Rethinking the Treatment of Older
Adults With Acute Myeloid Leukemia
Mark J. Levis, MD, PhD
Associate Professor of Oncology
The Sidney Kimmel Comprehensive Cancer Center
Johns Hopkins University
Disclosure of Conflicts of Interest
Mark J. Levis, MD, PhD, discloses that he has served as
an advisor/consultant for Teva Pharmaceuticals and Ambit
Biosciences Corp.
Unapproved Use Disclosure
The University of Cincinnati College of Medicine and i3
Health require CME faculty (speakers) to disclose to
attendees when products or procedures being discussed
are off-label, unlabeled, experimental, and/or
investigational (not FDA approved), and any limitations
on the information that is presented, such as data that
are preliminary or that represent ongoing research,
interim analyses, and/or unsupported opinion.
Dr. Levis discloses that he will discuss off-label uses of
decitabine and sorafenib.
Learning Objectives

Assess methods to classify and determine the prognosis
of older adults with acute myeloid leukemia (AML)

Explain how patient characteristics and risk stratification
affect treatment selection

Evaluate efficacy and safety data on existing and novel
therapies for older adults with AML
AML: Scope of the Problem
• Annual US diagnoses: 7,820
• Annual US deaths: 5,930
• Annual US diagnoses: 6,770
• Annual US deaths: 4,440
AML is a clonal malignant proliferation of myeloid blast cells
in the marrow with impaired normal hematopoiesis.
Siegel et al, 2013.
Age-Specific AML Incidence Rates
200
180
160
Incidence
140
120
Males
Females
35-39
40-44
All
100
80
60
40
20
0
16-24
25-29
30-34
45-49
50-54
55-59
60-64
Patient Age (yrs)
Juliusson et al, 2009.
65-69
70-74
75-79
80-84
85-89
90+
MRC Trials: Younger Adults 15 to 59 Years (n=7,704)
MRC = United Kingdom Medical Research Council.
Burnett, 2012.
MRC Trials: Older Adults 60+ Years (n=3,541)
Burnett, 2012.
Traditional Paradigm for the
Treatment of AML
Complete
response
Induction
therapy
Consolidation
chemotherapy
Allogeneic
transplant
Relapse?
Complete
response?
Primary
refractory
Salvage
therapy
Modern Paradigm for the Treatment of AML
Complete
response
Risk
Stratify
Allogeneic
transplant
Consolidation
chemotherapy
Risk
Stratify
Induction
therapy
Primary
refractory
Relapse?
Salvage
therapy
Complete
response?
Common Induction Regimens Used
in Adult Patients With AML
Agents
Doses
“7 + 3” induction
Cytarabine (100–200 mg/m² infusion x 7 d)
and anthracycline (daunorubicin, idarubicin,
or mitoxanrone x 3 d)
Intensified induction
Various combinations of Ara-C, etoposide,
anthracycline (ICE, ADE, IA, etc.)
Low-dose Ara-C
20 mg bid for 10 d
Azacitidine
75 mg/m2 daily for 5–10 d
Decitabine
20 mg/m2 daily for 5 d
Ara-C = cytarabine; ICE = idarubicin/cytarabine/etoposide;
ADE = daunorubicin/cytarabine/etoposide; IA = idarubicin/cytarabine.
National Comprehensive Cancer Network (NCCN), 2013.
Common Consolidation Regimens
Used in Adult Patients With AML
Agents
Doses
“HiDAC” (4 cycles)
Cytarabine (3,000 mg/m²) infused over 3 hrs
bid on Days 1, 3, and 5
Allogeneic transplant
Either myeloablative or nonmyeloablative,
with an HLA-matched or alternative donor
Low-dose Ara-C
20 mg bid for 10 d at 4–6 wk intervals
Azacitidine
75 mg/m2/d for 5–10 d, repeated monthly
Decitabine
20 mg/m2/d for 5 d, repeated monthly
Hi-DAC = high-dose cytarabine; HLA = human leukocyte antigen.
NCCN, 2013.
How do older patients with AML fit
into this modern paradigm?
AML Therapy in Elderly Americans
Age group (yrs)
85
65–74
75–84
1,132
1,082
443
2,657
Received chemotherapy
(%)
44
24
6
30
Hospitalized (%)
89
91
83
89
Hospital/SNF days (%)
33
30
27
31
Median survival (mos)
3
2
1
2
15
19
20
17
N
Hospice (%)
SNF = skilled nursing facility.
Menzin et al, 2002.
Total
Survival in Elderly AML by Therapy

3,317 elderly patients aged ≥65 years with AML

1,193 (36%) received chemotherapy (younger, fewer
comorbidities)

888 patients matched in both cohorts
Survival
Median (mos)
1-Yr (%)
Overall
4.4
NA
Chemotherapy
6.1
 30
No therapy
1.7
 10
NA = not applicable.
Menzin et al, 2006.
Supportive Care Is Effective but
Insufficient as a Primary Treatment
Symptom
Treatment
Fungal infections
Azole antifungals (posaconazole, voriconazole, echinacandins, amphotericin-B)
Bacterial infections
Broad-spectrum antibiotics
Viral infections
Acyclovir, valacyclovir
Leukocytosis
Hydroxyurea
Neutropenia
G-CSF (filgrastim), GM-CSF (sargramostim) during post-remission therapy
Anemia/thrombocytopenia
Tumor lysis syndrome
Cognitive decline
Leukocyte-depleted products for transfusion and irradiated blood products for
patients receiving immunosuppressive therapy; screen for cytomegalovirus
Prophylaxis with intravenous hydration with diuresis, urinary alkalinization,
allopurinol; treatment with rasburicase
Patient monitoring for nystagmus, dysmetria, slurred speech, and ataxia before
each dose of cytarabine
Nausea/vomiting
Serotonin receptor antagonists (ondansetron)
Ocular toxicity
Saline or steroid drops in both eyes during cytarabine therapy
Oral mucositis
Mouthwash with viscous lidocaine, Maalox, and injectable diphenhydramine
NCCN, 2013; Rogers, 2010; Higa et al, 1991; Jabbour et al, 2006; Harris et al, 2008.
“Standard” Chemotherapy
vs. Nonintensive

DNR + Ara-C vs. “watch and wait” (hydroxyurea)
– CR in 58% vs. 0%
– Median survival: 21 vs. 11 weeks
– Survival at 2.5 years: 13% vs. 0%

Ara-C SQ 20 mg/m2 for 21 days vs. “7 + 3”
–  CR with “7 + 3”: 52% vs. 32%
–  induction death with “7 + 3”: 31% vs. 10%
– Similar survival and CR duration
DNR = daunorubicin; CR = complete response; SQ = subcutaneously.
Lowenberg et al, 1989; Tilly et al, 1990.
Pts considered for remission induction therapy (%)
Intention to Induce by Age and
Region (Swedish Registry)
Region
Pts = patients.
Juliusson et al, 2006.
Survival Among Patients Ages 70–79
(region, sample size)
APL = acute promyelocytic leukemia; RI = resistive index.
Juliusson et al, 2006.
Low-Dose Ara-C vs. Hydroxyurea ±
ATRA in Elderly AML or High-Risk MDS

217 elderly patients aged ≥60: 155 aged ≥65 years,
58 secondary AML, 30 high-risk MDS

Ara-C 20 mg bid x 10 every 4–6 weeks vs.
hydroxyurea
na
CR (%)
1-Year OS (%)
aData
Ara-C
102
18
27
not available for all patients.
ATRA = all-trans retinoic acid; MDS = myelodysplastic syndromes.
Burnett et al, 2007.
Hydroxyurea
99
1
3
P
NA
0.00006
0.0009
Conventional vs. Escalated-Dose
Daunorubicin
Daunorubicin
Daunorubicin
45 mg/m2
90 mg/m2
No. (%)
No. (%)
411
402
Age, median [range] (yrs)
67 [60–79]
67 [60–83]
WHO PS 0 or 1
363 (88)
354 (88)
43 (10)
42 (10)
98 (24)
82 (21)
221 (54)
259 (64)
49 (12)
44 (11)
Total patients (n)
PS 2
Unfavorable cytogenetics
CR
Early death
WHO = World Health Organization; PS = performance status.
Lowenberg et al, 2009.
Conventional vs. Escalated-Dose
Daunorubicin, Survival by Age
Lowenberg et al, 2009.
Conventional vs. Escalated-Dose
Daunorubicin, Survival by Age (cont.)
Lowenberg et al, 2009.
Frontline Azacitidine
• Sample of 165 patients treated with azacitidine 75 mg/m2 ±
VPA and ATRA ; 32% had 20%–29% marrow blasts
• Median age, 74 yrs (31–91); 83% 65 years; median cycles,
4; median follow-up, 16 mos
Response
CR + CRi
No. (%)
19 + 3 (13)
PR
10 (6)
HI
28 (17)
19%
• Median response duration, 6.9 months
• Median survival, 9.4 months; 1-year OS, 37%
VPA = valproic acid; ATRA = all trans retinoic acid; CRi = complete response with incomplete
hematologic recovery; PR = partial response; HI = hematologic improvement.
Thépot et al, 2009.
Azacitidine Prolongs Survival
in WHO-Defined AML




113 older patients with 20%–29% blasts (WHO AML)
Median age 70 years; poor cytogenetics 24%
55 randomly assigned to AZA, 58 to conventional care
regimens (IC 11, LDAC 20, BSC 27)
Median follow-up, 20 months; median cycles, 8 (1–39)
Parameter
AZA
CCR
P value
CR (%)
18
16
NS
Median OS
24.5
16.0
0.005
Hospitalization (pt/yr)
3.4
4.3
0.03
Infection (pt/yr)
0.58
1.14
0.003
AZA = azacitidine; IC = intensive chemotherapy; LDAC = low-dose cytarabine;
BSC = best supportive care; CCR = conventional care regimen; NS = not significant.
Fenaux et al, 2010.
Initial Conclusions
 Modern
AML treatment requires risk
stratification at multiple time points
 Treatment
confers a survival benefit over
supportive care, even in older AML patients
Risk Stratification
(Questions to Consider for Each Patient)
 Will
the patient survive treatment?
 How
likely is it that a patient will achieve
remission?
– What type of induction therapy should be used?
 If
a remission is achieved, will the patient
benefit from consolidation?
– What type of consolidation therapy should be
used?
Thirty-Day Mortality of AML Induction
Therapy: Effect of PS
Age (yrs)
<56
PS
56–65
66–75
>75
Early Death (%)
0
2
11
12
14
1
3
5
16
18
2
2
18
31
50
3
0
29
47
82
Appelbaum et al, 2006.
Proportion of AML (Non-APL) Patients,
PS 0 to 4 at Diagnosis
Pts per WHO performance status (%)
100%
90%
80%
70%
60%
WHO 0
WHO I
50%
WHO II
WHO III
40%
WHO IV
Missing
30%
20%
10%
0%
16-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89
Age (yrs)
Juliusson et al, 2009.
90+
All
Prognostic Model: MD Anderson
CR
Rate
8-Wk
Mortality
1-Yr
Survival
Age ≥75 yrs
■
■
■
Poor performance status
■
■
■
Unfavorable karyotype
■
■
■
Anemia
■
Leukocytosis
■
Antecedent hematologic disease
■
■
■
Creatinine >1.3 mg/dL
■
■
■
Prognostic Factor
■
Elevated lactate dehydrogenase
Treated in laminar flow room
Kantarjian et al, 2006.
■
■
■
Prognostic Model Predicts Survival
0
1–2
≥3
121
568
301
Survival, median (mos)
1-yr (%)
2-yr (%)
18
63
35
7
33
19
1
9
3
CR (%)
72
51
24
8-wk mortality (%)
10
26
57
Survival
n
Kantarjian et al, 2006.
Cytogenetic Risk Categories
Unfavorable
Favorable
1. Complex karyotype
2. Monosomy karyotype
3. Deletion of 5 or 7
4. t(6;9)
5. inv(3)
6. 11q23 (MLL gene)
1. inv(16)
2. t(8;21)
3. t(15;17)
Intermediate
Everything else
MLL = mixed lineage leukemia; inv = inversion; t = translocation.
Grimwade et al, 2001; Slovak et al, 2000.
Unfavorable Risk Cytogenetics
Increase With Age
100%
35
39
39
55
56
51
Incidence of pts with risk cytogenetics
90%
80%
70%
60%
50%
48
Unfavorable
Intermediate
40%
45
30%
20%
10%
17
6
0%
<55
56-65
Age (yrs)
Appelbaum et al, 2006.
5
4
66-75
>75
Favorable
Molecular Risk Categories
 FLT3/ITD
 NPM1
mutations = unfavorable risk
mutations = favorable risk
– In the absence of a FLT3/ITD mutation
 CEBPA
mutations = favorable risk
– In the presence of double mutations
 C-KIT
mutations = unfavorable risk
– In the context of core binding factor AML
FLT3 = fms-related tyrosine kinase 3; ITD = internal tandem duplication; NPM1 = nucleophosmin;
CEBPA = CCAAT/enhancer binding protein, alpha; C-KIT = type III tyrosine kinase growth factor receptor.
Kottaridis et al, 2001; Dohner et al, 2005; Taskesen et al, 2011; Paschka et al, 2006.
AML Categories Defined by Cytogenetic and
Molecular Abnormalities in All Adults
NPM1c
Other
int. risk
CEBPA
FLT3/ITD
CBF
(inv[16], t[8;21])
Poor-risk
cytogenetics
(5q-; 7q-; inv[3],
complex, etc.)
NPM1c = mutated nucleophosmin; CBF = core-binding factor; int. = intermediate.
Kottaridis et al, 2001; Dohner et al, 2005; Taskesen et al, 2011; Paschka et al, 2006.
APL
AML Categories Defined by Cytogenetic and
Molecular Abnormalities in Older Adults
NPM1c
Other
int. risk
CEBPA
FLT3/ITD
CBF
(inv16, t8;21)
APL
Poor-risk
cytogenetics
(5q-; 7q-; inv[3],
complex, etc)
Kottaridis et al, 2001; Dohner et al, 2005; Taskesen et al, 2011; Paschka et al, 2006.
Karyotype Influence on Patient Survival (%)
Karyotype Significantly Impacts
CR and OS in Elderly AML
100
90
80
Favorable (7%): t(15;17),
t(8;21), inv(16)
72
70
60
Intermediate (79%):
normal, all others
53
50
34
40
Unfavorable (14%):
complex (>5 abnormal)
26
30
15
20
10
2
0
Grimwade et al, 2001.
CR
OS (5-year)
DFS and OS of Patients Age ≥60 Years (A and B) and Age
≥70 Years (C and D) With Diploid AML by NPM1 Status
Wt = wild type; mut = mutation.
Becker et al, 2010.
Overall Survival of Older AML Patients
With or Without a FLT3/ITD Mutation


Patients enrolled on UK MRC AML16 trial
Treated with intensive induction
Lazenby et al, 2014.
Nonmyeloablative Allogeneic Transplant
in Patients by Decade
Median follow-up,
2.1 years
PFS = progression-free survival; OS = overall survival.
Kasamon et al, 2013.
Delaying Treatment Safe for Older Patients
Sekeres et al, 2009.
More Conclusions

Performance status and karyotype have a major impact
on the likelihood of surviving induction therapy in older
AML patients

Adverse karyotypes are more common in older AML
patients

Molecular and cytogenetic features influence outcomes
in older AML patients the same way they do in younger
AML patients

If possible, treatment of an older AML patient should be
delayed until an initial risk stratification can be performed
Novel Agents in Clinical
Development
Selected Novel Agents in Clinical
Trials for Older Patients With AML
Class
Examples
Purine analog
Clofarabinea
DNA methylation inhibitor
Azacitidine, decitabinea
Histone deacetylase (HDAC)
inhibitor
Vorinostatb, pracinostatb
Anti-CD33 antibody conjugate Gemtuzumab ozogamicina,b
Immunomodulatory agent
Lenalidomidea
FLT3 kinase inhibitor
Quizartinibb, PLX3397b, ASP2215b
Polo-like kinase (PLK1)
inhibitor
Volasertibb
Novel cytotoxics
CPX-351b
aOff-label.
bInvestigational.
Slide adapted from Ravandi F, 2012.
Clofarabine
NH2
N
N
HO
Rationally designed
purine analog

Resistant to
deamination and
phosphorolysis

Inhibition of DNA
synthesis and repair

Inhibitor of RNR and
DNA polymerase

Induction of apoptosis
N
N
Cl

O
F
HO
RNR = ribonucleotide reductase.
Montgomery et al, 1992.
Clofarabine Frontline Monotherapy
in Elderly AML Patients
Parameter
N
CR (%)
OR (%)
DOR
Age 70
69
33
39
15
AHD
41
39
51
Intermediate CG
46
48
54
Unfavorable CG
62
32
42
OR = overall response; DOR = duration of response;
AHD = antecedent hematologic disorder; CG = cytogenetics.
Kantarjian et al, 2010.
8.6+
15
9.5
OS
7.2
12
12
7.2
Clofarabine for Newly-Diagnosed Older AML Patients



Median age: 74 years
Clofarabine 20 mg/ m2 for 5 days vs. low-dose Ara-C
CR rate:
– Clofarabine: 22%
– Low-dose Ara-C: 12%
Burnett et al, 2013.
Epigenetic Therapy
DNA Methylation
Histone Modification
Phosphorylation
MMMM
Methylation
Acetylation
Azacitidine
Decitabine
Pracinostat
Vorinostat
Frontline Decitabine in Older
Patients With AML
N
CR
(%)
55
24
18
28
9
20
28
25
<1000
41
29
1,000 to 10,000
11
9
3
0
All Patients
Presenting Bone Marrow Blast (%)
<30
30 to <50
≥50
Presenting PBC
>10,000
PBC = absolute peripheral blood count.
Cashen et al, 2010.
Ten-Day Schedule of Decitabine for Older
Patients With Untreated AML
Percent Response
CR
Incomplete CR
100
80
60
40
20
0
All Patients Age <74
(N = 53)
(N = 25)
Blum et al, 2010.
Age 74+
(N = 28)
Normal
Complex Monosomy
Karyotype Karyotype 7 / del(7q)
(N = 21)
(N = 16)
(N = 11)
Decitabine vs. Treatment Choice
TC = treatment choice (best supportive care or low-dose cytarabine).
Kantarjian et al, 2012.
E2906 Trial on Clofarabine


Newly-diagnosed AML, age >60
Multicenter, cooperative group study
“7 + 3”/HiDAC
Newlydiagnosed
AML
Randomize
HLA-matched
sibling?
Complete
response?
Allogeneic
transplant
Follow
Randomize
Clofarabine
Eastern Cooperative Oncology Group (ECOG), 2012.
Decitabine
maintenance
Gemtuzumab Ozogamicin
Castaigne et al, 2012.
Lenalidomide
Risk Group (ELN)
CR (%)
CRi (%)
PR (%)
RD (%)
ED (%)
Favorable
14
14
14
57
0
Intermediate-1
25
0
17
50
8
Intermediate-2
17
8
8
42
25
Adverse
18
18
9
27
27
• First-line azacitidine then lenalidomide
• ORR 40%, including 28% CR/CRi
• Common adverse events were gastrointestinal,
fatigue, and myelosuppression
ELN = European Leukemia Net; ORR = overall response rate; RD = resistant
disease; ED = early death.
Pollyea et al, 2013.
Patients achieving positive outcomes (%)
Quizartinib Induces a High Response
Rate in Older Patients With
Relapsed/Refractory FLT3/ITD AML
100
80
7%
60
40
51%
20
CRc = CR + CRi + CRp.
Cortes et al, 2012.
21%
FLT3/ITD
N=110
CR/CRp
CRi
 16 of 110 (15%) patients
PR
remained alive for >12
months after taking
CRc 58%
quizartinib and were
classified as long-term
survivors
Frontline Volasertib + LDAC vs. LDAC in
Elderly Patients
Event-Free Survival
Maertens et al, 2012.
CPX-351: Liposomal Daunorubicin
and Cytarabine
Parameter
CPX-351
(n=26)
“7 + 3”
Regimen
(n=15)
12 (80.0)
Pts with 2 risk factors (%)
23 (88.5)
Pts with 3 risk factors (%)
3 (11.5)
3 (20.0)
CR (%)
11 (42.3)
4 (26.7)
CRi (%)
7 (26.9)
0
18 (69.2)
4 (26.7)
60-d mortality (%)
1 (3.8)
6 (40.0)
Median EFS (mos)
9.1
1.1
CR + CRi (%)
Median OS (mos)
Lancet et al, 2012.
23 (88.5)
12 (80.0)
Case Study 1: Transplantation
Case Study 1
 A 67-year-old woman presents with low-grade
fever, anemia, thrombocytopenia, and leucopenia
 Has no comorbid conditions or antecedent
hematologic disorder; organ functions are normal
 Bone marrow exam reveals AML and cytogenetic
analysis reveals loss of a translocation between
chromosome 9 and 11 at band q23 in 17 out of 20
metaphases
What is the recommended therapy for this patient?
Case Study 1 (cont.)
 She receives induction with cytarabine,
daunorubicin, and etoposide
 Achieves a CR
•
•
Remission marrow shows normal karyotype
Reduced performance status, ineligible for
further therapy until Day 70
 Undergoes a nonmyeloablative allogeneic
transplant with her HLA-matched sister as
donor
 She is in ongoing remission 1 year after her
diagnosis
•
Normal performance status
Case Study 2: Favorable Risk
Case Study 2
 A 72-year-old man presents in December 2010 with
dyspnea and a white count of 149,000
 No comorbid conditions or history of an antecedent
hematologic disorder
 Diagnosis: AML
 Normal karyotype; NPM1c
What treatment would you recommend?
Case Study 2 (cont.)
 Receives induction therapy with cytarabine and
idarubicin (“7 + 3”)
 Achieves a CR
 Started on HiDAC consolidation therapy
 Relapses after 22 months
 Re-induced with HiDAC and achieves a second
remission
 Enrolled in a clinical trial for maintenance antiinterleukin-3 receptor (CD123) antibody
 Remission is ongoing
Case Study 3: Progression of AML
Case Study 3
 A 71-year-old man presents with fever, profound
fatigue, anemia, and circulating blasts
• ECOG PS of 3
• Bone marrow biopsy, 30% blasts
• Complex cytogenetics, including loss of
chromosomes 5 and 7
 Other past medical history:
• Chronic myelomonocytic leukemia for 1 year
• Emphysema
• Chronic atrial fibrillation/flutter; on anticoagulation
therapy
• Stage III rectal colorectal adenocarcinoma, neoadjuvant radiation therapy, post-operation chemo 3
years prior
What treatment would you recommend?
Case Study 3 (cont.)
 5-azacitidine 75 mg/m2 for 5 days per cycle; gets
monthly treatment as outpatient
 Peripheral blood cleared of blasts
 PS improves
 Bone marrow shows persistent blasts after 6 cycles
 Disease progression nearly a year later
• ECOG PS still 1
 Referred for a clinical trial
Case Study 4: Other AML subtypes
Case Study 4




A 75-year-old woman presents in February 2010
with bruising and petechiae
Reports some bleeding when brushing her teeth
WBC is 9.3 with 71% promyelocytes, Plt 12, and
Hgb 8.4
Bone marrow exam is consistent with APL. You
send a specimen for cytogenetic and molecular
studies
What treatment would you recommend?
WBC = white blood cell count; Plt = platelet count; Hgb = hemoglobin count.
Case Study 4 (cont.)

Receives ATRA/daunorubicin and achieves CR
 Consolidation with arsenic and ATRA
 Currently in ongoing remission
Key Takeaways

Older patients can benefit from treatment in addition to
supportive care
 Risk stratification prior to induction is particularly
important for older AML patients
 Older AML patients are more likely to have unfavorable
karyotypes
 Cytogenetic and molecular abnormalities influence the
outcome in older AML patients the same way they do in
younger AML patients
 Patients should be treated in clinical trials whenever
possible
 Novel agents, as well as novel combinations of
established agents, are currently under investigation
References
Appelbaum FR, Gundacker H, Head DR, et al (2006). Age and acute myeloid leukemia. Blood, 107(9):3481-3485.
Becker H, Marcucci G, Maharry K, et al (2010). Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically
normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: a Cancer and
Leukemia Group B study. J Clin Oncol, 28(4):596-604.
Blum W, Garzon R, Klisovic RB, et al (2010). Clinical response and miR-29b predictive significance in older AML patients treated
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