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.


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.


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 <12 months, 84%; CR1 duration >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<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.


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.


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.

Author notes

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