When, How, and What Cell Source
for Transplantation in ALL CR1
Hillard M. Lazarus, MD, FACP
Professor of Medicine
Director...
ADULT ACUTE LYMPHOBLASTIC LEUKEMIA
Definitions In This Presentation
Philadelphia chromosome t(9;22)(q34;q11) negativePhila...
ADULT ACUTE LYMPHOBLASTIC LEUKEMIA
Background
• Pediatric ALL: 85% cure rate
• Adult ALL: Different biology and treatment ...
AH Goldstone, MRC, ECOG. Blood 111: 1827-1833, 2008.
ADULT ACUTE LYMPHOBLASTIC LEUKEMIA
MRC UKALL XII / ECOG 2993: N=1,929...
Factors at Presentation Prognosis Association
Age Worse with increasing age
CNS involvement Slightly worse outcome
WBC cou...
Factors After Therapy Prognosis Association
Time to initial response Adverse: no CR within 4 weeks
Minimal residual diseas...
ACUTE LYMPHOBLASTIC LEUKEMIA
“BCR-ABL-Like”
JR Downing, CG Mullighan. Am Soc Hematol Educ Prog 118-22, 508,
2006.
PROSPECTIVE POST-REMISSION TRIALS
Chemotherapy vs Autograft vs Allograft
Design and Outcome
ADULT ACUTE LYMPHOBLASTIC LEUKEMIA
Autologous Transplant vs Chemotherapy
AH Goldstone, MRC, ECOG. Blood 111: 1827-1833, 20...
ADULT ALL POST-REMISSIONADULT ALL POST-REMISSION
> 100 Patients/Trial: Age 15-64 Years> 100 Patients/Trial: Age 15-64 Year...
TRANSPLANT INTENT-TO-TREAT TRIALS
Pitfalls Donor vs No Donor Studies
• Donor / no donor assigned @ different time points
•...
ALTERNATIVE DONORS
Graft Source Considerations
Time-censoring bias may improves URD outcome:
correction required
J Mehta. ...
ACUTE LYMPHOBLASTIC LEUKEMIA
Matched-Related vs Matched-Unrelated Donor
O Ringden, CIBMTR. Blood 113: 3110-3118,
N=483
N=1...
ALTERNATIVE GRAFT SOURCES IN ALL
UCB vs Matched Unrelated Donor: Retrospective
Author/
Group
No. Pts TRM/NRM Relapse DFS/L...
GRAFT SOURCES IN ALL CR1 Ph-
UCB vs Matched Related & Unrelated Donor
S Nishiwaki, Japan Society for HCT. Proc ASCO 2012 (...
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, 1...
ADULT ACUTE LYMPHOBLASTIC LEUKEMIAADULT ACUTE LYMPHOBLASTIC LEUKEMIA
Reduced Intensity ConditioningReduced Intensity Condi...
0
25
50
75
100
0 2 4 6 8 10
ACUTE LYMPHOBLASTIC LEUKEMIA Ph-
RIC vs Full-Intensity in CR1/CR2: Survival
Survival(%)
Years
...
Remission Induction/Consolidation; start donor search
Randomize (stratify by):
Intent: chemotherapy vs HCT after Blinatumu...
MINIMAL RESIDUAL DISEASE
Theoretic Time Course Leukemia
Minimal Residual Disease (MRD) Assessment
M Brüggemann, et al. Blood 2012
100
10-1
10-2
10-...
MINIMAL RESIDUAL DISEASE
Methodologies
• Detection sensitivity at least 1:10,000 cells
• Molecular
• Clonal rearrangements...
ADULT ACUTE LYMPHOBLASTIC LEUKEMIAADULT ACUTE LYMPHOBLASTIC LEUKEMIA
Better Outcome MRDBetter Outcome MRDnegneg
vs MRDvs M...
MINIMAL RESIDUAL DISEASE: ALL
Kiel MRD ConferenceKiel MRD Conference
M Brüggemann, Kiel MRD Conference. Leukemia 24: 521-5...
MINIMAL RESIDUAL DISEASE: ALL
MRD Positive Patients
R Bassan, Northern Italian Leukemia Group. Blood 113: 4153-4162, 2009
...
MINIMAL RESIDUAL DISEASE
Unresolved Issues
• Greater use in Europe; need to penetrate USA & other areas
• Time to perform ...
SUMMARY
Factors to Consider For Transplant
ALL CR1 PATIENTS AGE 35-70 YRALL CR1 PATIENTS AGE 35-70 YR
Likelihood To Recommend TransplantLikelihood To Recommend Trans...
ALL CR1 PATIENTS AGE 35-70 YRALL CR1 PATIENTS AGE 35-70 YR
Factors Affecting Transplant ConditioningFactors Affecting Tran...
ALL CR1 PATIENTS AGE 35-70 YRALL CR1 PATIENTS AGE 35-70 YR
Factors Affecting Graft SourceFactors Affecting Graft Source
Va...
ALL CR1 PATIENTS AGE 35-70 YRALL CR1 PATIENTS AGE 35-70 YR
Recommendations and *ParadoxRecommendations and *Paradox
Given ...
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UPFRONT TRANSPLANT IN ALL-HL

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  • At this meeting, Dr. David Marks will present the results of a similar study from the CIBMTR comparing RIC BMT to full intensity conditioning BMT in patients with Ph neg ALL in first or second CR. In this CIBMTR study the RIC group had a median age of 45 years vs 28 years for the full intensity conditioning group, but overall survival was similar as shown here.
  • UPFRONT TRANSPLANT IN ALL-HL

    1. 1. When, How, and What Cell Source for Transplantation in ALL CR1 Hillard M. Lazarus, MD, FACP Professor of Medicine Director of Novel Cell Therapies University Hospitals Case Medical Center Case Western Reserve University
    2. 2. ADULT ACUTE LYMPHOBLASTIC LEUKEMIA Definitions In This Presentation Philadelphia chromosome t(9;22)(q34;q11) negativePhiladelphia chromosome t(9;22)(q34;q11) negative ““Adults” = ageAdults” = age >> 35 years35 years
    3. 3. ADULT ACUTE LYMPHOBLASTIC LEUKEMIA Background • 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
    4. 4. AH Goldstone, MRC, ECOG. Blood 111: 1827-1833, 2008. ADULT ACUTE LYMPHOBLASTIC LEUKEMIA MRC 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
    5. 5. 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 expression T-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-like Favorable: high hyperdiploid; del 9q Molecular abnormalities Adverse: JAK2; IKFZ1; PAX5; TLX3; BAALC Favorable: 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.
    6. 6. 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.
    7. 7. ACUTE LYMPHOBLASTIC LEUKEMIA “BCR-ABL-Like” JR Downing, CG Mullighan. Am Soc Hematol Educ Prog 118-22, 508, 2006.
    8. 8. PROSPECTIVE POST-REMISSION TRIALS Chemotherapy vs Autograft vs Allograft Design and Outcome
    9. 9. ADULT ACUTE LYMPHOBLASTIC LEUKEMIA Autologous Transplant vs Chemotherapy AH Goldstone, MRC, ECOG. Blood 111: 1827-1833, 2008. Autotransplants not efficacious (unlike Ph pos ALL)
    10. 10. ADULT ALL POST-REMISSIONADULT ALL POST-REMISSION > 100 Patients/Trial: Age 15-64 Years> 100 Patients/Trial: Age 15-64 Years Group/Yea r No. Pts Disease-Free Survival or Overall Survival Donor No Donor PETHEMA 2005 156 OS: 40% @ 5 yr 49% @ 5 yr MRC- ECOG 2008 1031 High-risk OS: 41% @ 5 yr Standard-risk OS: 62% @ 5 yr 35% @ 5 yr 52% @ 5 yr HOVON 2009 257 DFS: 60% @ 5 yr 42% @ 5 yr JALSG 2011 649 High-risk OS: 54% @ 10 yr Standard-risk OS: 38% @ 10 yr 40% @ 10 yr 25% @ 10 yr
    11. 11. TRANSPLANT INTENT-TO-TREAT TRIALS Pitfalls 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
    12. 12. ALTERNATIVE DONORS Graft Source Considerations Time-censoring bias may improves URD outcome: correction required J Mehta. Blood 112: 447-448, 2008
    13. 13. ACUTE LYMPHOBLASTIC LEUKEMIA Matched-Related vs Matched-Unrelated Donor O Ringden, CIBMTR. Blood 113: 3110-3118, N=483 N=189 Leukemia-FreeSurvival
    14. 14. ALTERNATIVE GRAFT SOURCES IN ALL UCB 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
    15. 15. GRAFT SOURCES IN ALL CR1 Ph- UCB vs Matched Related & Unrelated Donor S Nishiwaki, Japan Society for HCT. Proc ASCO 2012 (abstract 95 UCB, ‘CB’ 388 related, ‘RD’ 434 unrelated, ‘URD’ Overall Survival Cumulative incidence relapse
    16. 16. REDUCED INTENSITY CONDITIONING Relying On “Allogeneic Effect”
    17. 17. 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)
    18. 18. ADULT ACUTE LYMPHOBLASTIC LEUKEMIAADULT ACUTE LYMPHOBLASTIC LEUKEMIA Reduced 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
    19. 19. 0 25 50 75 100 0 2 4 6 8 10 ACUTE LYMPHOBLASTIC LEUKEMIA Ph- RIC vs Full-Intensity in CR1/CR2: Survival Survival(%) Years Full-intensity conditioning (n=1,428) Reduced-intensity conditioning (n=93) DI Marks, CIBMTR. Blood 116: 366-374, 2010.
    20. 20. 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
    21. 21. MINIMAL RESIDUAL DISEASE
    22. 22. Theoretic Time Course Leukemia Minimal 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 limit Morphology Lower limit MRD assay Sensitivity limit MRD assay MRD-based remission assessment Proportionleukemiccells
    23. 23. MINIMAL RESIDUAL DISEASE Methodologies • 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
    24. 24. ADULT ACUTE LYMPHOBLASTIC LEUKEMIAADULT ACUTE LYMPHOBLASTIC LEUKEMIA Better Outcome MRDBetter Outcome MRDnegneg vs MRDvs MRDpospos 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
    25. 25. MINIMAL RESIDUAL DISEASE: ALL Kiel MRD ConferenceKiel MRD Conference M Brüggemann, Kiel MRD Conference. Leukemia 24: 521-535, 2010 M 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)
    26. 26. MINIMAL RESIDUAL DISEASE: ALL MRD Positive Patients R Bassan, Northern Italian Leukemia Group. Blood 113: 4153-4162, 2009 MRD pos @ 16 & 22 wk correlated with 10 wk
    27. 27. MINIMAL RESIDUAL DISEASE Unresolved 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)
    28. 28. SUMMARY Factors to Consider For Transplant
    29. 29. ALL CR1 PATIENTS AGE 35-70 YRALL CR1 PATIENTS AGE 35-70 YR Likelihood To Recommend TransplantLikelihood To Recommend Transplant Variable Favor 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
    30. 30. ALL CR1 PATIENTS AGE 35-70 YRALL CR1 PATIENTS AGE 35-70 YR Factors Affecting Transplant ConditioningFactors Affecting Transplant Conditioning Variable Favor Myeloablative Conditioning Favor Reduced-Intensity Conditioning Age 35-55 years 56-70 years Comorbidities absent present
    31. 31. ALL CR1 PATIENTS AGE 35-70 YRALL CR1 PATIENTS AGE 35-70 YR Factors 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
    32. 32. ALL CR1 PATIENTS AGE 35-70 YRALL CR1 PATIENTS AGE 35-70 YR Recommendations 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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