Although treatment approaches for HR-MDS and AML may overlap, the diseases have different US Food and Drug Administration–approved treatment options. In either disease, conversations about initial therapy may involve discussions of therapeutic intensity, side effects, anticipated duration of remissions, and quality-of-life issues. Patients who are younger and medically fit may be more accepting of the side effects associated with aggressive treatment, and they may be candidates for allogeneic hematopoietic stem cell transplantation. In contrast, patients who are older and medically frail might opt for lower-intensity treatment with fewer side effects or perhaps supportive care alone, in some circumstances. Chronological age is just one of the many factors that guide treatment. By taking a holistic approach to each individual, treatment decisions can be tailored to the patient’s medical fitness and comorbidities, as well as their preferences and goals.

Traditionally, the hypomethylating agents (HMAs), including azacitidine and decitabine, have been shown to reduce symptoms, improve quality of life, and prolong survival in a subset of patients with HR-MDS. Thus, HMAs are the backbone of low-intensity treatment; however, they are not the most active of compounds. The combination of an HMA with venetoclax, a BCL-2 inhibitor, or ivosidenib/enasidenib in patients with IDH1/IDH2 mutation has been a positive development in AML and is also promising in HR-MDS; the early data have been very positive, in my opinion.

If the standard of care for HR-MDS were optimal, there might be a reluctance on the part of patients to participate in clinical trials, but what we are seeing is the opposite (ie, patients want to be on these study protocols because the current standard is suboptimal). For such patients, we may administer a low-intensity regimen of decitabine and venetoclax, with the goal of getting more of them to achieve remission, which allows for more patients to proceed to allogeneic stem cell transplantation.

Thus, I think that it is necessary to change the perception of treatment futility and encourage eligible patients to enroll in clinical trials. Such trials might offer patients different, less-intense dosing schedules of established drugs, investigational new therapies and novel targeted combinations, and/or immune-based therapies. Once these investigational trials reach accrual, we will have sufficient data to establish the safety and efficacy of these novel treatments, and we hope for the approval of more treatment options for HR-MDS. Ongoing research will also continue to explore the use of targeted therapy for driver mutations in various settings, including in combination with immune checkpoint inhibitors in AML. It is important that patients have genomic analysis done so as not to miss an opportunity for targeted treatment. I am optimistic that, with the novel therapies that are under investigation, more of the medically frail population will have a better chance of achieving remission.