P687: EARLY RESULTS OF A PHASE II STUDY EVALUATING THE ADDITION OF ASCIMINIB TO ERADICATE MINIMAL RESIDUAL DISEASE IN CHRONIC MYELOID LEUKEMIA

Background: The successful use of tyrosine kinase inhibitors (TKIs) has markedly improved prognosis of chronic myeloid leukemia (CML) to almost normal life expectancy. With this success, the goal of therapy has shifted towards increasing chances of treatment-free remission (TFR) by eradicating minimal residual disease (MRD). Pre-clinical studies suggest that the addition of the allosteric BCR::ABL inhibitor asciminib could be used to target CML MRD (Wylie, Nature 2017). Aims: To evaluate efficacy of combining asciminib with TKIs in patients (pts) with persistent CML MRD. Methods: We designed a phase II study investigating the addition of asciminib to either dasatinib or nilotinib in pts with CML MRD (NCT04216563). As part of eligibility, MRD was defined as a complete cytogenetic response (CCyR) but a detectable BCR::ABL transcript. Specifically, eligible pts were those who never achieved MMR after 18 months (mos), or no MR4.5 after 36 mos, or those with loss of MMR or MR4.5, or those with a BCR::ABL transcript plateau in the last 12 mos. Patient must have had CML treatment for at least 2 years, and no change in their TKI or dosage in 6 mos prior to enrollment. Asiminib 40 mg BID was added to either dasatinib or nilotinib in 2 separate arms while continuing the same dose of their TKI received prior to enrollment. The primary endpoint or molecular response success was defined as ≥1 log reduction or disappearance of BCR::ABL by 12 mos of the combination. Pts with MR4.5 sustained for 2 years, can discontinue one or both therapies (attempt TFR). The severity of CML symptoms and their interference with daily life were assessed through the MD Anderson Symptom Inventory for CML (MDASI-CML, scores of 0 to 10, with 10 as the worst). Results: Between 11/2020 and 02/2023, 7 pts were enrolled. The median age was 49 years (range, 32-66). Three were females, 2 enrolled on the nilotinib arm and 5 on the dasatinib arm. The median time from CML diagnosis was 43 mos (range, 29 – 76), with a median of 1 prior line of therapy (range, 1-3). The median duration of treatment with asciminib + TKI was 21 mos (range 0.1 – 23.6) with a median follow-up of 21 mos. One patient withdrew consent after 3 days of treatment because of grade 2 myalgia, the rest continue to receive treatment on study. Otherwise, treatment was well tolerated with grade 1-2 adverse events, and no grade 3 events. Treatment-related adverse events included grade 1-2 elevated lipase (n=2), grade 2 elevated creatinine (n=1), grade 1 elevated amylase, grade 1 headache and grade 1 arthralgia (n=1, each). With the addition of asciminib, 3 (43%) pts had undetectable disease as their best response, with one patient having a sustained undetectable transcript. These pts had been treated for a median of 63 mos (range 43 – 76) prior to enrollment and had detectable disease at CCyR (n=1), MMR (n=1) and MR 4.5 (n=1) at baseline. By 12 mos, 4 of 6 evaluable pts achieved the primary endpoint (1 pt had not reached 12 mos, 1 withdrew consent assessed as not meeting this endpoint). Responses by patient are shown in the figure. Conclusion: The addition of asciminib to nilotinib or dasatinib was safe and improved molecular response in 4 of 7 pts in this early analysis. The study continues to enroll pts. Keywords: treatment-free remission, Asciminib, BCR::ABL, Chronic myeloid leukemia