Anakinra for Prevention of Poor Graft Function in MDS Allo-HSCT

Background and Rationale. Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by ineffective hematopoiesis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only potentially curative approach for MDS; however, a subset of patients develops poor graft function (PGF)-defined as persistent cytopenias in two or more lineages despite achievement of full donor chimerism (≥95%)-following otherwise successful engraftment. PGF is associated with significant morbidity, recurrent infections, transfusion dependence, and increased non-relapse mortality, and no standard therapy exists.

Preclinical and translational evidence implicates the interleukin-1 (IL-1) inflammatory pathway in the bone marrow failure of MDS. Sustained low-level IL-1 signaling suppresses bone marrow mesenchymal stromal cells (MSCs) from secreting stem cell factor (SCF), a critical cytokine for hematopoietic stem cell (HSC) survival and self-renewal, thereby causing failure of the marrow microenvironment's hematopoietic supportive capacity. Pharmacologic blockade of IL-1 signaling with the interleukin-1 receptor antagonist (IL-1Ra, Anakinra) can reverse this process and restore stromal supportive function in experimental models. Beyond the post-transplant setting, chronic IL-1 signaling also drives HSC dysfunction, including progression of clonal hematopoiesis and transformation to MDS or acute myeloid leukemia (AML). Importantly, a prior phase 2 trial of IL-1 inhibition in lower-risk MDS demonstrated hematologic improvement without an increased risk of leukemic transformation, supporting the safety of IL-1 blockade with respect to disease acceleration.

Study Hypothesis. Based on these findings, this study hypothesizes that early administration of Anakinra after allo-HSCT in patients with MDS-by inhibiting IL-1 signaling, improving the bone marrow microenvironment, and reducing the occurrence of PGF-does not increase the risk of post-transplant relapse.

Study Design. This is a prospective, multicenter, open-label, single-arm phase 1/2 study comprising two parts. Part 1 (dose-escalation) uses a standard 3+3 design to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of subcutaneous Anakinra administered thrice weekly from day 0 through day +28 after allo-HSCT; dose levels are 100 mg, 200 mg, and 300 mg, with dose-limiting toxicities assessed during the treatment and observation period. Unlike conventional cytotoxic agents for which the recommended dose equals the MTD, Anakinra is a biologic agent for which the optimal biological dose may be lower than the MTD; the RP2D will therefore be selected by integrating safety, IL-1 pathway inhibition, and preliminary biological activity. Part 2 (efficacy-validation) administers Anakinra at the RP2D subcutaneously thrice weekly from day 0 through day +28 after allo-HSCT; the primary efficacy endpoint is the cumulative incidence of PGF by day +100, assessed against historical controls. Secondary endpoints include overall survival, non-relapse mortality, cumulative incidence of relapse, acute and chronic graft-versus-host disease and post-transplant relapse risk.