19-28z CAR T-Cell Efficacy and Toxicity in Adults With R/R B-Cell ALL CCO Independent Conference Coverage* of the 2016 ASCO Annual Meeting, June 3-7, 2016 *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. ALL, acute lymphoblastic leukemia; R/R, relapsed/refractory. This activity is supported by educational grants from Amgen, Ariad, Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.

19-28z CAR T Cells in Relapsed/Refractory B-Cell ALL: Background Autologous T cells modified to express CAR that targets B-cell antigen CD19 When infused back into pt, will target CD19-positive tumor cells and induce cell death Phase I trial evaluated impact of preinfusion disease burden on long-term outcomes with CD19-targeted CAR T cells in adult pts with relapsed or refractory CD19-positive B-cell ALL[1] This analysis examined the impact of disease burden at time of CAR T-cell infusion on clinical outcome and toxicity[2] ALL, acute lymphoblastic leukemia. 1. ClinicalTrials.gov. NCT01044069. 2. Park JH, et al. ASCO 2016. Abstract 7003. Slide credit: clinicaloptions.com

19-28z CAR T Cells in R/R B-Cell ALL: Study Design Adult pts with relapsed/refractory CD19-positive B-cell ALL (N = 51) Autologous T cells derived by leukapheresis Pt pretreatment Salvage chemotherapy during T-cell expansion Bone marrow blast count to determine disease burden Conditioning chemotherapy on Day -2 Cyclophosphamide (n = 42) Fludarabine + cyclophosphamide (n = 9) ALL, acute lymphoblastic leukemia; R/R, relapsed/refractory. Slide credit: clinicaloptions.com Park JH, et al. ASCO 2016. Abstract 7003.

19-28z CAR T Cells in R/R B-Cell ALL: Dosing and Assessment 19-28z CAR T-cell infusion; dosing based on disease burden 3 x 109 CAR T cells/kg in pts with minimal disease (< 5% blasts in BM); n = 20 (39%) Dose reduced to 1 x 109 CAR T cells/kg in pts with morphologic disease (≥ 5% blasts in BM or extramedullary disease); n = 31 (61%) Disease assessment: Days 28-35 Median follow-up: 8.5 mos ≥ 6 mos: 58% ≥ 1 yr: 34% ALL, acute lymphoblastic leukemia; BM, bone marrow; R/R, relapsed/refractory. Slide credit: clinicaloptions.com Park JH, et al. ASCO 2016. Abstract 7003.

19-28z CAR T Cells in R/R B-Cell ALL: Patient Characteristics Morphologic Disease (n = 31) Minimal Disease (n = 20) Median age at infusion, yrs (range) 18-29, % 30-59, % ≥ 60, % 40 (24-73) 26 58 16 53 (22-74) 20 50 30 Median prior lines of therapy, n (range) 2, % 3, % ≥ 4, % 3 (2-7) 48 2 (2-4) 60 25 15 Prior blinatumomab, % 36 5 Prior allogeneic HSCT, % 42 Philadelphia chromosome positive, % 23 40 ALL, acute lymphoblastic leukemia; HSCT, hematopoietic stem cell transplantation; R/R, relapsed/refractory. Slide credit: clinicaloptions.com Park JH, et al. ASCO 2016. Abstract 7003.

19-28z CAR T Cells in R/R B-Cell ALL: Clinical Response Morphologic Disease (n = 30) Minimal Disease (n = 20) CR, % 77 90 MRD-negative CR, % 90 (n = 21) 78 (n = 18) Mean time to CR, days (SD) 20 (9) 25 (9) CR seen across analyzed subgroups, including disease burden, prior blinatumomab, prior HSCT, number of prior therapies, Philadelphia chromosome status, and age 39% of pts achieving CR proceeded to allogeneic HSCT (equal incidence in morphologic and minimal disease cohorts) 45% MRD-negative CR pts relapsed; 27% of these were CD19 positive 27% MRD-negative CR pts disease free for > 1 yr ALL, acute lymphoblastic leukemia; HSCT, hematopoietic stem cell transplantation; MRD, minimal residual disease; R/R, relapsed/refractory; SD, standard deviation. Slide credit: clinicaloptions.com Park JH, et al. ASCO 2016. Abstract 7003.

19-28z CAR T Cells in R/R B-Cell ALL: OS Response Morphologic Disease (n = 31) Minimal Disease (n = 20) Median OS, mos 9.0 NR Median OS in MRD-negative CR, mos 17.0 Median OS follow-up: 13.0 mos After CAR T cells, MRD negativity had prognostic implications Post–CAR T-cell HSCT does not appear to affect survival ALL, acute lymphoblastic leukemia; HSCT, hematopoietic stem cell transplantation; MRD, minimal residual disease; NR, not reached. Slide credit: clinicaloptions.com Park JH, et al. ASCO 2016. Abstract 7003.

19-28z CAR T Cells in R/R B-Cell ALL: Safety AE, % Morphologic Disease (n = 31) Minimal Disease (n = 20) Severe CRS 42 5 Grade 3/4 NT 35 20 Severe CRS + grade 3/4 NT 23 Severe CRS or grade 3/4 NT 55 Grade 5 toxicity 10* *n = 3: 2 pts with sepsis/multiorgan failure, 1 pt with seizure but unknown cause of death (all received higher CAR T-cell dose prior to dose modification). AE, adverse event; ALL, acute lymphoblastic leukemia; CRS, cytokine release syndrome; NT, neurologic toxicities; RFS, relapse-free survival; R/R, relapsed/refractory. Some AEs managed with tocilizumab and/or steroids; no effect on RFS or OS Slide credit: clinicaloptions.com Park JH, et al. ASCO 2016. Abstract 7003.

19-28z CAR T Cells in R/R B-Cell ALL: Conclusions CR and MRD-negative CR rates > 75% regardless of pretherapy disease burden[1] Durable responses and survival benefits in subset of patients without subsequent allogeneic HSCT (regardless of disease burden) Benefit of allogeneic HSCT after 19-28z CAR T cells unclear Lower incidence of severe CRS and neurologic toxicities in pts with minimal disease burden prior to pre–T-cell infusion Single-arm phase II trial of 19-28z CAR T cells in R/R B-cell ALL ongoing (ROCKET)[2] ALL, acute lymphoblastic leukemia; CR, complete remission; CRS, cytokine release syndrome; HSCT, hematopoietic stem cell transplantation; MRD, minimal residual disease; R/R, relapsed/refractory. Park JH, et al. ASCO 2016. Abstract 7003. ClinicalTrials.gov. NCT02535364. Slide credit: clinicaloptions.com

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