Sequential Combination of Low-Intensity Chemotherapy (Mini-hyper-CVD) Plus Inotuzumab Ozogamicin with or without Blinatumomab in Patients with Relapsed/Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL): A Phase 2 Trial
Authors: Sasaki Koji , Kantarjian Hagop M. , Ravandi Farhad , Short Nicholas J , Kebriaei Partow , Huang Xuelin , Rytting Michael E. , Jain Nitin , Konopleva Marina Y. , Garcia-Manero Guillermo , Champlin Richard E , Kadia Tapan M. , Cortes Jorge E. , Estrov Zeev E. , Takahashi Koichi , Mace Morgan , Khouri Maria , Nasnas Patrice , Jacob Jovitta , Garris Rebecca E. , Jabbour Elias J. 
Published: October 2019

Abstract
Background:
The combination of low intensity therapy with inotuzumab ozogamicin improved survival compared to intensive chemotherapy and to single agent inotuzumab ozogamicin in first salvage (Jabbour et al. Cancer. 2018 (in press)). The incidence of veno-occlusive disease (VOD) is minimized with weekly divided dosage and reduced dose of inotuzumab ozogamicin per cycle.
Blinatumomab single agent improves survival in relapsed / refractory ALL compared to that of standard chemotherapy. The sequential addition of blinatumomab to mini-hyper-CVD + inotuzumab ozogamicin might further improve survival and minimize the risk of veno-occlusive disease (VOD) by allowing a reduction of inotuzumab dose and spacing allogeneic stem cell transplant (ASCT) from the last dose of inotuzumab.
Methods:
Patients with relapsed / refractory Philadelphia chromosome negative ALL were eligible. The mini-hyper-CVD (cycles 1, 3, 5, 7) comprised cyclophosphamide (150 mg/m2 every 12 h on days 1-3), vincristine (2 mg flat dose on days 1 and 8), and dexamethasone (20 mg on days 1-4 and days 11-14) without anthracycline. Even cycles (cycles 2, 4, 6, 8) comprised methotrexate (250 mg/m2 on day 1) and cytarabine (0.5 g/m2 given every 12 h on days 2 and 3). Rituximab and intrathecal chemotherapy were given for first 4 courses. Inotuzumab ozogamicin was originally given on day 3 of the first four cycles at the dose of 1.3-1.8 mg/m2 at cycle 1, followed by 1.0-1.3 mg/m2 in subsequent cycles. After 67 pts were treated, an amendment was made to incorporate 4 cycles of blinatumomab after 4 cycles of mini-hyper-CVD + inotuzumab ozogamicin. Inotuzumab ozogamicin was given on days 2 and 8 at the dose of 0.6 and 0.3 mg/m2 at cycle 1, respectively, followed by days 2 and 8 at the dose of 0.3 and 0.3 mg/m2 at subsequent cycles; blinatumomab was continuously infused over 28 days every 42-day cycle for 4 cycles. The decision to proceed with ASCT was based on the discretion of the treating physician after discussion with the patient.
Results:
From 2/2013 to 5/2018, 84 patients were enrolled and treated including 17 patients with mini-hyper-CVD + inotuzumab + blinatumomab. The median follow-up is 31 months (range, 0.1-64.1). Patient characteristics and outcome are summarized in Table 1. The median age was 35 years (range, 9-87), and 23% of patients had received prior ASCT. The overall response rate was 80% (CR, 58%, CRp/CRi, 21%). These rates were 92% in S1 (primary refractory, 100%; CR1 duration <12 months, 82%; CR1 duration >12 months, 100%) and 56% in S2, and 60% in S3 or higher. Among 64 evaluable patients for minimal residual disease (MRD) assessment, 51 patients (80%) achieved negative MRD by 6-color flow cytometry with higher rates of negative MRD at 85% in salvage 1. Thirty four patients (40%) received ASCT. Three-year CR duration and overall survival (OS) rates were 49% and 33%, respectively (Figure 1). The median OS was 25 months, 6 months, and 7 months in salvage 1, salvage 2, and salvage 3 or more, respectively (p=0.001). Historical comparison showed median OS of 14 months and 6 months in hyper-CVD + inotuzumab ozogamicin +/- blinatumomab and inotuzumab ozogamicin single agent, respectively (p=0.001) (Figure 2). Among the 79 evaluable patients, VOD was observed in 9 (11%). The incidence of VOD was reduced from 9/61 (15%) with single dose of inotuzumab ozogamicin to 0/18 (0%) with weekly divided dose schedule. Of the 17 patients treated with mini-hyper-CVD + inotuzumab ozogamicin + blinatumomab, 3 patients underwent ASCT (2, haploidentical transplant; 1, cord blood transplant).
Conclusion: The combination of inotuzumab ozogamicin plus/minus blinatumomab with low-intensity mini-hyper-CVD chemotherapy is effective and shows encouraging results in patients with relapsed/refractory ALL. The risk of VOD can be minimized with fractionated inotuzumab ozogamicin dosing.

Disclosures
Sasaki: Otsuka Pharmaceutical: Honoraria. Ravandi:Xencor: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Abbvie: Research Funding; Orsenix: Honoraria; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Macrogenix: Honoraria, Research Funding; Macrogenix: Honoraria, Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Bristol-Myers Squibb: Research Funding. Short:Takeda Oncology: Consultancy. Jain:Verastem: Research Funding; Abbvie: Research Funding; Abbvie: Research Funding; BMS: Research Funding; Seattle Genetics: Research Funding; Genentech: Research Funding; Cellectis: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pfizer: Research Funding; Novimmune: 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; Infinity: Research Funding; Genentech: Research Funding; Infinity: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Servier: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: 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; Incyte: Research Funding; Servier: Research Funding; Pharmacyclics: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Incyte: Research Funding; Verastem: 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; ADC Therapeutics: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Servier: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Stemline Therapeutics: Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Kadia:Pfizer: Consultancy, Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Research Funding; Abbvie: Consultancy; Abbvie: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Celgene: Research Funding; BMS: Research Funding; Novartis: Consultancy. Cortes:Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding. Jabbour:Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Pfizer: Consultancy, Research Funding.