Today, we can truly personalize the interrogation of a patient’s disease through next-generation sequencing. We can identify mutations in nearly 95% of patients with MDS and AML. At one time, these genomic alterations were mainly prognostic, but today they currently guide treatment. AML research has been the leader in terms of targeted therapies in myeloid malignancies, but it is also an exciting time right now for MDS research, with studies investigating novel targeted, immune-based, and combination therapies.

Some targets are mainly applicable to AML. For instance, FLT3 mutations may be targeted by midostaurin or gilteritinib and are present in approximately one-third of patients with AML, but they occur only very rarely in MDS. For patients with FLT3-mutated AML, there is a clear survival benefit with the FLT3 tyrosine kinase inhibitor midostaurin combined with 7+3 chemotherapy in the frontline setting. In the relapsed/refractory setting, gilteritinib monotherapy has demonstrated a survival advantage compared with salvage chemotherapy. Somatic mutations in IDH1/IDH2 (ie, ivosidenib and enasidenib, respectively) are also actionable. Taken together, they occur in approximately 20% of patients with AML, but these mutations are less frequent in patients with MDS.

In TP53-mutated disease, whether AML or MDS with excess blasts, the clinical and pathologic features are often shared, and overall survival is poor. In patients with TP53 mutations, the combination of hypomethylating agents (HMAs) and venetoclax has demonstrated improved response rates but has not shown survival benefit. There is some research suggesting that TP53 may alter the BCL-2 target, resulting in primary venetoclax resistance. Investigational efforts to restore p53 function are ongoing. For instance, the combination of the p53 reactivator eprenetapopt (APR-246) and azacitidine was given a breakthrough therapy designation for the treatment of patients with MDS and a susceptible TP53 mutation, and a phase 3 trial with this combination recently completed enrollment. In addition, there is an ongoing study investigating the efficacy of triplet therapy with azacitidine, eprenetapopt, and venetoclax.

So, it is an exciting time for research into novel HMA combinations as frontline therapy in high-risk MDS and AML. For example, the combination of the CD47 inhibitor magrolimab with azacitidine has had synergistic activity for higher-risk MDS and has received a breakthrough therapy designation by the US Food and Drug Administration. A randomized phase 3 trial of combination therapy vs azacitidine therapy alone has been initiated. Additionally, the TIM-3 inhibitor MBG453 in combination with an HMA has shown increased response rates, and a study of MBG453 in combination with azacitidine and venetoclax in patients with AML who are unfit for chemotherapy is ongoing. Pevonedistat is a novel NEDD8-activating enzyme inhibitor that recently received breakthrough therapy designation for higher-risk MDS. Recent phase 2 data demonstrated that approximately 50% of patients treated with pevonedistat and the HMA azacitidine achieved complete remission.

Still, it is important to note that, although there is an impact at diagnosis with such frontline treatment, AML and MDS mutations are dynamic and may change over time, and we need to better understand mechanisms of resistance. Furthermore, while we have made great strides with novel HMA combinations in the frontline setting, we need additional research to identify molecular subsets of patients who may be more likely to respond to particular novel therapies and combinations.