Reduced Intensity BMT for Immune Dysregulatory and Bone Marrow Failure Syndromes Using Post-Transplant Cyclophosphamide

• Status: Recruiting
• Trial end date: 2026-12-31
• Target enrollment: 0
• Participant gender: All

Summary

This is a Phase II prospective trial to assess the rates of donor engraftment using reduced intensity conditioning (RIC) hematopoietic stem cell transplant (HSCT) and post-transplant cyclophosphamide (PTCy) for patients with primary immune deficiencies (PID), immune dysregulatory syndromes (IDS), and inherited bone marrow failure syndromes (IBMFS).

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Treatments: Alemtuzumab; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Melphalan; Mycophenolic Acid; Tacrolimus

Criteria

Inclusion Criteria:

• Confirmed diagnosis of:

• Primary Immune Deficiencies:

• Chronic granulomatous disease (CGD)

• Wiskott-Aldrich syndrome (WAS)

• Hyper-Immunoglobulin M (IgM) syndrome

• Common variable immunodeficiency (CVID)

• Leukocyte adhesion deficiency-1 (LAD-1)

• Severe Combined Immunodeficiency (SCID)

• Immune Dysregulatory Syndromes:

• Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome

• Hemophagocytic lymphohistiocytosis (HLH)

• Inherited Bone marrow failure disorders

• Congenital amegakaryocytic thrombocytopenia (CAMT)

• Diamond Blackfan anemia (DBA)

• Shwachman Diamond Syndrome (SDS)

• Thrombocytopenia Absent Radii (TAR)

• Glanzmann's thrombasthenia (GT)

• Kostmann syndrome

• Other PID, IDS, and IBMFS diagnoses as deemed appropriate by the PI.

• Available donor as follows:

• Cohort A

--- Fully HLA matched sibling or other first-degree family member.

• Cohort B

--- Fully HLA matched unrelated 10/10 donor using high-resolution DNA-based typing at the following genetic loci: HLA-A, -B, -C, DRB1, and DQB1.

• Cohort C

• Mismatched unrelated donor at 8 or 9/10 alleles, using high-resolution typing as above.

• HLA-haploidentical family members of any degree who match at least one allele of each of the following genetic loci: HLA-A, -B, -C, DRB1, and DQB1. A minimum match of 5/10 is therefore required, and will be considered sufficient evidence that the donor and recipient share one HLA haplotype.

• The patient and/or legal guardian must sign informed consent for BMT.

• Patients with adequate organ function as measured by

• Cardiac: Left ventricular ejection fraction (LVEF) at rest must be ≥ 35%. For patients aged <13 years, shortening fraction (SF) > 25% by echocardiogram or LVEF by multigated acquisition scan (MUGA) may be used.

• Hepatic: Bilirubin ≤ 3.0 mg/dL; and alanine aminotransferase (ALT), aspartate aminotransferase (AST), and Alkaline Phosphatase (ALP) < 5 x upper limit of normal (ULN).

• Renal: Serum creatinine within normal range for age, or if serum creatinine outside normal range for age, then renal function (creatinine clearance or glomerular filtration rate (GFR)) > 40 mL/min/1.73m2.

• Pulmonary: forced expiratory volume-one second (FEV1), forced vital capacity (FVC), diffusing capacity of the lungs for carbon monoxide (DLCO) > 50% predicted (corrected for hemoglobin); if unable to perform pulmonary function tests, then O2 saturation > 92% on room air.

• Karnofsky or Lansky performance status ≥70%

• Females and males of childbearing potential must agree to practice 2 effective methods of contraception at the same time, or agree to abstinence.

Exclusion Criteria:

• Patients will not be excluded on the basis of sex, racial or ethnic background.

• Positive leukocytotoxic crossmatch.

• Prior allogeneic stem cell transplant.

• Uncontrolled bacterial, viral, or fungal infection at the time of enrollment. Uncontrolled is defined as currently taking medication and with progression or no clinical improvement on adequate medical treatment.

• Diagnosis of idiopathic aplastic anemia, Fanconi Anemia, Dyskeratosis Congenita, or other short telomere syndrome.

• Seropositivity for the human immunodeficiency virus (HIV)

• Active Hepatitis B or C determined by serology and/or nucleic acid test (NAT)

• Female patients who are diagnosed as pregnant by beta human chorionic gonadotropin (bHCG) testing (per institutional practice) or who are breast-feeding.

• Active malignancy or within the timeframe for significant concern for relapse of prior malignancy

Donor Eligibility:

• Donor must be medically, socially, and psychologically fit to donate

• Bone marrow should be requested from all allogeneic donors. Peripheral blood stem cells (PBSCs) are allowed only if the donor is unable or unwilling to give marrow, and no other bone marrow donor is available. Cord blood is not permitted.

• First-degree relatives should be tested for degree of HLA match, CMV serology, ABO type, and complete blood count (CBC). An unrelated donor search should be initiated at the time the patient is referred for BMT.

• Age ≥5 years

• Donors must meet the selection criteria as defined by the Foundation for the Accreditation of Hematopoietic Cell Therapy (FACT).

• Lack of recipient anti-donor HLA antibody in recipient Note: In some instances, low level, non-cytotoxic HLA specific antibodies may be permissible if they are found to be at a level well below that detectable by flow cytometry. This will be decided on a case-by-case basis by the PI and one of the immunogenetics directors.

• In inherited disorders, family members must be tested for carrier and disease status of the underlying disorders. In the event that family members are unaffected carriers, their eligibility as donors will be decided upon by the PI on a case-by-case basis.

• In the event that two or more eligible donors are identified, the donor will be selected per institutional standards. Suggested criteria include the following:

• Related is preferred over unrelated.

• The potential donor that is youngest in age is preferred.

• For CMV seronegative patients, a CMV seronegative donor is preferred. For CMV seropositive patients, a CMV seropositive donor is preferred.

• Red blood cell (RBC) compatibility, in order of preference:

• RBC cross match compatible

• Minor ABO incompatibility

• Major ABO incompatibility

• If the patient is male, male donors are preferred.