Tailoring Reduced-Intensity
Conditioning:
Applying Emerging Evidence to Clinical Practice
February 4, 2012
12:15-1:15 pm
Marcos J. de Lima, MD
Professor of Medicine
Department of Stem Cell Transplantation and
Cellular Therapy
M.D. Anderson Cancer Center
Houston, TX
Faculty Disclosures
Marcos J. de Lima, MD
Professor of Medicine
Department of Stem Cell Transplantation and Cellular Therapy
M.D. Anderson Cancer Center
Houston, TX
Research Grant – Celgene
Kaci Wilhelm, PharmD
Clinical Pharmacy Specialist
Blood and Marrow Transplant
M.D. Anderson Cancer Center
Houston, TX
No relevant financial relationships to disclose
Agenda
12:15-12:45 p.m.
Critical Decisions: Pretransplant Conditioning
- Marcos J. de Lima, MD
12:45-1:05 p.m.
Putting the Evidence into Practice: Optimized Dosing and
Administration of Reduced-Intensity Conditioning
Regimens
- Kaci Wilhelm, PharmD
1:05-1:15 p.m.
Faculty Panel: Questions & Answers
Critical Decisions:
Pretransplant Conditioning
Marcos J. de Lima, MD
M.D. Anderson Cancer Center
Houston, TX
Discussion Topics
• Historic perspective and definitions
• Donor and recipient-related covariates that influence transplant
outcomes and regimen choice
• Myeloablative versus reduced intensity regimens – can we really
compare them ?
• Donor – recipient issues that influence regimen choice
• We may not need to reduce dose intensity for all patients in the
6th and 7th decade of life
• Conclusions
Goal of Preparative Regimen
• Immunosuppression - adequate to
prevent rejection
• Cytoreduction - eradicate or control
malignancy (this element not needed if
disease is controlled by prior therapy)
• Stem cell space (not myelosuppression) allow donor cells to compete effectively
05/22/11
06/09/11
07/06/11
08/04/11
How did we get here?
• 1922, Fabricious-Moeller
– Shielding of legs of guinea pigs during TBI
decreased myelosuppression.
• 1952, Jacobsen/Lorenz
– Protection of TBI aplasia by injection of
spleen cells from syngeneic mice.
• 1956, Nowell/van Bekkum/Ford/Tausche
– Concept of radiation chimera.
Head of a Lion, the Mid-section of a Goat and
the Hindquarters of a Dragon
http://wpcontent.answers.com/wikipedia/commons/thumb/b/b3/Chimera_Apulia_Louvre_K362.jpg/180pxChimera_Apulia_Louvre_K362.jpg
BMT Landmarks
• 1955, Barnes and Loutit
– Carcinoma bearing mice exposed to lethal TBI with
syngeneic spleen cell transplantation had long lived
protection, but 50% of mice receiving allogeneic
spleen cells died before day 100 without tumors.
GVL and GVHD.
• 1958, Santos
– Lymphocytes (T-cells) mediate GVHD, and target
organs are lymphoid, skin, gut, and liver.
1996
Two-year Probability of Treatment-related Mortality
After Transplants for CML, 1992-1997
100
< 20 years
20 – 40 years
> 40 years
PROBABILITY, %
80
62%
60
53%
41%
40
38%
27%
20
17%
11%
9%
11%
0
HLA-ident Sib
Unrelated
Auto
Leukemia
TOS00_13.ppt
1990’s: How to improve
treatment-related mortality
and morbidity?
• Improvements in supportive care,
antibiotics, blood support, etc.
• Decrease the dose ?
Graft-vs-Malignancy Allogeneic SCT
• Much of the benefit of alloSCT is due to immune GVL
effect; therefore maximally ablative therapy may not be
needed.
• Lower dose nonmyeloablative preparative regimens
may be sufficient to prevent rejection.
• It was hypothesized that a reduced intensity,
nonmyeloablative allogeneic transplant could reduce
toxicity and allow successful treatment of older patients
and those with major comorbidities.
ASH-Orlando 1996
MDACC
Hadassah
Seattle
Graft-Versus-Tumor Effect
Graft-Versus-Host Disease
Graft-versus-Lymphoma Effect
Graft-versus-Leukemia Effect (GVL)
• Intrinsic disease susceptibility is different.
• Some diseases need more chemo / radiation
dose intensity than others.
Graft-versus-Leukemia Effect (GVL)
• + + + + Low grade lymphomas, chronic
myeloid and lymphocytic leukemias.
• + + Myelodysplastic syndrome and acute
myelogenous leukemia.
• + Acute lymphocytic leukemia.
Histocompatibility
Intensity
Review Question: Regarding the graftversus-leukemia effect, it is true that:
a) Donor neutrophils are the effector cells.
b) Chronic myelogenous leukemia is more
sensitive to the graft-versus-leukemia
effect than acute lymphoctye leukemia.
c) It is not influenced by the use of systemic
steroids.
d) It is rarely associated with graft-versushost disease.
Review Question: Regarding the graftversus-leukemia effect, it is true that:
a) Donor neutrophils are the effector cells.
b) Chronic myelogenous leukemia is
more sensitive to the graft-versusleukemia effect than acute
lymphoctye leukemia.
c) It is not influenced by the use of
systemic steroids.
d) It is rarely associated with graft-versushost disease.
Definitions
Myeloablative
Reduced-Intensity
• Profound
pancytopenia
within 1-3 weeks
• Irreversible
myelosuppression
• Require stem cell
support
• Significant and
prolonged
cytopenias
• Require stem cell
support
• Reduction in
alkylating agent
or TBI dose
Bacigalupo A, et al. Biol Blood and Marrow Transplant 2009.
Non-Myeloablative
• Minimal
cytopenias
• Autologous
recovery within
28 days
Myeloablative Dosing Thresholds
CIBMTR Operational Definitions
TBI > 5Gy single dose
TBI > 8Gy fractionated
Busulfan > 9mg/kg PO
Melphalan > 150mg/m2
Thiotepa > 10mg/kg
Total dose per course
Busulfan equivalent dosing: 7.2mg/kg IV or 288mg/m2
Giralt S, et al. Biol Blood Marrow Transplant 2009; Madden T, et al. Biol Blood Marrow Transplant 2007.
Engraftment
Graft
Host
Stem cell dose
T-cell dose
Graft-facilitating cells
Stromal stem cells?
Immunosuppression
Preparative Regimen
Post transplant Rx
Disease effects
Sensitization
Histocompatibility
Patient-related Variables
• Age
• Comorbidities
• Performance Status
• CMV Status
• Other Infections
Hematopoietic Cell TransplantationComorbidity Index (HCT-CI) for Non-Relapse
Mortality (NRM) and Survival after
Allogeneic HCT
Sorror M and Collaborators
Fred Hutchinson Cancer Research Center, Seattle, WA
and MD Anderson Cancer Center, Houston, TX
Diagnosis is AML in First Remission
- Individual Comorbidities
60
FHCRC
MDACC
% of patients
50
40
30
20
10
0
Lung
Liver
Cancer Cardiac Obesity Infection DM
Psych
Rheum
2-year NRM Stratified by HCT-CI Scores
Score 3
Score 1-2
Score 0
MDACC
Percent NRM
FHCRC
37
19
7
27
21
7
Years after HCT
Two-year Survival Stratified by HCT-CI Scores
Score 0
Score 1-2
Score 3
Percent survival
FHCRC
Years after HCT
MDACC
Race
• Genetics
• Social economic issues
• Access to treatment
Disease-related Variables
Disease status and survival
1.0
Cumulative Proportion Surviving
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
n= 433 patients with myeloid leukemias
0.0
0
20
40
60
80
Months
100
120
140
160
Disease-related Variables
• Previous treatment(s)
• Marrow microenvironment
• Susceptibility to the GVL effect
• Disease tempo
Donor-related Variables
Donor-related Variables
- Donor-recipient ABO compatibility
- CMV
- Parity
- Age (??)
- Availability
- Co-morbid conditions
The Graft
Graft
• Several institutional and/or investigator
biases.
• Donor choice (marrow versus PBPC).
• PBPC may be a better choice with reduced
intensity preparative regimens.
• De novo chronic GVHD with PBPC is a
serious problem.
• ASH 2011: results of randomized PBPC
versus marrow in unrelated donor
transplants.
Donor Type
Matched Sibling versus Unrelated
Donor Type
Cord Blood versus Unrelated Marrow
or Peripheral Blood Stem Cell
Effect of Graft Source on Unrelated Donor
Haemopoietic Stem-Cell Transplantation in
Adults with Acute Leukemia:
A Retrospective Analysis
N=1525 - transplanted between 2002 – 2006
UCB = 165
PBPC = 888
Bone marrow = 472
All myeloablative
Diagnoses: AML and ALL
Eapen et al. Lancet Oncol 2010.
Probability of Leukemia-Free Survival for Patients
IN REMISSION
Eapen et al. Lancet Oncol 2010.
NOT IN REMISSION
Donor-recipient Variables
65-year Old Patient with AML
Donor
Recipient
HLA-A*
02:01:01
01:01:01g
HLA-A*
03:01:01g
02:01:01
HLA-B*
35:03:01
35:03:01
HLA-B*
51:08
51:08
HLA-Cw*
04:CXBM
04:CXBM
HLA-Cw*
16:02
16:02
HLA-DRB1*
11:01
11:01
HLA-DRB1*
13:02:01
13:02:01
HLA-DRB3*
02:02:01
02:02:01
HLA-DRB3*
03:01
03:01
HLA-DQB1*
03:01:01
03:01:01
HLA-DQB1*
06:04:01
06:04:01
HLA-DQB1*
(03:22, 06:39)
(03:22, 06:39)
HLA-DPB1*
02:01:02
02:01:02
HLA-DPB1*
09:01
04:01:01
Anti HLA Antibodies
Anti B13, B27, B38, B39, B41, B45, B49, B50,
DR7, DR9, DR53, DQ2, DQ8, DP1, DP11,
DP13, DP15, DP17, DPB1*02:02
The patient's serum has reactivity against
HLA-DPB1*09:01 (827 MFI).
Are we transplanting older
patients ?
Unrelated Donor Transplants at MDACC
Median age and year of transplant
Correlation: r = .94021
Median age
60
55
Are we there yet?
50
NO!!
45
Median age of AML
Patients: mid 60’s.
40
MDS: mid 70
- late 70’s
35
30
25
1990
1992
1994
1996
1998
2000
Year
2002
2004
2006
2008
2010
Trends in Allogeneic Transplantation
by Recipient Age,* 1987-2007
100
Transplants, percent
<=20 yrs
80
21-40 yrs
41-50 yrs
60
51-60 yrs
>60 yrs
40
20
0
1987-1993
1994-2000
2001-2007
* Transplants for AML, ALL, CML, MM, NHL, CLL, MDS
Reduced Intensity (RIC) or NonMyeloablative (NMA) HCT CIBMTR Data
•
•
•
•
Years 1995-2005
≥ 40 years old or greater
Matched related or unrelated donor
MDS or AML in CR1 1,080 cases
– 545 AML CR1
– 535 MDS
• Data from 148 centers
McClune, et al. Blood 2008;112 (11):135a (Abstract #346)
TRM and Relapse of Patients 40+ Years Receiving
Nonmyeloablative Allogeneic HSCT for AML and MDS,
1995-2005, by Age
100
TRM
90
100
Relapse
90
80
80
65+ yrs
70
70
60-64 yrs
60
60
55-59 yrs
50
60-64 yrs
40-54 yrs
50
55-59 yrs
40
40
30
30
20
10
40-54 yrs
65+ yrs
p=0.66
0
0
1
2
Years
3
40
1
2
20
10
p=0.87
3
0
4
Years
Tp08_10.ppt
McClune, et al. Blood 2008;112 (11):135a (Abstract #346)
Does the intensity of the
preparative regimen matter?
It does – however, it is not the
same for all diseases.
It depends on the diagnosis
and the sensitivity to the graft
versus malignancy effect
Are there diseases in which
reducing the intensity may be worse
than otherwise?
A cautionary tale in AML and MDS.
It is not only the regimen:
stem cell source etc etc.
Effect of Regimen Intensity on
Transplant Outcome for AML/MDS
FAI - relapse
FAI - toxicity
De Lima et al Blood 2004
Comparing RIC vs
MA Caveats
 Notable absence of prospective RIC vs MA
conditioning studies….
 Level of evidence is not the highest
 Retrospective & Registry Studies
• Selection Bias
RIC
Graft Source
GVHD prophylaxis
Co-morbidity Score
Previous Transplant
(vs MA)
More likely PBSC
More likely CNI + MMF
Worse
More likely
Baseline different when you compare
PARAMESWARAN HARI
Review Question: Which of the
following statements is true?
a) Aging does not influence results of allogeneic
stem cell transplantation.
b) Remission status at transplant influences
treatment-related mortality.
c) There is extensive literature comparing outcomes
of myeloablative and reduced-intensity
preparative regimens in a randomized fashion.
d) Most patients with myelodysplastic syndrome
receive allogeneic transplants.
Review Question: Which of the
following statements is true?
a) Aging does not influence results of allogeneic
stem cell transplantation.
b) Remission status at transplant influences
treatment-related mortality.
c) There is extensive literature comparing
outcomes of myeloablative and reducedintensity preparative regimens in a randomized
fashion.
d) Most patients with myelodysplastic syndrome
receive allogeneic transplants.
100-day Mortality after Allogeneic Transplantation,
1998-2008
- by conditioning intensity NO
50
45
Transplants, %
40
Myeloblative
RIC
35
30
25
20
15
10
5
0
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Early mortality has improved for allogeneic transplants in
general. Patient selection is key !!
Adjusted Probability of
Overall Survival
Adjusted Probability, %
100
90
NST vs Myeloablative, p<0.01
80
NST vs RIC PB, p=0.02
70
RIC PB (N = 768)
60
Myeloablative (N = 3,731)
50
40
30
NST (N = 407)
20
10
RIC BM (N = 273)
0
0
1
2
3
4
5
Years
Wsp08_18.ppt
Are there situations in which
reduced-intensity
transplants have changed the
standard of care
for transplant?
Ablative Allo-BMT in
Indolent Lymphoma
Probability, %
100
Survival
DFS
Treatment-related mortality
Relapse
80
60
40
20
0
0
1
van Besien et al. Blood. 1998;92:1832-1836.
2
3
Years
4
5
6
NON-MYELOABLATIVE ALLOGENEIC SCT
Conditioning Regimen
Rituximab Fludarabine 30 mg/m2
Cyclophosphamide 750 mg/m2 1000 mg/m2
Rituximab
375 mg/m2
ASCT
Days
-13
-6 -5 -4 -3
0
+1
+8
• ATG 15 mg/kg daily, was given days –5 to –3 for mismatched or unrelated SCT.
• Tacrolimus and methotrexate were used for GVHD prophylaxis.
FCR Allo SCT for Low Grade
Lymphoma
1.0
0.9
0.8
0.7
0.6
0.5
0.4
C u m u l a ti ve Pro p o rt i o n Su rvi vi n g
Khouri et al Blood 2008
0.3
0.2
0.1
0.0
0
20
40
60
Mo nths Po st Tra nspla nt
80
10 0
12 0
Conditioning Regimen Intensity by
Histology Allogeneic Transplants for
Lymphoma in North America
200
RIC
Myeloablative
Transplants
150
FOLLICULAR
100
MANTLE
HODGKIN
50
0
Burkitt
Diffuse Large Follicular
Cell
Mantle Cell Peripheral T
Cell
Other NHL
Hodgkin
Graft vs. Lymphoma effect if any , varies by histology
Armand et al. Biol BMT 2008;14:418-25
BMT CTN Clinical Trials of Reduced
Intensity Allogeneic Transplantation
BMT CTN – Bone Marrow Transplant Clinical Trials Network
Study #
Disease
Study Question
BMT CTN 0102
Myeloma
Tandem Auto vs. Auto -> Allo RIC HCT
BMT CTN 0202
Foll. NHL
Autologous vs. Matched Sib Allo RIC HCT
BMT CTN 0502
AML CR1
RIC Allo HCT in pts 60 – 74 yrs
BMT CTN 0601
Sickle Cell
RIC URD HCT
BMT CTN 0603
Many
Haplo identical HCT with RIC
BMT CTN 0604
Many
Double Cord HCT with RIC
BMT CTN 0701
Foll. NHL
Sibling or URD HCT with RIC
BMT CTN 0901
MDS/AML
Myeloablative vs. RIC Allogeneic HCT
Ablative Regimens Are
Improving As Well!!
Intravenous Busulfan/Fludarabine
Day
Bu
1

2

3

4

5
6
7
130 mg/m2 q d
Flu



*
rest* rest* HSCT
40 mg/m2 q d
GVHD prophylaxis: tacrolimus and “mini” methotrexate
*day of ATG if MUD or one-antigen mismatched related donor
Borje Andersson
Myeloablative IV Busulfan and Fludarabine
for Patients Older Than 54 years
Years 2002-2008
- n=74
Related or unrelated donors (50% / 50%)
Age ≥ 55 years (median, 58 years; range, 55-66 years)
Cytogenetics : poor (27%); intermediate (68%); good (5%)
Complete remission at transplant (54%)
Diagnosis: AML (81%) / MDS (19%)
Al-Atrash et al. Blood 2008 112: Abstract 2999.
Myeloablative IV Busulfan and Fludarabine
for Patients Older Than 54 Years
Cumulative Incidence
Treatment-related Mortality
Grade II-IV Acute GVHD
Al-Atrash et al. Blood 2008 112: Abstract 2999
Myeloablative IV Busulfan and Fludarabine
for Patients Older Than 54 Years
Al-Atrash et al. Blood 2008 112: Abstract 2999
Reduced-intensity Conditioning
• Use has increased over the last decade.
• There are no randomized comparisons of
regimen intensity - it is a matter of
convictions, egos, tradition, careers, and
institutional data and experience.
• Little controversy: older patients and patients
with medical comorbidities.
Conditioning Regimen Intensity:
(some) Take Home Messages
• Age does not influence outcomes with RIC/NMA for
AML, up to age 65 (+/-!!).
• HCT with RIC/NMA offers a possibility to cure AML in
the elderly in up to 30-50 % of patients (you can’t
myeloablate most patients in the late 60’s and early
70’s!!).
• Usual prognostic factors do apply (ie cytogenetics
etc).
• Disease status at transplant is the most important
predictor for post transplant outcome.
Review Question: Given that reduced-intensity
regimens are usually associated with lower
treatment-related mortality, it is true that:
a) All patients with acute myelogenous leukemia
should receive this type of regimen.
b) All patients with myelodysplastic syndrome should
receive this type of regimen.
c) There is frequently a tradeoff between less
treatment-related mortality and higher relapse rate.
d) Disease susceptibility to the graft-versus-leukemia
is the same for all hematologic malignancies.
Review Question: Given that reduced-intensity
regimens are usually associated with lower
treatment-related mortality, it is true that:
a) All patients with acute myelogenous leukemia
should receive this type of regimen.
b) All patients with myelodysplastic syndrome should
receive this type of regimen.
c) There is frequently a tradeoff between less
treatment-related mortality and higher relapse
rate.
d) Disease susceptibility to the graft-versus-leukemia
is the same for all hematologic malignancies.
To Ablate or Not…
•Patients with some indolent diseases have more to lose
with a high-risk approach upfront (especially now with new
medications!):
- CML in chronic phase that is refractory to imatinib and
other TKI but remain in chronic phase.
- Low grade lymphoma.
- CLL.
- Low grade MDS.
- Multiple myeloma
To Ablate or Not…
• In the absence of controlled trials RIC
regimens should be considered standard for:
– Hodgkin’s Disease
– Myeloma
– Older patients
– Heavily pretreated patients or those with
significant co-morbidities
– Most patients with CLL and NHL
Future Directions
• Better definition of risk for treatment-related
mortality.
• Incorporation of new agents.
• Better integration with standard treatment.
• Conjugation with graft engineering and post
transplant pharmacologic and immunologic
manipulations.
Conclusions
• The major contribution is the realization that
patients in the 7th and 8th decades of life can
have allogeneic transplants.
• Major obstacles to cure are delayed or poor
immune recovery, graft-versus-host disease
and disease relapse.
• Relapse rates are higher than in
myeloablative transplants for certain
diseases.
To ablate or Not,
That Is the Question…
• Controlled trials are needed to establish
whether RIC is superior to conventional
allografting or standard therapy in most
hematologic malignancies.
• These trials will need to be performed in
single diseases and selected disease stages
to be clinically informative.
• The issue of preparative regimen of choice is
unresolved.
Acknowledgments
Edwin P. Alyea III, MD
Dana Farber Institute
Brenda Sandmaier, MD
Fred Hutch – Seattle
Marcelo Pasquini, MD
Parameswaran Hari, MD
CIBMTR
Sergio Giralt, MD - NY
Department of Stem Cell Transplantation
M D Anderson Cancer Center
Richard Champlin
Borje Andersson
Elizabeth Shpall
Roy Jones
Stefan Ciurea
Simrit Parmar
Jeffrey Molldrem
Uday Popat
Paolo Anderlini
Partow Kebriaei
Yago Nieto
Issa Khouri
Chitra Hosing
Martin Korbling
Michael Andreef
Qaiser Bashir
Image Credit: NASA/JPL/Space Science Institute