Imatinib to Increase RUNX1 Activity in Participants With Germline RUNX1 Deficiency

Overview

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.

Background: * Runt-related transcription factor 1 (RUNX1) gene is located on chromosome 21 and encodes an important regulator of hematopoiesis. People normally inherit one functional copy from each parent. * RUNX1 function is highly dose dependent as both too little as well as too much RUNX1 activity is associated with development of hematologic malignancy. The focus of this protocol is participants with germline RUNX1 mutations resulting in too little RUNX1 activity. * Germline heterozygous RUNX1 mutations are inherited in an autosomal dominant manner and cause a disorder called Familial Platelet Disorder with associated Myeloid Malignancy (FPDMM). Patients with one deleterious germline RUNX1 mutation often have haploinsufficiency although some mutations are associated with a dominant negative effect. * Clinically, patients with germline RUNX1 mutations have aberrant megakaryocytic development, which often results in quantitative and/or qualitative platelet defects. Patients often have easy bleeding or bruising, although some cases are subclinical, and they may present to clinicians with hematologic malignancy. * Patients with germline RUNX1 mutations have 35-45% lifetime risk of developing myeloid hematologic malignancies including MDS and AML. Increased risk of B-ALL, T-ALL and other hematologic malignancies is also associated with deleterious germline RUNX1 mutations. * Deleterious RUNX1 mutations are known to be associated with high-risk malignancy with poor response to upfront chemotherapy and require hematopoietic stem cell transplantation (HSCT). * Imatinib is a dual SFK and ABL inhibitor that is FDA approved and indicated for treatment of CML, ALL, MDS/MPD, aggressive systemic mastocytosis (ASM) as well as hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL). * ABL physically associates with RUNX1, phosphorylates key tyrosines within the RUNX1 inhibitory domain and negatively regulates RUNX1 transcriptional activity. * We hypothesize that imatinib will decrease RUNX1 tyrosine phosphorylation thereby increasing RUNX1 protein activity to a level closer to that expected for 2 normal copies of RUNX1. We also hypothesize that normal levels of RUNX1 protein activity will ameliorate platelet dysfunction and bleeding symptoms via objective measures. * We expect this study to inform the biologically relevant endpoints for a subsequent phase II efficacy study, which would also seek to determine if longer term imatinib administration could prevent malignant transformation. Objectives: * To determine the dose of imatinib for dose expansion in participants with pathogenic or likely pathogenic germline RUNX1 mutations during the dose escalation phase * To determine the safety of imatinib in participants with pathogenic or likely pathogenic germline RUNX1 mutations during the dose expansion phase Eligibility: * Age \>=18 years * Participants with deleterious germline RUNX1 mutations as defined by ClinGen with adequate organ function and no history of hematologic malignancy. Design: * This is a phase Ib study with 2 cohorts (participants with and without pathogenic or likely pathogenic RUNX1 mutations) and 3 arms (2 for imatinib administration and 1 for biobanking control). * A standard 3+3 non-randomized dose-escalation design will be used in the first arm, with orally administered imatinib tested at 2 dose levels from 300 to 400 mg daily for 28 days for participants with pathogenic or likely pathogenic germline RUNX1 mutations. * Participants will have PK/PD evaluations during Arm 2 (expansion phase). * An expansion cohort will be treated at the maximum tolerated dose (MTD) in Arm 2, daily for 12 weeks. Participants who are treated on the dose escalation phase may also be treated in the expansion phase after an appropriate wash out period of 28 days. * The third arm is for unaffected family control participants with wildtype RUNX1 or healthy volunteers who may choose to enroll to donate blood or marrow but will not be treated. * Up to 13 evaluable participants will be enrolled for dose escalation, 12 participants in the expansion cohort, and up to 25 unaffected controls contemporaneously whenever feasible.