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 B-Cell Acute Lymphoblastic Leukemia
Authors: Haddad Fadi , Kantarjian Hagop , Short Nicholas J. , Sasaki Koji , Ravandi Farhad , Kebriaei Partow , Huang Xuelin , Jain Nitin , Konopleva Marina , Garcia-Manero Guillermo , Champlin Richard E. , Kadia Tapan M. , Takahashi Koichi , Daver Naval , Khoury Joseph D. , Jorgensen Jeffrey L. , Wang Sa A , Jacob Jovitta , Garris Rebecca , O'Brien Susan M. , Jabbour Elias J. 
Published: November 2021

Abstract

Background:
Patients (pts) with relapsed-refractory (R-R) acute lymphoblastic leukemia (ALL) have dismal prognosis. Inotuzumab ozogamicin and blinatumomab monotherapy demonstrated high efficacy in the R-R setting. The combination of low-intensity chemotherapy with mini-hyper-CVD (mini-HCVD) and inotuzumab showed promising activity in R-R ALL. Adding sequential blinatumomab to this regimen might further improve outcomes. This analysis aims to evaluate the efficacy and safety of inotuzumab ozogamicin plus low-intensity chemotherapy with or without blinatumomab in R-R ALL.
Methods:
Eligible pts were diagnosed with Philadelphia chromosome-negative B-cell ALL. Odd cycles of mini-HCVD (cycles 1, 3, 5, 7) consisted of cyclophosphamide (150 mg/m 2 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) consisted of cytarabine (0.5 g/m 2 given every 12 h on days 2 and 3) and methotrexate (250 mg/m 2 on day 1). During the first 4 courses, pts received rituximab when CD20 expression was ≥20%, and intrathecal chemotherapy. Initially, inotuzumab was administered on day 3 of the first 4 cycles at the dose of 1.3-1.8 mg/m 2 at cycle 1, followed by 1.0-1.3 mg/m 2 in subsequent cycles. Pts received maintenance therapy with POMP, consisting of 1 year of monthly prednisone 50 mg/d for 5 days and vincristine at 2 mg every month, along with 3 years of 6-mercaptopurine 50 mg twice daily and weekly oral methotrexate 10 mg/m 2. An amendment to the protocol was made after the inclusion of 67 pts to add 4 cycles of blinatumomab after 4 cycles of the combination mini-HCVD + inotuzumab. Inotuzumab was given on days 2 and 8 at the dose of 0.6 and 0.3 mg/m 2 in cycle 1, respectively, followed by days 2 and 8 at the dose of 0.3 and 0.3 mg/m 2 in subsequent cycles; blinatumomab was continuously infused over 28 days every 42-day cycle for 4 cycles. Maintenance therapy was reduced to 12 cycles of POMP with 1 cycle of blinatumomab after each 3 cycles of POMP for a total of 4 cycles. The decision to undergo allogeneic hematopoietic cell transplantation (HCT) was based on the discretion of the treating physician after discussion with the patient.
Results:
Between February 2013 and April 2021, 108 pts were enrolled and treated, including 41 pts with mini-HCVD + inotuzumab + blinatumomab. The median follow-up is 34 months (range, 2-100). Pts characteristics and outcomes are summarized in Table 1. The median age was 37 years (range, 17-87). Seventy-seven pts (71%) were treated in salvage(S)1, and 31 (29%) in S2 and beyond. Twenty-one pts (19%) had received prior HCT.
Eighty-nine pts responded, for an overall response rate (ORR) of 83% (CR, 62%, CRp/CRi, 21%). ORR was 93% in S1 (primary refractory, 100%; CR1 duration &lt;12 months, 84%; CR1 duration &gt;12 months, 95%), 59% in S2, and 57% in S3 or higher. Among 87 responding pts who were evaluable for measurable residual disease (MRD), 71 pts (82%) achieved MRD negativity by multicolor flow cytometry, with higher rates of MRD negativity in S1 (86%). Forty-seven pts (44%) proceeded to HCT, overall.
Three-year CR duration and overall survival (OS) rates were 48% and 37%, respectively (Figure 1). The 3-year OS rates for pts treated in S1 and S2+ were 46% and 16%, respectively (P=0.001) (Figure 2). Pts who achieved MRD negativity had higher 3-year OS rate of 58% compared to 8% in pts who were MRD-positive at best response (P=0.0003). The combination of mini-HCVD + inotuzumab +/- blinatumomab resulted in a significantly longer median OS compared to inotuzumab monotherapy (14 months vs 6 months; P&lt;0.0001). In a landmark analysis among all responding pts, 3-year OS rates were similar between pts who underwent subsequent HCT and those who did not (51% vs 47%, respectively; P=0.85).
Veno-occlusive disease (VOD) was observed in 10 of the 108 pts (9%), and its incidence was reduced from 13% with single dose of inotuzumab to 2% with fractionated dose schedule (P=0.056). Among the 41 pts treated with mini-HCVD + inotuzumab + blinatumomab, 18 pts proceeded to HCT; of whom 1 patient developed VOD.
Conclusion:
With longer follow-up, promising outcomes continue to be observed with the combination of mini-HCVD + inotuzumab ozogamicin +/- blinatumomab in pts with R-R ALL. Using a fractionated inotuzumab schedule with sequential blinatumomab can help mitigate the risk of VOD. Outcomes appear similar whether or not subsequent HCT is performed.
Figure 1 Figure 1.

Disclosures
Kantarjian: Jazz: Research Funding; Immunogen: Research Funding; Aptitude Health: Honoraria; Ipsen Pharmaceuticals: Honoraria; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria; Astra Zeneca: Honoraria; Amgen: Honoraria, Research Funding; Ascentage: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria; AbbVie: Honoraria, Research Funding; Astellas Health: Honoraria. Short: Takeda Oncology: Consultancy, Research Funding; Novartis: Honoraria; AstraZeneca: Consultancy; Astellas: Research Funding; NGMBio: Consultancy; Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy, Honoraria. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Ravandi: AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Novartis: Honoraria; Amgen: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Prelude: Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Jain: Incyte: Research Funding; Precision Biosciences: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Pfizer: Research Funding; Servier: Honoraria, Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Fate Therapeutics: Research Funding; AstraZeneca: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; TG Therapeutics: Honoraria; Beigene: Honoraria; Janssen: Honoraria; Aprea Therapeutics: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding. Konopleva: Cellectis: Other: grant support; Calithera: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; KisoJi: Research Funding; Agios: Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding. Kadia: Sanofi-Aventis: Consultancy; Ascentage: Other; Cellonkos: Other; Genfleet: Other; Astellas: Other; AstraZeneca: Other; Pulmotech: Other; Pfizer: Consultancy, Other; Novartis: Consultancy; Liberum: Consultancy; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Cure: Speakers Bureau; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. Takahashi: Celgene/BMS: Consultancy; Novartis: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy. Daver: Hanmi: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Novimmune: Research Funding; Astellas: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Glycomimetics: Research Funding; Trillium: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Khoury: Stemline Therapeutics: Research Funding; Angle: Research Funding; Kiromic: Research Funding. Wang: Stemline Therapeutics: Honoraria. O'Brien: Kite, Regeneron, Acerta, Caribou, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Research Funding; Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, AbbVie, Alexion, Verastem, Juno Therapeutics, Vida Ventures, Autolus, Johnson and Johnson, Merck, Bristol Myers Squibb, NOVA Research Company, Eli Lill: Consultancy. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding.