Abstracts Clinical Lymphoma, Myeloma & Leukemia September 2023 S350 MR4, MR4.5, complete hematological response, BCR::ABL1IS ≤1% at/ by scheduled time points, duration of and time to first MMR, MR4, and MR4.5, time to treatment failure, event-free survival, progressionfree survival, overall survival, and time to discontinuation due to lack of efficacy, treatment failure, disease progression, suboptimal response, or death; and change from baseline in overall scores and individual scales of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires QLQ-C30 and QLQ-CML24. Conclusions: Recruitment began in November 2022. As of May 16, 2023, 94 patients have been randomized and are receiving treatment; 10 more are in screening. Patients will be treated until approximately 64 discontinuations of either study treatment due to AEs occur. Treatment duration is expected to be 2–4.5years. Keywords: asciminib, CML, TKI, nilotinib CML-593 The Novel BCR::ABL1 Allosteric Inhibitor HS‑10382/TERN‑701 is Potent Against Mutations Resistant to Active Site Tyrosine Kinase Inhibitors (TKIs) and Acts Synergistically With TKIs in BCR::ABL1+ Cancer Cell Lines Benjamin Parsons MSc1, Christopher Jones PhD1, Danni Sun PhD2, Yunfan Li PhD2, Xiaogang Lian PhD3, Xiaolei Wang PhD3, Yundong Sun PhD3, Yuanfeng Zhou PhD2, Jeffrey Jasper PhD1 1Terns Pharmaceuticals, Inc, Foster City, USA. 2Translational Medicine Center, Shanghai Hansoh Biomedical Co, Shanghai, China. 3Jiangsu Hansoh Pharmaceutical Group Co., Ltd., Jiangsu, China Context: Although tyrosine kinase inhibitors (TKIs) targeting the ATP-binding site of the BCR::ABL1 oncoprotein are effective therapeutics for chronic myeloid leukemia (CML), patients often develop drug resistance due to ATP-site mutations that inhibit drug binding. TERN-701/HS-10382 acts allosterically to Specifically Target the ABL Myristoyl Pocket (STAMP) of BCR::ABL1, resulting in its inhibition. TERN-701/HS-10382 is designed to circumvent the resistance of active site mutations, with the potential for synergistic combinations with active site TKIs. Objective: To characterize the potency, selectivity, and ability of TERN-701/HS-10382 to work synergistically with active site TKIs. Methods: Substrate phosphorylation assays were used to assess the effect of TERN-701/ HS-10382 on BCR::ABL1 and other kinases. The ability of TERN701/HS-10382 to inhibit the proliferation of wild-type and mutant CML cell lines was assessed using CellTiter-Glo®. Synergy between TERN-701/HS-10382 and active site TKIs was assessed using both fixed molar combinations and expanded combination matrices, with interactions quantified using the Bliss, HSA, and Loewe models. Results: TERN-701/HS-10382 inhibited native BCR::ABL1 in in vitro biochemical assays with an IC50 = 0.4 nM and inhibited cell proliferation in native and mutant cell lines with IC50s of 0.6 – 34.7 nM, depending on genetic background and BCR::ABL1 mutation status. TERN-701/HS-10382 retained activity against the clinically relevant T315I mutation. With respect to selectivity, in an in vitro kinase panel, TERN-701/HS-10382 did not inhibit any kinase by >50% at 1 µM, including full-length ABL1. TERN-701/HS-10382 was highly potent and selective against only BCR::ABL1+ cell lines in cancer cell line panel and was more selective than asciminib. In vitro combination studies revealed that TERN-701/HS-10382 works synergistically with multiple TKIs in the K562 cell line and additively in the Ku812 line. Conclusions: TERN-701/HS-10382 is a potent and selective allosteric inhibitor of BCR::ABL1 in cellfree and cell-based assays and screens, with comparable potency and synergy profiles to that of asciminib while potentially being more selective. TERN-701/HS-10382 retains activity against the T315I gatekeeper mutation, which confers resistance to all approved active site TKIs except for ponatinib, which has known safety liabilities. These data support the continued development of TERN-701/ HS-10382 for the treatment of CML. Keywords: CML, chronic myeloid leukemia, tyrosine kinase inhibitors, allosteric inhibition CML-640 Case Report of Metachronous Ph+ and Ph Myeloproliferative Neoplasms Kamoliddin Olimjonov MD1, Anna Pirkhalo MD2, Elizaveta Efremova MD2, Bekhzodkhon Bakhodirov MD1, Eldor Iskhakov MD, PhD3, Vasily Shuvaev MD, PhD2,4, Irina Martynkevich PhD2, Elena Motyko MD2, Anna Kirienko MD2, Darya Kustova MD2 1Republican Specialized Hematological Scientific and Practical Medical Center, Tashkent, Uzbekistan. 2Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russian Federation. 3Center for the development of professional qualification of medical workers, Tashkent, Uzbekistan. 4Russian Medical Academy of Postgraduate Education, Moscow, Russian Federation Female patient, born in 1953. Polycythemia vera was diagnosed May, 2010 with CBC: HB-18.0 g/dL, platelets (PLT) 479×109/p, WBC 11x109/l; BANS-5, SEG-70, LYM-13, MON-5, BAS-1, EOS6. Histology of bone marrow: Proliferation of three hematopoietic sprouts, MF-1, polycythemia vera. Allele burden of JAK2V617F was 50%. Patient was treated with hydrea and phlebotomy. Since 2019: leukocytosis, a shift of the leukocyte formula to blasts, an increase in splenomegaly. CBC in February, 2020: HB 8.8-g/dL, WBC122.0x109/L, PLT-144x109/L, BLASTS-2, with all intermediate forms, EOS-2.5%, BAS-3.5%. Suspicion of AML. Examined February, 2020: BMA –no blastosis. Cytogenetic BMA -46, XX, t(9;22)(q34;q11) [20]. PCR in February, 2020: BCR::ABL (p210) (t(9;22)) (option b2a2) detected, CALR, MPL, JAK2, ASXL1 not detected, allele burden of JAK2V617F 0%. Histology of BM performed March, 2020: Myeloid tissue 80-100% MF–1, Coll–1, Os–2. Diagnosis: CML, CP on 20 February, 2020. Hasford 1442.54 (INT). Sokal 1.33, EUTOS 93, ELTS 2.9388 (HIGH). Imatinib 400 mг /c 28 February, 2020. 3 month: CHR, BCR::ABL - 1.462%; 12 month: CHR, CCyR, BCR::ABL – 0.232%. PCR 10 March, 2021: 0.070%, MMR. Due to non-hematological intolerance (vomiting, diarrhea), second-line - nilotinib 800mg/day from 11 March, 2021. From April of 2021 thrombocytosis, leukocytosis was detected. RQ-PCR 9 June, 2021: BCR::ABL-0%, splenomegaly +7cm. Allele burden JAK2 V617F was 34%. CBC 20 September, 2021: HGB -
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