The Combination of Asciminib with ATP Competing Tyrosine Kinase Inhibitors Might Overcome the Negative Impact of ASXL1 Mutations on Molecular Response in Newly Diagnosed CML Patients

Clones characterized by gene mutations independent of BCR::ABL1 have been identified in approximately 20-30% of newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase with mutations in epigenetic modifier genes (e.g., ASXL1, TET2, DNMT3A) being the most common. We previously reported an inferior molecular response rate to nilotinib therapy in CML patients harboring ASXL1 mutations at diagnosis (TIGER study, NCT01657604, Schönfeld et al. Leukemia 2022;36:2242-9). Here, we sought to evaluate the clinical impact of these mutations in newly diagnosed CML patients treated with asciminib in combination with ATP competing tyrosine kinase inhibitors. The “Frontline asciminib in combination study” (FASCINATION, NCT03906292) is an ongoing multicenter, prospective, open-label, interventional phase II trial to evaluate efficacy and tolerability of asciminib in combination with conventional ATP-competing BCR::ABL1 inhibitors (imatinib, nilotinib, dasatinib). The primary endpoint was the rate of MR⁴ (BCR::ABL1 transcripts ≤0.01% on the International Scale, IS) at month 12. Between 2019 and 2022, 144 patients were recruited from 21 sites in Germany and 125 patients started the combination therapy with asciminib. Median age at diagnosis was 45.5 years (range, 19.0-89.0) and 66% were male. A total of 119 CML patients were investigated by targeted next-generation sequencing covering 54 myeloid leukemia-associated genes. Mutation status was correlated with the primary endpoint of the study. At diagnosis, 24/119 CML patients (20%) carried mutations in addition to BCR::ABL1 affecting the genes ASXL1, ATRX, BCOR, BCORL1, CBLB, CEBPA, CUX1, DNMT3A, ETV6, IKZF1, KDM6A, RAD21, STAG2, TET2, and ZRSR2. Five patients showed mutations in more than one gene. ASXL1 mutations were observed in 9 patients (8%, median age 45 years, range 32-65 years; ELTS low risk, n=5; intermediate risk, n=2; high risk, n=2). At month 12, 8/9 (89%) and 7/9 (78%) patients harboring ASXL1 mutations at diagnosis showed MMR and MR⁴, respectively. In comparison, patients with other mutations or no mutation had MR⁴ rates of 33% and 34%, respectively. In conclusion, mutations in addition to BCR::ABL1 are common at diagnosis of CML. The combination of asciminib with ATP competing drugs might be able to overcome the negative impact of ASXL1 mutations with regard to molecular response. However, the optimal therapy for CML patients with ASXL1 mutations needs to be defined within future studies.