Low-Dose Sirolimus for the Treatment of RUNX1 Familial Platelet Disorder

Inclusion criteria

• Patient has provided signed, informed consent before initiation of any study specific procedures
• Aged ≥ 18 years at the time of signing the informed consent
• Confirmed pathogenic/likely pathogenic (P/LP) germline RUNX1 variant per ClinGen Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) RUNX1-specific variant curation rules
• Patient must be willing to provide a bone marrow sample at time of screening and at the end of treatment with sirolimus
• Platelet count of ≥ 50,000/µL
• Creatinine clearance (CrCl) of ≥ 60 mL/min; estimated using the Cockcroft Gault formula or measured by 24 hour urine collection. Exceptions will be allowed, at the discretion of the investigator, for cases of a concomitant medication that alters renal function
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 × upper limit of normal (ULN)
• Total bilirubin \< 1.5 × ULN
• Left ventricular ejection fraction (EF) \> 50% or at the discretion of the investigator

Exclusion criteria

• Known allergy to sirolimus
• History of major bleeding events that are clinically relevant in the judgement of the investigator or non-major bleeding events that cannot be controlled using SOC practices
• Any known history of lymphoma, myelodysplastic syndrome (MDS), or other hematologic malignancy using International Working Group criteria
• Prior treatment with sirolimus or a rapalog, mTOR inhibitor, or B-cell-depleting therapy within 28 days before study day 1
• Treatment with strong inhibitors of cytochrome P450 3A4 (CYP3A4; e.g., ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, and clarithromycin), strong inducers of CYP3A4 (e.g., rifampin and rifabutin), other drugs that could increase sirolimus blood concentrations (e.g., bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, letermovir, protease inhibitors \[e.g., ritonavir, indinavir, boceprevir, and telaprevir\], metoclopramide, nicardipine, troleandomycin, and verapamil), other drugs that could decrease sirolimus blood concentrations (e.g., carbamazepine, phenobarbital, phenytoin, rifapentine, St. John's Wort \[Hypericum perforatum\]), or drugs with blood concentrations that could increase (e.g., verapamil) within 7 days before study day 1, or at the discretion of the investigator
• Use of cannabidiols that increase blood levels of sirolimus, within 7 days before study day 1 or at the discretion of the investigator
• Myocardial infarction within 6 months before study day 1, congestive heart failure (New York Heart Association \> class II)
• Total cholesterol \> 300 mg/dL or triglyceride \> 400 mg/dL
• Arterial thrombosis (e.g., stroke or transient ischemic attack) within 6 months before study day 1
• Infection requiring intravenous anti-infective treatment within 1 week of study day 1
• Live vaccines (e.g., measles, mumps, rubella, oral polio, Bacillus Calmette-Guerin \[BCG\], yellow fever, varicella, and TY21a typhoid) within 28 days before study day 1
• Known diagnosis of tuberculosis is exclusionary to provide protection against reactivation of infections by the immunosuppressive activity of the study drug sirolimus
• The enrollment of a patient with a history of infection with hepatitis B virus (HBV) but with undetectable HBV deoxyribonucleic acid (DNA) by standard institutional testing can be considered after consultation with the investigator
• Patients with history of chronic hepatitis C virus (HCV) must have documentation of completed curative standard of care (SOC) antiviral therapy
• Patients with history of HIV infection must be well-managed with SOC antiretroviral therapy (highly active antiretroviral therapy \[HAART\])
• Patients with history of Epstein-Barr may be considered after consultation with the treating physician
• Participants who are pregnant may become pregnant, or who are breastfeeding
• Because adequate and well-controlled studies of the impact of sirolimus on fetuses currently do not exist, study approved contraception must be used from start of study therapy to 12 weeks after the last dose of sirolimus
• Adequate and well-controlled studies of infants fed breastmilk from patients undergoing sirolimus therapy do not exist and breastfeeding during study treatment is prohibited