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When, How, and What Cell Source for Transplantation in ALL CR1
Hillard M. Lazarus, MD, FACPProfessor of Medicine
Director of Novel Cell TherapiesUniversity Hospitals Case Medical Center
Case Western Reserve University
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ADULT ACUTE LYMPHOBLASTIC LEUKEMIADefinitions In This Presentation
Philadelphia chromosome t(9;22)(q34;q11) negativePhiladelphia chromosome t(9;22)(q34;q11) negative
““Adults” = age Adults” = age >> 35 years 35 years
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ADULT ACUTE LYMPHOBLASTIC LEUKEMIABackground
• Pediatric ALL: 85% cure rate
• Adult ALL: Different biology and treatment results
• ~ 90% complete remission in age < 60 yr
• But despite arduous, long term therapy:
• 5-yr survival 30-40% in pts < age 60 yr
• 5-yr survival <15% in pts > age 60 yr
7% survival @ 5 years after relapse: few 2nd chances
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AH Goldstone, MRC, ECOG. Blood 111: 1827-1833, 2008.
ADULT ACUTE LYMPHOBLASTIC LEUKEMIAMRC UKALL XII / ECOG 2993: N=1,929
JM Rowe, MRC & ECOG. Blood 106: 3760-3767, 2005
INDUCTION
RandomizeAssign
Sibling Allograft
Autograft Consolidation/Maintenance
HLA donor< 50 (or 55) yr
No donor
High-dose methotrexate x 3
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Factors at Presentation Prognosis Association
Age Worse with increasing age
CNS involvement Slightly worse outcome
WBC count at diagnosis
Adverse: B cell >30,000/μL; T cell >100,000/μL
Immunophenotype B-ALL: Adverse for CD20 and CD25 expressionT-ALL: Adverse for CD13; Favorable for CD1a
Cytogenetic abnormalities
Adverse: t(9;22); t(4;11); t(1;19); complex (>5); low hypodiploid; near tetraploid; BCR-ABL-likeFavorable: high hyperdiploid; del 9q
Molecular abnormalities Adverse: JAK2; IKFZ1; PAX5; TLX3; BAALCFavorable: TLX1
ADULT ACUTE LYMPHOBLASTIC LEUKEMIA Clinical and Laboratory Risk Factors
JM Rowe. Br J Haematol 144: 468-483, 2009.B Oran, DJ Weisdorf. Curr Opin Hematol 18: 395–400, 2011.R Bassan, D Hoelzer. J Clin Oncol 29: 532-543, 2011.J-M Ribera. Curr Opin Oncol 23: 692–699, 2011.
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Factors After Therapy Prognosis Association
Time to initial response Adverse: no CR within 4 weeks
Minimal residual disease Adverse: detection at various times
ADULT ACUTE LYMPHOBLASTIC LEUKEMIA Clinical and Laboratory Risk Factors (con’t)
JM Rowe. Br J Haematol 144: 468-483, 2009.B Oran, DJ Weisdorf. Curr Opin Hematol 18: 395–400, 2011.R Bassan, D Hoelzer. J Clin Oncol 29: 532-543, 2011.J-M Ribera. Curr Opin Oncol 23: 692–699, 2011.
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ACUTE LYMPHOBLASTIC LEUKEMIA“BCR-ABL-Like”
JR Downing, CG Mullighan. Am Soc Hematol Educ Prog 118-22, 508, 2006.ML den Boer, Erasmus. Lancet Oncol 10: 125–134, 2009.
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PROSPECTIVE POST-REMISSION TRIALS
Chemotherapy vs Autograft vs Allograft
Design and Outcome
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ADULT ACUTE LYMPHOBLASTIC LEUKEMIAAutologous Transplant vs Chemotherapy
AH Goldstone, MRC, ECOG. Blood 111: 1827-1833, 2008.
Autotransplants not efficacious (unlike Ph pos ALL)
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ADULT ALL POST-REMISSIONADULT ALL POST-REMISSION> 100 Patients/Trial: Age 15-64 Years> 100 Patients/Trial: Age 15-64 Years
Group/Year
No. Pts
Disease-Free Survival or Overall Survival Donor No Donor
PETHEMA2005
156 OS: 40% @ 5 yr 49% @ 5 yr
MRC-ECOG2008
1031 High-riskOS: 41% @ 5 yrStandard-riskOS: 62% @ 5 yr
35% @ 5 yr
52% @ 5 yr
HOVON 2009
257 DFS: 60% @ 5 yr 42% @ 5 yr
JALSG2011
649 High-riskOS: 54% @ 10 yrStandard-riskOS: 38% @ 10 yr
40% @ 10 yr
25% @ 10 yr
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TRANSPLANT INTENT-TO-TREAT TRIALSPitfalls Donor vs No Donor Studies
• Donor / no donor assigned @ different time points
• “Geography” of locating sibs affects search time–If no sib, ? assign to “no donor” @ diagnosis
• Older studies: do not address unrelated donors
• “Relatively” less-intense induction– CALGB AYA study 10403
• Not all “donor” assignments go to transplant–Physician bias and patient refusal
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ALTERNATIVE DONORS
Graft Source Considerations
Time-censoring bias may improves URD outcome: correction requiredJ Mehta. Blood 112: 447-448, 2008
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ACUTE LYMPHOBLASTIC LEUKEMIAMatched-Related vs Matched-Unrelated Donor
O Ringden, CIBMTR. Blood 113: 3110-3118, 2009.
N=483
N=189
Leu
kem
ia-F
ree
Su
rviv
al
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ALTERNATIVE GRAFT SOURCES IN ALLUCB vs Matched Unrelated Donor: Retrospective
Author/Group
No. Pts TRM/NRM Relapse DFS/LFS/OS
Eapen:CIBMTR,
EBMT
165 UCB
1360 MUD
33% @ 2 yr
40% @ 2 yr
-
-
44% @ 2 yr
50% @ 2 yr
Atsuta:Japan
114 UCB
222 MUD
24% @ 2 yr
25% @ 2 yr
31% @ 2 yr
24% @ 2 yr
49% @ 2 yr
57% @ 2 yr
Ferra:GETH,
PETHEMA
87 UCB
62 MUD
31% @ 1 yr
48% @ 1 yr
29% @ 5 yr
29% @ 5 yr
33% @ 5 yr
22% @ 5 yr
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GRAFT SOURCES IN ALL CR1 Ph-UCB vs Matched Related & Unrelated Donor
S Nishiwaki, Japan Society for HCT. Proc ASCO 2012 (abstract #6533).
95 UCB, ‘CB’388 related, ‘RD’434 unrelated, ‘URD’
Overall Survival
Cumulative incidence relapse
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REDUCED INTENSITY CONDITIONING
Relying On “Allogeneic Effect”
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Evidence For GVL Effect In Adult ALL? Evidence For GVL Effect In Adult ALL? YesYes
PL Weiden, FHCRC. NEJM 300: 1068-1073, 1979
• 163 allografts without GVHD vs 79 allografts with GVHD• Relative relapse rate 2.5 times lower with GVHD (p<0.01)
• Anti-leukemia effect more marked in ALL than AML
AH Goldstone, UK MRC & ECOG. Blood 111: 1827-1833, 2008
• 239 pts: relapse rate 24% for donor vs 49% no donor (p<0.00005)
• High-risk: 37% relapse rate donor vs 63% no donor (p<0.00005)
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ADULT ACUTE LYMPHOBLASTIC LEUKEMIAADULT ACUTE LYMPHOBLASTIC LEUKEMIAReduced Intensity ConditioningReduced Intensity Conditioning
Author/Center No. Pts (CR1) Relapse DFS/LFS/OS
Stein:City of Hope
24 (11) 21% @ 2 yr 62% @ 2 yr
Bachanova:U Minnesota
22 (12) 36% @ 3 yr 50% @ 3 yr
Cho:Korea
37 (30) 20% @ 3 yr 64% @ 3 yr
Nishiwaki:Japan
26 (21) 26% @ 2 yr 63% @ 2 yr
Mohty:EBMTR
127 (105) 47% @ 2 yr 32% @ 2 yr
Marks:CIBMTR
93 (55) 35% @ 3 yr 45% @ 3 yr
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0
25
50
75
100
0 2 4 6 8 10
ACUTE LYMPHOBLASTIC LEUKEMIA Ph-RIC vs Full-Intensity in CR1/CR2: Survival
Su
rviv
al (
%)
Years
Full-intensity conditioning(n=1,428)
Reduced-intensity conditioning(n=93)
DI Marks, CIBMTR. Blood 116: 366-374, 2010.
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Remission Induction/Consolidation; start donor search
Randomize (stratify by): Intent: chemotherapy vs HCT after Blinatumumab; MRD status
Blinatumomab No Blinatumomab
Chemotherapy ± Blinatumomab versus HCT (optional)
Intensification
MRD Assessment
E1910 INTERGROUP New diagnosis Ph-, Age 35-70 Yr
CR
Bispecific anti-CD3, anti-CD19 antibody
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MINIMAL RESIDUAL DISEASE
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Theoretic Time Course LeukemiaMinimal Residual Disease (MRD) Assessment
M Brüggemann, et al. Blood 2012
100
10-1
10-2
10-5
10-4
10-3
Complete remission Hematologic relapse
MRD relapse
MRD persistence
Complete MRD response
Detection limitMorphology
Lower limit MRD assay
Sensitivity limitMRD assay
MRD-based remission assessment
Pro
po
rtio
n le
uk
emic
ce
lls
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MINIMAL RESIDUAL DISEASEMethodologies
• Detection sensitivity at least 1:10,000 cells
• Molecular
• Clonal rearrangements of T cell Receptor (TCR) genes
• Clonal rearrangement immunoglobulin (Ig) genes
• Flow cytometry
• Leukemia-associated phenotye (flow)
• FUTURE: high-throughput sequencing universally amplifies antigen-receptor gene segments: more sensitive; use E1910
M Faham, D Campagna, et al. Blood 2012
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ADULT ACUTE LYMPHOBLASTIC LEUKEMIAADULT ACUTE LYMPHOBLASTIC LEUKEMIABetter Outcome MRDBetter Outcome MRDnegneg vs MRD vs MRDpos pos PatientsPatients
R Bassan, Northern Italy Leukemia Group. Blood 113: 4153-4162, 2009
MRDneg patients = < 10-4 via PCR @ wk 16 & totally undetectable @ wk 22; all other patients classified MRDpos
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MINIMAL RESIDUAL DISEASE: ALLKiel MRD ConferenceKiel MRD Conference
M Brüggemann, Kiel MRD Conference. Leukemia 24: 521-535, 2010M Brüggemann, et al. Blood 2012
Technique Advantage Disadvantage
PCR Ig genes & TCR genes
high sensitivity
highly standardized
stability of DNA
time-consuming
requires extensive knowledge/experience
expensive
Multiparameter flow cytometry
quantitative
rapid
applicable most pt
low cellularity
requires extensive knowledge/experience
less sensitive 3-4 color (most now use 6 color)
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MINIMAL RESIDUAL DISEASE: ALLMRD Positive Patients
R Bassan, Northern Italian Leukemia Group. Blood 113: 4153-4162, 2009
MRD pos @ 16 & 22 wk correlated with 10 wk
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MINIMAL RESIDUAL DISEASEUnresolved Issues
• Greater use in Europe; need to penetrate USA & other areas
• Time to perform assay; real-time availability
• Determine optimal methodologies
• Standardization of methodologies and definitions
• Ensure comparability
• Which time points to assay?
• Increased cost; who will pay?
• Effect of change in therapy?
• Transplant (positive) vs no transplant (negative)
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SUMMARY
Factors to Consider For Transplant
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ALL CR1 PATIENTS AGE 35-70 YRALL CR1 PATIENTS AGE 35-70 YRLikelihood To Recommend TransplantLikelihood To Recommend Transplant
VariableFavor Transplant
Does Not Favor Transplant
Clinical & laboratory risk high-risk standard-risk
Induction & consolidation “adult” regimen “pediatric” regimen
Sibling-matched donor available none available
Minimal residual disease (MRD): result @ 12-16 weeks
positive negative
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ALL CR1 PATIENTS AGE 35-70 YRALL CR1 PATIENTS AGE 35-70 YRFactors Affecting Transplant ConditioningFactors Affecting Transplant Conditioning
Variable Favor Myeloablative Conditioning
Favor Reduced-Intensity Conditioning
Age 35-55 years 56-70 years
Comorbidities absent present
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ALL CR1 PATIENTS AGE 35-70 YRALL CR1 PATIENTS AGE 35-70 YRFactors Affecting Graft SourceFactors Affecting Graft Source
Variable Favor MUD Favor UCB
Institutional experience
8/8 alleleic graft, especially marrow(rather than blood)
“Center of Excellence”, extensive UCB experience
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ALL CR1 PATIENTS AGE 35-70 YRALL CR1 PATIENTS AGE 35-70 YRRecommendations and *ParadoxRecommendations and *Paradox
Given greater use of more intensive induction & consolidation therapy in younger patients: **potentially more transplants in older patients
**Anthony H. Goldstone, MD
• Age <35 yr, enroll on “peds intensity” regimen:• ? whether abrogates need for transplant • ? age at which regimen not tolerated by adults
• Age 35-45 yr – gray area, assess risk factors• strongly consider hematopoietic cell transplant
• Age > 45 yr – consider transplant, possibly RIC