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.

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

• INCLUSION CRITERIA:

• Affected participants (Recipients)

  • History of deleterious or suspected deleterious (defined as P/LP or VUS with RUNX1 phenotype) germline RUNX1 mutation as defined by ClinVar (nih.gov)
  • Histological confirmation of a myeloid malignancy - acute or chronic leukemia (<5% marrow blasts preferred) or myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) (<10% marrow blasts preferred). Participants may be treated on this study to achieve preferred blast cutoffs. Participants with poorly responsive or relapsed disease remain eligible and may proceed as the graft-versus-leukemia (GVL) effect may produce cures.

Subjects requiring standard therapies to prepare for HCT should ideally be referred to this study in remission, if possible. However, sometimes disease status changes during evaluation for HCT and it is necessary to establish disease control through the administration of standard therapies during evaluation for HCT. If ongoing therapy for the underlying disease outside of the NIH is not in the best interest of the subject according to the clinical judgment of the NIH PI, then the subject may receive standard treatment for his/her underlying hematologic malignancy as a bridge to HCT on this protocol, prior to starting the research phase of the study. If it becomes apparent that the subject will not be able to proceed to HCT, then he/she must come off study. Subjects receiving standard therapy will be told about the therapy, associated risks, potential benefits, alternatives to the proposed therapy, and the availability of receiving the same treatment elsewhere, outside of a research protocol.

• Availability of a haploidentical donor (HLA-match only).

• Age >= 4 and <= 70 years

• Karnofsky (>=16 years) or Lansky (<16 years) >=60%

• For human immunodeficiency virus (HIV)-infected participants, participant must be on effective anti-retroviral therapy, without uncontrolled opportunistic infection and have approval via Transplant Infectious Disease consultation. Consider donor with CCR5(delta)32 homozygosity for these participants.

• For individuals with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load (VL) must be undetectable on suppressive therapy, if indicated.

• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with active HCV infection who are currently on treatment must have an undetectable HCV VL.

• Contraception as follows:

  ---Women of child-bearing potential (WOCBP) must agree to use highly effective contraception (hormonal, intrauterine device [IUD], abstinence, surgical sterilization) at the study entry and up to and 12 months post conditioning and/or post-transplant.

• Men that can father a child must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) at the study entry and up to 12 months posttransplant or 4 months after conditioning if transplant is not done. We also will recommend men that can father children with partners that can bear children ask their partners to be on highly effective birth control (hormonal, IUD, surgical sterilization). Men that can father children must not freeze or donate sperm within the same period.

• Breastfeeding participants must be willing to discontinue breastfeeding during the study and for 12 months post-transplant or 1 week after conditioning if transplant is not done.

• Willingness to remain in the NIH hospital or, if discharged, stay close to the NIH (30 minutes drive), for a minimum of 100 days after transplant or longer if there are complications. The participants must commit to having an adult caregiver with them during the first 100 days after the transplant

• Participants or parent/guardian/legally authorized representative must be able to understand and willing to sign a written informed consent document.

• Additional criteria for recipients suitable for MAC

  • Age <= 65 years

  • HCT-CI <4

  • Pulmonary function tests (PFTs): Forced expiratory volume in the first second (FEV1) and adjusted diffusion capacity of carbon monoxide (DLCO) >=66%, without dyspnea at rest or oxygen requirement. If too young to cooperate with PFTs, must have >=92% oxygen saturation on room air and no dyspnea at rest.

  • Left ventricular ejection fraction (LVEF) >=50% by echocardiogram (ECHO) or Multigated Acquisition (MUGA) scan (101)

  • Recipients must have adequate organ function as defined below:

    • Total bilirubin <1.5 x institutional upper limit of normal (iULN) (unless Gilbert disease, hemolysis)
    • Aspartate aminotransferase (AST) / Alanine aminotransferase (ALT) <=2.5 x iULN (unless therapy related and will improve in discussion with the National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK])
    • Creatinine within normal institutional limits or 24-hour urine or calculated creatinine clearance >=60 mL/min/1.73 m^2 for individuals with creatinine levels above institutional normal (calculated using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation)

• Additional criteria for recipients suitable for RIC

  • Age <=70 years

  • PFTs: FEV1 and DLCO >=50%, without dyspnea at rest or oxygen requirement. If too young to cooperate with PFTs, must have >=92% oxygen saturation on room air and no dyspnea at rest

  • LVEF >=40% by ECHO or MUGA obtained within 2 months of HSCT (Children s Oncology Group [COG] criteria).

  • Recipients must have adequate organ function as defined below:

    • Total bilirubin <2.5 x iULN (unless Gilbert disease, hemolysis)
    • AST/ALT <3.5 x iULN (unless therapy related and will improve in discussion with NIDDK)
    • Creatinine within normal institutional limits or 24-hour urine or calculated creatinine clearance >=50 mL/min/1.73 m^2 for individuals with creatinine levels above institutional normal (calculated using the CKD-EPI equation)

• Unaffected participants

  • Haploidentical donors

    ----Age >=4 years

  • Participants or parent/guardian must be able to understand and willing to sign a written informed consent document.

  • Unaffected family members

    • Age >=18 years
    • If the participant is a blood relative of the recipient, participant must be negative for RUNX1 mutations by molecular testing
    • Participants must be able to understand and willing to sign a written informed consent document.

EXCLUSION CRITERIA:

-All participants

• Recipients who are receiving any investigational agent except virus specific T cells (VST)
• Active non-hematologic malignancies
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to the drugs used in study.
• Participants with the following cardiac conditions: symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (except atrial fibrillation if cleared by cardiology consultation)
• Participants without access to medical care at home.
• Positive serum or urine beta-human chorionic gonadotropin (beta-hCG) test at screening
• Uncontrolled intercurrent illness evaluated by history, physical exam, and laboratory studies or situations that would limit compliance with study requirements, interpretation of results or that could increase risk to the participant

This study will comply with the NIH Data Management and Sharing (DMS) Policy, which applies to all new and ongoing NIH-funded research in the IRP, as of January 25, 2023, that is associated with a ZIA, with a clinical protocol that undergoes scientific review and/or will involve genomic data sharing.

Data will be made available as soon as possible or at the time of associated publication. Data not published in a manuscript will be shared via public source once the data set completes QC.

Clinical data will be made available upon request and with the permission of the study PI. Genomic data are made available via dbGAP through requests to the data custodians.