Myelodysplastic syndrome - Emerging treatments

Venetoclax plus azacitidine

In one phase 3 trial, the addition of venetoclax (a B-cell lymphoma-2 [BCL-2] inhibitor) to azacitidine increased response rate, but did not improve survival, in patients with treatment-naive, intermediate-, and higher-risk myelodysplastic syndrome (MDS).[89] National Comprehensive Cancer Network (NCCN) guidelines recommend venetoclax plus a hypomethylating agent (such as azacitidine) as an option for cytoreduction in intermediate- and higher-risk patients (transplant and non-transplant candidates).[14] However, this combination is not commonly used in current clinical practice. The US Food and Drug Administration (FDA) has granted orphan drug designation and breakthrough therapy designation for venetoclax in combination with azacitidine for the treatment of patients with previously untreated higher-risk MDS.

Ivosidenib plus azacitidine

NCCN guidelines recommend combination treatment with ivosidenib (an isocitrate dehydrogenase 1 [IDH1] inhibitor) plus azacitidine as an option for intermediate- and higher-risk MDS patients with IDH1 mutations (transplant and non-transplant candidates).[14] However, this combination is not commonly used in current clinical practice. The FDA has approved ivosidenib for the treatment of adult patients with relapsed or refractory MDS with a susceptible IDH1 mutation. Ivosidenib has been granted orphan drug designation for the treatment of myelodysplastic syndromes by the European Medicines Agency (EMA).

Olutasidenib

Olutasidenib, an IDH1 inhibitor, is being investigated in MDS patients with IDH1 mutations as single-agent therapy and in combination with azacitidine.[90] One phase 1/2 open-label study demonstrated an overall response rate of 33% (n=2/6) of patients with intermediate-, high-, or very-high-risk MDS treated with olutasidenib alone. An overall response of 69% (n=11/16) was achieved in patients treated with a combination of olutasidenib plus azacitidine.[90] NCCN guidelines recommend olutasidenib alone for intermediate or lower-risk MDS patients with IDH1 mutations who have thrombocytopenia, neutropenia, or symptomatic anaemia that is unresponsive to treatment or has relapsed. For intermediate- and higher-risk MDS patients with IDH1 mutations (transplant and non-transplant candidates), NCCN guidelines recommend olutasidenib in combination with azacitidine (as a first-line option) or alone (second-line).[14] Olutasidenib is not currently approved by the FDA for MDS.

Enasidenib

One phase 2 study of enasidenib (an isocitrate dehydrogenase 2 [IDH2] inhibitor) reported an overall response rate of 43.1% with enasidenib monotherapy in higher risk patients with IDH2 mutated MDS. Overall survival of 14.9 months was reported in patients with relapsed or refractory disease, and 25.5 months in patients treated with enasidenib first-line.[91]

Eltanexor

Eltanexor (a second-generation oral selective inhibitor of nuclear export) has shown promise in a phase 1/2 open-label study of patients with higher-risk MDS refractory to hypomethylating agents.[92] The FDA has granted orphan drug designation and fast-track designation for eltanexor as monotherapy for the treatment of patients with relapsed or refractory intermediate-, high-, or very-high-risk MDS. The EMA has granted orphan drug designation to eltanexor for the treatment of MDS.