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4043 The Addition of Inotuzumab Ozogamicin to Hyper-CVAD Plus Blinatumomab Further Improves Outcomes in Patients with Newly Diagnosed B-Cell Acute Lymphoblastic Leukemia: Updated Results from a Phase II StudyClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster III
Hematology Disease Topics & Pathways:
Research, clinical trials, Lymphoid Leukemias, ALL, Clinical Research, Combination therapy, Diseases, Therapies, Lymphoid Malignancies
Monday, December 12, 2022, 6:00 PM-8:00 PM

Nicholas Short, MD1, Elias Jabbour, MD2, Farhad Ravandi, MD2, Musa Yilmaz, MD3, Tapan M. Kadia, MD3, Philip A. Thompson, MBBS2, Xuelin Huang, PhD4*, Marina Konopleva, MD, PhD1, Alessandra Ferrajoli1, Nitin Jain, MD3, Koji Sasaki, MD2, Walid Macaron, MD, MSc2*, Yesid Alvarado, MD2, Gautam Borthakur, MD2, Courtney D. DiNardo, MD, MSCE2, Maro Ohanian, DO2*, Steven M. Kornblau, MD2, Min Zhao2*, Monica Kwari, BSN2, Jennifer Thankachan2*, Christopher Loiselle, BS2*, Ricardo Delumpa, BSN2*, Rebecca Garris2* and Hagop Kantarjian, MD5

1Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
3Department of Leukemia, MD Anderson Cancer Center, Houston, TX
4Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
5Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: Blinatumomab and inotuzumab ozogamicin (INO) both improve overall survival (OS) compared with chemotherapy in patients (pts) with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). Blinatumomab is also FDA-approved for eradication of persistent or recurrent measurable residual disease (MRD) after initial ALL-directed therapy. We hypothesized that early incorporation of blinatumomab in pts with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell ALL would lead to deeper and more durable responses, reduce relapses, and improve survival. We subsequently amended this study to add INO in order to further improve outcomes.

Methods: We conducted a phase II study to evaluate the efficacy and safety of hyper-CVAD with sequential blinatumomab, with or without INO, in pts with newly diagnosed Ph-negative B-cell ALL. Pts 14-59 years of age with newly diagnosed Ph-negative B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts had to have a performance status of ≤3, total bilirubin ≤2 mg/dl, creatinine ≤2 mg/dl, and no significant CNS pathology (except for CNS leukemia). Pts received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to 4 cycles, followed by 4 cycles of blinatumomab at standard doses. Pts with CD20+ disease (≥1% cells) received 8 doses of ofatumumab (2000 mg) or rituximab (375 mg/m2). Eight doses of prophylactic IT chemotherapy were given. Maintenance was with alternating blocks of POMP (given in maintenance cycles 1-3, 5-7, 9-11, and 13-15) and blinatumomab (given in maintenance cycles 4, 8, and 12). Those with high-risk disease features started blinatumomab after 2 cycles of hyper-CVAD. Beginning with pt #39, INO at a dose of 0.3 mg/m2 on day 1 and 8 was added to the 2 cycles of MTX/Ara-C and to 2 cycles of blinatumomab consolidation (4 total cycles with INO).

Results: As of June 2022, 62 pts have been treated (38 without INO and 24 with INO). Pt characteristics are summarized in Table 1. The median age was 34 years (range, 18-59 years). 32 pts (52%) had ≥1 high-risk pretreatment characteristic at enrollment (e.g. poor-risk cytogenetics, CRLF2 positivity by flow and/or TP53 mutation). 14 pts were in CR at enrollment, 7 of whom were MRD-negative by flow.

Among 48 pts with active disease at study entry, 100% achieved CR, with 81% achieving CR after the first cycle. MRD negativity by 6-color flow cytometry was achieved in 37/53 evaluable pts (70%) after 1 cycle and 48/53 evaluable pts (91%) overall. Two of the 5 pts who did not achieve MRD negativity were later found to have a NUP214::ABL1 fusion, 1 had KMT2A rearrangement, and 2 are still early in treatment and have received only 1 cycle.

The median duration of follow-up is 23 months (range, 1-63 months). Overall, 6 pts (10%) relapsed while on study, 20 pts (32%) underwent stem cell transplantation (SCT) in first remission (2 of whom relapsed post-SCT), 2 pts (3%) died in CR, and 34 pts (55%) remain in continuous remission without SCT. All relapses occurred in pts with ≥1 poor-risk feature(s), and no relapses have occurred beyond 2 years from the start of treatment.

For the entire cohort, the 3-year continuous remission duration (CRD) and OS rates were 83% and 84%, respectively (Figure 1). The 3-year OS rate for pts without a high-risk baseline feature was 90% and was 78% for pts with ≥1 high-risk feature. In a landmark analysis, there was no difference in outcomes between pts who underwent SCT in first remission versus those who did not (3-year OS: 86% versus 88%). In the INO group, only 1 pt has relapsed and none has died. This pt had CNS disease at the time of enrollment and had a CNS-only relapse after 16 months of remission. The estimated 1-year CRD and OS rates in the INO cohort were both 100% (Figure 2).

Treatment was overall well-tolerated. One pt discontinued blinatumomab due to a related adverse event (grade 2 encephalopathy and dysphasia). No pts discontinued INO due to toxicity, and no cases of veno-occlusive disease have been observed.

Conclusion: The addition of INO to hyper-CVAD with sequential blinatumomab is safe and highly effective as frontline treatment of Ph-negative B-cell ALL. This study shows the feasibility of incorporating both INO and blinatumomab into the frontline treatment of pts with B-cell ALL. Outcomes of the pts treated in the INO cohort are particularly promising.

Disclosures: Short: Novartis: Consultancy; Astellas: Research Funding; Takeda Oncology: Consultancy, Research Funding; Pfizer: Consultancy; Stemline Therapeutics: Research Funding; AstraZeneca: Consultancy; Amgen: Consultancy, Honoraria. Jabbour: Spectrum: Research Funding; Takeda: Other: Advisory Role, Research Funding; Amgen: Other: Advisory Role, Research Funding; Bristol Myers Squibb: Other: Advisory Role, Research Funding; Genentech: Other: Advisory Role, Research Funding; Pfizer: Other: Advisory Role, Research Funding; Adaptive Biotechnologies: Other: Advisory Role, Research Funding; AbbVie: Other: Advisory Role, Research Funding. Ravandi: AstraZeneca: Consultancy; Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Xencor: Research Funding; Biomea Fusion, Inc.: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Prelude: Research Funding; Syos: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Amgen: Honoraria, Research Funding. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Kadia: Abbvie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Agios: Consultancy; Glycomimetics: Research Funding; Genfleet: Research Funding; AstraZeneca: Research Funding; Delta-Fly: Research Funding; Amgen: Research Funding; cyclacel: Research Funding; Genentech: Consultancy, Research Funding; Ascentage: Research Funding; Servier: Consultancy; cellenkos: Research Funding; Astex: Honoraria; Pfizer: Research Funding; Astellas: Research Funding; Iterion: Research Funding; PinotBio: Consultancy; Novartis: Consultancy; JAZZ: Consultancy, Research Funding; Regeneron: Research Funding. Thompson: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; AbbVie, Gilead, Janssen, Pharmacyclics, Adaptive Biotechnologies, Genentech, Amgen: Honoraria; AbbVie, Gilead, Janssen, Pharmacyclics, Adaptive Biotechnologies, Genentech: Consultancy; AbbVie, Pharmacyclics, Adaptive Biotechnologies, Genentech: Research Funding. Konopleva: Sanofi: Other: grant support, Research Funding; Novartis: Patents & Royalties, Research Funding; Rafael Pharmaceutical: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ablynx: Other: Grant support, Research Funding; Calithera: Other: Grant Support, Research Funding; Cellectis: Consultancy, Other: Grant support, Research Funding; Eli Lilly: Consultancy, Patents & Royalties, Research Funding; Reata Pharmaceuticals: Current equity holder in private company, Patents & Royalties; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kisoji: Consultancy, Honoraria; Amgen: Consultancy; Forty-Seven: Consultancy, Honoraria, Other: Grant support; Stemline Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grant support, Research Funding; Genentech: Consultancy, Other: grant support, Research Funding; AbbVie: Consultancy, Other: grant support, Research Funding. Ferrajoli: 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; Beigene: Research Funding. Jain: Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support; Medisix: Research Funding; TransThera Sciences: Research Funding; Servier Pharmaceuticals LLC: Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support, Research Funding; ADC Therapeutics: Research Funding; Cellectis: Honoraria, Research Funding; Loxo Oncology: Research Funding; Takeda: Research Funding; Mingsight: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; TG Therapeutics: Honoraria; Pharmacyclics, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Ipsen: Honoraria; CareDx: Honoraria; Genentech, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; Beigene: Honoraria; MEI Pharma: Honoraria; Novalgen: Research Funding; Fate Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Pfizer: Research Funding; Dialectic Therapeutics: Research Funding; Newave: Research Funding; Cellectis: Honoraria, Research Funding; Incyte Corporation: Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding. Sasaki: Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Otsuka Pharmaceuticals: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Alvarado: BerGenBio: Research Funding; Astex Pharmaceuticals: Research Funding; Daiichi-Sankyo/Lilly: Research Funding; Jazz Pharmaceuticals: Research Funding; Sun Pharma: Research Funding; FibroGen: Research Funding. Borthakur: Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding. DiNardo: Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; Foghorn: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Cleave: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; LOXO: Research Funding; Novartis: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Forma: Research Funding; AbbVie: Consultancy, Research Funding; Astex: Research Funding; GenMab: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Honoraria; Jazz: Honoraria; Takeda: Honoraria. Kantarjian: Jazz Pharmaceuticals: Research Funding; ImmunoGen: Research Funding; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; NOVA Research: Honoraria; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria.

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*signifies non-member of ASH