How to discover the exceptional venetoclax responders in AML/MDS?

A retrospective study of a large cohort of patients with acute myeloid leukaemia (AML) and high-risk myelodysplastic syndrome (MDS) revealed a rare subset of patients with mutations in DDX41 where 11 of 12 patients achieving a negative measurable residual disease state after treatment with venetoclax in combination with hypomethylating agents. This study indicates the importance of identifying DDX41-mutated patients at diagnosis so as to achieve higher cure rates following venetoclax plus hypomethylating treatment. Acute myeloid leukaemia (AML) and high-risk myelodysplastic syndrome (MDS) is the most frequent aggressive blood cancer in adults with its 5-year overall survival below 25%,1 where state-of-the-art diagnostics include advanced genomics for prognostication and therapy planning.2 Venetoclax, the inhibitor of the anti-apoptotic Bcl-2 protein, has rapidly emerged as standard of care in unfit AML, combined with hypomethylating agents (HMAs). Due to its efficiency, the paradigm of front-line intensive chemotherapy is challenged adverse risk AML.3 In this issue, Nanaa et al. present a real-world analysis of more than 4500 patient with AML and high-risk MDS, analysing DDX41 mutations and sensitivity to venetoclax and HMA.4 Of the 12 patients identified with DDX41 mutation, all responded and 11/12 turned negative for measurable residual disease (MRD). Furthermore, there was observed a haematological response before a bone marrow response. This suggests an extraordinary response to venetoclax and HMA in AML/MDS with DDX41 mutation that should be confirmed in other patient cohorts and trials. Venetoclax and HMA seem not to have a companion diagnostic that predict long-term response. Interestingly, the efficiency of venetoclax has not been strongly correlated to Bcl-2 family protein expression, even if good antibodies are available for flow cytometry and immunohistochemistry. BH3 ratios seem to predict therapy response but is not available in standard diagnostics.5 However, certain mutations in the AML cells seem to identify venetoclax responders. Specifically, the somatic mutations in splicing factor genes, NPM1 and IDH1/2 likely predict response to venetoclax.6, 7 Since 11 of 12 of the DDX41-mutated patients in the study of Nanaa et al. responded with MRD negativity, the predictive power of a DDX41 mutation may be much stronger than other reported biomarkers of response. This strong therapeutic effect may mimic a type of genetic interaction where the combination of two genetic events results in cell death: synthetic lethality. Synthetic lethality is previously described for Bcl-2 inhibition combined with p53 activation in AML.8 In the model organisms Caenorhabditis elegans, its DDX41 ortholog has been identified as a component of the spliceosome, and genetic analyses revealed synthetic lethal interactions with spliceosomal components.9 Interestingly, venetoclax may be more effective in AML with mutations in genes associated with the spliceosome.7 Future studies are needed to understand the mechanisms behind the therapeutic effect of venetoclax and HMA in DDX41-mutated patients. Patients with the DDX41 mutation presented by Nanaa et al. seems to be exceptional responders. Identifying genetic biomarkers for extraordinary responders will help us to provide more precise therapy.10 However, next-generation sequencing of AML is usually targeted sequencing of 40–50 genes, and other mutations predicting response may be lost. However, identifying DDX41-mutated patients as exceptional responders to venetoclax plus HMA will help us to bring more AML patients to allogeneic transplant and cure. This should bring unfit patient into a long-term disease control. And inspire the research to identify more biomarkers for precision therapy with available drugs in AML and MDS.