Allogeneic Hematopoietic Stem Cell Transplantation Following Anti-CD19 BiTE® Blinatumomab in Adult Patients with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)
Authors: Stein Anthony , Topp Max S. , Goekbuget Nicola , Bargou Ralf C. , Dombret Hervé , Fielding Adele K. , Larson Richard A. , Rambaldi Alessandro , Schiller Gary , Zugmaier Gerhard , Jia Catherine , Maniar Tapan , Huber Birgit , Nagorsen Dirk , Kantarjian Hagop , Forman Stephen J. 
Published: October 2019

Abstract
Introduction: Improvements in the therapeutic options available for adult relapsed/refractory (r/r) B-precursor ALL are required. Blinatumomab is an investigational bispecific T-cell engager (BiTE®) antibody construct that redirects cytotoxic T cells to lyse CD19-positive B cells. Based on encouraging clinical data from a small phase 2 study (Topp MS et al. J Clin Oncol. 2014;32(15s): abstract 7005), we conducted a large confirmatory open-label, single-arm, multicenter phase 2 study of blinatumomab in patients with r/r B-precursor ALL. The aim of the present analysis from this phase 2 study was to characterize those patients who proceeded to allogeneic hematopoietic stem cell transplantation (HSCT) after achieving complete remission (CR)/complete remission with partial hematologic recovery (CRh*) with blinatumomab treatment.
Methods: Eligible patients (≥18 years) had Philadelphia chromosome-negative r/r B-precursor ALL with one of the following negative prognostic factors: primary refractory, 1st relapse within 12 months of 1st remission, relapse within 12 months of HSCT, or ≥2nd salvage. Blinatumomab was given by continuous IV infusion (4 weeks on/2 weeks off) for up to 5 cycles. The primary endpoint was CR/CRh* within the first 2 cycles. Secondary endpoints included overall survival (OS), relapse-free survival (RFS), HSCT realization rate, 100-day mortality following HSCT, and adverse events.
Results: 189 patients with a median age (range) of 39 (18‒79) years were enrolled and received blinatumomab for a median (range) of 2 (1‒5) cycles. At enrollment, 74 (39%) patients had received ≥2 prior salvage therapies, 64 (34%) had received prior HSCT, and 105 (56%) had ≥75% bone marrow blasts.
43% (81/189) of patients achieved CR/CRh* within 2 cycles, with similar rates of remission observed in both the HSCT-naïve (42%; 52/125) and prior HSCT (45%; 29/64) groups. In total, 32/81 responders (CR, n=28 and CRh*, n=4) underwent HSCT during blinatumomab-induced remission, yielding a transplantation realization rate for blinatumomab responders of 40% (Table 1). 52% (27/52) of the HSCT-naïve patients and 17% (5/29) of patients who had received prior HSCT proceeded to on-study HSCT during blinatumomab-induced remission. These 32 transplants occurred after a median of 2 (1-5) cycles of therapy, with 11 (34%) patients receiving myeloablative conditioning pre-HSCT, 12 (38%) reduced intensity conditioning, and 9 (28%) unknown regimens. Twenty-two (69%) patients used unrelated donors (stem cells derived from blood, n=11; bone marrow, n=6; cord blood, n=5), 7 (22%) used related donors including 6 siblings (blood, n=5; bone marrow, n=1) and 1 haploidentical mother (blood), with 3 (9%) donor types and stem cell sources unknown. Six patients achieving CR/CRh* after 2 cycles of blinatumomab underwent HSCT but were not included in the transplantation realization rate of 40% due to receiving subsequent antineoplastic therapy before HSCT conditioning (Table 1). Among the 43 patients who achieved CR/CRh* within 2 cycles of blinatumomab treatment but never reached HSCT, 20 (47%) had undergone prior HSCT, 7 (16%) were ≥65 years, and 2 (5%) were ≥65 years and had received prior HSCT (Table 1).
Figure 1 Figure 1.
At the time of the primary analysis (data cut-off in October 2013), with median follow-up of 9.8 months, median (95% CI) OS for the 189 blinatumomab-treated patients was 6.1 (4.2‒7.5) months. When censoring for HSCT, median OS was 5.1 (4.1‒7.1) months; although the medians are slightly different, the curves with and without HSCT censoring largely overlap. Median RFS was 5.9 months with and without censoring for HSCT. Nine patients died at any time after HSCT, with 5 deaths due to infection, 3 due to disease progression, and 1 due to graft-versus-host disease (GvHD). Three of these deaths (2 infections and 1 GvHD) were within 100 days of HSCT. The 100-day post-HSCT mortality rate was 11%.
Summary: This large phase 2 study demonstrated antileukemia activity of single-agent blinatumomab in heavily pretreated or aggressive r/r ALL, irrespective of prior HSCT. The data suggest that blinatumomab enables patients to reach HSCT, with 11% 100-day mortality post-HSCT. Two-thirds of patients who did not reach HSCT after responding to blinatumomab were either ≥65 years old or had received prior HSCT. Longer follow-up is required to assess the role of HSCT in patients achieving CR/CRh* after treatment with blinatumomab.

Disclosures
Stein: Amgen Inc.: Membership on an entity's Board of Directors or advisory committees. Off Label Use: This presentation will discuss the off-label use of blinatumomab, as this agent is not approved for use by the FDA, EMA or any other regulatory authorities.. Topp:Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Goekbuget:Amgen Inc.: Consultancy, Honoraria, Research Funding. Bargou:Amgen Inc.: Consultancy, Honoraria. Dombret:Amgen Inc.: Honoraria, Research Funding. Larson:Amgen Inc.: Consultancy, Research Funding. Rambaldi:Amgen Inc.: Consultancy. Zugmaier:Amgen Reseach (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Jia:Amgen Inc.: Employment, Equity Ownership. Maniar:Amgen Inc.: Employment, Equity Ownership. Huber:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Nagorsen:Amgen Inc.: Employment, Equity Ownership, Related to blinatumomab Patents & Royalties. Kantarjian:Amgen Inc.: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding.