NCT07524530

Stem Cell Transplantation for Participants With Germline RUNX1 Associated Blood Cancers

Phase II Haploidentical Hematopoietic Stem Cell Transplantation for Participants With Germline RUNX1 Associated Hematologic Malignancies

• Status: Not Yet Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 98 (estimated)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 4 Years – 70 Years
• Healthy volunteers: Not accepted

Summary

Background: Some blood cancers can be caused by germline variants (changes) in a person s RUNX1 gene. Germline variants are genetic inherited changes a person is born with. Stem cell transplants are used to treat many diseases including blood cancers. Stem cell transplantation for patients with germline RUNX1 mutation driven blood cancers is standard of care and available in most major medical centers. The difference with this transplantation protocol is that it is prospective, only available to participants with germline RUNX1 variants and designed to determine the extent to which tailoring chemotherapy and supportive care medication doses for each individual patient may improve outcomes compared to data derived from retrospective transplantation protocols for patients with RUNX1 varinats which is less accurate. Objective: The primary objective of this protocol is to determine how tailored doses of chemotherapy and supportive care medications may improve disease free survival as compared to historical/expected disease free survival. Eligibility: People aged 4 to 70 years with blood cancer caused by a RUNX1 gene mutation. Other participants are also needed: (1) stem cell donors; (2) relatives who do not have a mutation in the RUNX1 gene; and (3) healthy volunteers. Design: Participants with blood cancer will be screened during approximately 1-3 months before transplatation. They will have blood tests and tests of their heart and lung function. A sample of bone marrow may be taken. A flexible tube (central line) will be inserted into a vein in participants chest or lower neck. This line will remain in place during the hospitalization and be used to draw blood and administer drugs. These lines are almost always transitioned to a peripherally inserted central catheter (PICC) line at the time of hospital discharge. Participants will be inpatient for 4 to 5 weeks. They will receive drugs to prepare their body for the stem cell transplant. Some may also receive radiation treatment. Other tests will include imaging scans. The stem cell transplant will be given through the central line. After discharge from the clinic, participants will have follow-up visits at least once per week for approximately 100 days. Then they will have follow-up clinic visits for 3 years. Donors, relatives, and healthy volunteers may provide samples of blood, stool, and saliva. Adults may also opt to provide samples of skin and bone marrow.

Detailed description

Background: * 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 germline RUNX1 mutations often have aberrant megakaryocytic development, resulting in quantitative and/or qualitative platelet defects, easy bleeding and bruising, aberrant DNA damage response, and 35-45% lifetime risk of developing hematologic malignancies. Additional phenotypic (e.g., gastrointestinal and allergy/immunology symptoms) and genotypic (e.g., early acquisition of secondary somatic mutations) characteristics have been described through the longitudinal NIH RUNX1 Natural History Study. * 259 families with germline RUNX1 mutations have been described in the literature and it is estimated that there may be 5,515 families with germline RUNX1 mutations worldwide. The genome-first UK BioBank cohort study reported that germline RUNX1 mutations increase the risk of hematologic malignancies in general (Odds Ratio 66) and myeloid malignancies (OR 210) in particular (p \<= 0.001). * Somatic RUNX1 mutations have long been associated with poor prognosis hematologic malignancies usually prompting hematopoietic stem cell transplantation (HSCT) referrals. Somatic and germline RUNX1 mutations may appear indistinguishable without confirmatory genetic testing from a true germline tissue. * There has been scant outcomes data comparing patients with somatic vs. germline RUNX1 mutations after HSCT. A recent retrospective Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 22 patients with germline RUNX1 mutations compared to 302 patients with somatic RUNX1 mutations found that germline RUNX1 mutations are associated with greater likelihood of acute myeloid leukemia (AML) arising from myelodysplastic syndrome (MDS), primary induction failure, and measurable residual disease (MRD) positivity at time of HSCT as compared to patients with somatic RUNX1 mutations. Patients with germline RUNX1 mutations had 36.4% disease free survival (DFS) vs. 60.8% DFS for patients with somatic RUNX1 mutations at 1 year post transplantation (p\<0.024). The donors and regimens used were very diverse. * This is the first prospective transplantation protocol for participants with germline RUNX1-aassociated myeloid malignancies. Objective: -To determine the proportion of participants with disease free survival (DFS) at 1 year post haploidentical transplantation. Eligibility: * Affected participants (Recipients) * Deleterious or suspected deleterious germline RUNX1 mutation * Confirmed myeloid malignancy * Confirmed allogeneic HSCT donor (Human Leukocyte Antigen \[HLA\] match only * Age \>= 4 years * Unaffected participants * Haploidentical donors ---Age \>= 4 years * Family members and healthy volunteers * Age \>= 18 years Design: * This is an open label, nonrandomized Phase II study with 1 affected Cohort and 1 unaffected Cohort * Participants in the affected Cohort will be divided into two conditioning Arms prior to receiving a HSCT at day 0 * Myeloablative conditioning (MAC): Recipients will receive cyclophosphamide intravenously (IV) at 50 mg/kg/day on Days -6 and -5 and busulfan IV from Day - 4 to Day -1 at 17.5-20 mg/hr/L per day. * Reduced intensity conditioning (RIC): Recipients will receive fludarabine IV at 20 mg/hr/mL from Days -5 to -2, cyclophosphamide IV at 14.5 mg/kg/day on Days - 5 and -4, and total body irradiation (TBI) at 4 Gy on Day -1. * Participants in the unaffected Cohort will not receive treatment but may donate biospecimens for research. * Up to 84 evaluable participants will be enrolled

Conditions

• Core Binding Factor Alpha Subunits
• Hematologic Neoplasms
• Leukemia
• Lymphoma

Interventions

Type	Name	Description
DRUG	Cyclophosphamide	For Arm 1 myeloablative conditioning, given on days -6 and -5 at 50 mg/kg/day IV. For Arm 2 reduced intensity conditioning, give on day -5 and day -4 at 14.5 mg/kg IV once daily. GVHD prophylaxis for all recipients, 50mg/kg IV on Day 3 and Day 4 post HSCT.
DRUG	Busulfan	For Arm 1 myeloablative conditioning, given on day -4 to day -1. The daily busulfan area under the curve goal is 4263-4872 mcMolar x min daily or 17.5-20 mg/hr/L per day (70-80 mg\*hr/L over 4 days).
DRUG	Fludarabine	For Arm 2 reduced intensity conditioning, given once daily on days -5 through day -2. The cumulative fludarabine area under the curve is 20 mg\*hr/mL
RADIATION	Total Body Irradiation	Form Arm 2 reduced intensity conditioning, total 4 Gy, fractionated 2 Gy twice per day, given on day -1.
BIOLOGICAL	Hematopoietic stem cells	Given on Day 0. The target dose is any dose \> or equal to 7 x 10\^6 and \<= 10 x 10\^6 CD34+ cells/kg recipient body weight.
DRUG	Tacrolimus	GVHD prophylaxis for all recipients. Given intravenously at a dose of .02 mg/kg from Day 5 until Day 100.
DRUG	Mycophenolate Mofetil	GVHD prophylaxis for all recipients. Given at a dose of 15 mg/kg three times a day from Day 5 through Day 35.

Timeline

• Start date: 2026-04-22
• Primary completion: 2033-06-01
• Completion: 2036-06-01
• First posted: 2026-04-13
• Last updated: 2026-04-17

Locations

1 site across 1 country: United States