age > 60 (13%) (90 patients) [19]. Even in
patients age < 60 median survival among MK1 patients is
only about 6 months [26].
Unfavorable without MK. This most commonly includes
patients with monosomies of chromosomes 5 or 7, deletions of the long arm of chromosome 5, abnormalities of
the long arm of chromosome 3. Their CR rates even in
younger patients rarely exceed 60–65%.
Intermediate. Some restrict this category to patients with
a normal karyotype (NK) while others also include patients
with abnormalities other than those in categories (a)-(c).
NK is the most frequent cytogenetic finding and has the
most variable prognosis with standard therapy, ranging
from cure to never achieving CR.
Molecular markers
Given the extremely heterogeneous outcome of NK AML
testing for molecular abnormalities is of most use in this
subset [27].
Established markers.
NPM1 and FLT3 ITD. Approximately 50% of NK patients will have an NPM1 mutation
and 1/3 an internal tandem duplication (ITD) in the FLT3
gene. Such patients tend to present with high WBC. On average patients with mutated NPM1 but without FLT3 ITD
have prognoses similar to those seen in CBF AML [28]. In
contrast patients with a FLT3 ITD typically have prognoses
resembling those in the ‘‘unfavorable without MK’’ group
[28]. However, the effect of a FLT3 ITD likely depends on
the presence of other mutations (for example, an NPM1
92
mutation lessens the effect of a FLT3ITD) or the amount of
the mutant ITD protein (allelic burden). For example, data
from the MRC in the United Kingdom indicate that the difference in cumulative incidence of relapse between patients
with allelic burdens >50% and patients with allelic burdens
1–49% is similar to the difference between patients in the
1–49% group and patients without an ITD [29].
CEBPA. Mutations in this gene occur in 10% of patients
with NK AML [28]. It too confers a favorable prognosis, particularly in patients with double mutations and without a
FLT3 ITD. The profound effect of NPM1, FLT3 ITD, and
CEBPA status on outcome in NK AML (Fig. 2) suggests
that assessment of these mutations should be routinely
done in newly diagnosed AML. For example, comparison of
patients with and without sibling donors for myeloablative
HCT suggests that patients in the NPM1/FLT3 ITD2 or the
CEBPA 1 subtypes do not benefit from HCT, while patients
with other genotypes do (Fig. 3) [28]. Similarly, the 30% 3year survival rate following standard therapy in patients
aged 70 or above with NPM1 mutations (Fig. 4) [30] suggests that some of these patients might be less enthusiastic about participation in a clinical trial than other similarly
aged patients.
CKIT. Approximately 20–30% of patients with t(8;21) or
inv(16) have a CKIT mutation. The cumulative incidence of
relapse at 5 years has been estimated as 30–35% for
patients with either t(8;21) or inv(16) but without a CKIT
mutation vs. 70% for t(8;21) patients with a CKIT mutation
and 80% for inv(16) patients with a mutation in exon 17 of
CKIT [31]. However because CKIT mutations are do not
appear to affect outcome in the more common subtypes of
AML (for example, NK AML) it is probably practical to test
for these mutations only once the patient is known to have
inv(16) or t(8; 21).
Other markers. Currently, 85% of patients with NK AML
have a mutation [27], although the prognostic significance
of some of these is unclear. However, routine testing for
the following may become advisable in the near future.
DNMT3a. Mutations in DNA methyltransferase 3a
[DNMT3a] occur predominantly in patients with intermediate
American Journal of Hematology
annual clinical updates in hematological malignancies: a continuing medical education series
Figure 4. (A) Disease-free (that is relapse-free) and (B) overall survival of patients age 60 years with cytogenetically normal de novo AML according to NPM1 mutation status. (C) Same as (A) but including only patents age 70. (D) Same as (B) but including only patents age 70 [30]. [Color figure can be viewed in the online
issue, which is available at wileyonlinelibrary.com.]
prognosis cytogenetics, including 25–35% of those with an
NK [32,33]. DNMT mutations are associated with mutations
in NPM1 and ITDs of FLT3. They seem to convey poorer
prognosis in NK AML, with this effect limited to patients who
are not NPM1/FLT3 ITD negative [33].
IDH. Mutations in isocitrate dehydrogenase 1 (IDH1) or 2
(IDH2) also have been found chiefly in patients with intermediate prognosis cytogenetics, with 2/3s–3/4s patients
having an NK. As with DNMT3a, the effect of mutations in
IDH1 has been reported to be context dependent. Thus,
IDH1 mutations are independently associated with lower
relapse rates in patients with, but higher relapse rates in
patients without, FLT3 ITDs [34]. IDH2 illustrates the potential influence of mutation site. While an IDH2 mutation at
R140 has been found to confer on patients with an otherwise intermediate prognosis a probability of relapse similar
to that found in patients with inv(16) or t(8;21), a mutation
at R172 confers a probability of relapse resembling that
seen in patients with unfavorable cytogenetics [35].
TET2. The TET2 gene provides yet another example of a
context dependent mutation. In particular, TET2 mutations,
which like the mutations described above, are most commonly found in NK AML, are independently associated with
inferior rates of CR, relapse-free survival, event-free survival, and survival but only in those NK patients who are
NPM1/FLT32 or CEBPA mutated [36].
Gene and protein expression. The prognostic influence of
some mutations, for example in the WT1 gene, has differed
in different series [37,38]. While such disparities may reflect
the presence/absence of other mutations or differences in
treatment, they may also reflect whether the mutation
results in expression of an abnormal protein. This possibility has prompted profiling of whole genome [39] and microRNA [40,41] expression DNA methylation [42,43] (as well
as expression studies of specific genes (BAALC and ERG
[27]), and studies of protein expression [44]. Several
reports indicate that these studies potentially add prognostic information independent of that provided by analyses of
NPM, FLT3, and CEBPA [39–43].
American Journal of Hematology
TABLE I. European Leukemia Net (ELN) Prognostic System [45]
Genetic group
Favorable
Intermediate I
Intermediate II
Adverse
Subsets
t(8;21)(q22;q22); RUNX1-RUNX1T1
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Mutated NPM1 without FLT3-ITD (NK)
Mutated CEBPA (NK)
Mutated NPM1 and FLT3-ITD (NK)
Wild-type NPM1 and FLT3-ITD (NK)
Wild-type NPM1 without FLT3-ITD (NK)
t(9;11)(p22;q23); MLLT3-MLL
Cytogenetic abnormalities other than favorable or adverse{
inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1
t(6;9)(p23;q34); DEK-NUP214
t(v;11)(v;q23); MLL rearranged
25 or del(5q); 27; abnl(17p); complex karyotype
Integration of cytogenetic, molecular genetic,
and clinical data
The European Leukemia Network (ELN) categorizes
patients into one of four groups depending on cytogenetic
and molecular genetic (NPM1, FLT3, and CEBPA) status
(Table I) [45]. An unpublished supplement to the ELN system is depicted in Table II. This recognizes five groups and
differs from the ELN in that it (a) recognizes the unique significance of MK, (b) weighs FLT3 ITDs somewhat more
unfavorably than the ELN, and (c) uses CKIT mutation status to discriminate among patients with ‘‘favorable’’ cytogenetics [inv(16) or t(8;21)]. While cytogenetics and molecular
genetic data provide the most important prognostic information, clinical covariates should also be considered.
t- AML. Many of the studies explicating on the role of various mutations have been done in patients with de novo
AML. However data from the German AML Study Group
[46] indicate that, after accounting for cytogenetics, NPM
and FLT3 ITS status, patients with therapy-related AML
have increased rates of relapse and shorter survival than
patients without such a history. Shorter survival in younger
patients (age < 60) chiefly reflects higher probabilities
of death in CR, particularly after HCT, perhaps owing to
93
annual clinical updates in hematological malignancies: a continuing medical education series
TABLE II. Author’s Modification of ELN System
Prognostic group
Best
Intermediate 1
Intermediate 2
Intermediate 3
Worst
Subsets
TABLE III. Frequency of Early Death (Within 30 days of Start of 3 1 7 Therapy) According to Age and Performance Status (PS) in Southwest Oncology
Group (SWOG) Studies [4]
a
t(8;21)
inv(16)a or t(16;16)
NK with mutated NPM1 and no FLT3 ITD
NK with double-mutated CEBPA (NK)
NK with wild-type NPM1 and no FLT3-ITD
Cytogenetic abnormalities other than best or unfavorable
FLT3-ITD
Unfavorable cytogenetics without MK
MK
a
Patients with inv(16) or 6t(8;21) and CKIT mutations should be considered as
belonging to the intermediate 1 group as should patients with t(8;21) and a WBC
index > 20 and patients age > 65 and possibly patients with inv(16) age > 35.
Age < 56
PS 0
PS 1
PS2
PS3
3/129 (2%)
6/180 (3%)
1/46 (2%)
0/9
Age 56–65
8/72
6/11Fo2
6/34
7/24
(11%)
(5%)
(18%)
(29%)
Age 66–75
9/73
20/126
16/52
9/19
(12%)
(16%)
(31%)
(47%)
Age > 75
2/14
7/40
7/14
9/11
(14%)
(18%)
(50%)
(82%)
TABLE IV. Effect of HCT in First CR on Relapse-Free Survival (RFS) and Survival (OS) [55]
Hazard rate (95% CI)
cumulative toxicity of cancer treatment but primarily reflects
higher rates of relapse in older patients.
Antecedent hematologic disorder. Although not studied in
as much detail as t-AML an AHD has also been shown to
be adversely affect outcome independent of cytogenetic
status [13].
WBC count. Increasing circulating blast count confers a
poorer prognosis in patients with t(8;21) [24] (and particularly in patients with t(15;17) [9].
Age and performance status. Much of the relation
between age and therapeutic resistance (relapse or no CR
despite not incurring TRM) reflects age’s association with tAML, an AHD or unfavorable cytogenetics [4,5]. Similarly,
much of age’s influence on early death reflects an association between age and performance status (PS) [4,47]. Of
these, PS is the most important. For example, patients
aged >75 but with PS 1 have lower early death rates than
patients aged 66–75 with PS 2 (Table III) [4]. It is likely that
some of age’s effect on early death will also be due to an
association with various comorbidities (for example, obesity
and diseases of heart, lung, liver, and kidney).
Given these associations, it is not surprising that the
prognosis of older patients (typically age > 60–65) is very
variable following 3 1 7. Various prognostic systems have
been developed for older patients [48–50], although these
typically do not account for NPM, FLT3, and CEBPA status,
Although it is well known that AML clinical trials enroll only
a small minority of older patients with AML who likely have
better prognoses than patients who are not enrolled, many
of these prognostic systems emanate from countries [48–
50] where a larger government role in health care makes it
likely that the patients reported in studies are more representative than would be the case in the United States.
Management of ‘‘Favorable’’ Patients
(Fig. 1, ‘‘Best’’ in Table II)
Given the data depicted in figure and Tables I and II,
these are prime candidates for standard therapy containing
an anthracycline and ara-C (3 1 7). However, strong consideration should be given to using increased doses of daunorubicin during induction and ara-C once in CR. ECOG
randomized patients aged < 60 to standard doses of ara-C
1 either daunorubicin at 45 or 90 mg/m2 daily 3 3 during
induction and showed higher CR rates (70% vs. 57%) and
longer survival (medians of 24 vs. 16 months) for patients
given the higher dose with this effect limited to patients
with favorable or intermediate cytogenetics [51]. The
HOVON performed a similar study in older patients and
found that in patients aged 60–65 the higher dose produced higher rates of CR (73% vs. 51%), EFS, and survival
(38% vs. 23% at 2 years); benefit was most apparent in
patients with inv(16) or t(8;21) [52]. Fourteen years ago
CALGB showed that favorable (i.e., already anthracyline
and ara-C-sensitive) patients benefited most from increased
94
Cytogenetic
risk
Patients in
Donor group
Patients in
No donor group
RFS
OS
Favorable
Intermediate
Unfavorable
188
864
226
359
1635
366
1.06 (0.80–1.42
0.76 (0.68–0.85)
0.69 (0.57–0.84)
1.07 (0.83–1.38)
0.83 (0.74–0.93)
0.73 (0.59–0.90)
Hazard rate < 1.0 favors HCT over chemotherapy or autologous transplant.
Cytogenetic risk assessed by SWOG/ECOG or MRC criteria with results not materially affected by criteria used.
doses of ara-C, leading to widespread use of ara-C at 3 g/
m2 twice daily on days 1, 3, and 5 for several cycles as
post-CR therapy [53]. However, data from recent randomized studies suggest that a dose of 1 g/m2 bid 3 6 days is
sufficient [54]. Whether the benefit of dose escalation also
applies to NPM1/FLT3 ITD2 AML is not known, but the
principle that dose escalation is most beneficial to patients
already sensitive to standard doses seems likely to apply.
Generally speaking the risk of relapse in favorable
patients is not high enough to justify the risk (both short
and very long term) of HCT in first CR. This is illustrated in
Fig. 3 for NPM1/FLT3ITD2 patients and in Table IV for
patients with inv(16) or t(8;21). Table IV is derived from a
meta-analysis of trials comparing myeloablative HCT (primarily from sibling donors) with continued chemotherapy
(or autologous transplant) in patients in first CR [55]. To
avoid bias, the authors compared patients with and without
donors, rather than patients who were or were not transplanted; 70–80% of patients with donors were transplanted.
Although donor–no donor comparison is not free of problems [56], particularly when use is made of unrelated
donors, generally if the donor group does better so would
patients who actually receive HCT.
As noted above the prognosis of favorable patients is far
from uniform. Specifically the prognosis of those inv(16) or
t(8;21) patients with CKIT mutations [31], WBC > 10,000
(for t[8;21]) [24], or age > 60 [22] [>35 for inv(16)] [23]) is
such that they might be more willing to consider HCT
(reduced intensity for older patients) or drugs such as
desatinib that inhibit CKIT and that are being evaluated in
clinical trials in patients with inv(16) or t(8;21).
Management of Patients with MK or Unfavorable
Karyotypes without MK (Fig. 1, ‘‘Worst’’ and
‘‘Intermediate 3’’ in Table II)
Whereas prognosis with standard therapy should prompt
its use, albeit with dose escalation, in the typical favorable
risk patient, prognosis with standard therapy should prompt
use of investigational therapy in almost all patients with
unfavorable cytogenetics, particularly with MK. As noted in
the second paragraph in the ‘‘Risk Stratification’’ section,
strong consideration should be given to beginning such
therapy during induction.
What this therapy should entail is far from clear. Higher
dose daunorubicin does not appear beneficial in such
American Journal of Hematology
annual clinical updates in hematological malignancies: a continuing medical education series
Figure 5. (A) Overall survival and (B) relapse-free survival following HCT according to cytogenetic risk [63]. [Color figure can be viewed in the online issue, which is
available at wileyonlinelibrary.com.]
patients [51,52], recalling findings from CALGB that
whether patients were randomized to post-CR ara-C doses
of 3 g/m2 BID on days 1, 3, and 5, 400 mg/m2 daily 3 5 by
continuous infusion (CI) or 100 mg/m2 daily 3 5 by CI had
no effect on outcome [54]. The rapid entry into trials of
many new drugs makes virtually any list of ‘‘new drugs in
trial’’ incomplete and outdated. However, some of the more
commonly investigated drugs have included the following:
Nucleoside analogs
The Polish Acute Leukemia Group has reported a
randomized study showing that addition of cladribine to 3 1
7 (daunorubcin at 60 mg/m2) produced a higher rate of CR
after a single course despite similar or less toxicity [57].
This has sparked interest in clofarabine, which is structurally related to cladribine and fludarabine but more active, at
tolerable doses than the latter. Burnett et al. found that, after adjusting for other covariates, CR and survival rates in
106 patients (median age 71) considered unfit for 3 1 7
and thus given clofarabine were higher than when similarly
unfit patients received low-dose ara-C (LDAC) and comparable with those observed when fitter older patients
received 3 1 7-like therapy [58]. Of note, CR rates with clofarabine were similar in patients with unfavorable and intermediate cytogenetics (44% vs. 52%). In 70 relatively fit
patients (median age 71) randomized to clofarabine or clofarabine 1 LDAC, the combination produced superior CR
(63% vs. 31%) and survival rates, but survival remained
short (median 11 months), even with the combination [59].
Further information about clofarbine’s role in newly diagnosed AML will likely be forthcoming from an ongoing
ECOG study randomizing older patients to 3 1 7 or clofarabine, albeit without ara-C and from MRC trials comparing
daunorubicin 1 clofarabine with daunorubicin 1ara-C for
both induction and ‘‘consolidation’’ therapy.
Hypomethylating agents (HAs): azacitidine
and decitabine
These drugs were first investigated in patients with MDS
some of whom had 21–30% blasts and were thus reclassified as AML. In the azacitidine trial [60] physicians first
declared a preference for supportive care only, LDAC, or 3
1 7 in a given patient. Patients were then randomized to
the selected conventional care regimen or azacitidine.
Among 113 AML patients (median age 70), median survivals were 24.5 months (azacitidine) and 16.0 months (conventional care) and were 12 months (azacitidine) and 5
months (conventional care) in the patients with unfavorable
cytogenetics. Too few patients received LDAC or 3 1 7 to
permit robust comparisons with azacitidine. However, unlike
LDAC or 3 1 7, achievement of CR with azacitidine did not
seem a precondition for longer survival.
American Journal of Hematology
Results of a trial randomizing patients aged 65
between decitabine at 20 mg/m2 daily 3 5 and physician’s
choice of LDAC or supportive care only were presented at
the 2011 meeting of the American Society of Clinical Oncology [61]. An ‘‘updated unplanned analysis’’ performed after 92% of patients had died showed median survival of 7.7
months for decitabine and 5.0 months for physicians’
choice (nominal P 5 0.03) The previously planned ‘‘final
analysis’’ done after 82% of patients had died showed the
same median survivals but P 5 0.10.
It remains unclear whether response to HAs correlates
with hypomethylation and, in particular, with re-expression
of silenced genes. Such a correlation might encourage further studies combining HAs and histone deacetylase inhibitors, which appear to cooperate with HAs in inducing reexpression of silenced genes.
Given the survival times noted above, I do not believe
that, at least as used alone, clofarabine, azacitidine, or decitabine obviously differ from standard therapy. Hence I find
it reasonable to recommend clinical trials, rather than these
drugs, for patients with unfavorable cytogenetics. Such a
trial might, for example, include use of azacitidine or decitabine in combination with other agents. In general, however,
it is very difficult to know which, if any, of several available
trials would be most beneficial for a given patient. Thus, I
generally recommend that patients participate in the most
logistically feasible trial. An obvious task for the future is to
move beyond the current focus on results that likely reflect
an average of more and less sensitive patients and to
identify patients who are more likely to respond to a given
therapy.
Hematopoietic cell transplantation (HCT)
The results in Table IV suggest that HCT is useful in first
CR in patients with unfavorable cytogenetics. However, the
median age of patients in the meta-analysis was only about
40, and most had sibling donors, raising questions as to
whether the same would apply in older patients or in
patients with matched unrelated donors. The past 20 years
have also seen the development of reduced intensity conditioning (RIC) regimens [62]. These reduce toxicity and are
associated with 100-day death rates of 10–15% depending
on comorbidities, but permit engraftment and subsequent
development of T-cell mediated graft-versus-AML effects
and allow patients in their 70s or with significant comorbidities to receive HCT. Results of large trials of RIC-HCT [63]
as well as donor–no donor [64] analyses suggest that
RIC-HCT is superior to chemotherapy in many older
patients (Fig. 5). Furthermore, modern typing techniques
have allowed matched unrelated donors to be identified for
most patients without sibling donors [65]. Although a true
95
annual clinical updates in hematological malignancies: a continuing medical education series
comparison of matched sibling and matched unrelated
donor HCT would require randomization of patients with
sibling donors to receive transplant from the sibling or a
matched unrelated donor such a trial is not feasible. With
this constraint and bearing in mind the increased difficulties
with donor–no donor analyses in the unrelated setting, data
suggest equivalent results with matched sibling and
matched unrelated HCT and that if HCT from a (living)
matched unrelated donor is not feasible, double cord blood
transplants are (at least) their equivalent [66–69].
However, several points are worthy of mention. First, donor–no donor analyses or even the more sophisticated
Mantel–Byar methodology [70] cannot substitute for a trial
randomizing patients with donors between immediate HCT
and HCT delayed until there is increasing evidence of
MRD. Second, the same covariates that predict poor outcome after chemotherapy (in particular cytogenetics and
MRD after consolidation therapy) do the same after HCT,
suggesting that chemotherapy and HCT are not as qualitatively different as often believed [17,63]. Third, it is clear
that immediate mortality after HCT is decreasing [71]; however, patients who are cured of AML after HCT have a 30%
decrease in life expectancy, consequent to the effects of
immunosuppression and development of second cancers
[72]. Most importantly, neither chemotherapy nor HCT are
satisfactory for patients with unfavorable cytogenetics.
Assume that those of such patients who enter CR have a
life expectancy of 12 months, consequent to relapse, without HCT. If, as Table IV indicates HCT reduces risk of death
to 0.73 in such patients life expectancy is still only 12/0.73
5 16–17 months. Indeed patients over age 60 who had MK
and received HCT in CR1 had only a 6% survival rate at 4
years [73].
Regardless of whether patients receive ablative or RICHCT the major cause of death remains relapse [63]. Trials
of new HCT ‘‘conditioning regimens’’ are in progress, involving for example clofarabine or anti-CD45 antibodies labeled
with 131I [74]. It seems likely that the future will see increasing use of immunotherapy [75] or ‘‘chemotherapy’’ to
reduce post HCT relapse. Trials of azacitidine and the FLT3
inhibitor quizartinib (AC220, see below) are ongoing for the
latter purpose [76]. In general new agents might be found
more effective if tested in patients in CR [77] rather than
with active disease, as is currently done.
Management of Patients with FLT3 ITD
(Intermediate 2 in Table II)
Many of the same considerations apply here as in the
preceding group. However, the use of FLT3 inhibitors is
worthy of discussion. Midostaurin (formerly PKC412) and
lestaurtinib (formerly CEP701) inhibit multiple kinases,
among them FLT3, whereas sorafenib and, particularly
AC220, are more specific for FLT3 and much more potent
FLT3 inhibitors. Each of the four drugs inhibits wild-type
FLT3, but more effectively inhibits FLT3 ITDs and has been
studied essentially exclusively in ITD positive patients. Midostaurin and lestaurtinib produced minor responses in
relapsed disease and are being studied in trials randomizing untreated patients to 3 1 7 ± the FLT3 inhibitor. A similar trial in 224 relapsed patients found no difference in CR
or survival between patients given chemotherapy ± lestaurtinib [78]. However, the ability of patients’ serum to inhibit
ITD 1 cell lines correlated with clinical response, suggesting that response rates might be higher with a more potent
inhibitor, such as AC220. This drug has considerable more
single agent activity in relapsed patients than midostaurin
or lestaurtinib [79] and is being combined with chemotherapy in untreated patients. Sorafenib, the only one of these
drugs currently available commercially, has also been com-
96
bined with chemotherapy [80], although a randomized trial
giving chemotherapy ± sorafenib suggests that the probability of great benefits in ITD1 disease is unlikely [81]. An
issue to consider in combining chemotherapy with FLT3
inhibitors is the ability of the former to increase serum concentrations of FLT3 ligand, which antagonizes the effect of
the FLT3 inhibitor [82]. Cytotoxicity as a result of FLT3 inhibition is greater at high-allelic burdens, perhaps because
blasts in patients with such burdens are more ‘‘addicted’’ to
FLT3 [82]. Because allelic burden is typically higher in
relapsed than in untreated patients, the former may benefit
more from potent FLT3 specific inhibitors, such as AC220,
and the latter from less potent FLT3 inhibitors with however
a broader spectrum of kinase inhibition [82].
Management of Intermediate Prognosis Patients
(Fig. 1, Intermediate 1 in Table II)
A case for standard therapy is relatively easy to make in
most ‘‘favorable’’ patients and similarly for investigational
therapy in ‘‘unfavorable’’ patients. However, experience suggests that, given the same expectations with standard therapy, some intermediate patients prefer investigational therapy while others, feeling that the investigational could be
worse than standard, opt for standard treatment. If this
option is selected, consideration should be given to using
escalated doses of daunorubicin and/or ara-C, as described
in the section on favorable patients.
For purposes of selecting treatment (standard vs. investigational), it would be desirable to have fewer patients in the
intermediate category and more in the favorable/unfavorable categories. In addition to the potential use for this purpose of the ‘‘other’’ markers described in the section on
‘‘Molecular Markers,’’ the future is likely to see increased
use of MRD monitoring for this purpose [83–85].
Duration of Postremission Therapy
It is generally held that no more than three to four
courses of post remission therapy are needed. Gardin et al.
have reported that in patients aged 65 and above six lowintensity post remission courses, given outside a hospital,
are associated with superior relapse-free survival and survival, as well fewer transfusions and less time in hospital,
than one higher-intensity course given in hospital [86].
MRD monitoring is likely to permit a more sophisticated
approach to this issue. In principle quantification of MRD,
for example, by multiparameter flow cytometry would permit
change of therapy in patients with persistent, or increasing
amounts, of MRD, continuation of the same therapy in
patients with decreasing amounts of MRD, and discontinuation of therapy in patients with no MRD.
Management of APL
APL is highly curable, although the cure rates of >90%
quoted in clinical trials are considerably higher than the
rates of 75% reported from large community-hospital databases [87]. The difference to some extent reflects patient
selection such as exclusion of patients who die before they
can be registered on a trial. Indeed death from CNS and/or
pulmonary hemorrhage within the first few days of presentation is the principal obstacle to curing APL and is particularly common in patients with WBC > 10,000. Crucial to
prevention of such death is prompt initiation of therapy at
earliest suspicion of the diagnosis [88], as discussed in the
section on ‘‘Diagnosis.’’ In addition to specific APL therapy
management consists of redressing the characteristic
thrombopenia and deficiencies of coagulation factors, for
example by checking platelet count, INR, and fibrinogen every 8–12 hr and administering platelets and blood products
to maintain a platelet count > 30,000, an INR < 1.5, and
fibrinogen > 150, while avoiding fluid overload. The most
American Journal of Hematology
annual clinical updates in hematological malignancies: a continuing medical education series
TABLE V. Prognostic Score for Patients with AML in First Relapse [96]
Prognostic factor
RFI, relapse-free interval from first complete remission, months
>18
7–18
6
CYT, cytogenetics at diagnosis
t(16;16) or inv(16)*
t(8;21)*
Othery
AGE, age at first relapse, years
35
36–45
>45
SCT, stem-cell transplantation before first relapse
No SCT
Previous SCT (autologous or allogeneic)
Points
0
3
5
0
3
5
0
1
2
0
2
Figure 6.
[96].
commonly used treatment for APL is ATRA 1 idarubicin
(AIDA) or daunorubicin. However, recent data suggest that
addition of ara-C (200 mg/2 daily 3 7) to daunorubicin 1
ATRA improves outcome [89]. A benefit for ara-C might
have been more difficult to discern with a daunorubicin
dose of 90 mg/2 (rather than 60 mg/m2) daily 3 3, but benefit/risk calculations argue for adding ara-C to daunorubicin
1 ATRA. It is now established that arsenic trioxide (ATO) is
a more effective agent in APL than ATRA; in particular single agent ATO can cure APL much more frequently than
single agent ATRA [90]. The combination of ATO 1 ATRA
appears at least as effective as AIDA in patients with WBC
< 10,000 and is being compared with AIDA in randomized
trials in such patients [91]. In patients with WBC > 10,000
benefit/risk considerations suggest the immediate administration of ATO 1 ATRA, and if the WBC is >20,000–
50,000 addition of anthracycline 1 ara-C. Although routinely unavailable, gemtuzumab ozogamicin is highly effective in APL [92]) and is being combined with ATO 1
ATRA in the current US Intergroup trial for newly diagnosed patients with WBC > 10,000. A complication of
therapy with ATRA, ATO or both is the ‘‘APL differentiation
syndrome’’ (APLDS). Potentially fatal, its principal symptoms are fever and dypsnea accompanied by signs of fluid
retention such as edema and pleural and/or pericardial
effusions. The majority of these patients will have progressive leukocytosis with the WBC being myelocytes, metamyelocytes, bands, and neutrophils. The response rate to
steroids is >95%. Some begin steroids prophylactically,
and others only when the WBC exceeds 10,000–20,000
or when symptoms develop [9]. The underlying pathology
is presumed to be ‘‘capillary leak.’’ The incidence does not
appear higher in patients given ATO 1ATRA rather than
either drug alone.
Once in CR benefit/risk arguments suggest younger
patients with initial WBC counts > 10,000 should receive
postremission therapy with ara-C in doses of 1–2 g/m2,
which has the added benefit of CSF penetration and hence
the potential to prevent CSF relapse, which has a cumulative incidence of 5% 3 years after achievement of CR [93].
Older patients, and perhaps younger ones as well, might
receive ATO, and ATRA (with intrathecal ara-C if they presented with WBC > 10,000) rather than anthracycline 1
ara-C; such an approach is being used by several European groups. Finally, MRD monitoring, most sensitively
using PCR to detect residual PML-RARa transcripts
appears likely to improve outcome, particularly in patients
presenting with WBC > 10,000 [94]). The risk of relapse of
patients with APL in CR is lower than the risk of early and
late complications after HCT, which is thus not justified in
patients with APL in CR1.
American Journal of Hematology
Survival after first relapse according to prognostic score in Table V
Management of Relapsed/Refractory AML
Here again the fundamental decision is between a standard (re-induction) regimen such as FLAG or mitoxantrone
1 etoposide, or an investigational regimen. The principal
predictor of response to standard therapy is duration of first
CR, with ‘‘primary refractory’’ patients assigned CR duration
of 0 [95]. Estey et al. reported that patients about to receive
their first re-induction attempt (first salvage) had a CR rates
of 60% (15 patients), 40% (30 patients), and 15% (160
patients) if their first CR durations were >2 years, 1–2
years, and <1 year, respectively. Patients who were about
to receive > first salvage with a first CR < 1 year had
essentially no chance of attaining a CR (58 patients, 96 salvage attempts 0 CR). Focusing more on survival Breems
et al. [96] developed a prognostic score based on 667
patients in first relapse (Table V). As seen in Fig. 6, most
patients were in the worst group and clearly are candidates
for investigational salvage regimens.
Future Directions
For many years, the primary goal of therapy was to produce and maintain a CR. The rationale was the demonstration that patients in CR lived longer than other patients.
Furthermore, the difference was entirely accounted for by
time spent in CR suggesting that the longer life expectancy
reflected chemotherapy’s ability to produce a CR and not a
better underlying prognosis in patients who achieved CR.
Recent reports, however, currently include CR and
responses the criteria for which are less than stringent than
CR; these are known as CRp, CRi, etc. While it appears
that prolonged survival likely requires CR, recent data suggest that patients who obtain responses such as CRp, CRi,
etc., may live longer than patients who live long enough to
have achieved CR, CRp, or CRi but do not do so [60,97].
This would put less emphasis on CR, and more on survival,
as an endpoint of therapy. As a corollary, patients would be
advised to stay on a given therapy longer in the absence of
CR. This might be important given that multiple courses of
newer drugs might be needed to see response. It should
be noted however that these patients might be showing
improvement short of ‘‘response’’ after a relatively few
courses, allowing patients not showing such improvement
to be removed from study before the full number of courses
had been administered.
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