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

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

doi:10.1182/bloodadvances.2024013275

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

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

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

3 Scopus 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 AUC_NONMEM). 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 AUC_NONMEM was 69.0 mg × h/L and correlated poorly with the AUC_CENTER (r² = 0.54). In patients with SCID, HLH-related, and neutrophil disorders with a busulfan AUC_NONMEM 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 AUC_NONMEM, plateauing at 90 mg × h/L. For patients with CID, the optimal AUC_NONMEM 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 AUC_NONMEM of 80 mg × h/ L (range, 70-90).

Original language	English (US)
Pages (from-to)	5137-5145
Number of pages	9
Journal	Blood Advances
Volume	8
Issue number	19
DOIs	https://doi.org/10.1182/bloodadvances.2024013275
State	Published - Oct 8 2024

Funding

J.-J.B. acknowledges support by the National Institutes of Health (NIH)/National Cancer Institute (NCI) Cancer Center Support Grant (P30 CA008748). C.L.E. was supported by the NIH\u2019s National Center for Advancing Translational Sciences (grants KL2TR002492 and UL1TR002494). I.H.B. receives support from Gardenia (Amsterdam University Medical Center) and the NIH (grant R34AI155318). This work was supported by funding from the Intramural Research Program, NIH, NCI, Center for Cancer Research (S.-Y.P.).

ASJC Scopus subject areas

Hematology

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10.1182/bloodadvances.2024013275

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Bognàr, T., Garcia-Rosa, M., Lalmohamed, A., Güngör, T., Hauri-Hohl, M., Prockop, S., Oram, L., Pai, S. Y., Brooks, J., Savic, R. M., Dvorak, C. C., Long-Boyle, J. R., Krajinovic, M., Bittencourt, H., Teyssier, A. C., Théoret, Y., Martinez, C., Egberts, T. C. G., Morales, E., ... Bartelink, I. H. (2024). Association of busulfan exposure and outcomes after HCT for patients with an inborn error of immunity. Blood Advances, 8(19), 5137-5145. https://doi.org/10.1182/bloodadvances.2024013275

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title = "Association of busulfan exposure and outcomes after HCT for patients with an inborn error of immunity",

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).",

author = "Tim Bogn{\`a}r and Moises Garcia-Rosa and Arief Lalmohamed and Tayfun G{\"u}ng{\"o}r and Mathias Hauri-Hohl and Susan Prockop and Layne Oram and Pai, {Sung Yun} and Jordan Brooks and Savic, {Rada M.} and Dvorak, {Christopher C.} and Long-Boyle, {Janel R.} and Maja Krajinovic and Henrique Bittencourt and Teyssier, {Anne Charlotte} and Yves Th{\'e}oret and Cary Martinez and Egberts, {Toine C.G.} and Erin Morales and Mary Slatter and Cuvelier, {Geoffrey D.E.} and Robert Chiesa and Wynn, {Robert F.} and Mary Coussons and Cicalese, {Maria P.} and Marc Ansari and Long, {Susan E.} and Ebens, {Christen L.} and Hannah Lust and Sonali Chaudhury and Nath, {Christa E.} and Shaw, {Peter J.} and Keogh, {Steven J.} and {van der Stoep}, {M. Y.C.Eileen} and Robbert Bredius and Lindemans, {Caroline A.} and Boelens, {Jaap Jan} and Bartelink, {Imke H.}",

year = "2024",

month = oct,

day = "8",

doi = "10.1182/bloodadvances.2024013275",

language = "English (US)",

volume = "8",

pages = "5137--5145",

journal = "Blood Advances",

issn = "2473-9529",

publisher = "American Society of Hematology",

number = "19",

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Bognàr, T, Garcia-Rosa, M, Lalmohamed, A, Güngör, T, Hauri-Hohl, M, Prockop, S, Oram, L, Pai, SY, Brooks, J, Savic, RM, Dvorak, CC, Long-Boyle, JR, Krajinovic, M, Bittencourt, H, Teyssier, AC, Théoret, Y, Martinez, C, Egberts, TCG, Morales, E, Slatter, M, Cuvelier, GDE, Chiesa, R, Wynn, RF, Coussons, M, Cicalese, MP, Ansari, M, Long, SE, Ebens, CL, Lust, H , Chaudhury, S, Nath, CE, Shaw, PJ, Keogh, SJ, van der Stoep, MYCE, Bredius, R, Lindemans, CA, Boelens, JJ & Bartelink, IH 2024, 'Association of busulfan exposure and outcomes after HCT for patients with an inborn error of immunity', Blood Advances, vol. 8, no. 19, pp. 5137-5145. https://doi.org/10.1182/bloodadvances.2024013275

TY - JOUR

T1 - Association of busulfan exposure and outcomes after HCT for patients with an inborn error of immunity

AU - Bognàr, Tim

AU - Garcia-Rosa, Moises

AU - Lalmohamed, Arief

AU - Güngör, Tayfun

AU - Hauri-Hohl, Mathias

AU - Prockop, Susan

AU - Oram, Layne

AU - Pai, Sung Yun

AU - Brooks, Jordan

AU - Savic, Rada M.

AU - Dvorak, Christopher C.

AU - Long-Boyle, Janel R.

AU - Krajinovic, Maja

AU - Bittencourt, Henrique

AU - Teyssier, Anne Charlotte

AU - Théoret, Yves

AU - Martinez, Cary

AU - Egberts, Toine C.G.

AU - Morales, Erin

AU - Slatter, Mary

AU - Cuvelier, Geoffrey D.E.

AU - Chiesa, Robert

AU - Wynn, Robert F.

AU - Coussons, Mary

AU - Cicalese, Maria P.

AU - Ansari, Marc

AU - Long, Susan E.

AU - Ebens, Christen L.

AU - Lust, Hannah

AU - Chaudhury, Sonali

AU - Nath, Christa E.

AU - Shaw, Peter J.

AU - Keogh, Steven J.

AU - van der Stoep, M. Y.C.Eileen

AU - Bredius, Robbert

AU - Lindemans, Caroline A.

AU - Boelens, Jaap Jan

AU - Bartelink, Imke H.

PY - 2024/10/8

Y1 - 2024/10/8

N2 - 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).

AB - 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).

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ER -

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

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