Tailoring Reduced-Intensity Conditioning: Applying Emerging Evidence to Clinical Practice February 4, 2012 12:15-1:15 pm
Feb 25, 2016
Tailoring Reduced-Intensity Conditioning:
Applying Emerging Evidence to Clinical Practice
February 4, 2012
12:15-1:15 pm
Marcos J. de Lima, MDProfessor of Medicine
Department of Stem Cell Transplantation and Cellular Therapy
M.D. Anderson Cancer CenterHouston, TX
Faculty DisclosuresMarcos J. de Lima, MD
Professor of MedicineDepartment of Stem Cell Transplantation and Cellular TherapyM.D. Anderson Cancer CenterHouston, TX
Research Grant – Celgene
Kaci Wilhelm, PharmDClinical Pharmacy SpecialistBlood and Marrow TransplantM.D. Anderson Cancer CenterHouston, TX
No relevant financial relationships to disclose
Agenda12:15-12:45 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, MDM.D. Anderson Cancer Center
Houston, TX
• 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
Discussion Topics
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.
http://wpcontent.answers.com/wikipedia/commons/thumb/b/b3/Chimera_Apulia_Louvre_K362.jpg/180px-Chimera_Apulia_Louvre_K362.jpg
Head of a Lion, the Mid-section of a Goat and the Hindquarters of a Dragon
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
TOS00_13.ppt
Two-year Probability of Treatment-related Mortality After Transplants for CML, 1992-1997
PRO
BABI
LITY
, %
0
20
40
60
80
100
HLA-ident Sib Unrelated Auto
17%
27%
41%38%
53%
62%
11% 9% 11%
Leukemia
< 20 years20 – 40 years> 40 years
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
SeattleHadassah
MDACC
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 graft-versus-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-versus-host disease.
Review Question: Regarding the graft-versus-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-versus-host disease.
Definitions
Myeloablative
•Profound pancytopenia within 1-3 weeks•Irreversible myelosuppression•Require stem cell support
Reduced-Intensity
•Significant and prolonged cytopenias•Require stem cell support•Reduction in alkylating agent or TBI dose
Non-Myeloablative•Minimal cytopenias•Autologous recovery within 28 days
Bacigalupo A, et al. Biol Blood and Marrow Transplant 2009.
Myeloablative Dosing Thresholds
CIBMTR Operational Definitions
TBI > 5Gy single doseTBI > 8Gy fractionatedBusulfan > 9mg/kg POMelphalan > 150mg/m2
Thiotepa > 10mg/kg
Giralt S, et al. Biol Blood Marrow Transplant 2009; Madden T, et al. Biol Blood Marrow Transplant 2007.
Total dose per courseBusulfan equivalent dosing: 7.2mg/kg IV or 288mg/m2
EngraftmentGraft Host
Immunosuppression Preparative Regimen Post transplant Rx
Disease effects Sensitization
Stem cell doseT-cell dose
Graft-facilitating cellsStromal stem cells?
Histocompatibility
Patient-related Variables
• Age• Comorbidities• Performance Status• CMV Status• Other Infections
Hematopoietic Cell Transplantation-Comorbidity 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
0
10
20
30
40
50
60 FHCRCMDACC
Diagnosis is AML in First Remission- Individual Comorbidities
Lung CancerLiver Obesity InfectionCardiac
% o
f pat
ient
s
DM Psych Rheum
2-year NRM Stratified by HCT-CI Scores
Years after HCT
Per
cent
NR
M
Score 0 Score 1-2 Score 3
FHCRC MDACC
7
1937
721
27
Two-year Survival Stratified by HCT-CI Scores
Years after HCT
Per
cent
sur
viva
l
FHCRC MDACC
Score 3Score 1-2Score 0
• Genetics
• Social economic issues
• Access to treatment
Race
Disease-related Variables
Disease status and survival
0 20 40 60 80 100 120 140 160
Months
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cum
ulat
ive
Pro
porti
on S
urvi
ving
n= 433 patients with myeloid leukemias
Disease-related Variables• Previous treatment(s)
• Marrow microenvironment
• Susceptibility to the GVL effect
• Disease tempo
Donor-related Variables
- Donor-recipient ABO compatibility
- CMV
- Parity
- Age (??)
- Availability
- Co-morbid conditions
Donor-related Variables
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
Eapen et al. Lancet Oncol 2010.
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 NOT IN REMISSION
Donor-recipient Variables
65-year Old Patient with AML
HLA-A* 02:01:01HLA-A* 03:01:01gHLA-B* 35:03:01HLA-B* 51:08HLA-Cw* 04:CXBMHLA-Cw* 16:02HLA-DRB1* 11:01HLA-DRB1* 13:02:01HLA-DRB3* 02:02:01HLA-DRB3* 03:01HLA-DQB1* 03:01:01HLA-DQB1* 06:04:01HLA-DQB1* (03:22, 06:39) HLA-DPB1* 02:01:02HLA-DPB1* 09:01
Donor Recipient01:01:01g02:01:0135:03:0151:0804:CXBM16:0211:0113:02:0102:02:0103:0103:01:0106:04:01(03:22, 06:39) 02:01:0204:01:01
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 ?
Median age and year of transplantCorrelation: r = .94021
1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010
Year
25
30
35
40
45
50
55
60
Med
ian
age
Unrelated Donor Transplants at MDACC
Are we there yet?
NO!!
Median age of AML Patients: mid 60’s.
MDS: mid 70 - late 70’s
Trends in Allogeneic Transplantationby Recipient Age,* 1987-2007
1987-1993 1994-2000 2001-20070
20
40
60
80
100
<=20 yrs
21-40 yrs
41-50 yrs
51-60 yrs
>60 yrs
* Transplants for AML, ALL, CML, MM, NHL, CLL, MDS
Tran
spla
nts,
per
cent
Reduced Intensity (RIC) or Non-Myeloablative (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
Tp08_10.ppt
0 1 3 4
100
0
20
40
60
80
90
10
30
50
70
2Years
TRM
65+ yrs60-64 yrs55-59 yrs40-54 yrs
p=0.66
Years0 1 3 4
0
100
20
40
60
80
90
10
30
50
70
2
Relapse
40-54 yrs
60-64 yrs55-59 yrs
p=0.8765+ yrs
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
De Lima et al Blood 2004
FAI - relapse
FAI - toxicity
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 (vs MA)Graft Source More likely PBSCGVHD prophylaxis More likely CNI + MMFCo-morbidity Score WorsePrevious Transplant 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 reduced-intensity preparative regimens in a randomized fashion.
d) Most patients with myelodysplastic syndrome receive allogeneic transplants.
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 20080
5
10
15
20
25
30
35
40
45
50
Myeloblative RIC
Tran
spla
nts,
%100-day Mortality after Allogeneic Transplantation,
1998-2008- by conditioning intensity -
Early mortality has improved for allogeneic transplants in general. Patient selection is key !!
NO
Adjusted Probability of Overall Survival
Wsp08_18.ppt
Adju
sted
Pro
babi
lity,
%
Years0 1 2 543
100
0
20
40
60
80
90
10
30
50
70
Myeloablative (N = 3,731)
RIC BM (N = 273)
RIC PB (N = 768)
NST (N = 407)
NST vs Myeloablative, p<0.01NST vs RIC PB, p=0.02
Are there situations in which reduced-intensity
transplants have changed the standard of carefor transplant?
Ablative Allo-BMT in Indolent Lymphoma
van Besien et al. Blood. 1998;92:1832-1836. Years
Prob
abili
ty, %
5432100
20
40
60
80
100
6
SurvivalDFSTreatment-related mortalityRelapse
Rituximab Fludarabine 30 mg/m2 Rituximab 375 mg/m2
Cyclophosphamide 750 mg/m2 1000 mg/m2
-13 -6 -5 -4 -3 0 +1 +8
ASCT
Days
NON-MYELOABLATIVE ALLOGENEIC SCT
Conditioning Regimen
• 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
0 20 40 60 80 100 120
Months Post Transplant
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cum
ulative Proportion S
urviving
Khouri et al Blood 2008
Burkitt Diffuse Large Cell
Follicular Mantle Cell Peripheral T Cell
Other NHL Hodgkin0
50
100
150
200RICMyeloablative
Conditioning Regimen Intensity by Histology Allogeneic Transplants for
Lymphoma in North America
Tran
spla
nts FOLLICULAR
MANTLE
HODGKIN
Graft vs. Lymphoma effect if any , varies by histologyArmand et al. Biol BMT 2008;14:418-25
BMT CTN Clinical Trials of Reduced Intensity Allogeneic Transplantation
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
BMT CTN – Bone Marrow Transplant Clinical Trials Network
Ablative Regimens Are Improving As Well!!
Intravenous Busulfan/Fludarabine
Day 1 2 3 4 5 6 7Bu 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
Al-Atrash et al. Blood 2008 112: Abstract 2999.
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%)
Myeloablative IV Busulfan and Fludarabine for Patients Older Than 54 years
Al-Atrash et al. Blood 2008 112: Abstract 2999
Cumulative Incidence Treatment-related Mortality Grade II-IV Acute GVHD
Myeloablative IV Busulfan and Fludarabine for Patients Older Than 54 Years
Al-Atrash et al. Blood 2008 112: Abstract 2999
Myeloablative IV Busulfan and Fludarabine for Patients Older Than 54 Years
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.
• 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…
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, MDDana Farber Institute
Brenda Sandmaier, MDFred Hutch – Seattle
Marcelo Pasquini, MDParameswaran Hari, MDCIBMTR
Sergio Giralt, MD - NY
Image Credit: NASA/JPL/Space Science Institute
Richard Champlin Borje AnderssonElizabeth Shpall Roy JonesStefan Ciurea Simrit ParmarJeffrey Molldrem Uday Popat Paolo Anderlini Partow Kebriaei Yago Nieto Issa Khouri
Chitra Hosing Martin KorblingMichael Andreef Qaiser Bashir
Department of Stem Cell TransplantationM D Anderson Cancer Center