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Multicenter Study
. 2024 Oct 8;8(19):5137-5145.
doi: 10.1182/bloodadvances.2024013275.

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

Tim Bognàr  1 , Moises Garcia-Rosa  2 , Arief Lalmohamed  1   3 , Tayfun Güngör  4 , Mathias Hauri-Hohl  4 , Susan Prockop  5 , Layne Oram  5 , Sung-Yun Pai  5   6 , Jordan Brooks  7 , Rada M Savic  7 , Christopher C Dvorak  7 , Janel R Long-Boyle  7 , Maja Krajinovic  8 , Henrique Bittencourt  8 , Anne-Charlotte Teyssier  8 , Yves Théorêt  8 , Cary Martinez  9 , Toine C G Egberts  1   3 , Erin Morales  9 , Mary Slatter  10 , Geoffrey D E Cuvelier  11 , Robert Chiesa  12 , Robert F Wynn  13 , Mary Coussons  13 , Maria P Cicalese  14   15   16 , Marc Ansari  17   18 , Susan E Long  19 , Christen L Ebens  19 , Hannah Lust  20 , Sonali Chaudhury  20 , Christa E Nath  21 , Peter J Shaw  21 , Steven J Keogh  21 , M Y Eileen C van der Stoep  22   23   24 , Robbert Bredius  22 , Caroline A Lindemans  25   26 , Jaap-Jan Boelens  2 , Imke H Bartelink  27   28
Affiliations
Multicenter Study

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

Tim Bognàr et al. Blood Adv. .

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.

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Conflict of interest statement

Conflict-of-interest disclosure: S.P. receives support for the conduct of sponsored trials through DFCI/BCH from Atara, AlloVir, and Jasper Therapeutics; consults for Cellevolve and Pierre Fabre; receives honorarium from Regeneron; and reports an IP license to Atara Biotherapeutics with all rights assigned to the Memorial Sloan Kettering Cancer Center. J.-J.B. received honoraria from Sobi, Sanofi, CTI, Smart Immune, Merck, and Advanced Clinical (all not related to this study). C.C.D. is a consultant for Jazz Pharmaceuticals and Alexion, Inc. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Correlation between the center-derived busulfan AUC and the validated AUC. The busulfan exposure calculated using the centers (AUCCENTER) vs the exposure estimation using a validated PK model (AUCNONMEM; centers denoted by color).
Figure 2.
Figure 2.
Propensity score–adjusted Fine-Gray Kaplan-Meier plots of event-free survival stratified for 3 AUC busulfan exposure groups (<70, 70-90, and >90 mg × h/L). Patients with (A) SCID, HLH-related, and neutrophil disorders, (B) SCID, (C) HLH-related, and (D) neutrophil disorders.
Figure 3.
Figure 3.
Donor chimerism stratified for AUC subgroups.
See this image and copyright information in PMC

References

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