A pilot study of low-dose sirolimus to increase hematopoietic function in patients with RUNX1 familial platelet disorder

Abstract Background: Familial Platelet Disorder with germline RUNX1 mutation (RUNX1-FPD) is a rare inherited syndrome characterized by thrombocytopenia, qualitative platelet dysfunction, and an estimated 40% lifetime risk of hematologic malignancies, including myelodysplastic syndrome, acute myeloid leukemia, and lymphoid neoplasms. RUNX1-mutant hematopoietic stem cells (HSCs) exhibit aberrant activation of mTORC1 signaling and heightened inflammatory response pathways, contributing to impaired platelet production and myeloid-bias of HSCs. In murine models, low-dose sirolimus mitigates inflammatory signaling, enhances megakaryopoiesis, and improves platelet function. Sirolimus has also demonstrated safety and potential disease modifying activity in familial adenomatous polyposis (FAP), another inherited cancer predisposition syndrome. In FAP, loss of APC leads to aberrant Wnt/β-catenin signaling and downstream mTORC1 activation, a pathway that shares key molecular features with RUNX1-FPD. These findings support the exploration of sirolimus as a preventive strategy to improve hematopoiesis and delay malignant progression in RUNX1-FPD. Methods: Eligible adults (≥18 years) with pathogenic/likely pathogenic germline RUNX1 mutations, platelet count ≥50×10³/μL, and adequate organ function receive sirolimus 2 mg daily for 6 months. Key exclusions include active or prior hematologic malignancy, mTOR inhibitor use, concurrent CYP3A4-modulating medications, uncontrolled bleeding, recent cardiovascular events, active infections, or chronic viral illnesses. The primary objective is to assess safety and tolerability; secondary endpoints include changes in platelet counts and function, evaluation of co-occurring somatic mutations, bleeding symptoms per ISTH-BAT score, and mTORC1 pathway activity. Results: As of August 2025, four patients have been enrolled, with a median age of 55 years (range 46–67); three females and one male. The median baseline platelet count was 113×10³/μL (range 62–169), BCOR was the most common co-mutation, present in three of four patients; one patient also had a DNMT3A mutation. The median baseline ISTH-BAT score was 7 (range 3–11), with scores ≥5 in females and ≥4 in males considered abnormal. Two patients have completed the full 6-month course of sirolimus, while the other two have completed 1 month. Both patients who completed 6 months demonstrated normalization of previously abnormal ISTH-BAT scores: one improved from 6 to 5, and the other from 11 to 3. Although not a formal endpoint, both patients who received 6 months of therapy reported subjective improvement of allergies and inflammatory symptoms, including chronic myalgias and arthralgias. Across all patients, 17 adverse events (AEs) were reported. Most were Grade 1 or 2, including nausea, gastroesophageal reflux (GERD), mucositis, rash/acne, epistaxis, and urinary tract infection. One Grade 3 AE (hemorrhoids) occurred. Gastrointestinal symptoms were the most frequently reported (in 3 of 4 patients). No serious AEs, dose-limiting toxicities, or treatment discontinuations were observed. Conclusions: Low-dose sirolimus appears well tolerated in patients with RUNX1-FPD. Adverse events are primarily low-grade and manageable, with no treatment discontinuations. Preliminary findings suggest potential clinical benefit, including improvement in bleeding symptoms and inflammatory complaints. These results support the safety and potential clinical activity of low-dose sirolimus in RUNX1-FPD. Study enrollment is ongoing (NCT06261060).