Eligibility Criteria
Age Range: 18 years to No maximum
Inclusion Criteria:
* Participants has provided signed, informed consent before initiation of any study specific procedures
* Aged ≥18 years at the time of signing the informed consent
* Confirmed P/LP germline RUNX1 variant per ClinGen Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) RUNX1-specific variant curation rules80
* Participants must be willing to provide bone marrow sample at time of screening and at the end of treatment with sirolimus
* Platelet count of ≥50,000/µL
* Adequate renal function: estimated glomerular filtration rate based on Modification of Diet in Renal Disease (MDRD) calculation, \>30 mL/min/1.73m2
* Adequate hepatic function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<3 × upper limit of normal (ULN) and total bilirubin \<1.5 × ULN
* Adequate cardiac function: left ventricular ejection fraction \>50%
Exclusion Criteria:
* Known allergy to sirolimus
* History of lymphoma or other hematologic malignancies
* Uncontrolled bleeding
* Any prior diagnosis of myelodysplastic syndrome 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; eg, ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, and clarithromycin), strong inducers of CYP3A4 (eg, rifampin and rifabutin), other drugs that could increase sirolimus blood concentrations (eg, bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, letermovir, protease inhibitors \[eg, ritonavir, indinavir, boceprevir, and telaprevir\], metoclopramide, nicardipine, troleandomycin, and verapamil), other drugs that could decrease sirolimus blood concentrations (eg, carbamazepine, phenobarbital, phenytoin, rifapentine, St. John's Wort \[Hypericum perforatum\]), or drugs with blood concentrations that could increase (eg, verapamil) within 7 days before study day 1
* Use of cannabidiol, which can increase blood levels of sirolimus, within 7 days before study day 1
* 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 (eg, 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 (eg, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid) within 28 days before study day 1
* Known diagnosis of chronic viral infection (eg, hepatitis B or C or HIV, and Epstein-Barr) or tuberculosis
* Women who are pregnant, may become pregnant, or who are breastfeeding