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Who, What and When: Transplant for Acute Lymphoblastic Leukemia

Brandon Hayes-Lattin September 1 3 , 2013. Who, What and When: Transplant for Acute Lymphoblastic Leukemia. Indications for Hematopoietic Stem Cell Transplants in the United States, 2010 (Inflation factor: Auto=1.25 (80%), Allo =1.05 (95%), All Transplants). Number of Transplants.

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Who, What and When: Transplant for Acute Lymphoblastic Leukemia

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  1. Brandon Hayes-Lattin September 13, 2013 Who, What and When: Transplant for Acute Lymphoblastic Leukemia

  2. Indications for Hematopoietic Stem Cell Transplants in the United States, 2010(Inflation factor: Auto=1.25 (80%), Allo=1.05 (95%), All Transplants) Number of Transplants Slide 8 SUM12_28.ppt

  3. ALL Survival SEER AYA Monograph, 2006

  4. “Myth of Second Remission” Forman and Rowe, Blood 2013;121:1077-1082

  5. Defining Role of Transplant in ALL • Consolidation • 75-90% of patients achieve complete remission • Relapse risk remains high • Potential benefit over chemotherapy • Myeloablativechemoradiotherapy • Graft-versus-Leukemia effect • Balance of risks • Early treatment-related toxicity • Late effects (GVHD)

  6. Predicting Risk

  7. Cytogenetic Risk(2008 WHO Classification) • Favorable • Hyperdiploidy (>50 chromosomes) • t(12;21) • ETV6-RUNX1 • Formerly TEL-AML • Unfavorable • Hypodiploidy (<44 chromosomes) • t(9;22) • BCR-ABL1 • Philadelphia chromosome • t(v;11q23) • MLL rearranged • t(4;11), t(9;11), t(11;19) • t(5;14) • IL3-IGH • t(1;19) • E2A-PBX1

  8. ALL Cytogenetics by Age Harrison CJ, Br J Haematol, 2008

  9. Hyper-CVAD

  10. Hyper-CVAD Good risk 0-1 5-year OS 62% Intermed risk 2-3 5-year OS 34% Poor risk 4-6 5-year OS 5%

  11. Minimal Residual Disease (16 week, GMALL) Overall survival p<0.0001 Only significant factor in multivariate analysis

  12. Novel Cytogenetic Abnormalities • Christine Harrison: advances in cytogenetic technology • Intrachromosomal amplification of chromosome 21 (iAMP21) • Multiple copies of RUNX1 • Older children/adolescents, present with low WBC, 5-year EFS 26% vs 83% Tricoli JV, JNCI, 2011. Harrison CJ, Br J Haematol, 2008

  13. Integrated Genomic Analysis AYA ALL • Charles Mullighan: B-cell precursors from patients in COG 9906, no known high-risk genetic alterations • Deletions and point mutations in IKZF1 (lymphoid transcription factor) • Increased risk of relapse HR 2.4 • Gene expression profiles similar to those of BCR-ABL1 patients • Resequencing found 11% with activating mutations in JAK1, JAK2, or JAK3 Tricoli JV, JNCI, 2011. Roberts, Cancer Cell, 2012

  14. Gene Expression Profiling in ALL • Cheryl Willman: 207 older children, high-risk (WBC >50), COG 9906 • 8 gene expression cluster groups • 2 associated with known cytogenetic abnormalites • 11q23 rearrangements MLL • t(1;19)E2a-PBX1 • 6 novel Zhang et al, Blood 2011

  15. Somatic alteration profiles Zhang et al, Blood, 2011

  16. Regimens

  17. Hyper CVAD

  18. R-Hyper-CVAD (CD20+, age <60) Rituximab 3-year OS 75% No rituximab 3-year OS 47%

  19. SURVIVAL: PEDIATRIC VS. ADULT REGIMENS Stock BLOOD 2008, pre-published online

  20. 100% FRALLE 93 (Pediatric) Age 15-20 Years (N = 77) 80% LALA 94 (Adult) 60% Age 15-20 Years (N = 100) Survival 40% France 20% 0% 0 1 2 3 4 5 6 Years 100% 100% DCOG 8599 (Pediatric) ALL97 (Pediatric) Age 15-18 Years (N = 47) 15-17 Years (N = 61) 75% 75% HO 8899 (Adult) Age 19-20 Years (N = 29) Survival Survival 50% 50% UKALLXII / E2993 (Adult) 15-17 Years (N = 67) Age 15-18 Years (N = 44) 25% 25% United Kingdom Netherlands 0% 0% 0 1 2 3 4 5 0 2 4 6 8 10 Years Years ALL age 15-21: Pediatric vs. Adult Therapy 100% CCG-1800 Series (Pediatric) 80% Age 16-21 Years (N = 175) 60% CALGB 8811-9511(Adult) EFS Age16-20 Years (N = 103) 40% 20-29 Years (N = 123) North America 20% 0% 0 2 4 6 8 10 Years

  21. ALL Survival: COG Chemotherapy Hunger et al. JCO 2012:20;1663-1669

  22. NCI Risk Classification at diagnosis (0232)

  23. High-Risk Therapy Based on AALL0232 (“PH” arm) • Induction • Prednisone x 28 days, age >10(increased osteonecrosis with dexamethasone) • Consolidation • Interim Maintenance #1 • High-dose methotrexate(5-year EFS 82% vs 75.4% with Capizzi methotrexate) • Delayed Intensification #1 • Slow Early Responders • Interim Maintenance #2 • Delayed Intensification #2 • Maintenance

  24. C10403: Intergroup ALL • Intergroup (CALGB, SWOG & ECOG) Phase II Clinical Trial for Adolescents and Young Adults With Untreated Acute Lymphoblastic Leukemia (ALL) • Ages 16-39 years • Specific Aims • Improve outcome of AYAs with ALL • Evaluate efficacy and toxicity of this regimen in patients up to age 39 years • Evaluate adherence of medical oncologists to a “pediatric” ALL regimen • Assessment of Drug Delivery • vincristine, peg-asparaginase and methotrexate

  25. COG Risk Classification at diagnosis (1131)

  26. AALL1131: Very High-Risk • Induction • Consolidation • Control, OR • Arm 1: fractionated cyclophosphamide, etoposide, OR • Arm 2: clofarabine, fractionated cyclophosphamide, etoposide • MRD Flow: hypodiploidy or induction failure - option of SCT • Interim Maintenance #1 • Delayed Intensification • Control, OR • Arm 1: fractionated cyclophosphamide, etoposide, OR • Arm 2: clofarabine, fractionated cyclophosphamide, etoposide • Interim Maintenance #2 • Maintenance

  27. Allogeneic Transplant

  28. Allo Transplant Conditioning Regimen • Cyclophosphamide + 1200 cGy TBI • Children and Adolescents, Tracey et al. BBMT 2013;19:255-259 • Neither TBI >1200 cGy nor addition of etoposide improves survival

  29. Survival after HLA-identical Sibling Donor Transplants for ALL, Age < 20 yrs, 2000-2010- by Disease Status - 100 100 90 90 80 80 70 70 Early (N=849) 60 60 Probability of Survival, % 50 50 Intermediate (N=1,203) 40 40 30 30 20 20 Advanced (N=210) 10 10 P < 0.0001 0 0 1 3 0 2 4 5 6 Years Slide 30 SUM12_7.ppt

  30. Survival after HLA-identical Sibling Donor Transplants for ALL, Age ³ 20 yrs, 2000-2010- By Disease Status - 100 100 90 90 80 80 70 70 60 60 Early (N=2,214) Probability of Survival, % 50 50 40 40 Intermediate (N=715) 30 30 20 20 Advanced (N=584) 10 10 P < 0.0001 0 0 1 3 0 2 4 5 6 Years Slide 32 SUM12_9.ppt

  31. ASBMT Evidence-Based Review: Children • Matched related Allo • In CR1 for very high risk Ph+ patients • Equivalent to or better than chemo in remission beyond CR1 • MUD • Insufficient evidence • Auto • Insufficient evidence • Regimens • TBI-containing regimens are recommended ASBMT 2006

  32. ASBMT Evidence-Based Review: Adult ALL, updated 2012 • Changed • Myeloablativeallo age <35 in CR1 (all risk groups) • RIC allo may produce similar results • Unchanged • Allo over chemotherapy in CR2 • Allo over Auto • Related similar to unrelated donor • New • In absence of suitable donor, auto may be appropriate • In absence of suitable donor, cord blood by me appropriate • Imatinib before and/or after SCT for Ph+ ALL yields significantly superior survival ASBMT 2012

  33. Allo in CR1? • Gupta et al. Blood 2013;121:339-350 • Available sibling, or randomized auto vs chemo • 13 studies, N=2962, excluding Ph+ • Age <35 having matched sibling OR 0.79 (p=0.0003) • Age 35+ having matched sibling OR 1.01 • Auto vs chemo OR 1.18 (CI 0.99-1.41)

  34. OHSU Adult Regimen Guidelines • Age <30 • per COG AALL 0232 (PH) - no transplant • If unable to complete 0232 or other high risk features (Ph+, persistent diasease) move to allo transplant • Open COG AALL 1131 • Age 30-60 • hyper-CVAD - CR1 allogeneic SCT • R-hyper-CVAD - consider no CR1 allogeneic SCT • Age 60+ • hyper-CVAD (reduced cytarabine) - consider CR1 reduced intensity allogeneic SCT • R-hyper-CVAD (reduced cytarabine) - consider CR1 reduced intensity allogeneic SCT • EWALL

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