Imatinib to Increase RUNX1 Activity in Participants With Germline RUNX1 Deficiency

Conditions: Inherited Bone Marrow Failure Syndrome, Familial Platelet Disorder With Predisposition to Myeloid Malignancies

Summary

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.

Eligibility Criteria

* INCLUSION CRITERIA- AFFECTED PARTICIPANTS ONLY * Affected participants must have a confirmed pathogenic or likely pathogenic germline RUNX1 variant by history. ClinGen expert variant curation panel criteria for pathogenicity will be utilized. * Affected participants must have a history of clinically significant bleeding as defined by history of abnormal ISTH-BAT score, use of anti-bleeding medications (e.g., amicar), history of platelet transfusion, abnormal PFA screen, abnormal TEG, abnormal platelet aggregation or abnormal platelet electron microscopy. * Bone marrow morphology, flow cytometry and cytogenetics confirmed by the NIH Department of Laboratory Medicine (DLM) at least within 12 months of initiating imatinib. * TSO500 performed by NCI Lab of Pathology within 12 months of initiating imatinib. * Substantial GI malabsorption is not suspected. * Participants with human immunodeficiency virus (HIV) on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial if their HAART medications do not interact with imatinib. * Participants with evidence of chronic hepatitis B virus (HBV) infection, on suppressive therapy with undetectable HBV viral load are eligible for this trial. Suppressive therapy medication may not interact with imatinib. * Participants with a distant history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with active HCV infection who are currently on treatment, with undetectable HCV viral load are eligible. If unknown HCV is detected upon screening- these participants will not be eligible for the study. INCLUSION CRITERIA- UNAFFECTED PARTICIPANTS ONLY * 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. INCLUSION CRITERIA- ALL PARTICIPANTS * Age \>=18 years. * ECOG performance status \=60%). * Participants must have adequate organ and marrow function as defined below: * leukocytes \>= 3,000/mcL * absolute neutrophil count \>= 1,500/mcL * platelets \>= 50,000/mcL (without transfusion support) * total bilirubin within normal institutional limits or \

Source: ClinicalTrials.gov (NCT06090669). StuddyBuddy aggregates publicly available trial information.