Phase Ib Study of Imatinib to Increase RUNX1 Activity in Participants With Germline RUNX1 Deficiency
Background: Runt-related transcription factor 1 (RUNX1) gene regulates the formation of blood cells. People with mutations of this gene may bleed or bruise easily; they are also at higher risk of getting cancers of the blood, bone marrow, and lymph nodes.
Objective: The purpose of the study includes determining which dose of imatinib is best for people with pathogenic or likely pathogenic RUNX1 mutations without blood cancers, and to determine whether there are any changes in platelet function and inflammatory markers.
Eligibility: Adults aged 18 and older with RUNX1 mutations. Healthy people without this mutation, including family members of affected participants, are also needed.
Design: Participants with the RUNX1 mutation will be screened. They will have a physical exam with blood tests. They will have a test of their heart function. They may need a new bone marrow biopsy if they haven't had one in the past year. Imatinib is a tablet taken by mouth once a day, every day, at home. Affected participants in different parts of the study will take imatinib for either 28 days or up to 84 days. They will fill out questionnaires about how they are feeling. For the first part of the study, participants will have blood tests every 2 weeks, either at home or at the NIH, while they are taking the imatinib. They will have a follow up visit, at home or at the NIH, when they are done taking imatinib on Day 28. Participants on the second part of the study will come to NIH on days 1 and days 84. They will have blood tests every 2 weeks (at home or the NIH) while they are taking imatinib. They may opt to have a bone marrow biopsy repeated after they finish their course of imatinib. Participants will have a follow-up visit (at home or the NIH) 30 days after they stop taking imatinib. Participants who do not have the RUNX1 mutation will have 1 clinic visit. They will have blood tests. They will fill out questionnaires. They may opt to have a bone marrow biopsy.
• Unaffected family members or healthy volunteers without RUNX1 mutation by pedigree or molecular testing Only participants who are related to the proband need to provide a molecular test.
• The last dosage of any platelet inhibiting medications was at least 2 weeks prior to enrollment and research sample acquisition.
• Age \>=18 years.
• ECOG performance status \<=2 (Karnofsky \>=60%).
• Participants must have adequate organ and marrow function as defined below:
‣ leukocytes \>= 3,000/mcL
⁃ absolute neutrophil count \>= 1,500/mcL
⁃ platelets \>= 65,000/mcL (without transfusion support)
⁃ total bilirubin within normal institutional limits or \<= 3 X the institutional upper limit of normal for participants with Gilbert s syndrome
⁃ AST(SGOT)/ALT(SGPT) \<= 2.5 X institutional upper limit of normal
⁃ creatinine within normal institutional limits OR creatinine clearance \>= 60 mL/min/1.73 m\^2 for participants with creatinine levels above institutional normal.
• NIDDK CKD-EPI equation GFR = 141 x min (Scr /kappa, 1)\^alpha x max(Scr /kappa, 1)\^-1.209 x 0.993\^Age x 1.018 \[if female\] x 1.159 \[if black\] where: Scr is serum creatinine in mg/dL, kappa is 0.7 for females and 0.9 for males, alpha is -0.329 for females and -0.411 for males, min indicates the minimum of Scr /kappa or 1, and max indicates the maximum of Scr /kappa or 1.
∙ Note: GFR is expressed in mL/min per 1.73 m\^2, Scr is serum creatinine expressed in mg/dL, age is expressed in years, kappa is 0.7 for females and 0.9 for males, alpha is -0.329 for females and -0.411 for males, min indicates the minimum of Scr /kappa or 1, and max indicates the maximum of Scr /kappa or 1. Race is self-identified.
• Women of child-bearing potential and men must agree to use effective contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for 30 days after the last administration of study drug.
• Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 30 days after the last administration of study drug
• Ability of participant to understand and the willingness to sign a written informed consent document.