# Randomized study of low versus moderate dose busulfan in transplant for severe combined immunodeficiency

> **NIH NIH U01** · CHILDREN'S HOSPITAL OF LOS ANGELES · 2021 · $526,140

## Abstract

Project Summary
 Severe combined immunodeficiency (SCID) is a group of genetic disorders that abrogate T cell
development and function. Allogeneic hematopoietic cell transplantation (HCT) is the standard treatment, for
the disease, which is typically fatal by age 2 years if not treated. HCT can be performed successfully in SCID
patients without the high dose pre-HCT busulfan conditioning typically used, due to the lack of functional T
cells. Despite restoration of T cell function, humoral immunity remains poor in many patients post-HCT. This
project seeks to test the efficacy and safety of a regimen of low dose, individualized targeted busulfan
compared to moderate dose in SCID patients at risk of poor humoral outcome undergoing non-matched sibling
donor HCT. We will target patients without active infection, leveraging the widespread implementation of
universal newborn screening in the United States. We hypothesize that in our proposed multi-institutional
randomized phase II trial patients receiving low dose busulfan will achieve similar outcomes compared to those
receiving moderate dose (myeloablative) busulfan, achieving both T and B cell immune reconstitution.
 In Aim 1, we will examine immunological and safety outcomes in trial participants. Patients who lack
matched sibling donors, confirmed to have the appropriate genotype, and who do not have active infection will
be recruited over 4 1/2 years. Within each of 2 genotype cohorts (IL2RG/JAK3, RAG1/RAG2), 32 patients will
be randomized to cumulative area-under-the-curve exposure of busulfan of 30 mg*h/L versus 60 mg*h/L (32
patients per cohort, 64 patients total). IL2RG/JAK3 patients will also receive rATG and RAG1/RAG2 patients
will receive rATG, fludarabine, and thiotepa. Stem cell sources include unrelated and haploidentical related
donor products that will be TCRαβ+/CD19+ depleted with no post-HCT GVHD prophylaxis. The primary
endpoint is protective antibody response to tetanus, a gold standard of normal humoral immune function in
children, by 2 years post-HCT. Secondary endpoints include reconstitution of T cell number, thymic output, cell
type specific chimerism, response to live viral vaccines at 3 years, survival, and incidence of HCT related
complications.
 In Aim 2, we will examine the correction of T and B cell abnormalities in depth. The central question is
whether mixed/split chimerism (donor-derived T cells with mixed chimerism in the B and myeloid
compartments) will nevertheless be associated with normal immune phenotype, function, repertoire and
tolerance in one or more genotypic cohorts. We hypothesize that generation of memory B cells, antibody-
secreting cells and correction of pre-existing abnormalities of the B cell receptor repertoire post-HCT will be
evident in all genotype cohorts and that the degree and quality of correction in the setting of mixed chimerism
will vary according to the biology of each genetic abnormality. We hypothesize that T cell exhaustion seen in
p...

## Key facts

- **NIH application ID:** 10232116
- **Project number:** 5U01AI126612-05
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **Principal Investigator:** Leslie S Kean
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $526,140
- **Award type:** 5
- **Project period:** 2017-08-24 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10232116

## Citation

> US National Institutes of Health, RePORTER application 10232116, Randomized study of low versus moderate dose busulfan in transplant for severe combined immunodeficiency (5U01AI126612-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10232116. Licensed CC0.

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