C066 | IMPACT OF LOW LEVELS OF MUTATIONS ON CLINICAL OUTCOME OF PATIENTS WITH CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE.

Treatment with TKIs has generated unprecedented rates of clinical and molecular responses in CML. Despite these impressive results, some CML pts fail their therapy or relapse after initial response because of resistance. Among resistance mechanisms, the emergence of BCR::ABL1 mutations represent the predominant cause, since mutations compromise TKIs contact points and induce BCR::ABL1 conformational changes incompatible with TKIs binding. The emergence of single, compound or low levels of BCR::ABL1 mutations (LLM) highlights the presence of CML genomic instability and of leukemic subclones linked to CML progression. Hence, we investigated the impact of LLM on the clinical outcome of CP-CML pts showing failure response according to ELN guidelines. Among 720 CP-CML pts followed by two hematological centers (Hematology Unit, AOU Policlinico Messina; Hematology and BMT Unit, AOU Policlinico Catania) between 2005 and 2025, 73 patients (10%) were identified and selected for mutation analysis because of resistance. All pts were treated frontline or in later lines with TKIs at conventional doses and gave written informed consent. Samples were centralized in the Center of Experimental Oncology and Hematology of Catania. Mutation analysis detected LLM in 27 out of 73 pts (37%) and driver mutations in 46/73 (63%). We found that pts with LLM showed at diagnosis a median BCR::ABL1/GUSIS transcript level of 26,2% whereas those expressing driver mutations had a median BCR::ABL1/GUSIS of 32,5%, in contrast to optimal responders (median BCR::ABL1/GUSIS 11,97%), Pts with LLM showed more compound mutations (92,6%) than pts with driver mutations (80,5%) and 49,5% of the pts with driver mutations also exhibited LLM. Outcome of the LLM cohort was: 55,5% acquired a major molecular response (MMR) or deeper with subsequent TKI-treatment, 22% showed no response, 15% had CML-related death, 7,5% received SCT. The outcome of those exhibiting driver mutations was: 45% acquired MMR or deeper with subsequent TKI-treatment, 25% showed no response, 28% had CML-related death and 2% received SCT. In summary, CP-CML pts with LLM showed inferior clinical responses as compared to optimal responders even though a proportion acquired benefit from alternative TKI-treatment. High BCR::ABL/GUSIS expression at diagnosis in CP-CML pts successively exhibiting LLM is indicative of higher amounts of BCR::ABL1 transcripts within each leukemic cell, thus representing a sign of possible CML progression.