ASH 2024 | An analysis of the impact of ASXL1 mutations in patients with CP-CML treated in the SUSTRENIM trial

Here at the 2024 ASH Annual Meeting, I will be presenting data on the clinical relevance of cancer gene mutations and particularly ASXL1 mutations in newly diagnosed chronic phase patients. This is currently a hot issue in chronic myeloid leukemia. For a long time we have believed that mutations in genes other than BCR-ABL were confined to blast crisis patients and only recently the power of next generation sequencing has revealed a not negligible degree, unexpected degree of genetic complexity in a good percentage of newly diagnosed chronic phase patients. These mutations have been detected in a variable proportion ranging from 18 to 30% of cases depending on the different studies. ASXL1 mutations are indeed the most frequent. They can be detected in up to 10% of newly diagnosed chronic phase patients. But there are contrasting data regarding their clinical relevance. Some studies showed an impact on the likelihood to achieve molecular response milestones or progression-free survival but most of these studies suffered from important limitations including the relatively heterogeneous treatment of the patients or the fact that the patients were not unselected. So we decided to address the impact of ASXL1 and cancer gene mutations on the depth of molecular response and the likelihood to becoming candidate and achieve treatment-free remission in patients enrolled in the SUSTRENIM clinical study. That is an international randomized study comparing nilotinib first line versus imatinib with proactive switch to nilotinib in case of not achievement of optimal response. We analyzed a consecutive series of 124 patients. I would like to remind that the protocol enrolled 448 patients. We analyzed a subset of these patients, those who signed the informed consent for donating a sample for these translational studies. The samples were analyzed by whole exome sequencing, but for the purpose of this analysis, we focus only on ASXL1 mutations and cancer gene mutations. And interestingly, we found no impact of ASXL1 mutations or cancer gene mutations on the depth of molecular response. So molecular response at three months, six months, 12 months, 24 months, 36 months, and 48 months. And there was no impact of ASXL1 mutations on the candidability to treatment for remission because 43% of ASXL1 positive patients versus 42% of ASXL1 negative patients became candidates for TFR. I remind that for the purposes of this study, patients who achieved the molecular response by 36 months and maintained it up to month 48 were eligible for treatment pre-remission attempt. So these data are a little bit contrasting with what has been reported so far and highlight the importance of further assessing the impact of these mutations and also warn against the premature incorporation of ASXL1 among high risk features in the next treatment recommendations.

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