Despite recent progress in the field, treatment for myelodysplastic syndromes (MDS) remains suboptimal. Hypomethylating agents such as azacitidine or decitabine are frontline treatment for those with high-risk disease, but primary or secondary resistance to such therapy is almost inevitable. No U.S. Food and Drug Administration (FDA)-approved strategies are available after such treatment failure, and expected survival time in such patients is six months or less.
Results from a recent phase II study published in Blood Advances provides evidence for the role of enasidenib in a subset of these patients who harbor a mutation in the isocitrate dehydrogenase enzyme 2 (IDH2) gene, both in newly diagnosed patients and refractory patients who have already received standard treatments.
Approximately 5% of patients with MDS bear a mutation in IDH2. Enasidenib, an oral inhibitor of IDH2, is currently FDA-approved for patients with relapsed or primary refractory acute myeloid leukemia (AML) who harbor such a mutation. Lead author, Courtney D. DiNardo, MD, of the University of Texas MD Anderson Cancer Center in Houston, noted that when used as a single agent, about 40% of IDH2-positive patients with relapsed AML respond to enasidenib. The drug is not cytotoxic; instead, Dr. DiNardo explained, it promotes successful maturation of granulocytes in responding patients.
Dr. DiNardo and colleagues designed the multicenter trial of safety and efficacy using two treatment arms in patients with MDS who were IDH2-positive (median patient age = 73 years). Arm A included 27 newly diagnosed patients who were treated with a combination of azacitidine and enasidenib. Arm B included 23 patients with relapsed or refractory disease who had previously received hypomethylating therapies; these patients received enasidenib alone.
Neutropenia was common and occurred in 40% of patients. As a result of three unexpected infection-related deaths among patients in Arm A, the initial protocol of continuous enasidenib for days one to 28 was shortened to two weeks on, followed by two weeks off, for the first three cycles of therapy.
However, Dr. DiNardo noted, overall safety outcomes were in line with previous experiences with enasidenib. She added, “The two main adverse events that clinicians should be concerned with are indirect bilirubin elevation and IDH-differentiation syndrome [IDH-DS].”
IDH-DS occurred in 16% of patients, a similar rate as in other enasidenib studies, and was managed in accordance with IDH-DS treatment guidelines.
Treatment-naïve patients in study arm A had an overall response rate (ORR) of 74%. For context, similar outcomes in such patients treated with azacitidine alone have shown an ORR of 35 to 40%. In study arm A, 37% of patients attained either complete remission (CR) or CR in the bone marrow with some improvement in peripheral blood counts. In patients who responded to the drug, the median duration of response was 32 months.
In refractory patients in arm B who received enasidenib monotherapy, the ORR was 35%, and 22% of patients achieved CR. Additionally, all patients who were able to have an allogeneic hematopoietic cell transplant after response to treatment continued in remission posttransplant (median follow-up = two years).
The authors did not specifically describe study limitations, but a few may be considered. The study ended shortly after the modification to the treatment protocol in treatment arm A, with only five patients receiving the revised version. Thus, one study limitation was that the authors could not determine the safety and efficacy of the modified treatment schedule. Additionally, the results might have been more impressive if a greater number of patients had been included; however, the study closed early in May 2021 due to difficulty enrolling appropriate patients during the COVID-19 pandemic.
Genetically defined treatment for MDS is limited. Lenalidomide is effective for low-risk patients with deletions in the long arm of chromosome 5, Dr. DiNardo noted, and luspatercept was recently approved for patients with isolated anemia and ring sideroblasts, frequently associated with mutations in SF3B1. But this work suggests expanded usage for genetically defined treatment in the future.
Dr. DiNardo concluded, “Overall, we found that enasidenib was effective in both cohorts, with durable responses in both study populations, which suggests the importance of molecular profiling to inform potential treatment strategies.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
DiNardo CD, Venugopal S, Lachowiez CA, et al. Targeted therapy with the mutant IDH2 inhibitor enasidenib for high-risk IDH2-mutant myelodysplastic syndrome [published online ahead of print, 2022 Aug 16]. Blood Adv. doi: 10.1182/bloodadvances.2022008378.