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Abstract Introduction CML is characterized by a reciprocal translocation of t(9;22)(q34;q11), leading to the BCR::ABL1 fusion gene. Most patients have a typical fusion transcript: e13a2 (b2a2) and/or e14a2 (b3a2). However, approximately 2% have an atypical fusion transcript (Cross, 2023) for which there is limited data available about prognosis and response to tyrosine kinase inhibitors (TKIs). Moreover, emerging data show that e13a3(b2a3) and e14a3(b3a3) atypical BCR::ABL1 translocations cannot be inhibited by allosteric TKIs targeting the myristoyl pocket (e.g. asciminib; Leske, 2024; Leyte-Vidal, 2024). In contrast, these translocations should be sensitive to active site TKIs. ELVN-001 is a highly selective active site TKI of BCR::ABL1 with broad pre-clinical activity against native and mutant BCR::ABL1. In patients with typical transcripts, ELVN-001 demonstrated favorable safety and tolerability across a wide range of doses, and encouraging preliminary efficacy was observed. Here, we first report tolerability and anti-CML activity of ELVN-001 in patients with atypical transcripts enrolled in ENABLE (NCT05304377), a phase 1 study of ELVN-001 in patients with previously treated CML. Updated data will be presented at the meeting. Methods Patients with previously treated chronic phase CML who had an atypical transcript received ELVN-001 orally at doses from 20 mg to 160 mg daily in the dose escalation phase of the ENABLE study. Testing for molecular response is non-standardized for atypical transcripts and was therefore assessed locally by individual molecular response (Schäfer, 2021). Results As of 28 April 2025, 6 patients were enrolled with atypical transcripts. Four patients had a baseline transcript available and thus could be assessed for efficacy. One patient with e13a3 was enrolled. The patient discontinued prior imatinib and nilotinib due to lack of efficacy, had a concurrent diagnosis of MDS (treated with dasatinib plus azacitidine), a prior allogeneic myeloablative stem cell transplant, and was last treated with asciminib (discontinued due to lack of efficacy). The patient received ELVN-001 at 80 mg QD (224 days on study), achieved a > 1 log decrease in transcript and has not experienced any TEAEs. One patient with e13a3 transcript and T315I/S348L mutations was enrolled. The patient discontinued prior nilotinib and ponatinib due to lack of efficacy, had an allogeneic myeloablative stem cell transplant and was subsequently treated with ponatinib and asciminib (alternating; discontinued due to intolerance and/or lack of efficacy). The patient received ELVN-001 at 120 mg QD (449 days on study), had a decrease in transcript from 0.95% to 0.15% and has not experienced any TEAE >G2. One patient with e19a2 transcript and a T315I mutation was enrolled. The patient discontinued prior nilotinib, dasatinib, ponatinib, asciminib and a combination of asciminib and ponatinib due to lack of efficacy. The patient received ELVN-001 at 80 mg QD with dose escalation to 120 mg QD (505 days on study), achieved a >1 log decrease in transcript and has not experienced any TEAE >G2. One patient with e1a3 transcript was enrolled. The patient discontinued prior bosutinib due to intolerance (transcript remained >10%) and prior dasatinib, ponatinib and asciminib due to lack of efficacy. The last therapy prior to ELVN-001 was allogeneic stem cell transplantation followed by 2 donor lymphocyte infusions. The patient received ELVN-001 at 80 mg BID (80 days on study), had a decrease in transcript from 43% to 18% and has not experienced any TEAE >G2. Two patients with e1a2 transcript were enrolled. Both patients had no baseline transcript available and are therefore not efficacy evaluable. However, on study, transcripts remained stable. One patient discontinued prior bosutinib and dasatinib due to lack of efficacy, received ELVN-001 at 120 mg QD (176 days on study) and has not experienced any TEAE >G2. Another patient discontinued prior imatinib, radotinib and dasatinib due to lack of efficacy, received ELVN-001 at 20 mg QD with dose escalation up to 120 mg QD (537 days on study) and has not experienced any TEAE >G2. Conclusions ELVN-001 demonstrated encouraging anti-CML activity in patients with atypical transcripts, including in patients with the e13a3 transcript, which is resistant to TKIs targeting the myristoyl pocket.