Blinatumomab for Minimal Residual Disease (MRD) in Adults with B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL): Median Overall Survival (OS) Is Not Reached in Complete MRD Responders at a Median Follow-up of 53.1 Months
Authors: Goekbuget Nicola , Dombret Hervé , Zugmaier Gerhard , Bonifacio Massimiliano , Graux Carlos , Faul Christoph , Topp Max S. , Brüggemann Monika , Taylor Kate , Bargou Ralf 
Published: October 2019

Abstract

Background: When adults with BCP-ALL achieve hematologic complete remission with intense chemotherapy, approximately 30% have persistent or recurrent MRD by real-time quantitative polymerase chain reaction or flow cytometry (Brüggemann et al, Blood 2006;107:1116-23). MRD is the strongest predictor of relapse in BCP-ALL. Blinatumomab is a bispecific antibody construct that redirects T cells to kill CD19+ target cells. In a multinational, single-arm study (BLAST; NCT01207388) in adults with BCP-ALL and presence of MRD, we previously reported that 78% (88/113) of evaluable patients achieved a complete MRD response after cycle 1 of blinatumomab treatment (Gökbuget et al, Blood 2018;131:1522-31). Patient incidences of grade 3 or 4 adverse events, including neurologic events (13%) or cytokine release syndrome (2%), were consistent with previous blinatumomab studies. After a minimum patient follow-up of 18 months, median OS was 36.5 months (95% confidence interval [CI]: 19.8 to not estimable).
Objective: This report describes long-term OS for adults with BCP-ALL and MRD, with a minimum patient follow-up of 3 years after blinatumomab treatment.
Methods: The BLAST study enrolled adults with BCP-ALL in first (CR1) or subsequent (CR2+) hematologic complete remission after at least 3 intensive chemotherapy blocks, with MRD (at least 10-3) at least 2 weeks after the last chemotherapy. All patients received blinatumomab 15 µg/m2 per day for up to 4 cycles. Each cycle was 4 weeks of continuous infusion and 2 weeks off. Complete MRD response was defined as no target amplification, with a minimum sensitivity of 10-4. After MRD response assessment at the end of cycle 1, patients could undergo allogeneic hematopoietic stem cell transplantation (HSCT) at any time. Kaplan-Meier estimates of OS were determined, overall and by complete MRD response in cycle 1, after long-term follow-up (a minimum patient follow-up of 3 years). A conditional landmark of 45 days (the end of cycle 1) was used for the subgroup analyses by complete MRD response.
Results: Of the 116 patients with MRD who received blinatumomab, OS was evaluated for the 110 patients with Philadelphia chromosome-negative (Ph-) BCP-ALL and less than 5% blasts at enrollment, including 74 who received HSCT while in continuous complete remission (CCR) after blinatumomab. With a median follow-up of 53.1 months, median OS was 36.5 months (95% CI: 22.0 to not estimable), and a plateau was reached (Figure 1A). In this analysis, 30 of 74 (40.5%) patients with HSCT in CCR and 12 of 36 (33.3%) patients without HSCT were alive in CCR. Analyses of OS by complete MRD response after cycle 1 in 107 patients excluded those with no central MRD assay (n=1) or inadequate MRD test sensitivity (n=2). In this population, median OS was not estimable (95% CI: 27.3 months to not estimable) among complete MRD responders (n=85) and 12.5 months (95% CI: 3.2 to 39.7) among MRD nonresponders (n=22; p=.002 by log-rank test; Figure 1B). In the subset of patients who received HSCT in CCR, median OS from HSCT was not estimable (95% CI: 25.7 months to not estimable) among complete MRD responders (n=61) and 16.1 months (95% CI: 1.1 to not estimable) among MRD nonresponders (n=10). In the subset of patients with MRD in CR1, median OS was not estimable (95% CI: 29.5 months to not estimable) among complete MRD responders (n=60) and 10.6 months (95% CI: 2.7 to 39.7) among MRD nonresponders (n=13).
Conclusions: In this multinational study of adults with BCP-ALL in hematologic complete remission with persistent MRD or MRD relapse at baseline, median OS was 36.5 months after blinatumomab treatment, with median long-term follow-up of 53.1 months, and OS reached a plateau. Median OS was not estimable (ie, not reached) among the patients who had achieved a complete MRD response after cycle 1 of blinatumomab treatment, or among the subsets of patients who had achieved a complete MRD response with blinatumomab either in CR1 or with subsequent HSCT in CCR. These results provide further support for the long-term benefits in OS associated with blinatumomab treatment in adults with BCP-ALL and MRD.

Disclosures
Goekbuget: Kite / Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Other: Travel support, Research Funding; Pfizer: Consultancy, Other: Travel support, Research Funding; Amgen: Consultancy, Other: Travel support, Research Funding. Dombret:Kite Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharma: Consultancy, Honoraria, Research Funding; Ariad (Incyte): Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Agios: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Ambit (Daiichi Sankyo): Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Immunogen: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria, Other: Travel expenses; Karyopharm: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; Shire-Baxalta: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau. Zugmaier:Amgen Inc.: Consultancy, Employment, Patents & Royalties: 20170327581, 9688760, 20170122947, 9486475, 20160208001, 9192665, 20150071928, 8840888, 20140227272, 20140228316, 20130323247, 20130287774, 20130287778, 20110262440, 20100112603, 7700299, 20070037228. Bonifacio:Incyte: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Research Funding; Bristol Myers Squibb: Consultancy. Topp:Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Boehringer Ingelheim: Research Funding. Brüggemann:Amgen: Consultancy, Research Funding, Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau; PRMA: Consultancy; Affimed: Research Funding; Incyte: Consultancy; Regeneron: Research Funding. Taylor:Amgen: Employment, Equity Ownership. Bargou:Novartis: Consultancy, Honoraria; Cellex: Consultancy, Honoraria; Gemoab: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Patents & Royalties: Blinatumomab.