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When, How, and What Cell Source for Transplantation in ALL CR1

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. ADULT ACUTE LYMPHOBLASTIC LEUKEMIA Definitions In This Presentation.

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When, How, and What Cell Source for Transplantation in ALL CR1

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  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. ADULT ACUTE LYMPHOBLASTIC LEUKEMIADefinitions In This Presentation Philadelphia chromosome t(9;22)(q34;q11) negative “Adults” = age > 35 years

  3. 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

  4. ADULT ACUTE LYMPHOBLASTIC LEUKEMIA MRC UKALL XII / ECOG 2993: N=1,929 INDUCTION HLA donor No donor < 50 (or 55) yr Randomize Assign High-dose methotrexate x 3 Sibling Allograft Autograft Consolidation/ Maintenance JM Rowe, MRC & ECOG. Blood 106: 3760-3767, 2005 AH Goldstone, MRC, ECOG. Blood 111: 1827-1833, 2008.

  5. 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. 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. 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.

  8. PROSPECTIVE POST-REMISSION TRIALS Chemotherapy vsAutograftvs Allograft Design and Outcome

  9. ADULT ACUTE LYMPHOBLASTIC LEUKEMIAAutologous Transplant vs Chemotherapy Autotransplantsnotefficacious (unlike Ph pos ALL) AH Goldstone, MRC, ECOG. Blood 111: 1827-1833, 2008.

  10. ADULT ALL POST-REMISSION> 100 Patients/Trial: Age 15-64 Years

  11. 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

  12. ALTERNATIVE DONORSGraft Source Considerations Time-censoring bias may improves URD outcome: correction required J Mehta. Blood 112: 447-448, 2008

  13. ACUTE LYMPHOBLASTIC LEUKEMIA Matched-Related vs Matched-Unrelated Donor Leukemia-Free Survival N=483 N=189 O Ringden, CIBMTR. Blood 113: 3110-3118, 2009.

  14. ALTERNATIVE GRAFT SOURCES IN ALL UCB vs Matched Unrelated Donor: Retrospective

  15. GRAFT SOURCES IN ALL CR1 Ph- UCB vs Matched Related & Unrelated Donor Overall Survival 95 UCB, ‘CB’ 388 related, ‘RD’ 434 unrelated, ‘URD’ Cumulative incidence relapse S Nishiwaki, Japan Society for HCT. Proc ASCO 2012 (abstract #6533).

  16. REDUCED INTENSITY CONDITIONINGRelying On “Allogeneic Effect”

  17. Evidence For GVL Effect In Adult ALL? Yes • 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. Blood111: 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. ADULT ACUTE LYMPHOBLASTIC LEUKEMIAReduced Intensity Conditioning

  19. ACUTE LYMPHOBLASTIC LEUKEMIA Ph-RIC vs Full-Intensity in CR1/CR2: Survival Full-intensity conditioning (n=1,428) Survival (%) Reduced-intensity conditioning (n=93) Years DI Marks, CIBMTR. Blood 116: 366-374, 2010.

  20. E1910 INTERGROUP New diagnosis Ph-, Age 35-70 Yr Remission Induction/Consolidation; start donor search CR Intensification MRD Assessment Randomize (stratify by): Intent: chemotherapy vs HCT after Blinatumumab; MRD status Blinatumomab No Blinatumomab Bispecific anti-CD3, anti-CD19 antibody Chemotherapy ± Blinatumomab versus HCT (optional)

  21. MINIMAL RESIDUAL DISEASE

  22. Theoretic Time Course LeukemiaMinimal Residual Disease (MRD) Assessment 100 10-1 10-2 Complete remission Hematologic relapse Detection limit Morphology 10-3 MRD persistence 10-4 Proportion leukemic cells 10-5 MRD relapse Lower limit MRD assay Sensitivity limit MRD assay Complete MRD response MRD-based remission assessment M Brüggemann, et al. Blood 2012

  23. 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

  24. ADULT ACUTE LYMPHOBLASTIC LEUKEMIABetter Outcome MRDnegvsMRDposPatients MRDneg patients = < 10-4 via PCR @ wk 16 & totally undetectable @ wk 22; all other patients classified MRDpos R Bassan, Northern Italy Leukemia Group. Blood 113: 4153-4162, 2009

  25. MINIMAL RESIDUAL DISEASE: ALLKiel MRD Conference M Brüggemann, Kiel MRD Conference. Leukemia 24: 521-535, 2010 M Brüggemann, et al. Blood 2012

  26. MINIMAL RESIDUAL DISEASE: ALLMRD Positive Patients MRD pos @ 16 & 22 wk correlated with 10 wk R Bassan, Northern Italian Leukemia Group. Blood 113: 4153-4162, 2009

  27. 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)

  28. SUMMARY Factors to Consider For Transplant

  29. ALL CR1 PATIENTS AGE 35-70 YRLikelihood To Recommend Transplant

  30. ALL CR1 PATIENTS AGE 35-70 YRFactors Affecting Transplant Conditioning

  31. ALL CR1 PATIENTS AGE 35-70 YRFactors Affecting Graft Source

  32. ALL CR1 PATIENTS AGE 35-70 YRRecommendations and *Paradox • 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 Given greater use of more intensive induction & consolidation therapy in younger patients: *potentially more transplants in older patients *Anthony H. Goldstone, MD

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