Abstracts Clinical Lymphoma, Myeloma & Leukemia September 2023 S336 20th August 1953 Hospital, Casablanca, Morocco Surveillance Epidemiology and End Results data revealed an ageadjusted incidence rate of 1.5/100,000 cases per year, with a CML median age of onset of 65 years and incidence that increases with age. This is a retrospective descriptive study of CML patients >60 years, within our department, over 16 years [January 2004-December 2020]. All patients whose diagnosis was confirmed by t(9; 22) on bone marrow karyotype and/or BCR-ABL transcript on FISH were included. The disease was classified as chronic (CP), accelerated (AP), or acute transformation (AT) phase of CML according to the WHO 2016 classification. The treatment was generic imatinib. A total of 55/256 patients were included in this study, i.e, 21% of the total series. Their median age was 65 years [60-88 years], with a sex ratio (M/F):0.7. Forty-four patients (80%) had no pathological history, smoking (5%), exposure to pesticides (7%), and neoplasia in the family (7%). The most frequent reason for consultation was splenomegaly (65%), with an average splenic overhang of 10 cm [425 cm]. Major hyperleukocytosis >100,000/mm3 was found in 65% of cases. The Sokal score was low (31%), intermediate (23%), and high (46%). Karyotype was done in 52 patients, of which 90% had t(9;22), and 11% had FISH objectifying BCR-ABL rearrangement. Nine patients had ACA at diagnosis. Different phases in our series were: chronic (95%), accelerated (2%), and CML TA (3%). Imatinib treatment in CPs resulted in RCyC in 24/52 patients (46%), partial remission (1%), 11% in failure, and 17 patients (32%) had no status. In patients in RCyC, we performed RT-PCR in 16 patients (67%): 5 were in MR3, 3 in MR4.0, 2 in MR4.5, 2 in MR5.0, no MR in 1, and RMP in 3 patients. In this category (PC): 32 patients are alive (61%), 2 deceased (3%), and 18 lost to follow-up (15%). Treatment toxicity was usually hematologic and extra hematologic and didn’t lead to treatment discontinuation. Imatinib should be considered for elderly patients because of its lower toxicity and efficacy. We were hampered by the absence of RT-PCR monitoring for molecular follow-up, our study’s 46% RCyC rate, which remains below the literature. Keywords: CML, elderly, imatinib, molecular follow up CML-305 Discovery of a Selective PROTAC Degrading Untamable BCR::ABL1 Compound Mutants in Chronic Myelogenous Leukemia (CML )and Philadelphia Chromosome‑Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Milad Rouhimoghadam PhD1, Hua Tang PhD2, Briana Bates MSc1, Junzhuo Liao PhD2, Daniela Uribe-Cano BS1, Weiping Tang PhD2, Michael Deininger MD, PhD3 1Versiti Blood Research Institute, Milwaukee, USA. 2University of Wisconsin-Madison, Madison, USA. 3Versiti Blood Research Institute, Milawukee, USA The oncogenic BCR::ABL1 tyrosine kinase is the defining molecular feature of CML and a key driver in approximately 30% of Ph+ ALL cases. Point mutations within BCR::ABL1 gene are the best characterized mechanism of resistance to tyrosine kinase inhibitors (TKIs). BCR::ABL1 compound mutants (≥ 2 mutations in the same BCR-ABL1 molecule) are present in some patients with failure to multiple ABL1 inhibitors, conferring high levels of resistance to all approved TKIs. In addition to mutation status, the kinase-independent functions of BCR::ABL1 can contribute to leukemogenesis, reflecting a scaffold function of BCR::ABL1. Disruption of these functions will require elimination of BCR::ABL1 protein which can be achieved with Proteolysis-Targeting Chimeras (PROTACs). BCR::ABL1-targeted PROTACs reported so far are active in micromolar range and their ability to degrade BCR::ABL1 compound mutants have yet-to-be evaluated. No clinical BCR::ABL1-targeted PROTACs has been reported. As a first step toward generating an effective therapeutic strategy to selectively target and degrade native and compound mutant BCR::ABL1, we synthesized 4 series of PROTACs (>500 compounds) which consist of either ponatinib or asciminib as a target warhead linked to either to DCAF-1 or CRBN-recruiting ligands via different linkers. Utilizing our high-throughput screening platform, we identified the LPA-81 which encompass asciminib as a targeting warhead domain and a CRBN ligand as an E3 ligase recruiter that potently degrade BCR::ABL1 with the maximal level of degradation (Dmax) of 98% and a DC50=0.01μmol/L within 24hours via proteasomal machinery. Notably, LPA-81 is capable of degrading BCR::ABL1 oncoprotein that harbor single and/or compound mutations at concentration as low as 0.1 μmol/L. We further demonstrated the strong synergy between ponatinib and LPA-81 leading to increase in degradation potency of LPA-81 against BCR::ABL1 compound mutants. Mechanistically, we discovered that LPA-81 enhances the binding affinity of ponatinib to the ATP site of BCR::ABL1 which results in the formation of stable assembled inactive conformation of BCR::ABL1, a conformational state which is required for optimal degradation of BCR::ABL1 via LPA-81. More importantly, LPA-81 is highly selective and exhibited favorable pharmacokinetics in vivo. Altogether, our data suggest that LPA-81 has a potential to advance to clinical trials in BCR::ABL1-positive leukemia. Keywords: CML, BCR::ABL1, PROTAC, degrader, TKI CML-310 Early Cytogenetic or Molecular Landmark Response to Ponatinib Treatment Predicts Outcomes in Heavily Pretreated Patients With Chronic‑Phase Chronic Myeloid Leukemia (CP‑CML) in PACE: 5‑Year Data Martin C. Müller MD1, Jorge Cortes MD2, Charles Chuah MD3, Daniel J. DeAngelo MD, PhD4, Michael Deininger MD, PhD5, François Guilhot MD6, Timothy Hughes MD, MBBS7, Franck E. Nicolini MD, PhD, HDR8, Javier Pinilla-Ibarz MD, PhD9, Delphine Rea MD, PhD10, Gianantonio Rosti MD11, Neil P. Shah MD, PhD12, Moshe Talpaz MD13, Vickie Lu PhD14, Thihan Padukkavidana PhD14, Hagop M. Kantarjian MD15 1Institute for Hematology and Oncology (IHO GmbH), Mannheim, Germany. 2Georgia Cancer Center, Augusta, USA. 3Singapore
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