Dataset Information

Low Exposure Busulfan Conditioning to Achieve Sufficient Multilineage Chimerism in Patients with Severe Combined Immunodeficiency.

ABSTRACT: After allogeneic hematopoietic cell transplantation (HCT), the minimal myeloid chimerism required for full T and B cell reconstitution in patients with severe combined immunodeficiency (SCID) is unknown. We retrospectively reviewed our experience with low-exposure busulfan (cumulative area under the curve, 30 mg·hr/L) in 10 SCID patients undergoing either first or repeat HCT from unrelated or haploidentical donors. The median busulfan dose required to achieve this exposure was 5.9 mg/kg (range, 4.8 to 9.1). With a median follow-up of 4.5 years all patients survived, with 1 requiring an additional HCT. Donor myeloid chimerism was generally >90% at 1 month post-HCT, but in most patients it fell during the next 3 months, such that 1-year median myeloid chimerism was 14% (range, 2% to 100%). Six of 10 patients had full T and B cell reconstitution, despite myeloid chimerism as low as 3%. Three patients have not recovered B cell function at over 2 years post-HCT, 2 of them in the setting of treatment with rituximab for post-HCT autoimmunity. Low-exposure busulfan was well tolerated and achieved sufficient myeloid chimerism for full immune reconstitution in over 50% of patients. However, other factors beyond busulfan exposure may also play critical roles in determining long-term myeloid chimerism and full T and B cell reconstitution.

SUBMITTER: Dvorak CC

PROVIDER: S-EPMC7384257 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Low Exposure Busulfan Conditioning to Achieve Sufficient Multilineage Chimerism in Patients with Severe Combined Immunodeficiency.

Dvorak Christopher C CC Long-Boyle Janel J Dara Jasmeen J Melton Alexis A Shimano Kristin A KA Huang James N JN Puck Jennifer M JM Dorsey Morna J MJ Facchino Janelle J Chang Catherine K CK Cowan Morton J MJ

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20190312 7

After allogeneic hematopoietic cell transplantation (HCT), the minimal myeloid chimerism required for full T and B cell reconstitution in patients with severe combined immunodeficiency (SCID) is unknown. We retrospectively reviewed our experience with low-exposure busulfan (cumulative area under the curve, 30 mg·hr/L) in 10 SCID patients undergoing either first or repeat HCT from unrelated or haploidentical donors. The median busulfan dose required to achieve this exposure was 5.9 mg/kg (range, ...[more]

PMID: 30876930

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Project description:The pharmacokinetics of low-dose busulfan (BU) were investigated as a nonmyeloablative conditioning regimen for autologous gene therapy (GT) in pediatric subjects with adenosine deaminase-deficient severe combined immunodeficiency disease (ADA SCID). In 3 successive clinical trials, which included either γ-retroviral (γ-RV) or lentiviral (LV) vectors, subjects were conditioned with BU using different dosing nomograms. The first cohort received BU doses based on body surface area (BSA), the second cohort received doses based on actual body weight (ABW), and in the third cohort, therapeutic drug monitoring (TDM) was used to target a specific area under the concentration-time curve (AUC). Neither BSA-based nor ABW-based dosing achieved a consistent cumulative BU AUC; in contrast, TDM-based dosing led to more consistent AUC. BU clearance increased as subject age increased from birth to 18 months. However, weight and age alone were insufficient to accurately predict the dose that would consistently achieve a target AUC. Furthermore, various clinical, laboratory, and genetic factors (eg, genotypes for glutathione-S-transferase isozymes known to participate in BU metabolism) were analyzed, but no single finding predicted subjects with rapid versus slow clearance. Analysis of BU AUC and the postengraftment vector copy number (VCN) in granulocytes, a surrogate marker of the level of engrafted gene-modified hematopoietic stem and progenitor cells (HSPCs), demonstrated gene marking at levels sufficient for therapeutic benefit in the subjects who had achieved the target BU AUC. Although many factors determine the ultimate engraftment following GT, this work demonstrates that the BU AUC correlated with the eventual level of engrafted gene-modified HSPCs within a vector group (γ-RV versus LV), with significantly higher levels of granulocyte VCN in the recipients of LV-modified grafts compared to recipients of γ-RV-transduced grafts. Taken together, these findings provide insight into low-dose BU pharmacokinetics in the unique setting of autologous GT for ADA SCID, and these dosing principles may be applied to future GT trials using low-dose BU to open the bone marrow niche.

Project description:Background: Severe combined immunodeficiency (SCID) is characterized by arrested T lymphocyte production and B lymphocyte dysfunction, resulting in life-threatening infections. Early diagnosis of SCID through population-based newborn screening (NBS) optimizes clinical management and outcomes, and also permits identification of previously unknown factors essential for human lymphocyte development. Methods: SCID was detected, prior to onset of infections, by NBS of T cell receptor excision circles, a biomarker for thymic output. Upon confirmation, the affected baby was treated by allogeneic hematopoietic cell transplantation (HCT). The genetic cause was sought by exome sequencing of the patient and parents, followed by functional analysis of a prioritized candidate gene using human hematopoietic stem cells (HSC) and zebrafish embryos. Results: An infant with leaky SCID, craniofacial and dermal abnormalities, and absent corpus callosum had his immune deficit fully corrected by HCT. Exome sequencing revealed a heterozygous, de novo, missense mutation pN441K in BCL11B. The mutant Bcl11b protein had dominant negative activity, abrogating the ability of wild type Bcl11b to bind DNA, arresting T cell lineage development and disrupting HSC migration, revealing a novel function of Bcl11b. The patientâs defects, recapitulated in Bcl11b-deficient zebrafish, were reversed by ectopic expression of intact, but not mutant, human BCL11B. Conclusions: Newborn screening facilitated treatment and identification of a novel etiology for human SCID. Coupling exome sequencing with candidate gene evaluation in human HSC and in zebrafish revealed that a constitutional BCL11B mutation causes human multisystem anomalies with SCID, while also revealing a novel, pre-thymic role for Bcl11b in hematopoietic progenitors. 3 samples were analyzed in duplicate, Sample 1 was human HSC transduced with GFP only lentivirus which served as controls, Sample 2 was human HSC transduced with lentivirus expressing FLAG-tagged WT BCL11B and GFP, Sample 3 was human HSC transduced with lentivirus expressing FLAG-tagged mutant BCL11B and GFP

Dataset Information

Low Exposure Busulfan Conditioning to Achieve Sufficient Multilineage Chimerism in Patients with Severe Combined Immunodeficiency.

Publications

Low Exposure Busulfan Conditioning to Achieve Sufficient Multilineage Chimerism in Patients with Severe Combined Immunodeficiency.

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