Enasidenib Shows Promise as Post-Transplant Maintenance in IDH2-Mutated AML

Amandeep Salhotra, MD

In a pilot trial (NCT03728335) assessing the use of enasidenib (Idhifa), an IDH2 inhibitor, as post-hematopoietic stem cell transplant (HCT) maintenance therapy for patients with IDH2-mutated acute myeloid leukemia (AML), the treatment demonstrated high feasibility and favorable survival outcomes.¹ 

According to the final results from the study, 80% of patients completed all planned 24 cycles of enasidenib therapy, with 1- and 2-year leukemia-free survival rates of 100%, and 93% and 87% chronic graft-vs-host disease (GVHD)-free and relapse-free survival (RFS), respectively. For safety, enasidenib was well-tolerated, with manageable adverse events (AEs) observed among patients.

The completed multicenter trial was performed at City of Hope and Moffitt Cancer Center. A total of 15 patients who had undergone allogeneic HCT with IDH2-mutated AML were included in the study. Patients who were in complete remission (CR) at day +30 post-HCT, with an ECOG performance status of ≤2, and adequate marrow function were eligible for the study, provided they had no active acute GVHD.

The median age of those enrolled was 58 years (range 24-77), with 40% male and 60% female. The majority of patients were Caucasian (67%). Pre-HCT remission status included 73% in CR1, 20% in CR2, and 6% with measurable residual disease.

Once enrolled, enasidenib was administered to patients at its FDA-approved dose of 100 mg/day, starting between days 50 and 120 post-HCT, and continued for up to 2 years in 28-day cycles. Maintenance therapy was well-tolerated, with treatment delays and dose reductions common due to hematologic toxicities.

Overall, this study showed that enasidenib as a post-HCT maintenance therapy for IDH2-mutated AML is safe and feasible, with promising survival outcomes.

“Based on these results, we plan to expand our study, and we plan to enroll 20 more patients to this clinical trial,” said Amandeep Salhotra, MD, in an interview with Targeted Oncology^TM.

In the interview, Salhotra, assistant professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope, further discussed the background and findings from the trial.

Blood cancer cells under the microscope: © stock_acc - stock.adobe.com

Targeted Oncology: What was the rationale behind this pilot study?

Salhotra: In patients who undergo an allogeneic stem cell transplantation, relapse remains a common and clinical problem. Approximately 30% to 40% of the patients who undergo transplant relapse, depending on the risk factors, such as whether they are MRD-positive, do they have detectable mutation, what is the intensity of conditioning, and so forth. In order to reduce the relapse, there are various strategies. One can either intensify the conditioning, get them into a better disease control status, or add post-transplant maintenance strategies.

The study that we presented was using an FDA-approved drug called enasidenib, which blocks the IDH2-mutant pathway, which is activated in acute myeloid leukemia. The goal was to see if the study is feasible and if the patients can tolerate the drug, and how are the relapse rates in patients who are treated on the study.

What are some of the unmet needs in the AML treatment space?

The unmet needs are the patients with TP53 mutations, so our high-risk [patients with] AML patients, and the patients who cannot get into a remission and cannot undergo an allogeneic stem cell transplantation.

What were some of the goals or end points of the study?

The primary end point was safety and tolerability. This was a pilot feasibility study, so we wanted to see if the FDA-approved dose can be added in for patients, and how tolerable it is. One of the secondary objectives was [to look at] the clinical outcomes or the relapse rates and the composite outcome of GVHD and relapse-free survival.

Can you summarize the findings?

Fortunately, of the 15 patients who were treated in the study, none of them relapsed. We have a follow-up of almost 2 years, and the median duration of follow-up for these patients has continued. They completed their 24 months of treatment, and nobody has relapsed, and that translates into a high, chronic GVHD relapse-free survival of almost 85% in patients at the 2-year mark. That is a fantastic outcome for our patients with IDH2-mutated AML. Based on these results, we plan to expand our study, and we plan to enroll 20 more patients to this clinical trial.

Are there any takeaways for the community or practicing oncologists?

It is feasible to add the medication, and we hope that as we enroll more patients, we get more safety and efficacy data. We hope the community would be open to adding these maintenance strategies in patients who undergo an allogeneic stem cell transplant. Of course, we will try to get it into the National Comprehensive Cancer Network compendia, which would make it a little bit more to have access to these medications.

Again, the primary objective was safety and tolerability, and of the 15 patients who enrolled, at least 12 patients were able to complete the whole 24 months of maintenance. There were only 3 patients who had to discontinue the medication for various reasons, lost to follow-up or because of some toxicity, but the majority of the patients stayed on study, and they completed the study. So, this was a very feasible trial.

REFERENCE:

Salhotra A, Bejanyan N, Yang D, et al. Multicenter pilot clinical trial of enasidenib as maintenance therapy after allogeneic hematopoietic cell transplantation (alloHCT) in patients with acute myeloid leukemia (AML) carrying IDH2 mutations. Presented at: 2024 Transplantation and Cellular Therapies Meeting; February 21-24, 2024; San Antonio, TX. Abstract 10.