Outcomes of hypomethylating agent (HMA)-based therapy in patients with myelodysplastic syndrome with fibrosis

Abstract Background: The 2022 WHO classification introduced Myelodysplastic Syndrome with fibrosis (MDS-f) as a distinct morphological category, defined by either 5-19% bone marrow blasts or 2-19% peripheral blood blasts with grade 2-3 reticulin fibrosis. Treatments with hypomethylating agents (HMA) have been shown to improve survival in patients with high-risk MDS, and as the only known disease modifying agents, are considered a mainstay of treatment. Given the historically poor outcomes in MDS-f, we aimed to formally evaluate outcomes of hypomethylating agent (HMA)-based therapy in this redefined subgroup. Objective To evaluate the efficacy of HMA-based therapy in patients with WHO 2022-defined MDS-f. Design: This was a retrospective, observational, single center study of patients with WHO 2022-defined MDS-f treated with an HMA, identified through systematic review of the Moffitt Cancer Center MDS Database. Patients with MDS with increased blasts (MDS-IB) served as matched controls. Patients with MDS with biallelic TP53 inactivation (MDS-biTP53) with and without underlying fibrosis who had received HMA were also included for analysis as a separate category from MDS-IB per WHO 2022 classification. Endpoints The primary endpoint was overall response rate (ORR) to HMA therapy, assessed using the IWG 2023 criteria. Secondary endpoints included overall survival (OS) and incidence of severe treatment-emergent hematologic and infectious adverse events within 90 days of initiation of therapy. Results The study included 92 patients with MDS-f (82 with response data) and 538 patients with MDS-IB (455 with response data). Baseline characteristics, including IPSS-R and IPSS-M risk scores, were similar between both groups. The majority of patients in both the MDS-f and MDS-IB groups received HMA as monotherapy (77.2% and 77.1%, respectively) and in the frontline (96.7% and 98%, respectively). In patients with MDS-f, the ORR (CR+CRh+CRuni+CRbi+PR+HI) was 35.4% compared to 51% in MDS-IB patients (p=0.006). Median OS for the entire cohort was 19.9 months. MDS-f patients had a shorter median OS of 18.9 months (95% CI 16.1-21.7), compared to 26.2 months (95% CI 23.2-29.1) for MDS-IB patients (p=0.048). Interestingly, in the subset of HMA + Venetoclax-treated patients, median OS was similar between the MDS-f and MDS-IB patients. Among MDS-biTP53 patients (n=191), survival appeared similar between those with and without fibrosis [10.9 months (95% CI 9.2-12.5), compared to 13.0 months [(95% CI 11.2-14.8) (p=0.09), respectively]. In the MDS-f cohort, the incidence of treatment-emergent grade IV neutropenia and thrombocytopenia during HMA treatment was 73.2 and 55.6%, respectively. The incidence of grade III or IV infectious complications (documented infection or febrile neutropenia) was 48.2%. Among the 14 patients in the MDS-f cohort who received hypomethylating agent (HMA) therapy in combination with Venetoclax, the rates of treatment-emergent grade IV neutropenia/thrombocytopenia and grade III/IV infectious complications were comparable to those observed in the overall cohort of HMA-treated MDS-f patients, as well as those patients who received HMA monotherapy. Conclusion This is the first report of outcomes amongst WHO 2022-defined MDS-f patients treated with HMA-based therapy. Compared to patients with MDS-IB response rates and survival compared are inferior, along with higher rates of severe neutropenia, thrombocytopenia, and infectious events. The results support MDS-f as a distinctly poor prognostic subgroup. In addition, patients with MDS-biTP53 had similarly poor outcomes following HMA therapy, irrespective of underlying fibrosis, reaffirming MDS-biTP53 as an adverse subgroup. Taken together, these results underscore the need to further develop and optimize treatment strategies in this poor prognostic MDS subgroup.