Abstracts Clinical Lymphoma, Myeloma & Leukemia September 2023 S310 University Medical Center, Hackensack, NJ, USA. 24MedStar Georgetown University Hospital, Washington, DC, USA. 25Oregon Health & Science University, Portland, OR, USA. 26Baylor Scott & White Health, Dallas, TX, USA. 27Case Western Reserve University, Cleveland, OH, USA. 28D2V Clinical, Raleigh-Durham, NC, USA. 29Actinium Pharmaceuticals, New York, NY, USA. 30Loxo Oncology at Lilly, Stamford, CT, USA. 31David H. Koch Center for Cancer Care at Memorial Sloan Kettering Cancer Center, New York, NY, USA Background: Patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) have dismal outcomes, and <20% undergo allogeneic hematopoietic stem cell transplantation (alloHSCT). Those with venetoclax failure have worse outcomes (median survival, 2–3 months) without alloHSCT. SIERRA investigated the use of iodine-131 apamistamab (Iomab-B), a 131I-labeled anti–cluster of differentiation (CD)-45 monoclonal antibody, to enable alloHSCT in patients with active R/R AML; Iomab-B was compared with conventional care (CC). Aim: To report outcomes from SIERRA patients with failed targeted therapies. Methods: Patients >55 years of age with R/R AML were randomized (1:1) to receive Iomab-B followed by fludarabine, total body irradiation (2 Gy), and alloHSCT or CC (physician’s choice of therapy, including targeted agents and alloHSCT if leukemia-free). Crossover to Iomab-B– based alloHSCT was permitted for CC patients with progression or without complete remission. Results: Of 153 patients, 94 (61%) received targeted therapies, including inhibitors of B-cell lymphoma 2 (BCL-2; venetoclax; 65%), fms-like tyrosine kinase 3 (FLT-3; 24%), and isocitrate dehydrogenase (IDH; 10%) prior to randomization, with a balanced distribution between groups. In the CC group, 27 (35%) received targeted therapies as salvage prior to alloHSCT; of those, 7 (26%) responded and received alloHSCT. Eleven of 20 nonresponders (55%) crossed over to receive Iomab-B followed by alloHSCT. All patients who received Iomab-B (n=66) underwent alloHSCT vs 14 (18.2%) in the CC group. Of evaluable patients (Iomab, 59; CC, 64), durable complete remission (dCR) was achieved in 13 (22%) vs 0. Of the 13 dCR patients, 10 (77%) had prior targeted-therapy failure and 7 (54%) had venetoclax failure; 1-year survival was 90% (9/10) in all prior targeted therapy–failure patients and 85% (6/7) in those with prior venetoclax failure. The overall safety of the groups with and without prior targeted therapy was comparable. Conclusion: Patients with failure of targeted therapies, including venetoclax, were able to undergo alloHSCT with the Iomab-B–led regimen. Of those who achieved dCR with Iomab-B, >70% had previous targeted-therapy failure, including >50% with previous venetoclax failure. The majority of dCR patients were long-term survivors. Iomab-B significantly improves outcomes in patients with prior targeted-therapy failure. (www.sierratrial. com or clinicaltrials.gov NCT02665065). Keywords: acute myeloid leukemia, bone marrow transplant, radioimmunotherapy, conditioning, targeted therapy, phase III AML-522 COVALENT‑101: Phase I Study of BMF‑219, a Covalent Menin Inhibitor, in Adult Patients With AML, ALL (With KMT2A/MLL1 Rearrangements, NPM1 Mutation), DLBCL, MM, and CLL/SLL (NCT05153330) Farhad Ravandi MBBS, MD1, Jeffrey Lancet MD2, Adrian Alegre Amor MD3, Talha Badar MBBS, MD4, Jacqueline Barrientos MD5, Asad Bashey MD, PhD6, Juan Miguel Bergua Burgues MD7, Emily Curran MD8, Jeroen Janssen MD, PhD9, Deepa Jeyakumar MD10, Ashwin Kishtagari MD11, Pau Montesinos MD, PhD12, Daniel Morillo MD13, Aaron Rosenberg MD, MS14, Gary Schiller MD15, Uzma Ahmed MD16, Alex Cacovean MD16, Steve Morris MD16, Courtney Follit PhD16, Clarissa Mandap BSN16, Thomas Butler MS, MBA16, Hetty Carraway MD, MBA17 1The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 2Moffitt Cancer Center, Tampa, FL, USA. 3Hospital Universitario de La Princesa, Madrid, Spain. 4Mayo Clinic, Jacksonville, FL, USA. 5Mount Sinai Medical Center, Miami Beach, FL, USA. 6Blood & Marrow Transplant Group of GA (Northside Hospital), Atlanta, GA, USA. 7Hospital San Pedro de Alcantara, Cáceres, Spain. 8University of Cincinnati Medical Center, Cincinnati, OH, USA. 9Radboud University Medical Center, Nijmegen, Netherlands. 10University of California, Irvine, Irvine, CA, USA. 11Vanderbilt University Medical Center, Nashville, TN, USA. 12Hospital Universitari i Politecnic La Fe, Valencia, Spain. 13Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain. 14UC Davis Comprehensive Cancer Center, Sacramento, CA, USA. 15UCLA Department of Medicine, Los Angeles, CA, USA. 16Biomea Fusion, Redwood City, CA, USA. 17Cleveland Clinic, Cleveland, OH, USA Context: Menin, a protein involved in transcriptional regulation, impacting cell-cycle control, apoptosis, and DNA-damage repair, plays a direct role in oncogenic signaling in multiple cancers. Preclinical data from BMF-219, an investigational, highly selective, orally bioavailable, small-molecule covalent inhibitor of menin, show sustained potent abrogation of menin-dependent oncogenic signaling. BMF-219 is the first investigational menin inhibitor in clinical development to show potential as a therapeutic agent in hematologic malignancies outside of acute leukemia (AL), specifically in subsets of diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM), and chronic lymphocytic leukemia/ small lymphocytic leukemia (CLL/SLL). Objective: To determine independently, for each cohort/indication, the optimal biological dose (OBD) and recommended phase II dose (RP2D) of BMF-219 oral monotherapy. Key secondary objectives include further evaluation of safety and tolerability, characterization of pharmacokinetics and pharmacodynamics, and assessment of antitumor activity. Design: Phase I, prospective, open-label, nonrandomized, dose-escalation and dose-expansion study of BMF-219 in relapsed or refractory (R/R) AL, DLBCL, MM, and CLL. Using an accelerated titration design, doses of BMF-219 will be escalated in single-subject cohorts, independently for each indication, until 1 patient experiences
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