Pharmacokinetics/Pharmacodynamic Relationship in Busulfan Conditioning Regimen: Results from a Large Pediatric Cohort Undergoing Hematopoietic Stem-Cell Transplantation

• Published in: Blood 2014-12, Vol.124 (21), p.425-425
• Main Authors: Paci, Angelo, Neven, Benedicte, Poinsignon, Vianney, Faivre, Laura, Bourget, Philippe, Broutin, Sophie, Dufour, Christelle, Dalle, Jean-Hugues, Galambrun, Claire, Devictor, Bénédicte, Bleyzac, Nathalie, Kemmel, Veronique, De Berranger, Eva, Gandemer, Virginie, Vannier, Jean Pierre, Ranarivelo, Jean Pierre, Jubert, Charlotte, Pétain, Aurélie, Benhamou, Ellen, Nguyen, Laurent, Moshous, Despina, Vassal, Gilles
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V124.21.425.425

▪ Background: Busulfan (Bu) is the corner stone of hematopoietic stem-cell transplantation (HSCT) regimens with a narrow therapeutic window (TW). Graft rejection or toxicities are reported according to plasmatic exposure. In very young children, Bu exhibits large pharmacokinetic (PK) variability. Bu clearance was demonstrated to be non-linearly related to body weight (BW) and thus BW is used to optimally define the Bu dosage in children [Vassal et al., CCP 2006]. Search for additional data to confirm the TW and to describe clinical outcomes is still a topical question to better understand Pk/Pd relationship and to safely use Bu in young children and infants. Objective: To study the Pk/Pd relationship of Bu in pediatric recipients of bone marrow transplantation (BMT) receiving Bu-based conditioning regimens (CR). To correlate early toxicities (mainly hepatic veno-occlusive disease (VOD), non infectious pulmonary disease (niPD) and outcome i.e. overall survival (OS) at last follow up with type of CR, the underlying diseases, age at transplantation and Pk of busulfan Patients and Method: This multicenter prospective observational study included 307 pts transplanted between 2006 and 2013 from 14 French Pediatric BMT units; median age at transplantation was 18.4 months [1.3-289], with a median BW of 11.3 kg [3.4-82]. 100 pts were younger than 1 year, 71 pts < 9 kg and 171 pts < 16 kg. Patients were mostly affected by non-malignant diseases (primary immune deficiency (n=143), inherited metabolic disorders (n=50), hemoglobinopathies (n=20) while 78 patients suffered from malignant disease. 257 patients received allogenic HSCT (genoidentical donor n=79, matched unrelated donor n=33, mismatch unrelated donor n=18, haploidentical intra-familial donor n=59, other mismatched intra familial donor n=8 or unrelated cord blood n=51) and 41 autologous BMT. All patients received Bu-based conditioning regimen in combination with cyclophosphamide (BuCy n=119), fludarabine (BuFlu n=88), melphalan (BuMel n=36) or thiotepa (BuTTP n=3). 40 patients received BuFlu associated with a second alkylating agent (Mel, TTP or Cy), 12 patients received BuCy associated with a third agent (Mel or VP16). Serotherapy was given in 70% of the patients. Starting doses of Bu were given according to the European SmPC or EBMT-ESID recommendations. The median posology was 1 mg/kg 4x/day for 4 days [0.6-1.3 mg/kg]. PK was assessed on plasma samples with area under the curve (AUC) evaluation from the 1