Association of busulfan exposure and outcomes after HCT for patients with an inborn error of immunity

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment strategy for patients with inborn errors of immunities (IEIs). The objective of this study was to assess the optimal busulfan exposure before allogeneic HCT for patients with an IEI who received an IV busulfan-based conditioning regimen. Patients from 17 international centers were included. The main outcome of interest was event-free survival (EFS). Patients were categorized into 4 IEI subgroups: combined immunodeficiency (CID), severe combined immunodeficiency (SCID), neutrophil disorders, and hemophagocytic lymphohistiocytosis (HLH)-related disorders. Busulfan exposure was calculated by individual centers (area under the curve [AUC]CENTER) and re-estimated using a nonlinear mixed-effects model (NONMEM; exposure defined as AUCNONMEM). Overall, 562 patients were included: 173 (30.8%) with CID, 154 (27.4%) with SCID, 101 (18.0%) with HLH-related disorders, and 134 (23.8%) with neutrophil disorders. The median busulfan AUCNONMEM was 69.0 mg × h/L and correlated poorly with the AUCCENTER (r2 = 0.54). In patients with SCID, HLH-related, and neutrophil disorders with a busulfan AUCNONMEM of 70 to 90 mg × h/L, 2-year EFS was superior to <70 mg × h/L, and >90 mg ×h/L. Full donor chimerism increased with higher busulfan AUCNONMEM, plateauing at 90 mg × h/L. For patients with CID, the optimal AUCNONMEM for donor chimerism was found to be >70 mg × h/L. Improved EFS and higher donor chimerism may be achieved by targeting a cumulative busulfan AUCNONMEM of 80 mg × h/L (range, 70-90). Our study stresses the importance of uniformly using a validated population pharmacokinetic model to estimate AUCNONMEM.

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Publication Details

Journal
Blood Advances
Published
2024-09-27
DOI
https://doi.org/10.1182/bloodadvances.2024013275
Citations
10
Primary Topic
Immunodeficiency and Autoimmune Disorders
Type
article
Field-Weighted Citation Impact
2.40

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article

Association of busulfan exposure and outcomes after HCT for patients with an inborn error of immunity

Jaap Jan Boelens, Mathias Hauri‐Hohl, M. Y. Eileen C. van der Stoep, Geoff D.E. Cuvelier et al.
10 citations
Blood Advances
Immunodeficiency and Autoimmune Disorders
2.40
article

Association of busulfan exposure and outcomes after HCT for patients with an inborn error of immunity

Jaap Jan Boelens, Mathias Hauri‐Hohl, M. Y. Eileen C. van der Stoep, Geoff D.E. Cuvelier, Layne Oram, Sung‐Yun Pai, Anne-Charlotte Teyssier, Mary Coussons, Toine C. G. Egberts, Robbert G. M. Bredius, Christa E. Nath, Maja Krajinović, Tim Bognàr, Christen L. Ebens, Erin Morales, Maria Pia Cicalese, Moises Garcia-Rosa, Arief Lalmohamed, Hannah Lust, Christopher C. Dvorak, Caroline A. Lindemans, Susan E. Prockop, Peter J. Shaw, Janel Long-Boyle, Sonali Chaudhury, Robert Wynn, Mary Anne Slatter, Yves Théorêt, Henrique Bittencourt, Robert Chiesa, Susan E. Long, Tayfun Güngör, Steven J. Keogh, Imke H. Bartelink, C.A. Martinez, Jordan Brooks, Rada Savic, Marc Ansari
article en
10 citations

Abstract

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment strategy for patients with inborn errors of immunities (IEIs). The objective of this study was to assess the optimal busulfan exposure before allogeneic HCT for patients with an IEI who received an IV busulfan-based conditioning regimen. Patients from 17 international centers were included. The main outcome of interest was event-free survival (EFS). Patients were categorized into 4 IEI subgroups: combined immunodeficiency (CID), severe combined immunodeficiency (SCID), neutrophil disorders, and hemophagocytic lymphohistiocytosis (HLH)-related disorders. Busulfan exposure was calculated by individual centers (area under the curve [AUC]CENTER) and re-estimated using a nonlinear mixed-effects model (NONMEM; exposure defined as AUCNONMEM). Overall, 562 patients were included: 173 (30.8%) with CID, 154 (27.4%) with SCID, 101 (18.0%) with HLH-related disorders, and 134 (23.8%) with neutrophil disorders. The median busulfan AUCNONMEM was 69.0 mg × h/L and correlated poorly with the AUCCENTER (r2 = 0.54). In patients with SCID, HLH-related, and neutrophil disorders with a busulfan AUCNONMEM of 70 to 90 mg × h/L, 2-year EFS was superior to <70 mg × h/L, and >90 mg ×h/L. Full donor chimerism increased with higher busulfan AUCNONMEM, plateauing at 90 mg × h/L. For patients with CID, the optimal AUCNONMEM for donor chimerism was found to be >70 mg × h/L. Improved EFS and higher donor chimerism may be achieved by targeting a cumulative busulfan AUCNONMEM of 80 mg × h/L (range, 70-90). Our study stresses the importance of uniformly using a validated population pharmacokinetic model to estimate AUCNONMEM.

Blood AdvancesVol. 8(19)
Northwestern University (US), University of Geneva (CH), Lurie Children's Hospital (US), National Institutes of Health (US), University of Minnesota (US), Fairview Health Services (US), Memorial Sloan Kettering Cancer Center (US), Vita-Salute San Raffaele University (IT), University of California, San Francisco (US), Baylor College of Medicine (US), Utrecht University (NL), University of Zurich (CH), Leiden University Medical Center (NL), Great Ormond Street Hospital (GB), Newcastle upon Tyne Hospitals NHS Foundation Trust (GB), Centre Hospitalier Universitaire Sainte-Justine (CA), Children's Hospital at Westmead (AU), University Medical Center Utrecht (NL), CancerCare Manitoba (CA), University Hospital of Geneva (CH), Princess Máxima Center (NL), University Children's Hospital Zurich (CH), The San Raffaele Telethon Institute for Gene Therapy (IT), Texas Children's Hospital (US), Center for Cancer Research (US), Amsterdam University Medical Centers (NL), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Royal Manchester Children's Hospital (GB), Wilhelmina Children's Hospital (NL), Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US), Cancer Center Amsterdam (NL), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT), University College London (GB), University of Manitoba (CA)
National Institutes of Health, National Cancer Institute, National Center for Advancing Translational Sciences
Good health and well-being
Openalex Percentile: Top 11%
Immunodeficiency and Autoimmune Disorders
2.40
DOIOpen Access PDFOpenAlex
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