Review of Stem Cell Collection Data 2016 Ronan Foley, Professor, Director Stem Cell Laboratory, McMaster University

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1 1 Review of Stem Cell Collection Data 2016 Ronan Foley, Professor, Director Stem Cell Laboratory, McMaster University

2 Objectives 2 Review our national apheresis-based stem cell registry To evaluate the number of stem cell collections completed per annum To evaluate trends in stem cell products, donors and procedures Awareness of new cell-based technologies/collections

3 Stem Cell Transplants: Statement of the Problem (just one of several) Indications Eligibility/Age Timing Maintain content expertise Funding $$$$ Capacity Outpatient FACT HC Provinces Improve OS, PFS, TRM, Q of L

4 Disease-specific indications AML adult, pediatric ALL- adult, pediatric MDS CML CLL NHL Hodgkin lymphoma Multiple Myeloma Severe aplastic anemia and marrow failure Sickle cell disease Immune Deficiency Diseases Inherited Metabolic Disorders Thalassemia Other National guidelines and standards Ability to tighten up the field transplant eligibility coast to coast Referral timing guidelines Timing impact on outcome

5 Introduction 5 Procedures: Data collected from 23 centers. Adults and Children (i) autologous SCT Myeloma, T and B NHL, Burkitts, Primary CNS NHL (other), Germ Cell, MCL, FL, Hodgkins Lymphoma (ii) allogeneic donors healthy 8/8 MR, MUR, Haplotype, MA and NMA (iii) immunotherapy- therapeutic T cells, CAR-T, photopheresis (iv) research mononuclear cells

6 ASCT collections - Autologous 6 Procedures: Data collected from 23 centers. Adults and Children Autologous SCT procedures (N=1311 pts) vs 1972 procedures (N=1,224 pts) in % increase 2016 vs / 5.2% (procedures not entered ) Range:1-352 procedures Optia volumes larger (ie plasma reduction), less neutrophils

7 Number of CD34 cells infused after high-dose chemotherapy 7 Minimum: 2 x 10 6 /kg body weight Optimal: 5 x 10 6 / kg body weight

8 PBCD34+ count is a good predictor of the final CD34+ yield 8 Adapted from Hill QA, et al. An analysis of the optimal timing of peripheral blood stem cell harvesting following priming with cyclophosphamide and G-CSF. Bone Marrow Transplant. 2007;40(10):

9 9 Real time assessment Pre CD34+/ul x 0.3 x liters processed/ pt wt kg=# of CD34+ Vs. Interims (Flow cytometry)

10 Number of Procedures AutoSCT 2016 CAG MM NHL HL NB other Disease

11 Treatment Algorithm for MM in Ontario CR: Complete response VGPR: Very good partial response PR: Partial response SD: Stable disease PD: Progressive disease Symptomatic MM Age < 70 and Candidate for ASCT Transplanteligible and age? Age > 70 and NOT Candidate for ASCT Standard Induction Therapy 90% CyBorD,10% trial First-line VMP (preferred), MPT no maintenance, Clinical trials using Len/dex Stem Cell Mobilization Cy 2.5 g/m 2 + G-CSF Mel 200 mg/m 2 + ASCT (or trial) Tandem ASCT for high risk MM - LEN maintenance until progression - If high risk disease consider BTZ if available - Consider consolidation/maintenance clinical trials HIGH-RISK MM Defined as t(4;14), p53del t(14;16), plasma cell leukemia RVD, clinical trial Progression within 3 mo of ASCT Second-line* LEN/DEX+cyclo, RVd, CyBorD, salvage ASCT Third-line* add drug to LEN/DEX, CyBorD or POM/dex Fourth-line* POM + DEX, cyclo/pred, palliation *Patients treated second-line and beyond following relapse are those both transplant-eligible and -ineligible Tox, refractory relapse? Clini cal trials Adapted from Myeloma Canada Treatment Algorithm. May 2015

12 CIBMTR The CIBMTR performed a study on patients transplanted between 2008 and 2011 in the US and Canada 3 cohorts: 18 to 59 years (n = 5818) 60 to 69 years (n = 4666) >70 years (n = 946) Median OS was not reached for any cohort Myeloma-specific mortality was similar among cohorts at 12%, Sharma et al. Biol Blood Marrow Transplant, 2014

13 CIBMTR CIBMTR Sharma et al. Biol Blood Marrow Transplant, 2014

14 Adoptive T cell therapy: CAR-T cells CAR-T cells (Chimeric antigen receptor-t cells) T cells transduced with tumor-specific CAR CAR: Single fusion molecule with antigen specificity plus signaling domain Three types of CAR: First/second/generations Based on co-stimulatory receptors Cancer: Solid tumor & hematological malignancies Antigen specific domain Advantages of CAR T cells Live drug Tumor recognition independent of HLA (no HLA typing needed) Multiple antitumor immunomodulators can be engineered Target variety of antigens (protein, carbohydrate, glycolipid) Maus M V et al. Blood 2014;123:

15 AlloSCT collections 15 Procedures: Data collected from 23 centers. Adults and Children Allogeneic donors healthy 8/8 MR, MUR, single allele mismatch, Haplotype, MA and NMA 1. Mobilized PBSC G-CSF 10ug/kg x 5 d (many stem cells, many T cells) good for NMA and haploidentical 2. Marrow Harvest unstimulated (less T cells) 3. Cord Blood (ex vivo expansion) few stem cells but 4/6 match acceptable

16 AlloSCT collections 16 Procedures: 445 procedures captured in registry N=362 volunteer donors 17.8% increase in donors

17 Unrelated Transplants for Adults with AML, by Age and Year of Transplant Facilitated by NMDP/Be The Match SOURCE: National Marrow Donor Program/Be The Match 2015 fiscal year reports.

18 Acute Myelogenous Leukemia - Adult Unrelated HCT Improved Survival Over Time Transplants facilitated by NMDP/Be The Match Improved Survival Over Time AML YEAR OF HCT NUMBER OF CASES ONE-YEAR SURVIVAL TWO-YEAR SURVIVAL ,035 61% 49% ,036 58% 47% ,740 50% 40% ,858 33% 26% SOURCE: CIBMTR, the research program of NMDP/Be The Match

19 Allogeneic Hematopoietic Cell Transplantation (HCT) in the Eighth Decade of Life: How Much Does Age Matter? Sorror, ML 2017 ASBMT Age Years OS PFS Relapse NRM % 46% 34% 18% % 52% 28% 20% % 42% 35% 23% % 45% 32% 22% % 46% 35% 19% 1,637 consecutive NMA SCT adjusted by risk factors

20 Defining the less fit transplant patient OLD & FIT OLD & LESS FIT OLD & FRAIL

21 HCT Comorbitdity Index Calculator: Assesses pre-transplant organ impairment Arrythmia (score=1) Cardiovascular Comorbidity (score=1) Inflammatory Bowel Disease (score=1) Diabetes (score=1) Cerebro-Vascular Disease (score=1) Psychiatric disturbance (score=1) *requiring treatment (any) *low EF, CHF,CAD *continuous treatment 1mo prior *almost all important Hepatic Comorbidity (score =1-3) *Bili >1.5x, AST, ALT >2.5x, hep B/C (infection),cirrhosis Obesity score (score=1) BMI>35 Infection (score =1) Rheumatologic Comorbidity (score=2) Peptic Ulcer (score=1) Renal (score=2) *bacterial/fungal (presumed) *requiring specific treatment *>serum Creat 176, Hemodialysis/ renal transplant Pulmonary (score2-3) DLCO <65%, FEV1 <65%, O2 requirement Prior Solid tumor (score 3) Heart Valve disease (score3) Age (40) (score=1) *excluding BCC,SCC no treatment *prosthetic, any MV prolapse` Add up the points from each organ and overall HCT-CI score assigned (online)

22 HCT Comorbitdity Index Calculator: Assesses pre-transplant organ impairment Predicts NRM Prospectively validated CIBMTR allogeneic and autologous Pediatrics only HCT-CI >/= to 3 Sorror, M et al Blood 2005, Tandem Mtg, Hawaii 2016, Smith, A et al Blood 2011

23 Adult AML Indications/Early is Better 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. 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

24 Timing for HCT Consultation 1 Eligible for BMT HR-HLA typing HLA-A, B, C, DRB1 All siblings HLA typing LR-HLA-A, B, C HR-DRB1 (8/8) 25% chance of success 3 2 Unrelated Donor search -HR typing 8/8 match -Haplotype common - pick 3-5 potential rare pick 10+ potential -7/8 or 9/10 single allelle or antigen mismatch acceptable? -Secondary DQ, DP, DRB 3,4,5 -Donor specific antibodies (DSA) Unrelated Umbilical Cord Unit >4/6 HLA-A, B, DR (cell dose) HLA-C Time? Risk of relapse? 4 Haplo-identical Donor Multiple donors Siblings, parents, children, first degree relatives Mother (NIMA) Donor specific antibodies (DSA) KIR reactivity

25 Ethnic Composition of OneMatch Database

26 Concluding Remarks CAG Stem Cell Registry established thank you!! 2. Numbers of procedures appear well captured 3. Ability to monitor new cell-based therapies and collections will be very important going forward