Original Article Long-Term Survival of Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia Treated With Blinatumomab Max S. Topp, MD1; Nicola Gökbuget, MD2; Gerhard Zugmaier, MD, PhD3; Anthony S. Stein, MD4; Hervé Dombret, MD5; Yuqi Chen, PhD6; Josep-Maria Ribera, MD, PhD 7 ; Ralf C. Bargou, MD8; Heinz-August Horst, MD, PhD9; 10 and Hagop M. Kantarjian, MD BACKGROUND: Blinatumomab is a CD19 BiTE (bispecific T-cell engager) immuno-oncology therapy that mediates the lysis of cells ex- pressing CD19. METHODS: A pooled analysis of long-term follow-up data from 2 phase 2 studies that evaluated blinatumomab in heavily pretreated adults with Philadelphia chromosome–negative, relapsed/refractory B-cell precursor acute lymphoblastic leukemia was con- ducted. RESULTS: A total of 259 patients were included in the analysis. The median overall survival (OS) among all patients, regardless of response, was 7.5 months (95% confidence interval [CI], 5.5-8.5 months); the median follow-up time for OS was 36.0 months (range, 0.3- 60.8 months). The median relapse-free survival (RFS) among patients who achieved a complete remission (CR) or complete remission with partial hematologic recovery (CRh) in the first 2 cycles (n = 123) was 7.7 months (95% CI, 6.2-10.0 months); the median follow-up time for RFS was 35.0 months (range, 9.5-59.5 months). OS and RFS plateaued with 3-year rates of 17.7% and 23.4%, respectively. The cu- mulative incidence function of the time to relapse, with death not due to relapse considered a competing risk, for patients who achieved a CR/CRh within 2 cycles of treatment also plateaued with a 3-year relapse rate of 59.3%. For patients who achieved a CR/CRh with blinatumomab followed by allogeneic hematopoietic stem cell transplantation while in continuous CR, the median OS was 18.1 months (95% CI, 10.3-30.0 months) with a 3-year survival rate of 37.2%. CONCLUSIONS: These data suggest that long-term survival is possible after blinatumomab therapy. Cancer 2021;127:554-559. © 2020 Amgen GmbH. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. LAY SUMMARY: • Immuno-oncology therapies such as blinatumomab activate the patient’s own immune system to kill cancer cells. • This study combined follow-up data from 2 blinatumomab-related clinical trials to evaluate long-term survival in patients with relapsed and/or refractory B-cell precursor acute lymphoblastic leukemia at high risk for unfavorable outcomes. • Among patients who achieved a deep response with blinatumomab, one-third lived 3 years or longer. These findings suggest that long- term survival is possible after treatment with blinatumomab. KEYWORDS: acute lymphoblastic leukemia (ALL), bispecific T-cell engager (BiTE), blinatumomab, overall survival. INTRODUCTION Patients with relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL) have a poor prognosis, with allogeneic hematopoietic stem cell transplantation (HSCT) generally viewed as the only curative option.1-3 However, immuno-oncology therapy with blinatumomab, BiTE (a bispecific T-cell engager) molecule, has led to long-term sur- vival among responders even in the absence of HSCT.4 In a phase 3 study of heavily pretreated adults with R/R ALL, the median overall survival (OS) was 7.7 months in the blinatumomab group and 4.0 months in the chemotherapy group (P = .01). The median duration of follow-up was 11.7 and 11.8 months, respectively. The study was stopped early ­because the threshold for an OS benefit was met at the interim analysis.5 We pooled long-term follow-up data from 2 single-arm, phase 2 studies (NCT01209286 and NCT01466179) to assess the durability of response to blinatumomab in patients with R/R ALL.6,7 In the primary analyses of the 2 phase 2 studies, the median durations of follow-up for OS and relapse-free survival (RFS) were relatively short: 12.1 Corresponding Author: Gerhard Zugmaier, MD, PhD, Amgen GmbH, Munich, Germany (gerhardz@amgen.com). 1 Universitätsklinikum Würzburg, Würzburg, Germany; 2 Goethe University, Frankfurt, Germany; 3 Amgen GmbH, Munich, Germany; 4 Gehr Family Center for Leukemia Research, City of Hope, Duarte, California; 5 Saint Louis Hospital, University of Paris, Paris, France; 6 Amgen, Inc, Thousand Oaks, California; 7 Catalan Institute of Oncology– Germans Trias I Pujol Hospital, Josep Carreras Leukemia Research Institute, Badalona, Spain; 8 Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany; 9 University Hospital of Schleswig-Holstein, Kiel, Germany; 10 The University of Texas MD Anderson Cancer Center, Houston, Texas We thank Kathryn Boorer, PhD (KB Scientific Communications, LLC, supported by Amgen, Inc), and Julie Gegner, PhD (Amgen, Inc), for writing and editorial assistance in the preparation of this article and Robert Dawson (Cactus Communications, Inc, supported by Amgen, Inc) for assistance in editing and formatting the figures. Additional supporting information may be found in the online version of this article. DOI: 10.1002/cncr.33298, Received: July 1, 2020; Revised: September 11, 2020; Accepted: October 1, 2020, Published online November 3, 2020 in Wiley Online Library ­(wileyonlinelibrary.com) 554 Cancer   February 15, 2021 Long-Term Survival With Blinatumomab/Topp et al and 9.7 months, respectively, in the exploratory phase 2 TABLE 1. Baseline Characteristics study (n = 36)7 and 9.8 and 8.9 months, respectively, in Total Patients the confirmatory phase 2 study (n = 189).6 An additional Baseline Characteristic (n = 259) analysis of the 36 adults in the exploratory study after a Age, median (range), y 38 (18-79) median follow-up of 32.6 months found that a plateau Sex, No. (%) Male 160 (61.8) was reached for both RFS and OS.8 Here, we report the Female 99 (38.2) long-term RFS and OS from the pooled phase 2 studies Race, No. (%) White 205 (79.2) to further substantiate long-term survival outcomes after Asian 8 (3.1) therapy with blinatumomab. Black (or African American) 7 (2.7) American Indian or Alaska Native 1 (0.4) Native Hawaiian or other Pacific Islander 1 (0.4) MATERIALS AND METHODS Other 12 (4.6) Unknown 25 (9.7) The design and conduct of the 2 studies included in Primary refractory, No. (%) 25 (9.7) this analysis have been published.6,7 In brief, both were Prior relapses, No. (%) 1 146 (56.2) open-label, single-arm, phase 2 studies in adult patients ≥2 88 (34.0) with R/R B-cell precursor ALL. The study protocols Prior HSCT, No. (%) Yes 88 (34.0) were approved by the independent ethics committee No 171 (66.0) of each study site, and all patients provided written in- Bone marrow blasts formed consent before any study-specific procedures were No. 255 Mean (SD), % 66.7 (31.1) performed. Overall, 259 patients with Philadelphia Bone marrow blasts, No. (%) chromosome–negative disease were included in this anal- ≤5% 6 (2.3) >5 to <10% 10 (3.9) ysis; 2 patients with Philadelphia chromosome–positive 10 to <50% 61 (23.6) disease from the confirmatory study were excluded. ≥50% 178 (68.7) Unknown 4 (1.5) In both studies, a treatment cycle consisted of a Cytogenetic factors, No. (%) continuous intravenous infusion of blinatumomab for t(4;11) 16 (6.2) 4 weeks followed by a 2-week treatment-free interval.6,7 ECOG performance status, No. (%) 0 90 (34.7) Patients in the dose-finding part of the exploratory study 1 129 (49.8) received blinatumomab at 15 µg/m2/d over the entire 2 38 (14.7) Unknown 2 (0.8) treatment period; at 5 µg/m2/d in week 1 and then at 15 µg/m2/d thereafter; or at 5 µg/m2/d in week 1, at Abbreviations: ECOG, Eastern Cooperative Oncology Group; HSCT, hemat- opoietic stem cell transplantation; SD, standard deviation. 15 µg/m2/d in week 2, and at 30 µg/m2/d thereafter.7 Patients in the confirmatory study received blinatum- omab at 9 μg/d in week 1 and at 28 μg/d thereafter.6 proportion of patients who underwent HSCT, and the pro- Kaplan-Meier estimates of median OS and median portions of relapse-free survivors with and without HSCT. RFS and rates of OS and RFS were determined for the Cox regression modeling was used to explore the relation- overall patient population; the Kaplan-Meier estimate of ship between baseline and postbaseline factors and OS and median OS was also determined for patients who under- RFS; postbaseline factors were modeled as time-dependent went HSCT. Because a failure to consider competing risks covariates. can lead to biased results when the follow-up period is long, the cumulative incidence function of the time to RESULTS relapse, with death not due to relapse considered a com- In this pooled analysis of 259 patients, the baseline char- peting risk, was determined for patients who achieved a acteristics were similar to those of patients in individual complete remission (CR) or complete remission with par- trials (Table 1).6,7 The baseline characteristics, the number tial hematologic recovery (CRh) within 2 cycles. of treatment cycles, and the outcomes by RFS and OS sta- Patient clinical outcomes are presented by survival sta- tus with and without HSCT are provided in the support- tus: <36-month OS or ≥36-month OS (alive at the month ing information (Supporting Tables 1 and 2). The median 36 follow-up). Most events occur within 24 months of treat- OS was 7.5 months (95% confidence interval [CI], 5.5- ment initiation.1 The evaluated clinical outcomes were the 8.5 months) after a median follow-up duration of 36.0 best overall response in the first 2 cycles, the minimal residual months (range, 0.3-60.8 months; Fig. 1A). The median disease (MRD) response after blinatumomab (<10−4 detect- RFS for those who achieved a CR/CRh in the first 2 cycles able blasts by quantitative polymerase chain reaction), the (n = 123) was 7.7 months (95% CI, 6.2-10.0 months) Cancer   February 15, 2021 555 Original Article A 26  _   _ &HQVRUHG       26 .0(VWLPDWH 3UREDELOLW\RI26  _  _        _ __ _   _  ______ _ _ __ _     1XPEHURI3DWLHQWVDW5LVN