indications for allogeneic transplantation in acute and chronic … for allogeneic... ·...
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Indications for Allogeneic Transplantation in Acute and Chronic
Leukemia:What’s the evidence?
Steven Devine MDThe Ohio State University
Comprehensive Cancer Center
Large Adult AML Meta Analysis:Relapse free survival
Koreth JAMA 2009
Large Adult AML Meta Analysis:Overall Survival
Koreth JAMA 2009
ELN Cytogenetic/Molecular Classification of AML
Dohner et al, Blood, 2009
Distribution of the European LeukemiaNet genetic groups in younger (A) and older (B) adults with primary acute myeloid leukemia.
Mrózek K et al. JCO 2012;30:4515-4523
©2012 by American Society of Clinical Oncology
Outcome of patients with primary acute myeloid leukemia classified into the four European LeukemiaNet genetic groups according to the European LeukemiaNet recommendations.
Mrózek K et al. JCO 2012;30:4515-4523
©2012 by American Society of Clinical Oncology
HCT-Comorbidity Index and outcomes
Cornelissen et al, Nat Rev Clin Oncol, 2012
EBMT Risk Score and outcomes in AML
Cornelissen et al, Nat Rev Clin Oncol, 2012
MA RIC
ELN Recommendations for allografts in AML CR1
Cornelissen et al, Nat Rev Clin Oncol, 2012
Large Meta Analysis in Adult ALL
Pidala et al, Cochrane Database Syst Rev, 2011
Large Meta Analysis in Adult ALL:Impact on relapse
Pidala et al, Cochrane Database Syst Rev, 2011
Large Meta Analysis in Adult ALL:Treatment related mortality
Pidala et al, Cochrane Database Syst Rev, 2011
Large Meta Analysis in Adult ALL:Subset analysis
Pidala et al, Cochrane Database Syst Rev, 2011
Effect of donor versus no donor on overall mortality in each trial.
Gupta V et al. Blood 2013;121:339-350
©2013 by American Society of Hematology
Descriptive curve of overall survival by donor versus no donor.
Gupta V et al. Blood 2013;121:339-350
©2013 by American Society of Hematology
Effect of donor versus no donor on overall mortality in subgroups.
Gupta V et al. Blood 2013;121:339-350
©2013 by American Society of Hematology
Evidence based recommendations for Allografting Adult ALL in CR1
• Ph+ and t(4;11) in first remission− Role of TKI, autografts, reduced intensity regimens?− What if matched sibling not available?
• Age 18-35 (standard and other high risk)− Matched sib transplant (myeloablative) − What if matched sibling not available?
• Age >35 (standard and other high risk)− No clear evidence to support routine use
What is the evidence for transplantation in myelodysplastic syndrome?
• Patients under age 60− Markov decision analysis (Cutler et al, Blood, 2004)
Advantage for immediate transplantation for IPSS Int-2/high risk, not lower riskThese data are getting old!Only matched siblings analyzed
• Patients aged 60-70− Markov decision analysis (Koreth et al, ASH 2011)− Analyzed quality adjusted life expectancy (QALE)
comparing immediate RIC transplant to BSC or HMAOnly advantage in Int2/high risk groupOnly matched siblings analyzed
Impact of karyotype on posttransplant relapse.
Deeg H J et al. Blood 2012;120:1398-1408
©2012 by American Society of Hematology
Survival by 5-group cytogenetic classification.
Deeg H J et al. Blood 2012;120:1398-1408
©2012 by American Society of Hematology
Comparison of Outcomes after Related and Unrelated
Hematopoietic Cell Transplantation in Adults with Myelodysplastic Syndromes: A Report from the CIBMTR
A CIBMTR Cohort Analysis for Study CK12-04
CK12-04-12_1.ppt
Abstract 353
Adjusted Probability of Overall Survival for AML after Transplant
Prob
abili
ty o
f Sur
viva
l, %
Months0 6 12 362418
100
0
20
40
60
80
90
10
30
50
70
0
100
20
40
60
80
90
10
30
50
70
30
MRD (N=624)
8/8 MUD (N=1,193)
7/8 MUD (N=406)
Pointwise comparison at 3 years:MRD vs. 8/8 MUD P value = 0.97 MRD vs. 7/8 MUD P value = 0.767/8 MUD vs. 8/8 MUD P value = 0.71
Saber et al. Blood 2012; 119(17):3908-16
CK12-04-12_3.ppt
Background
Due to differences in patients characteristics and disease related factors, extrapolation from AML to MDS may be inappropriate.
Therefore disease specific analysis comparing outcomes post MUD HCT vs. MRD HCT in adult MDS patients was performed.
CK12-04-12_4.ppt
Adjusted Cumulative Incidence of Treatment-related Mortality for MDS
Inci
denc
e, %
Months0 6 12 362418
100
0
20
40
60
80
0
100
20
40
60
80
30
7/8 MUD (N=413)
8/8 MUD (N=112)
MRD (N=174)
Overall P-value=0.01 (2 df)Relative Risk (95% CI):8/8 MUD vs. MRD= 1.37 (1.01-1.85) 7/8 MUD vs. MRD= 1.71 (1.17-2.47) 7/8 MUD vs. 8/8 MUD=1.24 (0.90-1.70)
CK12-04-12_10.ppt
Adjusted Probability of Overall Survival for MDS
Adj
uste
d Pr
obab
ility
, %
Months0 6 12 362418
100
0
20
40
60
80
0
100
20
40
60
80
30
8/8 MUD (N=413)
7/8 MUD (N=112)
MRD (N=174)
Overall P-value=0.005 (2 df)8/8 MUD vs. MRD= 1.24 (0.98-1.56) 7/8 MUD vs. MRD= 1.62 (1.21-2.17) 7/8 MUD vs. 8/8 MUD=1.30 (1.01-1.68)
CK12-04-12_13.ppt
Other Prognostic Factors for DFSRisk of Death/
Relapse (95% CI) P-valueKPS
≥ 90% 1.00< 90% 1.36 (1.11-1.66) 0.002
IPSS at diagnosisLow-risk 1.00Int-1 1.12 (0.77-1.64) 0.53Int-2 1.39 (0.94-2.06) 0.09High-risk 2.22 (1.37-3.58) 0.001
CK12-04-12_16.ppt
Conclusions
In adults with MDS, 7/8 MUD HCT is associated with significantly inferior outcomes compared to MRD and 8/8 MUD
8/8 MUD HCT is also associated with an unfavorable trend in mortality compared to MRD
The differences in treatment failure is determined by an excess in TRM
These results should inform the HCT community, assist in counseling MDS patients, and in the design of clinical trials
CK12-04-12_19.ppt
What are the current recommendations in myelodysplastic syndrome?
• In younger patients (<60), allograft at diagnosis for Int2/high risk patients with matched sibling and probably 8/8 matched unrelated donor
− MA or reduced intensity?− What about other alternative donors (cord, haplo)?− Influence of revised prognostic systems?− Should all first get HMA or induction?
What if they are responding to HMA?• In older patients, matched sib RIC (and by extrapolation 8/8
MUD) at diagnosis only if Int2/high − Should they all get trial of HMA?
A Multi-Center Phase III Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplant to Hypomethylating Therapy or Best Supportive Care in
Patients Age 50 or Older with Intermediate-2 and High Risk Myelodysplastic Syndrome
BMT CTN 1102
January 2013
Ryotaro Nakamura, MDCorey Cutler, MD MPH
Hypothesis
• RIC Allogeneic Stem Cell Transplantation Offers a Survival Advantage over Non-Transplant Therapy in Patients Considered Candidates for Transplantation
Basic Design
• Donor vs. No Donor Comparison of Patients Referred for Transplantation– “Does Transplant Help”
• Intention to Treat • No mandate of transplant or non-transplant
regimen
Primary Objective- Compare the three-year overall survival probability between the two study arms using an intent-to-treat analysis
Arm 1: RIC alloHCT Arm 2: Non-Transplant Therapy / Best Supportive Care
Secondary Objectives- Compare leukemia-free survival (LFS) at 3 years from
enrollment- Compare QOL measures between treatment arms
Study Objectives
Eligibility• De novo MDS with CURRENT or PRIOR
Intermediate-2 / High-risk IPSS Score • Aged 50-75 years• Marrow (30 days) with < 20% blasts• Any therapy prior to registration• KPS > 70 / ECOG ≤ 1• NO specific lab testing eligibility
– Available tests + gestalt at transplantation consultation • No formal MUD search activated.
– Sibling donor search or with a known MRD or no MRD donor is allowed
• Treatment Compliance Planned– Intent to proceed to RIC transplantation if a donor is found– No intent to pursue alternative donor transplantation at the
time of enrollment
MDS Study Design
Significant and Rapid Improvement in Survival After Unrelated Donor
Hematopoietic Cell Transplantation: Analysis of National Marrow Donor Program
Facilitated Transplants from 2000 to 2009
Navneet S Majhail, MD, MSMedical Director, Health Services Research,
National Marrow Donor Program, Minneapolis, MN
Adjunct Associate Professor of Medicine, University of Minnesota, Minneapolis, MN
Abstract 234
Study Population
• 15,040 unrelated donor HCT recipients• Analyses stratified by age and diagnosis
Cohort 2000-2004N
2005-2009N
Malignant diseases, age <18 yrs 906 1017
Malignant diseases, age 18-59 yrs 3808 5745
Malignant diseases, age ≥60 yrs 412 1783
Non-malignant diseases 476 893
36
Practice Changes Over Time
3745 49
40
5968 74
64
0
20
40
60
80
100
%
Increased use of HLA 8/8 matched donor
37
*** *
2000-20042005-2009
* P < 0.05
23
47
77
2133
7887
26
0
20
40
60
80
100
%
Increased use of PBSC as graft source
Malignant ds, age <18 yrs
Malignant ds, age 18-59 yrs
Malignant ds, age ≥ 60 yrs
Non-malignant diseases
*
**
*
Overall Survival, 3-years
38
45 (42-48)%
55 (52-58)%
Malignant diseases, age <18 yrs
Non-malignant diseasesMalignant diseases, age ≥ 60 yrs
Malignant diseases, age 18-59 yrs
P<0.001 P<0.001
25 (21-30)%
35 (33-37)%
60 (55-64)%
69 (66-72)%
P<0.001
2000-2004
2005-2009
Treatment Related Mortality, 3-years
39
Malignant diseases, age <18 yrs
Malignant diseases, age ≥ 60 yrs
Malignant diseases, age 18-59 yrs
28 (25-31)%
2000-2004
2005-2009
21 (18-23)%
P<0.001
37 (35-38)%
28 (27-29)%
P<0.001
34 (30-39)%
31 (29-33)%
P=0.20
Multivariate Analyses for Overall Survival
CohortHazard Ratio (95% CI); Referent 2000-04
Adjusted for patient factors P-value Adjusted for patient
+ practice factors P-value
Malignant ds,age <18 yrs 0.75 (0.66-0.86) <0.001 0.82 (0.71-0.95) 0.008
Malignant ds,age 18-59 yrs 0.78 (0.74-0.82) <0.001 0.86 (0.80-091) <0.001
Malignant ds,age ≥60 yrs 0.76 (0.67-0.86) <0.001 0.78 (0.68-0.90) <0.001
Non-malignant diseases 0.68 (0.56-0.82) <0.001 0.78 (0.63-0.95) 0.01
40
20
05
-20
09
Patient factors: Age at HCT, gender, race/ethnicity, KPS/Lansky score, CMV status, coexisting diseases, time from diagnosis to HCT, diagnosis, disease risk (malignant ds.)Practice factors: Graft type, conditioning regimen intensity, HLA match, GVHD prophylaxis, T-cell depletion
Conclusions
• Significant and rapid improvement in survival following unrelated donor HCT from 2000 to 2009 for all age groups
• Survival improvements due to reduced TRM, and in certain populations, fewer relapses
• Better patient selection, increased availability of HLA-matched donors and practice changes partly explain survival improvements
• Reinforces the role of unrelated donor HCT as standard therapy for patients who need transplant and do not have HLA-matched sibling donors
41
CALGB 100103/BMT CTN 0502A Phase II Study of Allogeneic Transplant
for Older Patients with AML in First Morphologic Complete Remission Using a
Reduced Intensity Preparative Regimen
Steven M. Devine, Kouros Owzar, William Blum, Daniel DeAngelo, Richard M. Stone, Jack W Hsu, Richard E. Champlin, Yi-Bin A. Chen, Ravi Vij, James L
Slack, Robert J. Soiffer, Richard A. Larson, Thomas C. Shea, Vera Hars, Elizabeth Bennett, Sada Spangle, Sergio A Giralt, Shelly L Carter, Mary M.
Horowitz, Charles Linker, and Edwin P Alyea III on behalf of The Alliance and Blood and Marrow Transplant Clinical Trials Network
Abstract 230
Background • Outcomes in older patients with AML extremely poor
– Within CALGB, analysis of 600 AML patients age 60 and over with cytogenetics (Farag et al, Blood 2006)
• Complete remission (CR): 50%• 5-year overall survival (OS): 7%
• Results even in best CALGB group are still poor (n = 276)– CR1, Age 60-75– Received at least one consolidation cycle on trial
• 2-year disease free survival (DFS): 24%• 3-year DFS 17%
• Small series suggested relapse rates may be lower for selected older AML patients receiving reduced intensity conditioning (RIC) based allografts
CALGB 100103/BMT CTN 0502Demographics
• 9 patients cancelled; 123 Transplanted– Related: N=58; Unrelated N=65
• Patient Age– Median 65 (60-74); related: 64.5; unrelated: 66
• Patient gender– Male 76– Female: 47
• Cytogenetic risk (CALGB criteria)– Favorable: 1– Intermediate: 83– Adverse: 25– Missing: 14
• Donor age (median; range)– Related: 63 (43-81); Unrelated: 30 (19-55)
CALGB 100103/BMT CTN 0502Chronic GVHD (limited/extensive)
cGVHD at 2 yrs: 26% (95% CI: 17-34%)
CALGB 100103/BMT CTN 0502Relapse/TRM
Relapse TRM
Relapse and TRM by donor type
Relapse at 2 yrs: 47% (95% CI: 37-57%)
TRM at 2 yrs: 14%(95% CI: 7-21%)
CALGB 100103/BMT CTN 0502Disease free/Overall Survival
by donor type
DFS unrelated at 2 yrs: 38%(95% CI: 26-55%)
Prospective data is still limitedProposed new trial -Alliance/IntergroupPI Celalettin Ustun U Minnesota
AML—Age 60-75 Enroll on US Coop Group TrialCo-enroll on this trial-- Donor search
HCT by 20 Weeks if Donor found; if in CR and FitTest 2 year survival in 3 groups:
Donor/HCT allocated vs None ---- or Not fitFeasibility: How many HCTsSurvival and MorbidityQOL and Functional Recovery
Is there anything to say about CML and allografts?
• Very few patients are getting transplants• NCCN guidelines recommend consideration after failing
two lines of TKI or if T315I mutation found• If blast phase at diagnosis• Prior imatinib does not seem to worsen transplant outcomes• Relapse rates likely to be much higher• Role of MA vs RIC unclear
Indications for Allo SCT in CLL
• EBMT 2007 Dreger et al.− Consider allo transplant in:− Primary refractory CLL or early relapse (< 12 mo)
following PNA-based therapy− Relapse within 24 months following a PNA-based
regimen− Del 17p13.1 disease requiring treatment
Indications for Allo SCT in CLL
• Italian Society of Hematology− Consider if unfavorable biologic risk factors are present,
or− Non-response or early relapse following PNA-based
regimen
NCCN Guidelines
• Now basically mirror EBMT− Consider allo transplant in patients with del 17p as
consolidation after first therapy if response is demonstrated or
− In patients with early relapse (<2 years) following standard therapy
Unwritten Guidelines in CLL
• The development of novel therapeutics (b-cell receptor kinase inhibitors etc) has made the recommendation very difficult
• For patients with access to a clinical trial of a novel therapeutic, who otherwise would have been considered for allo, pursue clinical trial first
• Patients without access to a clinical trial, follow guidelines• At OSU, only transplant if failing BTK trial or if Eligible for
CALGB 100701/BMT CTN 0804
The Future of Transplant for CLL
• Will likely always have a role given the proven efficacy
• However, less toxic effective therapies must be tried and failed
• CAR-T therapies still in the wings . . .
Thank You!
Patient selection from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0303 clinical trial of transplantation with T-cell–depleted (TCD) grafts in acute myeloid
leukemia (AML) and the BMT CTN 0101 antifungal prophylaxis clinical trial (imm...
Pasquini M C et al. JCO 2012;30:3194-3201
©2012 by American Society of Clinical Oncology
(A) Cumulative incidence of neutrophil engraftment by treatment arm.
Pasquini M C et al. JCO 2012;30:3194-3201
©2012 by American Society of Clinical Oncology
(A) Cumulative incidence of leukemia relapse by treatment arm.
Pasquini M C et al. JCO 2012;30:3194-3201
©2012 by American Society of Clinical Oncology
A randomized phase III study of standard
cytarabine plus daunomycin (7+3) therapy
versus idarubicin with high dose cytarabine
(IA) with or without vorinostat in younger
patients with previously untreated acute
myelogenous leukemia
(SWOG 1203)
SWOG 1203: ObjectivesPrimary:
– To compare EFS between 7+3 vs IA vs vorinostat IA– To determine if it is possible to perform SCT in ≥ 60% of
patients in CR1 AML
Secondary:– To compare CR rates, RFS and OS between 3 arms– To compare survival at 1, 2 and 3 years between 3 arms– To study toxiciy profiles between the 3 arms– To estimate DFS in patients that receive SCT– To study impact of molecular and cytogenetic
alterations on outcome according to treatment
Design: schemaRANDOMIZATION(REG STEP 1)ARM 1: 7+3ARM 2: IAARM 3: Vorinostat IA
HR PATIENTREMISSIONREADY FOR TRANSPLANT
YES ALLO SCT(REG STEP 3)
NO
CONSOLIDATION(REG STEP 2)ARM 1 HDACARM2 IAARM 3 VORINOSTAT IA
HR PATIENTREMISSIONREADY FOR TRANSPLANT
YES
NMDP will assist on early HLA typing and accelerated search
TherapyARM 1: 7+3
– dauno 90 mg/m2 x days 1 to 3– Ara-C 100 mg/m2 CI days 1 to 7– Consolidation HDAC x 4
Arm 2: IA– Idarubicin 12 mg/m2 days 1 to 3– Ara-C 1.5 gm/m2 days 1 to 4– Consolidation IA x 6 cycles
Arm 3: Vorinostat IA– Vorinostat 500 mg po TID days 1 to 3– IA starts on day 4
Transplant per individual center
Design: StatisticsSample size
– Chemo objective: 705 eligible patients (235/arm)– Transplant objective: 53 eligible high-risk patients
in CR
Accrual– 171 patients/year– Estimate that accrual will complete is < 5 years
Accrual will continue until both objectives are met– If chemo randomization stops due to interim
analysis, accrual will continue for transplant with patients’ chemo determined by results of interim analysis
Design: Statistics, chemo objective
Cure design– Null: 35% of patients cured, median EFS for non-cured = 4.7 months– Alternative: 45% cured, median EFS for non-cured = 7.1 months
5 interim analyses– First two based on CR (at ≈1 year and 2 years). Arm(s) stopped for
harm/futility– Last three based on EFS (at ≈ 2.5, 3.5, and 4.5 years). Arm(s) stopped
for efficacy or futility
Current submission proposes proportional odds model for EFS. After discussions with CTEP, can modify to use Cox proportional hazards model (alternative average HR=1.46). Change would lead to:
– Power decrease 88% 85%– Probability stop null trial early increase 92% 97%All other #s (sample size, alpha level, type-1 error) the same
Design: Statistics
Transplant objective:– Our goal: transplant 60% eligible patients,
compared to historical rate of 40%– Estimate DFS among transplanted patients– Reasons for failure to be transplanted will be
carefully documented
CALGB 100103/BMT CTN 0502Accrual by Site
* Study suspended from 12/08 thru 11/09
Site # Registered*Dana Farber 31
Ohio State 22
University of Florida 13
MDACC 12
Mass General 10
Washington U 8
Mayo Arizona 6
14 others 1-3
132 total patients registeredTrial met accrual goal in 2/2011
CALGB 100103/BMT CTN 0502Induction/Consolidation
• Induction therapy– CR after one cycle: 73 (59%)– CR after 2 cycles: 50 (41%)– All but 9 received std 7+3 based (only 2 decitabine)
• Consolidation– None: 21 (17%)– One cycle: 62 (50%)– Two cycles: 29 (24%)– Missing: 11 (9%)
CALGB 100103/BMT CTN 0502Disease free/Overall Survival
Median follow up: 3.3 yrs (related: 3.9 yrs; unrelated: 2.9 yrs)
DFS at 2 yrs: 39%(95% CI: 30-50%)
OS at 2 yrs: 46%(95% CI: 36-57%)
CALGB 100103/BMT CTN 0502Causes of Death
Primary cause N (total 69)
Relapse 53Sepsis 6MI 2Pulmonary 3Second cancer 2HHV-6 encephalitis 1
RSV pneumonia 1
Unknown 1
Conclusions from CALGB 100103/BMT CTN 0502
• Disease free survival at 2 yrs appears to be improved compared to historical controls treated conventionally (lower limit 95% CI above historical 20%)
• Overall treatment related mortality has been relatively low (<15%) despite older age and use of unrelated donors
• Acute and Chronic GVHD incidence relatively low
• Relapse still by far the greatest cause of failure– Could ATG have contributed?
• Further prospective analysis of RIC allografts in older AML patients is planned through NCI cooperative groups and BMT CTN
CALGB 100801
• Prospective multi-center study of reduced intensity allografts in patients with MDS and older AML CR1 patients
• Attempts to optimize busulfan dosing and prevent relapse with post transplant azacytidine
• Currently actively enrolling, two thirds completed
Recent Innovations in Stem Cell Transplantation presented at ASH
• Increasing the specificity of cellular therapy– Chimeric antigen receptor (CAR) T-cells– Suicide gene transduced T-cells
• Creating viable options for patients without matched sibling donors– Improved outcomes with cord blood and
haploidentical transplantation
Recent Innovations in Stem Cell Transplantation presented at ASH
• Mitigating the risk of relapse via maintenance therapy– Lenalidomide maintnenance in myeloma– Use of PD-1 antibody to stimulate immunity– Post transplant brentuximab in Hodgkin lymphoma– Post transplant azacytidine
• Novel methods to prevent GVHD– CCR5 antagonism, bortezomib, post transplant
cyclophosphamide– Treg adoptive transfer or in vivo generation via
immunomodulating drugs
Protocol Team Members
Wael SaberJennifer Le-RademacherMary HorowitzShelly CarterBrent LoganNancy DiFronzoBill MerrittIris GerstenEric Leifer
Joe AlvarnasCorey CutlerMikkael SekeresSteve GoreRichard StoneJoe McGuirkFred AppelbaumDennis ConferJoycelynne Palmer
Stephen FormanGinna LaportRenee CarbyRyotaro Nakamura Guillermo Garcia-Manera
Coverage with Evidence Development
• CMS issued decision Aug 2010 allowing “coverage with evidence development (CED)”
Suggests insufficient evidence “..evidence does not demonstrate that the use of HCT improves health outcomes in Medicare beneficiaries with MDS.” “paucity of evidence regarding the use of HCT in patients with MDS who are 65 years or older”
Will cover costs of HCT if patients enrolled in a study that will provide CMS with data (“evidence”) to determine the value of the procedure in the Medicare population
To qualify for CED, a trial must address at least one of the following 3 questions
1. Prospectively, compared to Medicare beneficiaries with MDS who do not receive HCT, do Medicare beneficiaries with MDS who receive HSCT have improved outcomes?
2. Prospectively, in Medicare beneficiaries with MDS who receive HCT, how do IPSS score, patient age, cytopenias and comorbidities predict outcomes?
3. Prospectively, in Medicare beneficiaries with MDS who receive HCT, what treatment facility characteristics predict meaningful clinical improvement in outcomes?
Design – Treatment Assignment• Once Enrolled - 90 days maximum to
Donor/No Donor assignment– Based on likelihood of identifying donor after 90
days – NMDP data– Analysis as NO DONOR for events occurring prior
to assignment– Balances bias with those who arrive with known
donors and suffer early events– Intention to treat, even if:
• Declines transplant with known donor • Undergoes alternative donor transplant (no donor arm)
Statistics – Assumptions
Group Prob (95% CI) 2011 CIBMTR Registration
50-59 38 (27 – 50)% 265 (age 50-65)
≥ 60 33 (16 – 54)% 152 (age > 65)Combined 37 (27 – 47)% n = 417
CIBMTR 3 year OS for RIC Transplantation
Baseline Data – Azacytidine
Compassionate use program n = 282, (Itzykson et al, Blood 2011)
3 year OS = 20-25%
Donor
Availability
Total Sample size
(HCT, Non-HCT)
Three-year OS Power
HCT Non-HCT
60% 338
(203, 135)
35% 20% 84%
40% 25% 80%
70% 400
(280, 120)
35% 20% 84%
40% 25% 81%
POWER TO DETECT 15% INCREASE IN OS PROBABILITY IN THE TRANSPLANT ARM FOR VARIOUS SURVIVAL PROBABILITIES AND PROPORTIONS OF DONOR
AVAILABILITY
CIBMTR data: 420 patients/yr receive alloHCT from a MRD/MUD- Assumptions: 50% = Int-2/high risk IPSS (?underestimate)
Accrual rate = 40%- Annual enrollment: 84 patients/yr to the RIC alloHCT arm.
Donor Availability
60% 70%Donor 84 84No Donor 56 36
Total 140 120
• Estimated accrual duration: 2.5 - 3.5 years (donor/no-donor: 6:4 – 7:3)
• Accrual monitoring: Donor vs. No-donor, 50-64 vs. 65-75
Accrual
Biologic Correlates
• No planned analyses yet• Sample collection:
– Baseline: PBMCsCheek swabPossible Marrow (if avail)
– Post-Transplant: Relapse PBMCsMarrow (if avail)
- Co-enrollment on 1202 – GVHD Biomarkers
Data Collection
• Differential data collection on Transplant vs. No Transplant patients (not Donor vs No-Donor)
• CIBMTR Research Data on all Transplant recipients
• Non-Transplant Patients: Registering Transplant Center responsible for collection of:
– Vital Status– CBC data, leukemic transformation date
• SRG to perform QoL contact, obtain some info
Analysis Plan• Primary Endpoint: 3-year OS by intent-to-treat analysis
- as treated analysis
• Exploratory analyses to evaluate - Impact of hypomthelyating therapy on transplantation outcomes (i.e. OS, DFS, TRM, GVHD). The response to therapy, # of cycles, will be used in correlative analyses after RIC alloHCT.
- Subset of recently diagnosed patients who received hypomethylating therapy followed by RIC alloHCT vs. who received hypomethylating therapy not followed by RIC alloHCT
Questions this trial will not directly Answer
• What is the role of hypomethylating therapy pre-transplant?– Optimal # of cycles– Does response matter
• What is the best initial treatment for MDS?– Transplant vs. Azacytidine
• Possible subgroup analysis
Protocol Timeline• PRC Review / Approval Jan 2013
• Consent and FAQ documents included
• Needs Biomarker and Toxicity Committee Reviews
• Steps: Steering Committee ApprovalRelease to IRBsForms and Logistics being worked on now
Goal: Accrual before Q4 2013
Protocol Subject Status
CALGB 11002 Randomized phase II of decitabine-based induction for AML age ≥ 60
Active
SWOG 1117 Randomized phase II of azaciditine-based therapies for MDS
Active
SWOG 1203 Randomized phase III of standard 7+3 vs IA +/- vorinostat in AML age < 60
Approved
ECOG 1912 Randomized phase II/III of FCR vs PCI-32765 based therapies in younger CLL
Approved
Alliance 041202 Randomized phase III of bendamustine+ rituxan versus ibrutinib-based therapies in older CLL
Approved
ECOG 1910 Randomized phase III of blinatumomab in BCR/ABL-, B-cell ALL age 40-70
Approved
NCI Leukemia Steering Committee
HLA-Identical Sibling-Matched, CD34+ Selected, T cell Depleted Peripheral Blood Stem Cells Following Myeloablative
Conditioning For First or Second Remission Acute Myeloid Leukemia (AML): Results of Blood and Marrow Transplant
Clinical Trials Network
S Devine, S Carter, R Soiffer, M Pasquini, P Hari, A Stein, H Lazarus, C Linker, E Stadtmauer, E Alyea, C Keever-Taylor, and R O'Reilly
(BMT CTN) Protocol 0303
1 http://www.Cancer.gov2 Koreth, J et al. JAMA 2009
Acute Myeloid Leukemia (AML)
Most common leukemia diagnosis in adults1
Annual U.S. incidence: ~ 12,330 new cases diagnosed annuallyMortality is roughly 8,950 cases per yearAllogeneic SCT is the single most effective therapy currently available for the prevention of relapse and shows significant survival benefit in AML patients with intermediate and poor risk cytogenetics in first complete remission (CR1) 2
Reduced incidence of leukemic relapse and overall survival often not realized due to complications caused by GVHD
Acute GVHD (aGVHD) risk is 35-45%
33-67% of these patients will develop chronic GVHD (cGVHD), resulting in post transplant morbidity, mortality and reduced quality of life
Immunosuppressive agents used to prevent and treat aGVHD do not affect incidence of cGVHD; treatment options for cGVHD are poor
Graft Versus Host Disease (GVHD) Complicates Allogeneic Transplantation From Matched Related Donors (MRD)1-6
1 Ferrara J, et al. Lancet 2009 2 Chao N, et al. NEJM 1993 3 Devine S, et al. J Lab Clin Med 20034 Clift R, et al. Blood 1991 5 Nash R, et al. Blood,2000 6 Ratanatharathorn V, et al. Blood 1998
Single center studies show reduced GVHD without increased relapse rates in AML patients receiving T cell depleted (TCD) allografts in CR1,2
One randomized, prospective, multi-center TCD trial showed no increase in relapse in AML patients receiving TCD allografts3
BMT CTN 0303 Study Rationale
1 Aversa et al. Blood Cells Mol and Disease 20082 Pappadopoulos et al, Blood, 19983 Wagner, J. et al. Lancet 2005
Randomized, Prospective, Multi-center TCD trial Showed No Increase in Relapse in AML
Patients Receiving TCD Allografts
Wagner et al., Lancet 366:733, 2005
All Patients AML
BMT CTN 0303 Study Eligibility
AML in CR1 or CR2Age 18-65HLA-identical sibling availableNo more than 2 induction cycles of chemotherapy required to induce remissionNo more than six months from CR to transplant (three months for CR2)Other standard organ function criteriaNo uncontrolled bacterial/fungal/viral infectionsKarnofsky performance status > 70%
Primary endpoint:Disease-free survival at 6 months
BMT CTN 0303 Study Endpoints
Secondary Endpoints: Overall SurvivalDisease Free Survival at 2 yearsTransplant-Related MortalityRelapseAcute and chronic GVHDEngraftment/graft failureInfusional ToxicitiesProportion of grafts containing > 5 x 106 /kg CD34+
cells and < 1 x 105 /kg CD3+ cells Incidence of EBV reactivation and PTLD
BMT CTN 0303 Study Endpoints, continued
Site Patients Accrued
Dana Farber/Partners Cancer Center 18
Ohio State University 8
Memorial Sloan Kettering Cancer Center 7
Medical College of Wisconsin 7
City of Hope National Medical Center 3
University Hospitals of Cleveland 2
University of CA, San Francisco 1
University of Pennsylvania 1
TOTAL 47
Eight Centers Enrolled Patients onto BMT CTN 0303
44 patients were evaluable on study2 withdrew consent; 1 had disease progression prior to treatment
BMT CTN 0303Patient Characteristics
Patient Age Median (range) 46.3 (21-59 )
Donor age Median (range) 46.2 (16-63)
GenderMale 16 (36%)
Female 28 (64%)
Leukemia stageCR1 37 (84%)
CR2 7 (16%)
Cytogenetic Risk (CR1/CR2)
Favorable 0 / 2
Intermediate 25 / 3
Unfavorable 10 / 1
Unknown* 2 / 1
* Unknown cytogenetic risk due to lack of metaphase during testing
BMT CTN 0303 Patient Conditioning Regimen
CTN 0303 Donor Mobilization & Leukapheresis
Received daily G-CSF (16μg/kg/day subcutaneously) following screening and enrollmentLeukapheresis performed according to institutional standards commencing on Day 5 of G-CSFDaily leukapheresis with subsequent CD34+ cell selection using the CliniMACS® CD34 Reagent System continued until a post-selection target of CD34+ and CD3+ cells/kg recipient body weight was met
CTN 0303 Donor Mobilization & Leukapheresis
Received daily G-CSF (16μg/kg/day subcutaneously) following screening and enrollmentLeukapheresis performed according to institutional standards commencing on Day 5 of G-CSFDaily leukapheresis with subsequent CD34+ cell selection using the CliniMACS® CD34 Reagent System continued until a post-selection target of CD34+ and CD3+ cells/kg recipient body weight was met
Primary Endpoint6 Month Disease-Free Survival of >75%
Was Met
Prob
abili
ty
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
N=44
81.8% @ 6 months
Secondary EndpointsDisease-Free Survival at 2 years
All Patients By CR1/CR2*
By Stage
Prob
abili
ty
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
N=44
65.7% @ 1 yr 56.4%
@ 2 yrs
61.9% @ 2 yrs
28.6% @ 2 yrs
* 2º Endpoint of >70% for CR1 and >60% for CR2 were not met. However, historical data estimate 2 Yr DFS < 60% in CR11-3
1 Suciu Blood 2003 2 Brunet et al, Hematologica 20043 Cornelissen et al, Blood 2007
Secondary Endpoint2 Year Overall Survival Was 59.4%
Prob
abili
ty
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
N=44
77.3% @ 1 yr
59.4% @ 2 yrs
Secondary EndpointsNeutrophil/Platelet Engraftment
Analysis NMedian Days
to EngraftmentDay 30Estimate
Day 100 Estimate
Platelet Engraftment
>20K/µL 44 16 days
93.2% (95% CI: 85.2-100)
97.7 %(95% CI: 92-100)
Cumulative Incidence of Neutrophil
Engraftment >500/µL
44 12 days100%
(95% CI: 85.5-100)
• No primary graft failures • One secondary graft failure at Day +54 after initially engrafting on Day +12
Secondary Endpoint - Cumulative Incidence of Transplant-Related Mortality (1yr) was 13.6%
Safety endpoint of <30% TRM at 1 Year was not exceeded.
TRM at 2 years was 19.9% (95% CI: 7.1-32.7)
Prob
abili
ty
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
N=44
All Patients By CR1/CR2
13.6% (95% CI: 3.4-23.8)
Secondary Endpoint - Cumulative Incidence of EBV Reactivation 18% at 2 years
All Patients By CR1/CR2
13.6% (95% CI: 3.4-23.8)
Prob
abili
ty
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
N=44
Prob
abili
ty
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
First CR (N=37) Second CR (N=7)
18.2% @2 yrs 18.9%
14.3%
• 8 patients treated for EBV DNA levels >1000 copies/ml• One case of PTLD with subsequent death
Secondary Endpoint - Cumulative Rate of Relapse was 23.7% at 2 years
Prob
abili
ty
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
N=44
Prob
abili
ty
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
First CR (N=37) Second CR (N=7)
20.6% @ 1 yr
23.7% @2 yrs
57.1% @2 yrs
17.4%* @2 yrs
All Patients By CR1/CR2
* N=7 patients treated in CR2; 4 patients relapsed(95% Confidence Interval: 14.6-99.6%)
Secondary Endpoint- Cumulative Incidence of Acute GVHD (II/IV was 22.7%)
Prob
abili
ty
0.0
0.2
0.4
0.6
0.8
1.0
Days Post Transplant0 7 14 21 28 35 42 49 56 63 70 77 84 91 98
First CR (N=37) Second CR (N=7)
22.7% (95% CI: 10.2-35.2)
*No Grade IV GVHD observed
All Patients By CR1/CR2
Secondary Endpoint-Cumulative Incidence of Grade III/IV Acute GVHD was 4.5%
* No Grade IV GVHD observed
4.5%(95% C.I: 0 – 10.8%)
All Patients By CR1/CR2
Secondary Endpoint - Cumulative Incidence of Chronic GVHD (2 yrs) was 19%
Prob
abili
ty
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
First CR (N=37) Second CR (N=7)
19%(95% CI: 6.8-31.1)
Includes Limited and ExtensiveAll Patients By CR1/CR2
Secondary Endpoint - Cumulative Incidence of Extensive cGVHD (2 yrs) was 6.8%
Prob
abili
ty
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
p
N=44
6.8% (95% CI: 0-14.4)
All Patients By CR1/CR2
Causes of Death at2 Year Post Transplant
Cause NRecurrence 6
Infection 4
Idiopathic Pneumonia
Organ failure
Other*
2
2
1
PTLD 1Total 16
* Possibly cardiac related
HCT following myeloablative preparative regimen for patients with AML in CR1 or CR2 can be performed in a multicenter setting using a single TCD method without additional post transplant pharmacologic GVHD prophylaxis
All 1° and most 2º endpoints were met, demonstrating:81.8% Disease Free Survival 6 months post TX No primary graft failure; Consistent neutrophil and platelet engraftment Acute GVHD <23%. No Grade IV aGVHDChronic GVHD <19% at 2 yearsTRM <20% at 2 years Low risk of relapse, but dependent on remission status
The CliniMACS® CD34 System consistently produces a graft with > 5 x 106 CD34+ cells/kg and <1 x 105 C3+ cells/kg
Conclusions BMT CTN 0303