Remark: A phase II, open-label, multicenter study of orally administered romaciclib (RVU120) for the treatment of anemia in patients with lower-risk myelodysplastic neoplasms (LR-MDS)

Abstract

Abstract Background: Lower-risk myelodysplastic neoplasms (LR-MDS) are a group of clonal bone marrow disorders characterized by ineffective hematopoiesis, leading to chronic cytopenias and a risk of progression to acute myeloid leukemia. Despite being classified as lower risk, many patients experience debilitating anemia and reduced quality of life, with limited durable treatment options available. Romaciclib is an orally bioavailable small molecule inhibitor targeting mediator complex kinases CDK8 and its paralog CDK19. Previously published research confirmed romaciclib's potential to induce erythroid differentiation at clinically relevant doses on patient-derived CD34+ cells with acquired MDS/AML-like genetic aberrations resulting in erythroid dysfunction (Mazan et al., EHA 2025; Pakulska et al., Blood, 2021). Available data provide a compelling argument to investigate romaciclib in patients with LR-MDS. Aims: The primary objective of the REMARK study is to evaluate the proportion of patients with LR-MDS who have an erythroid response (HI-E) according to IWG 2018 criteria following treatment with romaciclib. Secondary objectives include safety and tolerability of romaciclib as well as QoL assessments. Methods: REMARK (NCT 06191263) is an ongoing phase 2 open label study of romaciclib orally administered in patients with LR-MDS. Romaciclib is taken orally at a starting dose of 150 mg every other day (q.o.d). in a 21-day treatment cycle from day 1 to day 13 (total of 7 doses per cycle). Response assessment will be carried out in cycle 9 according to IWG 2018 HI-E criteria. Patients who had an HI-E response during the 24-weeks observation period but lost this response before C9D1 or patients who never achieved an HI-E response during the 24-weeks observation period may be placed on a higher dose of 250 mg at the investigator's decision. If the higher dose is started, they will undergo up to 8 additional cycles of treatment on the higher dose. All patients will undergo EOT and 3 months of follow-up after their last dose of RVU120 within the study. An interim analysis is pre-specified to assess the response in the first 21 patients. Results: At the time of abstract submission, a total of 42 patients started treatment in the REMARK study, and 15 patients are ongoing. Results of the interim analysis will be reported at the conference. Based on preliminary data, at least one patient with high transfusion burden at baseline (≥8 RBC units in 16 weeks) achieved a major erythroid response according to IWG 2018 criteria in the 24-weeks observation period. This male patient was carrying an SF3B1 mutation, and ringsideroblasts were present at baseline. He received three prior lines of therapy with ESA, luspatercept, and lenalidomide. The analysis of additional patients is ongoing, including molecular profiling at baseline and during treatment. No new safety signal was identified in the REMARK study. A total of 343 adverse events were reported in 42 treated patients. The most common events assessed as at least possibly related to RVU120 were nausea (64 events), vomiting (49), asthenia (13), and inappetence (12). These events were leading to study discontinuation in some patients. Summary/ Conclusions: Despite the preliminary nature of the data, initial signs of clinical activity of romaciclib in patients with LR-MDS were observed. Ongoing analyses in the study aim at describing the clinical and molecular changes during treatment with romaciclib, at identifying the optimal dose and schedule as well as potential predictors of response.