https://orcid.org/0000-0003-3492-2778
Key Points
In the phase 3 SELECT MDS 1 trial, CR was similar between arms in patients with higher-risk MDS.
RARA gene overexpression/ RARa activation in myeloid malignancies warrant further investigation as biomarker-driven studies are feasible.
Higher-risk MDS (HR-MDS) with RARA gene overexpression is a subset of HR-MDS patients (pts) with an actionable target for tamibarotene, an oral and selective RARα agonist. Tamibarotene in combination with azacitidine (AZA) showed high complete remission (CR) rates in AML. SELECT-MDS-1 (NCT04797780) was a Phase 3 study comparing the activity of tamibarotene/ azacitidine (AZA) to placebo/AZA in newly diagnosed (ND) HR-MDS pts with RARA overexpression. Eligible patients had confirmed RARA overexpression by blood-based assay, untreated MDS with higher-risk features by IPSS-R and a bone marrow blast count >5%. Patients were randomized 2:1 to receive either tamibarotene/AZA or placebo/AZA, respectively. A total of 246 participants with HR-MDS and RARA overexpression were randomized with 164 and 82 in the tamibarotene/azacitidine and placebo/azacitidine groups, respectively. Baseline characteristics included: 69.9% male; median age 75 (38-93); primary MDS 89.8%; WHO 2016 classification MDS-EB-1 48%, MDS-EB-2 52%; median bone marrow blasts 9.0%; IPSS-R risk category intermediate (25.5%), high (35.7%), very high (38.9%). The study did not meet the primary endpoint of CR, with a p-value of 0.2084 for the treatment effect in the tamibarotene/AZA group compared to the placebo/AZA group. The CR rates were 23.81% and 18.75% in the tamibarotene/AZA and placebo/AZA groups, respectively. The use of tamibarotene-based therapy to target RARα as a novel approach in HR-MDS pts with RARA gene overexpression is not a paradigm which can augment response rates beyond HMA monotherapy. Further explorations of alternative approaches, including those with a biomarker, to alter the natural history of this disease are warranted.
