Transplant Outcomes and Referral Guidelines

Organizations ASBMT: American Society for Blood and Marrow Transplantation NMDP/Be The Match: National Marrow Donor Program (NMDP)/Be The Match CIBMTR: Center for International Blood and Marrow Transplant Research SCTOD: Stem Cell Therapeutic Outcomes Database BMT CTN: Blood and Marrow Transplantation Clinical Trials Network FACT: Foundation for the Accreditation of Cellular Therapy

Transplant Outcomes and Referral Guidelines Disclaimer: This presentation was prepared by the ASBMT Committee on Education. The content in these slides was developed by ASBMT, CIBMTR and NMDP/Be The Match. Attribution to the source is provided by distinctive branding of the slides for each of the 3 organizations.

Annual Number of Transplant Recipients in the US by Transplant Type Autologous Allogeneic 14000 Transplants 12000 10000 8000 6000 4000 2000 0 *2015 Data incomplete Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 4

Allogeneic Transplant Recipients in the US, by Donor Type HLA-iden Sib Other Relative URD-BM / PB URD / UCB 4500 4000 Transplants 3500 3000 2500 2000 1500 1000 500 0 *2015 Data incomplete Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 5

Trends in Autologous Transplants by Recipient Age* <60 years 60 years 100 Transplants, % 80 60 40 20 0 1993-1999 2000-2006 2007-2013 *Transplants for AML, ALL, NHL, Hodgkin Disease, Multiple Myeloma Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 6

Trends in Allogeneic Transplants by Recipient Age* <60 years 60 years 120 Transplants, % 100 80 60 40 20 0 1993-1999 2000-2006 2007-2013 *Transplants for AML, ALL, NHL, Hodgkin Disease, Multiple Myeloma Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 7

Advances and Outcomes

Causes of Death after Autologous Transplants done in 2012-2013 20% 1% 2% 7% 70% Primary Disease Infection Organ Failure Second Malignancy Other Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 9

Causes of Death after Unrelated Donor Transplants done in 2012-2013 20% 1% 37% 6% 17% Primary Disease GVHD Infection Organ Failure Second Malignancy Other 20% Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 10

Match likelihood Likelihood of Finding Unrelated Donor or Cord Blood by Race/Ethnic Group Patients 20 years, when searching adult donor, then cord blood 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Race or ethnic group of searching patient 8/8 HLA adult donor 7/8 HLA adult donor 6/6 HLA cord blood Gragert L, et al. N Engl J Med. 2014; 371(4): 339-348.

Transplants by Unrelated Cell Source

Numbers of Allogeneic HCTs in the US By Year and Donor Type HLA-id sibling Other relative 4000 Adult unrelated donor Related cord Unrelated Cord 3500 3000 2500 2000 1500 1000 500 0 2010 2011 2012 2013 2014 13

There has been a rapid rise in the use of haplo-identical donors 900 800 700 600 HAPLO Mism unrelated Other Relative Single Cord Double Cord Related Cord 500 400 300 200 100 0 2010 2011 2012 2013 2014 14

Role of Cord Blood in Transplants by Patient Race

Transplantation Timing Matters Early Stage Intermediate Stage Year Year Late Stage Patients transplanted earlier in their disease have better outcomes than patients with advanced disease, regardless of the degree of match. Year Pidala J. et al. Blood. 2014;124(16):2596-2606. 16

Advances: Timing and Planning Greater understanding of patient eligibility and timing of the transplant During stable disease During appropriate time in disease process NMDP/Be The Match & ASBMT Recommended Timing for Transplant Consultation guidelines Partnering for comprehensive treatment plan Ensures treatments given do not preclude transplant Allows patient to move quickly to transplant, if needed, before disease progresses or complications develop Allows adequate time for unrelated donor/umbilical cord blood search, if needed

Advances: Enhanced Matching Advances in HLA typing DNA-based HLA typing has led to a more precise match between donor and patient Knowledge of matching criteria, including which HLA loci are most significant to outcomes and use of permissive mismatches, has improved survival. Spellman SR, et al. Blood. 2012;120(2):259-265. Pidala J, et al. Blood. 2014;124(16):2596-2606

Summary All patients have a donor Growth of donor and cord blood registries, increased use of haploidentical HCT, more patients have access to transplant Timing of HCT matters Research shows that patients transplanted earlier in their disease have better outcomes than patients with advanced disease

Referral Consultation Timing NMDP/Be The Match and ASBMT - Recommended Timing for Transplant Consultation

Timely Referral Affects Survival Because disease stage at the time of transplant is the only factor under direct control of a physician, an early referral is perhaps the single most important step that can affect survival. Lee SJ, et al. Blood; 2007;110(13):4576-4583 21

Referral Guidelines Recommended Timing for Transplant Consultation Jointly published by the NMDP/Be The Match and ASBMT Provide a quick reference for timing of transplant consultation (autologous or allogeneic) Identify patients at risk of disease progression and, therefore, which patients should be evaluated for transplantation Type potential family members early after diagnosis; without a match, consider preliminary search of Be The Match Registry Transplant may not be indicated for all patients, but consultation ensures plans are in place for patients to move quickly to transplant and allows adequate time for unrelated donor or cord blood unit search

Timing for HCT Consultation Adult Leukemias and Myelodysplasia Acute Myelogenous Leukemia (AML) - Adult High-resolution HLA typing is recommended at diagnosis for all patients Early after initial diagnosis, all AML patients including: CR1 except favorable risk AML [defined as: t(16;16), inv 16, or t(8;21) without c-kit mutation; t(15;17); normal cytogenetics with NPM1 or isolated biallelic CEBPA mutation and without FLT3-ITD] Antecedent hematological disease (e.g., myelodysplastic syndrome (MDS)) Treatment-related leukemia Primary induction failure or relapse Presence of minimal residual disease after initial or subsequent therapy CR2 and beyond, if not previously evaluated NMDP/Be The Match & ASBMT Recommended Timing for Transplant Consultation, 2017.

AML Prognostic Risk Groups Based on Cytogenetic Risk and Molecular Profile (NCCN Guidelines) *Emerging data indicate that the presence of c-kit mutations in patients with t(8:21), and to a lesser extent inv(16), confers a higher risk of relapse. These patients are considered intermediate risk and should be considered for clinical trials, if available. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) AML v 2.2016

2017 ELN Risk Stratification by Geneticsa a b c d e Frequencies, response rates and outcome measures should be reported by risk category, and, if sufficient numbers are available, by specific genetic lesions indicated. Prognostic impact of a marker is treatment-dependent and may change with new therapies. Core-binding factor (CBF) AML Low, low allelic ratio (<0.50); high, high allelic ratio ( 0.50);semi-quantitative assessment of FLT3-ITD allelic ratio (using DNA fragment analysis) is determined as ratio of the area under curve (AUC) FLT3-ITD divided by AUC FLT3-wild type. The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse-risk gene mutations. Dohner H, et al. Blood. 2017; 129(4):424-447.

2016 ELN Risk Stratification by Geneticsa a b c d e Three or more unrelated chromosome abnormalities in the absence of one of the WHO-designated recurring translocations or inversions, i.e., t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3) or t(3;3), t(9;22). Defined by the presence of one single monosomy (excluding isolated loss of X or Y) in association with at least one additional monosomy or structural chromosome abnormality (excluding CBF AML). Low, low allelic ratio (<0.50); high, high allelic ratio ( 0.50);semi-quantitative assessment of FLT3-ITD allelic ratio (using DNA fragment analysis) is determined as ratio of the area under curve (AUC) FLT3-ITD divided by AUC FLT3-wild type. This mutation should not be used as an adverse prognostic marker if it co-occurs with favorable-risk AML subtypes. TP53 mutations frequently occur in AML with complex and monosomal karyotype. Dohner H, et al. Blood. 2017; 129(4):424-447.

Recommendations: Patients <60 in CR1: (LeukemiaNet) EH1 Intermediate-risk patients: HiDAC consolidation 3g/m2 every 12 hours on days 1,3,5 x 3-4 cycles is widely used; outcomes remain unsatisfactory Consider HCT for patients with: Intermediate-risk cytogenetics, low or intermediate transplant risk Normal cytogenetics and unfavorable markers: Unmutated (Wild-Type) NPM1 and FLT3-ITD mutation Unmutated (Wild-Type)CEBPA Adverse risk patients: HCT from matched related donor is treatment of choice Outcomes with matched unrelated donors is comparable Dohner H. et al. Blood 2010;115:453-474

Slide 27 EH1 Please look at this slides for modificate based on the Dohner 2017 paper. ENL took out Int I and I and just call it intermediate risk. Ellyce Hayes, 2/15/2017

Recommendations: Patients <60 in CR1: (LeukemiaNet) Limited data with small patient cohorts, patient selection bias and heterogeneity of conditioning regimens Allo-HCT for older patients is an active area of research, encourage clinical trial participation Reduced intensity conditioning (RIC) and nonmyeloablative (NMA) preparative regimens are associated with less transplant-related mortality(trm), allowing older patients to proceed to Allo-HCT Matched sibling versus matched unrelated donor AlloHCT resulted in similar survival in older AML patients. Dohner H. et al. Blood 2010;115:453-474 Devine S, et al. J Clin Oncol 2015:33:4167-4175 Dohner H, et al. Blood 2017; 129(4): 424-447

Allo-HCT in CR1 for AML: Systematic Review & Meta-Analysis 24 trials, 6,007 patients analyzed with fixed effects meta-analysis HR of relapse or death with allo-hct for AML-CR1 = 0.80(0.74-0.86) Significant RFS and OS benefit for allo-hct in intermediate- and poor-risk AML Koreth J et al. JAMA 2009;301(22):2349-61

BMT CTN PROTOCOL 0901 A Randomized, Multi-Center, Phase III Study of Allogeneic Stem Cell Transplantation Evaluating Regimen Intensity in Patients with Myelodysplastic Syndrome or Acute Myeloid Leukemia

BMT CTN 0901: Randomized Phase III design MDS/AML< 5% blasts MDS/AML 18-65 years PB/BM BM<5% blasts HCT-CI 4 MRD/MUD (7/8) (-) CNS (-) circ. blasts Randomization RIC regimens Flu/Bu2 Flu/Mel GVHD Prophylaxis per Institutional guidelines: T-depleted and post-transplant Cy excluded MAC Regimens 18 Month Overall Survival BMTCTN.net Flu/Bu4 Bu4/Cy Cy/TBI

Overall Survival by Treatment Arm RIC 67.7% P=0.07 (18 month pointwise) 9.7% difference (95% CI: -0.9%, 20.3%) MAC vs. RIC Scott BL, et al. Blood. 2015:126:LBA-8

Overall Survival by Disease Group Survival Probability Survival Probability RIC 85.2% RIC 63% Months MAC 27 RIC 27 25 26 25 26 23 25 Months 22 23 22 22 21 20 108 110 105 103 101 91 91 77 87 73 77 67 68 62

Relapse/Progression by Disease and Treatment Arm Incidence of Relapse AML RIC 50% MDS RIC 37% AML MAC 16.5% MDS MAC 3.7% MDS MDS AML AML 27 27 105 106 25 23 96 73 25 18 88 57 Months 23 17 84 52 22 16 79 51 21 15 69 46 19 13 56 43

Treatment-related Mortality P=0.02 (18 month pointwise) MAC 15.8% RIC 4.4% MAC 132 RIC 133 121 96 113 75 107 69 101 67 90 61 75 56 Scott BL, et al. Blood. 2015:126:LBA-8

Primary Cause of Death at 18 Months Cause of Death All Causes Relapse Organ failure GVHD Infection Sudden Death No. of Patients (%) MAC RIC 31 44 10 (32) 38 (86) 3 (10) 1 (2) 16 (52) 4 (10) 2 (6) 0 0 1 (2) 9 deaths occurred after 18 months. MAC arm: 1 patient died due to relapse and 1 patient died due to GVHD. RIC arm: 3 patients died due to relapse, 3 died due to GVHD and 1 patient died due to sepsis. Scott BL, et al. Blood. 2015:126:LBA-8

Survival after HLA Matched Sibling Donor Transplants for AML, 2003-2013 100 p<0.001 Probability, % 80 Early (n=7,988) 60 40 Intermediate (n=2,146) 20 Advanced (n=2,882) 0 0 1 2 3 Years 4 5 6 By Disease Status Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 37

Survival after Unrelated Donor Transplants for AML, 2003-2013 100 p<0.001 Probability, % 80 60 Early (n=8,804) 40 Intermediate (n=4,443) 20 Advanced (n=4,692) 0 0 1 2 3 Years 4 5 6 By Disease Status Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 38

Timing for HCT Consultation Adult Leukemias and Myelodysplasia Acute lymphoblastic leukemia (ALL) Adult High-resolution HLA typing is recommended at diagnosis for all patients Early after initial diagnosis, all ALL patients including: CR1 Primary induction failure or relapse Presence of minimal residual disease after initial or subsequent therapy CR2 and beyond, if not previously evaluated NMDP/Be The Match & ASBMT Recommended Timing for Transplant Consultation, 2017.

Allogeneic HCT in CR1 for ALL Clinical trials with conflicting results Benefit for high risk patients: LALA-87, LALA-94, GOEAL02 No benefit for high risk patients EORTC ALL3, PETHEMA ALL-3, MRC-UKALL XII/ECOG 2993 No benefit due to high early transplant-related mortality Cochrane review, 2011 14 trials, 3,157 patients >15 years old All studies with biologic randomization (sibling vs no donor) OS and DFS benefit in the Donor group Djulbegovic PJ, et al. The Cochrane Library 2011, Issue 10

Better Disease Control for ALL with Allo-HCT vs Chemo/auto-HCT MRC UKALL XII/ECOG trial 2993 1,913 patients accrued between 1993-2006, ages 15-59 Patients treated with induction x 2 cycles if in CR1 and sibling donor, assigned to HCT If no donor, patients randomized to chemo vs Auto-HCT Ph+ patients underwent HCT if matched unrelated donor or sibling donor Goldstone AH, et al. Blood, 2008;111:1827-1833

MRC UKALL XII/ECOG 2993: Results Goldstone AH, et al. Blood, 2008;111:1827-1833

MRC UKALL XII/ECOG 2993: Results 39% 43% 22% Survival of patients and donor vs no donor analysis: (A) All patients, including Ph+ (B) Ph neg and Ph+ Goldstone AH, et al. Blood. 2008;111:1827-1833

MRC UKALL XII/ECOG 2993: Results 40% 37% 53% 49% Survival of patients and donor vs no donor analysis: (C) Patients entered via MRC or ECOG (D) Donor vs no-donor for all Ph neg patients Goldstone AH, et al. Blood. 2008;111:1827-1833

MRC UKALL XII/ECOG 2993: Results 62% 52% 41% 35% Survival of patients and donor vs no donor analysis: (E) Donor vs no-donor for all Ph neg patients with high risk (F) Donor (vs no-donor) for Ph neg patients with standard risk. Goldstone AH, et al. Blood. 2008;111:1827-1833

Best Outcomes with Early HCT in Ph+ ALL Overall Survival by disease status at time of HCT. OS rates at 5 years for patients in CR1, CR2 and active disease Kebriaei P et al. Biol Blood Marrow Transplant 2011;584-592.

Improved Outcomes in AYA Patients with Pediatric-Inspired Regimens Adolescent and Young Adult (AYA) population defined by the NCI as 15-39 years old. Treatment approaches for AYA patients vary based on: Clinical trial availability Choice of regimen based on expertise/familiarity of treating center Whether patient enters as an adult or pediatric patient Literature to suggest that AYA patients treated on pediatric protocols have superior EFS and OS compared with patients treated on adult ALL protocols 5-year event-free survival (EFS) over 70%, approaching outcomes seen in younger children Monitor for poorer treatment tolerability, increased toxicity (hepatotoxicity) Curran E, Stock W, Blood. 2015;125(24):3702-10

Pediatric Inspired Therapy vs. AlloHCT in Ph negative ALL in CR1 422 HCT recipients aged 18-50 years with Ph neg ALL in CR1 reported to the CIBMTR vs. age-matched concurrent cohort of 108 Ph neg ALL CR1 patients treated with a Dana Farber Consortium pediatricinspired non-hct regimen. TRM higher in the HCT cohort (HCT 37% vs Chemo 6%, P<0.0001) DFS lower in the HCT cohort (HCT 40% vs Chemo 71%, P<0.0001) OS favored Chemo (HCT 45% vs Chemo 73%, P<0.0001) In multivariate analysis, sole factor predictive of shorter OS was HCT (HR 3.12[1.00-4.90], P<0.0001) Seftel MD et al. Am J Hematol. 2016;91(3):322-9.

Pediatric Inspired Therapy vs. Allo-HCT in Ph negative ALL in CR1 Comparison of outcomes of Chemotherapy only regimen (Chemo) and allogeneic hematopoietic cell transplantation (HCT) Seftel MD, et al. Am J Hematol. 2016;91(3):322-9.

Pediatric Inspired Therapy vs. Allo-HCT in Ph negative ALL in CR1 Outcomes comparison of chemo-only regimen and allo-hct Seftel MD et al. Am J Hematol. 2016;91(3):322-9.

Survival after HLA Matched Sibling Donor Transplants for ALL, Age 20 Years, 2003-2013 100 p<0.001 Probability, % 80 Early (n=2,643) 60 Intermediate (n=746) 40 20 Advanced (n=455) 0 0 1 2 3 Years 4 5 6 By Disease Status Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 51

Survival after HLA Matched Sibling Donor Transplants for ALL, Age <20 Years, 2003-2013 100 p<0.001 Probability, % 80 Early (n=793) 60 Intermediate (n=1,084) 40 Advanced (n=159) 20 0 0 1 2 3 Years 4 5 6 By Disease Status Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 52

Survival after Unrelated Donor Transplants for ALL, Age <20 years, 2003-2013 100 p<0.001 Probability, % 80 Early (n=1,117) 60 Intermediate (n=1,911) 40 Advanced (n=231) 20 0 0 1 2 3 Years 4 5 6 By Disease Status Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 53

MDS Decision Model

Markov Decision Model Cutler C S et al. Blood 2004;104:579-585

. MDS: Timing of HCT Depends on IPSS Score Cutler CS et al. Blood 2004;104:579-585

Markov decision model for Reduced Intensity Conditioning (RIC) HCT- MDS N = 514 patients 60-70 years of age RIC = 132 Best Supportive Care= 132 Growth Factor = 94 Hypomethylating agents = 165 Koreth J et al. JCO 2013;31:2662-2670

Monte Carlo analysis for low/intermediate-1 and higher IPSS risk MDS Koreth J et al. JCO 2013;31:2662-2670

Monte Carlo analysis for intermediate-2 and high IPSS risk MDS Koreth J et al. JCO 2013;31:2662-2670

Overall survival of non-hct cohorts stratified by low/intermediate (int)-1 and int-2/high IPSS in MDS Koreth J et al. JCO 2013;31:2662-2670

Overall survival of RIC-HCT cohorts stratified by low/intermediate (int)-1 and int-2/high IPSS in MDS Koreth J et al. JCO 2013;31:2662-2670

Timing for HCT Consultation Adult Leukemias and Myelodysplasia Myelodysplastic syndromes (MDS) Any intermediate or high IPSS or IPSS-R score Any MDS with poor prognostic features, including: Treatment-related MDS Refractory cytopenias Adverse cytogenetics Transfusion dependence Failure of hypomethylating agents NMDP/Be The Match & ASBMT Recommended Timing for Transplant Consultation, 2017.

Survival after Allogeneic Transplants for Myelodysplastic Syndrome (MDS), 2003-2013 100 p<0.001 Probability, % 80 60 Early (n=1,442) 40 Advanced (n=2,433) 20 0 0 1 2 4 5 6 By Disease Status for Pasquini MC, Zhu X. Current uses and outcomes of Unrelated Donor 63 hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 3 Years

Timing for HCT Consultation Adult Leukemias and Myelodysplasia Myeloproliferative Neoplasms (MPN) (including BCR-ABL-negative myeloproliferative neoplasms, myelofibrosis and later stages of polycythemia vera and essential thrombocytosis) Intermediate- or high-risk disease including: High-risk cytogenetics Poor initial response or at progression NMDP/Be The Match & ASBMT Recommended Timing for Transplant Consultation, 2017.

HCT for Myeloproliferative Neoplasm Heterogeneous group of disorders; survival ranging from 16 months to over 15 years Bone marrow transplant is the only curative modality However, transplant is associated with significant morbidity and mortality dependent on patient- and transplant-specific factors. Patient selection is therefore critical to maximize benefit versus risk balance. Gangat et al. JCO 2011;29(4):392-397

HCT for Myeloproliferative Neoplasm Most of the outcome data are from retrospective studies and relate to HCT for primary myelofibrosis or myelofibrosis (MF) evolved from other myeloproliferative neoplasms. DIPSS has as been validated as predictor for post-hct outcomes. DIPSS independent factors - karyotype (DIPSS plus) and gene mutation profile (JAK2/MPL/CALR or ASXL-1) may also be valuable for decision making No prospective HCT versus non-hct comparative studies Gangat N, et al. JCO 2011;29(4):392-397 Scott BL,et al. Blood 2012;119(11):2657-2664

HCT for Myeloproliferative Neoplasm In the largest study (n=438) outcomes with allo-hct versus non-hct approach were compared in primary MF patients grouped by DIPSS status DIPSS intermediate-2 or high risk patients clearly benefited from HCT. Low risk did better with non-hct approach. Intermediate-1 had similar survival with the two approaches Caveats: Only patients with primary MF were included Ruxolitinib was not used All patients were < 65 years old Kroger N, et al. Blood 2015; 25(21):3347-50

Relative risk of dying after receiving AHCT versus those treated with nonhct modalities Kroger N, et al. Blood 2015; 125(21): 3347-50

HCT for Myeloproliferative Neoplasm Generally accepted indications: Primary Myelofibrosis DIPSS Int-2 or High Risk High Risk karyotype and gene profile (even with low risk DIPSS) AML after MF Secondary MF after ET or PV ELN: < 5 years expected survival The balance of risk versus benefit has to be assessed for each patient individually. Early referral is strongly advocated to allow optimal patient selection and timing to ensure the highest likelihood of benefiting from HCT CMS coverage for myelofibrosis Coverage for patients under approved coverage for evidence development study

Survival after HLA Matched Sibling Donor Transplants for Myeloproliferative Diseases, 2003-2013 100 p=0.092 Probability, % 80 Myelofibrosis (n=596) 60 Other MPD (n=688) 40 20 0 0 1 2 3 Years 4 5 6 By Disease Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 70

Survival after Unrelated Donor Transplants for Myeloproliferative Diseases, 2003-2013 100 p=0.029 Probability, % 80 Myelofibrosis (n=732) 60 40 Other MPD (n=808) 20 0 0 1 2 3 Years 4 5 6 By Disease Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 71

Timing for HCT Consultation Adult Leukemias and Myelodysplasia Chronic myelogenous leukemia (CML) Inadequate hematologic or cytogenetic response to tyrosine kinase inhibitor (TKI) therapies Disease progression Intolerance to TKI therapies Accelerated phase Blast crisis (myeloid or lymphoid) NMDP/Be The Match & ASBMT Recommended Timing for Transplant Consultation, 2017.

Survival after HLA Matched Sibling Transplants for CML, 2003-2013 100 p<0.001 Probability, % 80 Chronic Phase (n=1,893) 60 Accelerated Phase (n=299) 40 Blast Phase (n=154) 20 0 0 1 2 3 Years 4 5 6 By Disease Status Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 73

Timing for HCT Consultation Adult Leukemias and Myelodysplasia Chronic Lymphocytic Leukemia (CLL) High-risk cytogenetics or molecular features (e.g., del(11q) or del(17p); ZAP70, CD38 positivity; unmutated Ig VH mutational status) Poor initial response Short initial remission Chemotherapy- or targeted therapy-resistant Richter's transformation NMDP/Be The Match & ASBMT Recommended Timing for Transplant Consultation, 2017.

Survival after Allogeneic Transplants for Chronic Lymphocytic Leukemia (CLL), 2003-2013 100 p<0.001 Probability, % 80 HLA Matched Sibling (n=1,333) 60 40 Unrelated Donor (n=1,646) 20 0 0 1 2 3 Years 4 5 6 By Donor Type Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 75

Timing for HCT Consultation Multiple Myeloma Multiple Myeloma All patients after initiation of therapy At first progression NMDP/Be The Match & ASBMT Recommended Timing for Transplant Consultation, 2017.

ASBMT Recommendations for Autologous SCT in Multiple Myeloma Shah et al, Biol Blood Marrow Transplant 2015; 21:1155-1166.

IFM/DFCI 2009/BMT CTN 1304/Alliance Parallel Phase 3 Study The Determination Trial Newly Diagnosed MM (HCT candidates; overall n= 1360; USA 660; France 700) Calibration MRD @ CR MRD MRD MRD @ CR MRD

Factors to Consider for Auto-HCT If HCT is delayed, collection of stem cells before extensive lenalidomide (len) exposure is recommended BMT CTN 1304 study - evaluating early vs delayed transplant in the era of new drugs. The French arm of the trial showed a PFS benefit but no OS benefit on interim analysis with len given for one year of maintenance Non randomized studies in patients >65 years show low mortality and potential benefit suggesting that age should not be a barrier to transplant referral BMT CTN 0702 study - auto-hct with maintenance therapy options Kumar S, et al. Leukemia. 2007;21:2035-42; Attal M, et al. Blood. 2015; 126:391; Merz M et al. Ann Oncol 2014;25:189-95

Allogeneic Transplant for Myeloma Myeloma-free graft and Graft versus Myeloma Effect Reduced Intensity conditioning regimens reduce transplant-related mortality Seven trials comparing auto auto versus auto/ric allo have been performed with no consistent benefits for PFS or OS CMS coverage - approved under coverage for evidence trial Shah N, et al. Biol Blood Marrow Transplant 2015; 21:1155-1166

Evaluating Auto/Allo Reduced Intensity Trials Randomized trials are not feasible Biologic Assignment - patients are assigned based on presence or absence of an HLA matched sibling Results are on intent to treat basis Drop out rates between first and second HCT vary Conditioning regimens Vary (Auto and Allo) High risk vs. standard risk patients included Length of follow up differs Shah N, et al. Biol Blood Marrow Transplant 2015; 21:1155-1166

Myeloma HCT Comparison Trials Bjorkstrand J. et al. J Clin Oncol 2011;29(22):3016-22; Gahrton G. Blood 2013; 121(25):5055-63; Garban F. Blood 2006;107(9):3474-80. Giaccone L Blood 2011;117(24):6721-7; Krishnan A. Lancet Oncol 2011;13:1195-1203

Survival after Transplants for Multiple Myeloma, 2003-2013 100 p<0.001 Autologous (n=37,385) Probability, % 80 Allogeneic (n=1,012) 60 40 20 0 0 1 2 3 Years 4 5 6 By Donor Type Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 83

Timing for HCT Consultation Lymphomas Non-Hodgkin Lymphoma Follicular Poor response to initial treatment Initial remission duration <12 months First relapse Transformation to diffuse large B-cell lymphoma NMDP/Be The Match & ASBMT Recommended Timing for Transplant Consultation, 2017.

Timing for HCT Consultation Lymphomas Non-Hodgkin Lymphoma Mantle Cell At diagnosis Other High-Risk Lymphomas At diagnosis NMDP/Be The Match & ASBMT Recommended Timing for Transplant Consultation, 2017.

Figure 4 GVHD is associated with GVL effect in Mantle Cell and Follicular Lymphoma Landmark analysis at 180 days after RIC allo-hct showing CI of relapse Urbano-Ispizua A et al. Biology of Blood and Marrow Transplant 2015; 21(10):746-1753.

ASBMT Recommendations for HCT in Non-Hodgkin Lymphoma Oliansky DM, et al. Biol Blood Marrow Transplant. 2011;17:20-47; Stiff PJ e,t al. N Engl J Med 2013;369:1681-1690 Gisselbrecht C, et al. J Clin Oncol. 2012;30:4462-4469

Survival after Autologous Transplants for Follicular Lymphoma, 2003-2013 100 p<0.001 Sensitive (n=2,627) Probability, % 80 60 Resistant (n=171) 40 20 0 0 1 2 3 Years 4 5 6 By Disease Status Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 89

Survival after Allogeneic Transplants for Follicular Lymphoma, 2003-2013 100 HLA Matched Sibling, Sensitive (n=920) p<0.001 HLA Matched Sibling, Resistant (n=159) Probability, % 80 60 40 Unrelated Donor, Sensitive (n=733) Unrelated Donor, Resistant (n=168) 20 0 0 1 2 3 Years 4 5 6 By Disease Type and Pasquini MC, Zhu X. Current uses and outcomes of Donor Type hematopoietic stem cell transplantation: CIBMTR Summary 90 Slides, 2015

Timing for HCT Consultation Lymphomas Non-Hodgkin Lymphoma Diffuse Large B-Cell or High-Grade Lymphoma Primary induction failure CR1 for patients with high or high-intermediate IPI risk At first relapse CR2 or subsequent remission Double hit (MYC and BCL-2 or BLC-6) at diagnosis NMDP/Be The Match & ASBMT Recommended Timing for Transplant Consultation, 2017.

Survival after Autologous Transplants for Diffuse Large B-cell Lymphoma (DLBCL), 2003-2013 100 p<0.001 Probability, % 80 Sensitive (n=10,644) 60 Resistant (n=712) 40 20 0 0 1 2 3 Years 4 5 6 By Disease Status Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 92

Outcomes for DLBCL patients undergoing allogeneic HCT after prior failed ASCT Fenske T et al., British Journal of Haematology 2016; 174(2):234-248 93

Prognostic index for DLBCL patients undergoing allohct after prior failed ASCT KPS < 80; Interval < 12 months; chemoresistant at allohct Fenske T, et al, British Journal of Haematology 2016; 174(2):234-248

Survival after HLA Matched Sibling Transplants for Diffuse Large B-cell Lymphoma (DLBCL), 2003-2013 100 p<0.001 Probability, % 80 60 Sensitive (n=802) 40 Resistant (n=238) 20 0 0 1 2 3 Years 4 5 Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 6 95

Survival after Transplants for Mantle Cell Lymphoma, 2003-2013 100 p<0.001 Autologous (n=4,360) Probability, % 80 Allogeneic (n=1,414) 60 40 20 0 0 1 2 3 Years 4 5 6 By Donor Type Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 96

Timing for HCT Consultation Lymphomas Hodgkin Lymphoma Primary induction failure At first or subsequent relapse CR2 or subsequent remission NMDP/Be The Match & ASBMT Recommended Timing for Transplant Consultation, 2017.

ASBMT Recommendations for Autologous SCT in Hodgkin Lymphoma Perales M et al., Biol Blood Marrow Transplant. 2015;21:971-983

ASBMT Recommendations for Allogeneic HCT in Hodgkin Lymphoma Perales M et al., Biol Blood Marrow Transplant. 2015;21:971-983

Survival after Autologous Transplants for Hodgkin Lymphoma, 2003-2013 100 p<0.001 Sensitive (n=7,824) Probability, % 80 Resistant (n=807) 60 40 20 0 0 1 2 3 Years 4 5 6 By Disease Status Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 101

Similar Survival after RIC AlloHCT for Lymphoma using Haplo Donors vs HLA-MUD PFS OS URD without ATG URD without ATG URD with ATG Haploidentical URD with ATG Haploidentical Kanate AS, et al. Blood 2016;127(7):938-47.

Survival after Allogeneic Transplants for Hodgkin Lymphoma, 2003-2013 100 p=0.002 Probability, % 80 HLA Matched Sibling (n=934) 60 40 Unrelated Donor (n=1,171) 20 0 0 1 2 3 Years 4 5 6 By Donor Type Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 103

Figure 1 Overall survival after allohct of different lymphoma subtypes Urbano-Ispizua A et al. Biol Blood Marrow Transplant 2015; 21(10): 1746-1753.

Pediatric Indications

Timing for HCT Consultation Pediatric Acute Leukemias and Myelodysplasia Acute Myelogenous Leukemia (AML) - Pediatric High-resolution HLA typing is recommended at diagnosis for all patients Early after initial diagnosis, all AML patients including: CR1 except favorable risk AML [defined as: t(16;16); inv 16; t(8;21); t(15;17); normal cytogenetics with NPM1 or isolated biallelic CEBPA mutation and without FLT3-ITD] Primary induction failure or relapse Monosomy 5 or 7 Age <2 years at diagnosis Treatment-related leukemia Presence of minimal residual disease after initial or subsequent therapy CR2 and beyond, if not previously evaluated NMDP/Be The Match & ASBMT Recommended Timing for Transplant Consultation, 2017.

Survival after HLA Matched Sibling Donor Transplants for AML, Age <20 Years, 2003-2013 100 p<0.001 Probability, % 80 Early (n=1,212) 60 Intermediate (n=280) 40 Advanced (n=232) 20 0 0 1 2 3 Years 4 5 6 By Disease Status Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 107

Timing for HCT Consultation Pediatric Acute Leukemias and Myelodysplasia Acute Lymphoblastic Leukemia (ALL) - Pediatric Infant at diagnosis High Risk CR1 including: Philadelphia chromosome positive WBC >100,000 at diagnosis 11q23 rearrangement Primary induction failure Presence of minimal residual disease after initial or subsequent therapy First relapse CR2 and beyond, if not previously evaluated NMDP/Be The Match & ASBMT Recommended Timing for Transplant Consultation, 2017.

Malignant disorders in Pediatrics: MDS Monosomy 5 or 7 Secondary MDS No treatment before proceeding to transplant unless transition to AML Matched sibling or unrelated donor transplant at diagnosis Myeloablative conditioning Outcomes comparable with both donor sources Oliansky D, et al. Biol Blood Marrow Transplant 2009;15:137-172 Strahm B el al. Leukemia 2011; 25:455 462

Non malignant disorders in pediatric patients: Aplastic Anemia Matched sibling transplant at diagnosis Immunosuppressive therapy while searching for unrelated donor in case a HLA identical sibling is not available Minimize number of transfusions to reduce graft failure Matched unrelated donor transplant if no response in 36 months Debate about proceeding to a 10/10 match in young patients if no HLA identical sibling available instead of immuno-suppressive therapy as outcomes are comparable Eapen M, et al Blood 2011; 118:2618-2621

Survival after Allogeneic Transplants for Severe Aplastic Anemia, <20 Years, 2003-2013 100 p<0.001 HLA Matched Sibling (n=1,318) Probability, % 80 Unrelated Donor (n=805) 60 40 20 0 0 1 2 3 Years 4 5 6 By Donor Type Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2015 113

Timing for HCT Consultation Non-Malignant Disorders Immune Deficiency Diseases (including Severe Combined Immunodeficiency syndromes, Wiskott-Aldrich syndrome, Omenn syndrome, X-linked lymphoproliferative syndrome, Kostmann syndrome) At diagnosis or if detected on newborn screening Hemoglobinopathies Sickle Cell Disease with aggressive course (stroke, end-organ complications, frequent pain crises) Transfusion-dependent Thalassemias At diagnosis NMDP/Be The Match & ASBMT Recommended Timing for Transplant Consultation, 2017.

Non Malignant disorders in Pediatric patients: Hemoglobinopathies Sickle cell disease and Thalassemia are curable with transplant Matched sibling donor transplants have better outcomes Graft failure and hepatic toxicity is an issue Matched unrelated and haploidentical HCT with reduced intensity conditioning regimens are being explored with ongoing trials Tolar J, et al. Bone Marrow Transplantation 2015; 50: 619 627 Walters M, et al. Biol Blood Marrow Transplant 2016; 22: 207-211

Timing for HCT Consultation Other Malignant Disorders Germ cell tumors Poor initial response Short initial remission Juvenile myelomonocytic leukemia (JMML) At diagnosis NMDP/Be The Match & ASBMT Recommended Timing for Transplant Consultation, 2017.

Timing for HCT Consultation Non-Malignant Disorders Inherited Metabolic Disorders (including Hurler's syndrome, adrenoleukodystrophy, and others) At diagnosis or if detected on newborn screening Hemophagocytic Lymphohistiocytosis (HLH) At diagnosis Severe Aplastic Anemia and other marrow failure syndromes (including Fanconi anemia, Diamond-Blackfan anemia, and others) At diagnosis NMDP/Be The Match & ASBMT Recommended Timing for Transplant Consultation, 2017.

From published guidelines to resources Print, online, mobile app Clinical toolkit: referral timing & post-transplant Clinical guidelines Mobile app/online clinical & patient guides Patient toolkit: post-transplant BeTheMatchClinical.org/guidelines 118

Post-Transplant Care

Survivorship Issues Following HCT Auto- and allo-hct survivors are at risk for early and late complications months to years following the procedure Complications include predictable early toxicities and late symptom burden Health-related quality of life, functional status, return to school and work, and social relationships may be affected Secondary complications, such as graft vs host disease (GVHD) in allo-hct survivors, create additional medical needs for HCT survivors

Survivorship Resources for HCT NS Majhail, JD Rizzo, SJ Lee et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Summary recommendations Screening and prevention of late complications in long term HCT survivors, by tissue/organ (e.g. dental assessment in transplant survivors exposed to total body irradiation or who have had chronic GVHD) Abbreviated table for 6 month, 1 year and annual screening recommendations, by organ system (e.g. cardiac, respiratory, renal, endocrine, others) Detailed text supporting each recommendation Majhail NS et al., BBMT 2012; 18:348-71.

Survivorship Resources for HCT Physician-facing resources (BeTheMatchClinical.org) Long term care guidelines following HCT Interactive tool for customizable list of screening recommendations Mobile application available Recommended vaccinations/schedule following HCT Patient-facing resources (BeTheMatch.org) Life after Transplant psychosocial and medical considerations, tailored to patients Patient friendly guidelines for post-hct care Ongoing projects NS Majhail et al. (PCORI award): impact of personalized posttransplant survivorship care plans upon patient education 122

Post-transplant Survivorship: Summary HCT offers life-saving or life-extending therapy for aggressive blood disorders The interaction of underlying disease, treatment, transplant exposures, and patient characteristics create risks for long term adverse health events that may impact functioning, quality of life, and survival Resources are available for oncologists and other physicians to help participate in the long-term care of transplant recipients Transplant specialists at transplant centers are always interested in working collaboratively with referring physicians to ensure optimal long term health outcomes for HCT survivors

Conclusions In the current era, almost all patients will have a suitable donor Optimal timing of HCT is critical to good outcomes Early referral to the transplant center ensures that the RIGHT patient gets transplanted at the RIGHT time with the BEST graft source Post transplant survivors are at risk for early and late complications months to years following HCT and need ongoing screening, preventive care and follow up

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