Therapeutic drug monitoring for either oral or intravenous busulfan when combined with pre- and post-transplantation cyclophosphamide

Abstract

Busulfan (Bu)/cyclophosphamide (Cy) is a standard conditioning platform for allogeneic transplantation. We developed a strategy separating the Cy into two pre/post-transplantation doses (PTCy), providing myeloablative conditioning and single-agent graft-versus-host disease (GVHD) prophylaxis. We investigated the impact of Bu route on treatment-related toxicity for 131 consecutive adult patients. Busulfan was administered in four daily divided doses either orally (n = 72) or intravenously (n = 59) with pharmacokinetics on the first-dose and as necessary on subsequent doses to achieve a target area-under-the-concentration-curve (AUC) of 800–1400 µmol*min/L per dose. BuCy/PTCy with pharmacokinetics is well-tolerated with low treatment-related toxicity. Hepatic veno-occlusive disease incidence was 6% with two fatal events. Bu administration route in the context of BuCy/PTCy did not statistically impact hepatotoxicity, GVHD, relapse, disease-free survival, or overall survival. The BuCy/PTCy platform has a low incidence of treatment-related toxicity, including hepatotoxicity, in hematologic malignancies when using pharmacokinetics for a target AUC of 800–1400 µmol*min/L, irrespective of Bu administration route.

Personalizing Busulfan-Based Conditioning: Considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee

“…As noted in FAQ3, whether patients in this study received BU TDM is unknown, but a survey of centers done shortly after the study suggested 50% to 60% of the centers who reported to CIBMTR used BU TDM [48]. This analysis contrasts with results that have not noted any increased risk in relapse rates when comparing similar regimens that differed only by the route of BU administration [67][68][69][70]. The effect of the administration route on SOS has also not been consistent: some reports found a significantly higher rate of SOS after oral BU when compared with after i.v.…”

“…The effects of oral versus i.v. BU on efficacy, toxicity, and pharmacokinetics on the outcomes of allogeneic HCT have been analyzed retrospectively [48,53,[63][64][65][66][67][68]. These studies are often confounded by heterogeneous patient populations, the use of BU TDM for only 1 of the administration routes, differences in the other conditioning regimen components, and BU exposure data not being available.…”

Reduced Risk of Sinusoidal Obstruction Syndrome of the Liver after Busulfan‐Cyclophosphamide Conditioning Prior to Allogeneic Hematopoietic Stem Cell Transplantation

“…The conditioning used prior to HSCT, mainly Bu‐based conditioning, is one of the most common causes of these toxicities and several strategies have been introduced to improve clinical outcome. Several serious complications, such as elevated liver enzymes, SOS, hemorrhagic cystitis, interstitial pneumonia, and mucositis have been correlated to high‐dose Bu …”

“…Several serious complications, such as elevated liver enzymes, SOS, hemorrhagic cystitis, interstitial pneumonia, and mucositis have been correlated to high-dose Bu. 1,2,18,28,29 In our center, we have developed several strategies over more than 20 years to reduce the incidence of the serious adverse effects, mainly SOS, improving both the clinical outcome and the patients' quality of life. Among patients receiving conventional Bu-based myeloablative conditioning prior to HSCT, the incidence of SOS decreased dramatically during 1995-2015.…”

Population Pharmacokinetic Analysis of Busulfan in Japanese Pediatric and Adult HCT Patients

“…2 Supratherapeutic concentrations lead to lethal toxicity, including pulmonary toxicity, 3 hepatic veno-occlusive disease, 4,5 and seizures, 6 while subtherapeutic concentrations lead to graft rejection and disease relapse. 7 Therapeutic drug monitoring (TDM) can reduce the incidence of seizures. 6 In addition to the narrow therapeutic index, specific busulfan exposures have been associated with important clinical outcomes in HCT patients.…”