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

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

4. ALL Survival SEER AYA Monograph, 2006

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

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

7. Predicting Risk

8. 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

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

10. Hyper-CVAD FactorScore Age: <40, 40-59, 60+0, 1, 2 KPS: 0-2, 3-40, 2 Hepatomegaly0, 1 WBC: 50k0, 2 Plt: >80, 20-80, <200, 1, 2 Philadelphia chromosome0, 2

11. 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%

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

13. 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

14. 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

15. 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

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

17. Regimens

18. Hyper CVAD

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

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

21. Years Survival HO 8899 (Adult) Age 15-18 Years (N = 44) DCOG 8599 (Pediatric) Age 15-18 Years (N = 47) Age 19-20 Years (N = 29) 100% 75% 50% 25% 0% 0246810 Netherlands United Kingdom Survival 100% 75% 50% 25% 0% 012345 UKALLXII / E2993 (Adult) 15-17 Years (N = 61) 15-17 Years (N = 67) ALL97 (Pediatric) Years ALL age 15-21: Pediatric vs. Adult Therapy North America EFS CALGB 8811-9511 (Adult) 02468 10 100% 80% 60% 40% 20% 0% Age 16-20 Years (N = 103) 20-29 Years (N = 123) Age 16-21 Years (N = 175) Years 100% 80% 60% 40% 20% 0% LALA 94 (Adult) 0123456 Survival France Age 15-20 Years (N = 100) FRALLE 93 (Pediatric) Age 15-20 Years (N = 77) Years CCG-1800 Series (Pediatric)

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

23. NCI Risk Classification at diagnosis (0232) Standard RiskHigh Risk Excluded (Very High Risk) Age1-10>10>30 WBC<50k>50k Other Prior steroid treatment or testicular disease t(9;22) BCR-ABL, hypodiploid

24. 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

25. 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

26. COG Risk Classification at diagnosis (1131) Standard Risk High RiskVery HighExcluded Age1-10>10>13>30 WBC<50k>50k Other Prior steroid treatment or testicular disease iAMP21, MML rearrangements, hypodiploidy t(9;22) BCR- ABL

27. 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

28. Allogeneic Transplant

29. 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

30. Survival after HLA-identical Sibling Donor Transplants for ALL, Age 20 yrs, 2000-2010 - by Disease Status - SUM12_7.ppt Slide 30 Years 026 13 45 0 20 40 60 80 100 10 30 50 70 90 0 20 40 60 80 100 10 30 50 70 90 Probability of Survival, % P < 0.0001 Early (N=849) Intermediate (N=1,203) Advanced (N=210)

31. Survival after HLA-identical Sibling Donor Transplants for ALL, Age 20 yrs, 2000-2010 - By Disease Status - Slide 32 Years 026 13 45 0 20 40 60 80 100 10 30 50 70 90 0 20 40 60 80 100 10 30 50 70 90 Probability of Survival, % P < 0.0001 Intermediate (N=715) Advanced (N=584) Early (N=2,214) SUM12_9.ppt

32. 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

33. ASBMT Evidence-Based Review: Adult ALL, updated 2012 Changed – Myeloablative allo 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

34. 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)

36. 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