Abstract 861. Stein AS, Topp MS, Kantarjian H, Gökbuget N, Bargou R, Litzow M, Rambaldi A, Ribera J-M, Zhang A, Zimmerman Z, Forman SJ

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1 Treatment with Anti-CD19 BiTE Blinatumomab in Adult Patients With Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (R/R ALL) Post-Allogeneic Hematopoietic Stem Cell Transplantation Abstract 861 Stein AS, Topp MS, Kantarjian H, Gökbuget N, Bargou R, Litzow M, Rambaldi A, Ribera J-M, Zhang A, Zimmerman Z, Forman SJ

2 Outcomes Are Poor for Patients With R/R ALL Following allohsct Median OS of patients with ALL who received allohsct and then relapsed Median OS Spyridonidis A et al 1 N = 465 Salvage therapies used in these studies 1,2 - Cytoreductive therapy +/- donor lymphocytes - Cytoreductive therapy +/- a second allohsct - allohsct without treatment Poon LM et al 2 N = 123 At 1 year 30% 17% At 2 years 16% 1% At 5 years 8% ALL, acute lymphoblastic leukemia; allohsct, allogeneic hematopoietic stem cell transplantation; OS, overall survival; R/R, relapsed/refractory 1. Spyridonidis A, et al. Leukemia. 2012;26(6): Poon LM, et al. Biol Blood Marrow Transplant. 2013;19(7):

3 BiTE Antibody Construct, Blinatumomab Blinatumomab is a bispecific T-cell engaging antibody (BiTE ) Blinatumomab redirects T cells to lyse CD19-positive malignant and nonmalignant B cells 1 CD19 is expressed in virtually all tested B-lineage ALL cells and throughout B-cell development 2,3 43% CR/CRh as monotherapy in R/R Philadelphia chromosome negative (Ph-) ALL 4 TCR T cell CD19 CD3 BiTE Blinatumomab B-precursor ALL cell CR, complete response; CRh, CR with partial hematologic recovery 1. Bargou R, et al. Science 2008;321(5891): Raponi S, et al. Leuk Lymphoma. 2011;52(6): Piccaluga P, et al. Leuk Lymphoma. 2011;52(2): Topp MS, et al. Lancet Oncol. 2015;16(1):57-66.

4 Objectives We conducted a large phase II study of single-agent blinatumomab in adult patients with Ph- R/R B-precursor ALL 1 CR/CRh rate was 43% Minimal residual disease (MRD) response rate among patients with CR/CRh was 82% The present exploratory analysis investigated relapse-free survival (RFS), overall survival (OS), and incidence of adverse events in 64 patients who relapsed following allohsct before enrollment in the phase II study 1. Topp MS, et al. Lancet Oncol. 2015;16(1):57-66.

5 Confirmatory Open-Label, Single-Arm, Multicenter Phase II Study 1 Screening and Enrollment Blinatumomab 28 μg/day* civ infusion 4 weeks on, 2 weeks off Up to 2 cycles Primary endpoint assessment Blinatumomab 28 μg/day civ infusion 4 weeks on, 2 weeks off Up to 3 cycles Consolidation Follow-up (up to 24 months) Study Endpoints Primary CR/CRh during the first two cycles Secondary included CR, CRh RFS OS HSCT realization Adverse events Exploratory included MRD response by PCR during the first two cycles HSCT Offered to Patients in CR/CRh *Only cycle 1, days 1 to 7: 9 μg/day CRh, complete response with partial hematological recovery of peripheral blood counts (platelets >50,000/μL and ANC >500/μL) civ, continuous intravenous; HSCT, hematopoietic stem cell transplantation; PCR, polymerase chain reaction 1. Topp MS, et al. Lancet Oncol. 2015;16(1):57-66.

6 Key Inclusion Criteria Patient Eligibility Adults ( 18 years) with Ph- B-precursor ALL Primary refractory disease Early relapse (duration of first remission 12 months) Relapse within 12 months of allohsct Any relapse or refractory disease after first salvage therapy 10% bone marrow blasts plus/minus measurable extramedullary disease ECOG performance status of 2 Key Exclusion Criteria AlloHSCT within 3 months of treatment start Active acute or active chronic (grade 2 to 4) GvHD, or systemic treatment for GvHD within 2 weeks before treatment start History or presence of clinically relevant CNS pathology (epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson disease, cerebellar disease, organic brain syndrome, psychosis) CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; GvHD, graft-versus-host disease

7 Demographics and Baseline Characteristics of Patients With Prior allohsct All Patients N = 64 Male, n(%) 43 (67) Median age, years (range) 32 (19-74) Age group, n (%) 18 to <35 years 40 (63) 35 to <55 years 13 (20) 55 to < 5 years 9 (14) 65 years 2 (3) Donor type, n (%) Haploidentical 1 (2) Sibling 29 (45) Unrelated 31 (48) Haploidentical/unrelated 1 (2) Received myeloablative conditioning regimens, n (%) 34 (59) History of acute or chronic GvHD, n (%) 19 (30) *Includes two patients who each had two allohsct

8 Demographics and Baseline Characteristics of Patients With Prior allohsct (cont d) Timing of last prior allohsct Median time from last prior allohsct or salvage therapy post allohsct to relapse, months (range) Median time from last prior allohsct to first dose of blinatumomab, months (range) Number of prior salvage therapies before blinatumomab, n (%) All Patients N = 64 6 (1-33) 10 (3-40) None 9 (14) 1 23 (36) 2 12 (19) 3 20 (31) Number of patients with prior salvage therapies after transplant but before blinatumomab, n (%) 38 (69)

9 Exploratory Analysis of Efficacy in Patients With Prior allohsct Hematologic response n / N Patients, N = 64 95% CI CR/CRh in first two cycles 29 / 64 45% CR in first two cycles 18 / 64 28% CRh in first two cycles 11 / 64 17% 9-29 CR/CRh in first cycle 22 / 29 76% Blast-free hypoplastic/aplastic bone marrow 4 / 64 6% 2-15 Failure to respond to therapy 12 / 64 19% Insufficient treatment duration 7 / 64 11% Transplant outcomes allohsct after CR or CRh 7 / 29 24% 100-day transplant-related mortality 14% 2-67 Molecular response* MRD response 16 / 18 89% Complete MRD response 15 / 18 83% MRD nonresponse 1 / 18 6% No MRD response assessment 1 / 18 6% Stein *Based AS, on et the al. number Blood. of 2015;126: patients who Abstract had achieved 861. CR within the first two cycles (n = 18).

10 RFS, % Relapse-Free Survival N = 29 Median RFS, months % CI Censored Time Since Achieving Remission, Months Patients at Risk Median (95% CI) follow-up: 12.4 ( ) months

11 OS, % Overall Survival N = 64 Median OS, months % CI Censored Months Patients at Risk Median (95% CI) follow-up: 16.6 ( ) months

12 Adverse Events (Regardless of Causality) Patients With Adverse Events, * n (%) Prior allohsct N = 64 ITT Population N = 189 Any grade 64 (100) 188 (99) Grade 3 20 (31) 72 (38) Grade 4 28 (44) 55 (29) Grade 5 (death) 8 (13) 28 (15) Grade 3 neurologic events 7 (11) 20 (11) Grade 3 cytokine release syndrome 2 (3) 3 (2) Grade 3 occurring in 5 patients Neutropenia 14 (22) 30 (16) Febrile neutropenia 13 (20) 49 (26) Anemia 11 (17) 27 (14) Thrombocytopenia 9 (14) 16 (9) Alanine aminotransferase increased 8 (13) 14 (7) Pyrexia 7 (11) 14 (7) Hypokalemia 6 (9) 13 (7) Leukopenia 6 (9) 15 (8) Pneumonia 6 (9) 17 (9) Aspartate aminotransferase increased 5 (8) 8 (4) Blood bilirubin increased 5 (8) 8 (4) Encephalopathy 5 (8) 6 (3) Hypotension 5 (8) 6 (3) White blood cell count decreased 5 (8) 9 (5) *During treatment until 30 days post treatment; graded using CTCAE, v4.0 ITT, intent to treat

13 Fatal Adverse Events (Regardless of Causality) Patients With Prior allohsct N = 64 Fatal adverse events, n* 8 Sepsis 1 Fusarium infection 1 Infection Septic shock 1 Candida infection 1 Enterococcal bacteremia 1 Disease progression Disease progression 1 Hemorrhage Gastrointestinal hemorrhage 1 Other Respiratory failure 1 *CTCAE, v4.0 Considered by the investigator to be possibly related to blinatumomab treatment None of the eight patients with prior allohsct who had fatal adverse events achieved CR/CRh

14 GvHD Events (Regardless of Causality) *During treatment until 30 days post treatment; graded using CTCAE, v 4.0 One patient had three different GvHD events Patients With Prior allohsct N = 64 Any grade Grade 1 Grade 2 Grade 3 Patients with GvHD events, * n (%) 7 (11) GvHD of the skin 4 (6) 1 (2) 2 (3) 1 (2) GvHD nonspecified 1 (2) 0 1 (2) 0 GvHD of the mouth 1 (2) 1 (2) 0 0 GvHD consisting of multiple events 1 (2) Arthralgia 0 1 (2) 0 Blood alkaline phosphatase increased 0 1 (2) 0 Blood bilirubin increased (2) There were no grade 4 or 5 GvHD events

15 Conclusions In this exploratory analysis of the phase II study of blinatumomab in R/R ALL 1 focusing on patients with prior allohsct (N = 64), the CR/CRh rate was 45% Median RFS (7.4 months) and OS (8.5 months) in patients with R/R ALL and prior allohsct were consistent with those previously reported for the full ITT population 1 Fatal adverse events occurred only in patients with uncontrolled leukemia Blinatumomab treatment did not appear to be associated with an increase in GvHD; all but one occurrences of GvHD were mild or moderate in severity The addition of other immunotherapies to the treatment regimen may be considered for future investigations in this population 1. Topp MS, et al. Lancet Oncol. 2015;16(1):57-66.