Phase II Study of Blinatumomab in Patients with B-Cell Lineage Acute Lymphocytic Leukemia with Positive Minimal/Measurable Residual Disease
Authors: Aboudalle Iman , Kantarjian Hagop M. , Short Nicholas J , Khouri Maria , Takahashi Koichi , Ohanian Maro N. , Borthakur Gautam , Konopleva Marina Y. , Daver Naval G. , Estrov Zeev E. , Alvarado Yesid , Jain Nitin , Ravandi Farhad , Garcia-Manero Guillermo , Velasquez Michelle , Nasnas Patrice , O'Brien Susan M. , Jabbour Elias J. 
Published: October 2019

Abstract
Background: The majority of adult patients (pts) with B-cell precursor acute lymphoblastic leukemia (B-ALL) can achieve complete remission (CR) with conventional multi-agent chemotherapy regimens, with only 30 to 50% of them achieving a long-term cure. Persistence of minimal/measurable residual disease (MRD) is associated with poor event-free and overall survival. Blinatumomab, a CD19/CD3 bispecific T-cell engager antibody construct, is capable of eradicating MRD in precursor B-ALL, and possibly prolong survival. We aimed to evaluate blinatumomab in pts with precursor B-ALL who did not achieve MRD negativity after initial therapy or who had MRD relapse.
Methods: This is an open-label, single-arm, phase II trial including pts with B-ALL in CR who had either not achieved MRD negativity or had MRD-positive relapse, starting any time after ≥3 months (mo) of frontline therapy, or in CR2 and beyond after at least 1 mo of salvage therapy. Positive MRD was defined as ≥1 x 10-4 by 6-color multi-parameter flow cytometry. MRD for pts with Philadelphia chromosome positive (Ph+) ALL was defined as BCR-ABL1 to ABL1 transcripts ratio of ≥ 0.1% IS by RT-PCR. Pts received continuous IV infusion of blinatumomab 28 µg/day over 4 weeks followed by 2 weeks treatment-free interval. For the first cycle, blinatumomab was initiated at 9 µg/day for 1 week and then escalated to 28 µg/day, if tolerated. A TKI of treating physician's choice was added to the regimen for pts with Ph+ ALL. Responders could receive up to 4 additional consolidation cycles, and subsequent allogeneic stem cell transplantation (ASCT) was offered depending on donor availability. Pts who do not proceed with ASCT may receive blinatumomab maintenance therapy with one cycle every 3 mo for up to 4 cycles (9 cycles total). Relapse-free survival (RFS) was the primary endpoint. Secondary endpoints were the MRD negativity rate at any time and after cycle 1, event-free survival, overall survival (OS), and safety profile.
Results: Between 12/2015 and 05/2017, we enrolled 17 pts with precursor-B ALL in CR. Baseline characteristics are shown in Table 1. Three pts (18%) had Ph+ ALL. Twelve pts (70%) were in CR1, and 5 pts (30%) were in CR2 and beyond. Eleven (65%) pts had persistent MRD, and 6 (35%) pts had MRD relapse.
Pts received a median of 2 cycles (range, 1-5) of blinatumomab. Thirteen out of the 17 pts (76%) achieved MRD negative status at a median time of 41 days (range, 29-92), 3 pts did not achieve a response after 2 cycles, and 1 pt progressed during the first cycle. Of the 13 responders, 12 pts (92%) responded after the first cycle; 1 pt responded after the second cycle. Of them, 6 pts (46%) proceeded to ASCT with median time from enrollment to ASCT of 3 mo (range, 2-6 mo).
Therapy was well tolerated. Blinatumomab-related adverse events of any grade were observed in 6 pts (35%). These adverse events included cytokine release syndrome in 3 pts (grade 3, n=1; grade 2, n=2), grade 3 encephalopathy (n=1), grade 3 psychosis (n=1), and grade 1 confusion (n=1). All resolved with supportive management. No pts discontinued blinatumomab due to adverse events. With a median follow-up of 14 mo (range, 2-30 mo), 12 pts (71%) are alive. 8 pts (62%) have remained in remission for more than one year, 5 of them had received ASCT. The 1-year OS and RFS rates were 75% and 68%, respectively (Figure 1).
Conclusion: Blinatumomab is well tolerated and is highly effective in eradicating MRD in pts with precursor B-ALL who have persistent MRD or who experience MRD relapse after intensive chemotherapy.

Disclosures
Short: Takeda Oncology: Consultancy. Konopleva:Immunogen: Research Funding; abbvie: Research Funding; cellectis: Research Funding; Stemline Therapeutics: Research Funding. Daver:ARIAD: Research Funding; Novartis: Consultancy; BMS: Research Funding; Incyte: Consultancy; Sunesis: Research Funding; Pfizer: Research Funding; Kiromic: Research Funding; Karyopharm: Research Funding; ImmunoGen: Consultancy; Pfizer: Consultancy; Sunesis: Consultancy; Otsuka: Consultancy; Incyte: Research Funding; Daiichi-Sankyo: Research Funding; Karyopharm: Consultancy; Alexion: Consultancy; Novartis: Research Funding. Jain:ADC Therapeutics: Research Funding; Pfizer: Research Funding; Pfizer: Research Funding; Astra Zeneca: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; BMS: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Infinity: Research Funding; Abbvie: Research Funding; Infinity: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Genentech: Research Funding; ADC Therapeutics: Research Funding; Genentech: Research Funding; BMS: Research Funding; Seattle Genetics: Research Funding; Adaptive Biotechnologioes: Research Funding; Incyte: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ravandi:Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Seattle Genetics: Research Funding; Orsenix: Honoraria; Macrogenix: Honoraria, Research Funding; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Jazz: Honoraria; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Abbvie: Research Funding. O'Brien:Sunesis: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Aptose Biosciences Inc.: Consultancy; Vaniam Group LLC: Consultancy; Regeneron: Research Funding; TG Therapeutics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy; Acerta: Research Funding; Kite Pharma: Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy; Celgene: Consultancy; Alexion: Consultancy; Astellas: Consultancy. Jabbour:novartis: Research Funding.