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

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Presentation on theme: "Who, What and When: Transplant for Acute Lymphoblastic Leukemia Brandon Hayes-Lattin September 13, 2013."— Presentation transcript:

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

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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:

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 year OS 62% Intermed risk year OS 34% Poor risk year OS 5%

12 Minimal Residual Disease (16 week, GMALL) Overall survival p< 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, 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, Roberts, Cancer Cell, 2012

15 Gene Expression Profiling in ALL Cheryl Willman: 207 older children, high-risk (WBC >50), COG 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 Years (N = 44) DCOG 8599 (Pediatric) Age Years (N = 47) Age Years (N = 29) 100% 75% 50% 25% 0% Netherlands United Kingdom Survival 100% 75% 50% 25% 0% UKALLXII / E2993 (Adult) Years (N = 61) Years (N = 67) ALL97 (Pediatric) Years ALL age 15-21: Pediatric vs. Adult Therapy North America EFS CALGB (Adult) % 80% 60% 40% 20% 0% Age Years (N = 103) Years (N = 123) Age Years (N = 175) Years 100% 80% 60% 40% 20% 0% LALA 94 (Adult) Survival France Age Years (N = 100) FRALLE 93 (Pediatric) Age Years (N = 77) Years CCG-1800 Series (Pediatric)

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

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 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 cGy TBI Children and Adolescents, Tracey et al. BBMT 2013;19: – Neither TBI >1200 cGy nor addition of etoposide improves survival

30 Survival after HLA-identical Sibling Donor Transplants for ALL, Age 20 yrs, by Disease Status - SUM12_7.ppt Slide 30 Years Probability of Survival, % P < Early (N=849) Intermediate (N=1,203) Advanced (N=210)

31 Survival after HLA-identical Sibling Donor Transplants for ALL, Age 20 yrs, By Disease Status - Slide 32 Years Probability of Survival, % P < 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: – 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 )

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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 – 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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