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
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
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
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
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.
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.
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.
PROSPECTIVE POST-REMISSION TRIALS
Chemotherapy vs Autograft vs Allograft
Design and Outcome
ADULT ACUTE LYMPHOBLASTIC LEUKEMIAAutologous Transplant vs Chemotherapy
AH Goldstone, MRC, ECOG. Blood 111: 1827-1833, 2008.
Autotransplants not efficacious (unlike Ph pos ALL)
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
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
ALTERNATIVE DONORS
Graft Source Considerations
Time-censoring bias may improves URD outcome: correction requiredJ Mehta. Blood 112: 447-448, 2008
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
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
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
REDUCED INTENSITY CONDITIONING
Relying On “Allogeneic Effect”
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)
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
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.
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
MINIMAL RESIDUAL DISEASE
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
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
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
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)
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
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)
SUMMARY
Factors to Consider For Transplant
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
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
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
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
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