Busulfan Once Versus Four Times Daily: Impact on Pharmacokinetics, Organ Toxicities and Survival After Allogeneic Hematopoietic Stem Cell Transplantation.

Therapeutic drug monitoring of busulfan (Bu) used as conditioning for allogeneic stem cell transplantation (allo-HSCT) is recommended as pharmacokinetics (PK) display variability. Since 2019, we give Bu 1x/d (Bu-Q24) instead of 4x/d (Bu-Q6) for practical convenience, despite limited studies evaluating the best way of application. Our aim was to analyze the correlation between Bu administration (Bu-Q6 versus Bu-Q24), Bu-PK and clinical outcome in adult patients receiving Bu as conditioning regimen for allo-HSCT. This was a retrospective study of 256 adult patients receiving a myeloablative chemotherapeutic regimen containing Bu to treat hematological malignancies. The population was separated into 2 groups according to Bu administration, namely Bu-Q6 and Bu-Q24. A total of 133 patients received Bu-Q6 and 123 Bu-Q24. Bu-Q6 patients were more commonly treated with cyclophosphamide and Bu-Q24 with fludarabine. Bu-Q6 showed lower cumulative area-under-the-curve (AUC) values than Bu-Q24 (63.78 mg*h/L in Bu-Q6 and 70.12 mg*h/L in Bu-Q24, P = .06). Only 44% of the patients fell within the 1st AUC FDA target range in Bu-Q6 versus 62% in Bu-Q24 (P < .01). Overall, Bu-Q24 appeared to be superior to Bu-Q6 for most outcomes, showing lower incidence of toxicity grade ≥ II (78% versus 90%, P = .02), with less uro-renal (14% in Bu-Q24 versus 26% in Bu-Q6; P = .02), pulmonary (2% versus 8%, P = .05) and gastro-intestinal toxicities (10% versus 17%, P < .01). Patient receiving Bu-Q24 had fewer infections (51% versus 65%; P = .04), particularly bacterial (33% versus 47%, P = .03) and fungal infections (10% versus 20%; P = .03). At 2 yr, Bu-Q24 tended to have lower treatment-related mortality (TRM) (5% versus 10%, P = .13), relapse rate (37% versus 42%, P = .55) and incidence of acute and chronic graft-versus-host-disease (24% versus 28%; 32% versus 36%, respectively). The overall survival (OS) was 81% (95% CI 74% to 89%) in Bu-Q24 and 69% (95% CI 62% to 77%, P = .03) in Bu-Q6. The only benefit of Bu-Q6 was mucositis grade ≥ III, with an incidence of 36% versus 60% in Bu-Q24 (P < .01). Patients with a cumulative AUC < 59.11 mg*h/L had the lowest TRM, without impact on the OS. Bu clearance was largely influenced by BMI and age > 60 yr. Bu administered once a day shows benefit both in the short and long term compared to Bu administered 4 times a day, but data are heterogeneus, Bu-Q24 being more commonly associated with use of fludarabine, Bu-Q6 with use of cyclophosphamide in this study.