Targeted Agents and Combination Therapies May Open Doors in MDS Management

Talha Badar, MBBS, MD

Treatments such as ivosidenib (Tibsovo) are revolutionizing the standard of care for subsets of patients with myelodysplastic syndrome (MDS), with other options like venetoclax (Venclexta) and menin inhibitors, pending inclusion in the treatment paradigm as well, according to Talha Badar, MBBS, MD.

In an interview with OncLive®, Badar, a hematologist/oncologist in the Departments of Hematology and Oncology (Medical) at Mayo Clinic in Jacksonville, Florida, discussed the implications of the 2023 FDA approval of ivosidenib for patients with MDS harboring IDH1 mutations. He also highlighted future directions for the treatment of patients, including ongoing and upcoming MDS and acute myeloid leukemia (AML) research efforts being made at Mayo Clinic. Badar provided further insights from this interview in another article.

OncLive: What has been the significance of the FDA approval of ivosidenib for patients with IDH1-mutated MDS?

Badar: IDH1 and IDH2 mutations are more commonly seen in patients with AML, and they’re less common in MDS. However, IDH1 inhibitors have been a welcome inclusion for patients with AML. [They are] shown to work in combination with azacitidine [Vidaza] in elderly patients with AML who are ineligible to receive intensive chemotherapy and who have an IDH1 mutation.

[Investigators have observed] the [efficacy] and tolerability of [ivosidenib in patients with IDH1-mutant MDS], knowing that IDH1 mutations do occur in patients with [this disease], although at a lesser frequency [than in AML], in approximately 3% of patients with MDS. Retrospective data showed that IDH1 mutations are more commonly associated with patients with MDS who have leukopenia or neutropenia. That finding led to a phase 1, first-in-human [AG120-C-001] study [NCT02074839] in patients with MDS, [which investigated] single-agent ivosidenib, an IDH1 inhibitor, at a dose of 500 mg daily. [This trial] showed an impressive overall response rate [with ivosidenib], and a complete response [CR] rate of 38.9%. These remission rates were durable, and the median duration of response [DOR] was [not estimable].

[Those findings led to] further consideration [of ivosidenib in MDS]. Another study using IDH1 inhibitors, [led by Groupe Francophone des Myelodysplasies], was the phase 2 IDIOME study [NCT03503409], in which investigators evaluated IDH1 inhibitors in patients with MDS who progressed on hypomethylating agent [HMA]–based therapy. Once patients with MDS progress on HMA therapy, historically, their outcomes are poor, with a median overall survival [OS] of approximately 6 to 9 months. Having therapy for that high-risk group of patients, more importantly, those who are ineligible for a bone marrow transplant would be a great strategy to achieve remission and improve response rates and quality of life [QOL]. Our [goal is to develop] therapies that are well tolerated [and do not have a] significant impact on patients’ QOL. The IDIOME study showed a CR rate of 46% [with ivosidenib monotherapy]. That was remarkable. The [median] DOR was 7.4 months, and the [median] OS was 14 months. [Those outcomes are] better than the historical data we have in patients with MDS who progress on HMAs.

Based on [the AG120-C-001] data, the FDA approved ivosidenib for patients with MDS with IDH1 mutations. Although [AG120-C-001 had] a small sample size of 18 patients, [these findings are] still promising for a disease in which we don’t have many therapies available, especially for patients who progress on HMA-based therapy.

What treatment developments are on the horizon for MDS management?

This is an exciting time. We have treatment options available based on randomized data for several groups of patients, [including] those with low-risk disease and predominant anemia, [as well as those with] high transfusion burdens. We have luspatercept-aamt [Reblozyl], and hopefully, based on the positive [phase 2/3] IMerge trial [NCT02598661] data, we’ll have [imetelstat] approved for patients with low-risk MDS and anemia who are transfusion dependent.

More recently, among high-risk patients, venetoclax has [caused a] paradigm shift in the management of elderly AML. Venetoclax has also elicited positive results in patients with MDS with high disease burden, based on phase 1 data. We are eagerly waiting for phase 3 data to come out from the [phase 3] Verona trial [NCT04401748], which [is comparing] azacitidine plus venetoclax vs azacitidine alone in patients with high-risk MDS.

The field is moving fast; it’s evolving with good, promising data. Now, hopefully, we can use [better prognostication methods when enrolling] patients in clinical trials to devise better treatment strategies and eventually improve patients’ long-term outcomes.

What ongoing hematologic oncology research at Mayo Clinic would you like to highlight?

Several clinical trials are ongoing at our institution. One [phase 1 trial (NCT02841540)] for patients with MDS with SF3B1 mutations [is investigating] a molecule targeting the spliceosome. [This agent] has shown activity among patients with low-risk MDS who require transfusion and are refractory to erythropoiesis-stimulating agent–based therapy. We are actively recruiting for this trial and have seen some good responses.

Secondly, menin inhibitors are in clinical trials and have had promising results among patients with AML who have NPM1 mutations or MLL gene rearrangements. We have several clinical trials [investigating menin inhibitors] open at our institution, [evaluating these inhibitors] as single-agent therapy for patients with relapsed/refractory AML or acute leukemia with NPM1 rearrangements. We are soon opening a combination trial with intensive, moderate-intensity, or low-intensity chemotherapy in combination with several menin inhibitors to use up front in patients with AML and NPM1 or MLL gene rearrangements. The initial data we have with these compounds is encouraging. We are optimistic [that when used] in combination [approaches, menin inhibitors] will improve outcomes for [patients with] high-risk [disease], such as [those with] MLL gene–rearranged acute leukemia, to improve response rates, achieve more durable response rates, and improve the outcomes of our patients.