Long-Term Follow-up of the Combination of Low-Intensity Chemotherapy Plus Inotuzumab Ozogamicin with or without Blinatumomab in Patients with Relapsed-Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Phase 2 Trial
Authors: Sasaki Koji , Kantarjian Hagop M. , Ravandi Farhad , Short Nicholas J. , Kebriaei Partow , Huang Xuelin , Jain Nitin , Konopleva Marina , Garcia-Manero Guillermo , Champlin Richard E. , Kadia Tapan M. , Takahashi Koichi , Daver Naval , Rafei Hind , Khoury Joseph D. , Jorgensen Jeffrey L. , Wang Sa A , Khouri Maria R , Jacob Jovitta , Garris Rebecca , O'Brien Susan M. , Jabbour Elias 
Published: November 2020

Background:

The outcome of patients with relapsed-refractory (R-R) acute lymphoblastic leukemia (ALL) is poor. Inotuzumab ozogamicin and blinatumomab are highly active single agents in R-R ALL. The combination of inotuzumab with low-intensity mini-hyper-CVD chemotherapy showed encouraging results in this patient population. The sequential addition of blinatumomab might optimize the efficacy of the regimen, reduce its toxicities, and further improve outcomes in R-R ALL. The aim of the analysis is to evaluate the efficacy and safety of inotuzumab ozogamicin plus low-intensity chemotherapy with or without blinatumomab in R-R ALL.

Methods:

Patients with relapsed-refractory Philadelphia chromosome-negative ALL were eligible. The mini-hyper-CVD (cycles 1, 3, 5, 7) were comprised of 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 anthracyclines. Even cycles (cycles 2, 4, 6, 8) were comprised of 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 the 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 allogeneic hematopoietic cell transplantation (HCT) was based on the discretion of the treating physician after discussion with the patient.

Results:

From 2/2013 to 9/2019, 96 patients were enrolled and treated including 29 patients with mini-hyper-CVD + inotuzumab + blinatumomab. The median follow-up is 36 months (range, 0.1-87.5). Patient characteristics and outcome are summarized in Table 1. The median age was 37 years (range, 17-87), and 20% of patients had received prior HCT. The overall response rate was 80% (CR, 57%, CRp/CRi, 20%). These rates were 91% in salvage(S) 1 (primary refractory, 100%; CR1 duration &lt;12 months, 84%; CR1 duration &gt;12 months, 94%) 61% inS2, and 57% in S3 or higher. Among 75 evaluable patients for minimal residual disease (MRD) assessment, 62 patients (83%) achieved negative MRD by multi-color flow cytometry with higher rates of MRD negativity in S1 (89%). Forty four patients (46%) received HCT. Three-year CR duration and overall survival (OS) rates were 32% and 33%, respectively (Figure 1). The 3-year OS rates for patients treated in S 1 and S 2+ were 42% and 13%, respectively (p=0.002). Historical comparison showed median OS of 13 months versus 6 months in hyper-CVD + inotuzumab ozogamicin +/- blinatumomab versus inotuzumab ozogamicin single agent, respectively (p&lt;0.001) (Figure 2). Among the 96 evaluable patients, VOD was observed in 10 (10%). The incidence of VOD was reduced from 9/67 (13%) with single dose of inotuzumab ozogamicin to 1/29 (3%) with fractionated dose schedule. Of the 17 patients treated with mini-hyper-CVD + inotuzumab ozogamicin + blinatumomab, 15 patients underwent HCT; among 15 patients, 1 patient developed VOD.

Conclusion: The long-term follow-up of the combination of inotuzumab ozogamicin plus/minus blinatumomab with low-intensity mini-hyper-CVD chemotherapy continues to show promising results in patients with relapsed/refractory ALL. The risk of VOD can be minimized with a fractionated inotuzumab ozogamicin followed by blinatumomab schedule.

Disclosures

Sasaki: Novartis: Consultancy, Research Funding; Otsuka: Honoraria; Pfizer Japan: Consultancy; Daiichi Sankyo: Consultancy. Kantarjian:Aptitute Health: Honoraria; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Oxford Biomedical: Honoraria; Novartis: Honoraria, Research Funding; BMS: Research Funding; Delta Fly: Honoraria; Janssen: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; Ascentage: Research Funding; Jazz: Research Funding; BioAscend: Honoraria; Abbvie: Honoraria, Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding. Ravandi:Macrogenics: Research Funding; Celgene: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria. Short:Astellas: Research Funding; Takeda Oncology: Consultancy, Honoraria, Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy. Kebriaei:Jazz: Consultancy; Amgen: Other: Research Support; Ziopharm: Other: Research Support; Pfizer: Other: Served on advisory board; Kite: Other: Served on advisory board; Novartis: Other: Served on advisory board. Jain:TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; ADC Therapeutics: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Incyte: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Ascentage: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Kisoji: Consultancy; Forty-Seven: Consultancy, Research Funding; Agios: Research Funding; Eli Lilly: Research Funding; Rafael Pharmaceutical: Research Funding; Calithera: Research Funding; Ablynx: Research Funding; AstraZeneca: Research Funding; Sanofi: Research Funding; Cellectis: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; AbbVie: Consultancy, Research Funding; Amgen: Consultancy; Genentech: Consultancy, Research Funding. Garcia-Manero:Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Novartis: Research Funding; Amphivena Therapeutics: Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Champlin:Takeda: Patents & Royalties; Omeros: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Cytonus: Consultancy; Johnson and Johnson: Consultancy; Actinium: Consultancy; Genzyme: Speakers Bureau. Kadia:Genentech: Honoraria, Research Funding; Astellas: Research Funding; Cyclacel: Research Funding; Cellenkos: Research Funding; Astra Zeneca: Research Funding; JAZZ: Honoraria, Research Funding; Celgene: Research Funding; Pulmotec: Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding; BMS: Honoraria, Research Funding; Incyte: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Ascentage: Research Funding. Daver:Fate Therapeutics: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rafei:United States Provisiona: Patents & Royalties: I have a filed patent. O'Brien:Pharmacyclics: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding; Vida Ventures: Consultancy; Pfizer: Research Funding; Celgene: Consultancy; Eisai: Consultancy; KITE: Research Funding; Regeneron: Research Funding; Amgen: Consultancy; Vaniam Group LL: Consultancy; AbbVie: Consultancy; Verastem: Consultancy; Janssen Oncology: Consultancy; Gilead: Consultancy; Sunesis: Research Funding; Alexion: Consultancy; Aptose Biosciences: Consultancy; Juno Therapeutics: Consultancy; GlaxoSmithKline: Consultancy; Astellas: Consultancy. Jabbour:Takeda: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding.