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.
- 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.
ALL PARTICIPANTS
Participants who are receiving any other investigational agents.
Participants who received prior hematologic malignancy directed therapy
Participants receiving medication that would affect platelet number or function (e.g., aspirin and anti-platelet medications
Sequential
imatinib
DrugImatinib at 300-400 mg PO QD based on arm assignment/dose level
TruSight Oncology
DeviceAssay sequencing platform to identify pathogenic genetic mutations in DNA and RNA
Determine the dose of imatinib for dose expansion in participants with pathogenic or likely pathogenic germline RUNX1 mutations during the dose escalation phase
Safety will be evaluated by the number of DLTs identified at each dose level. The number of DLTs at each dose level will be reported and used to determine the RP2D.
Determine the safety of imatinib in participants with pathogenic or likely pathogenic germline RUNX1 mutations during the dose expansion phase
Safety will be evaluated by the number of DLTs identified at each dose level.
Pharmacokinetics of imatinib in the RUNX1 population in the dose expansion phase
Change in measurement of drug levels in blood; assessed for potential differences in their study results before and after imatinib administration by an appropriate paired test.
Improvement in platelet dense granule structure by electron microscopy as compared to baseline in the dose expansion phase
Change in measurement; assessed for potential differences in their study results before and after imatinib administration by an appropriate paired test.
Change in platelet qualitative defects
Change in measurement; assessed for potential differences in their study results before and after imatinib administration by an appropriate paired test.
Safety of imatinib in the dose escalation phase
AEs are reported by type and grade, and frequency.
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