Effects of combined test dose and therapeutic drug monitoring strategy in exposure-directed busulfan

Abstract

Although exposure-directed busulfan (BU) dosing can improve allogeneic hematopoietic stem cell transplantation outcomes, there is still large variability in BU exposure with test-dose alone due to BU clearance change caused by drug interactions. We conducted a single-arm Phase II trial (UMIN000014077) using the combined test-dose and therapeutic drug monitoring strategy (PK-guided group) and compared the outcomes with an historical cohort receiving a xed-dose ( xed-dose group). The rst eight and second eight doses were adjusted based on the area under the blood concentration-time curve (AUC) of the test and rst doses, respectively. The BU clearance at the rst dose decreased in more patients receiving udarabine (FLU) than those receiving BU and cyclophosphamide (BU/CY) from the test dose. The simulated total AUC with test-dose only was signi cantly higher in patients receiving FLU than in those receiving BU/CY, but the simulated AUC with the combined strategy was comparable. The 100-day progression-free survival in PK-guided group was not inferior to that in xeddose group. For the FLU-containing regimens, the PK-guided group showed decreased relapse, and favorable overall survival at one year. The combined strategy effectively controlled the BU exposure close to the target levels, potentially improving e cacy, especially in patients receiving the FLU-containing regimen.Clinical Trial Registry #UMIN000014077 Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for hematologic malignancies or non-malignancies. Historically, busulfan and high-dose cyclophosphamide (BU/CY) or high-dose cyclophosphamide and 12 Gy total body irradiation (CY/TBI) has been used for standard pretransplant conditioning with myeloablative intensity. 1 Fludarabine and four-day busulfan (FLU/BU) regimen was developed to reduce treatment-related toxicity while maintaining the antitumor effects in elderly patients or patients with comorbidities. 2 According to a prospective randomized study from the Center for International Blood and Marrow Transplant Research comparing BU-based (mainly FLU/BU or BU/CY) and TBI-based regimens in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), the 2-year overall survival (OS) in patients who received BU-based regimens was signi cantly superior to that in patients who received the TBI-based regimen; thus, a BU-based regimen is now widely used for pretransplant conditioning. 3 In Japan, intravenous BU (IV BU) was approved for pretransplant conditioning in 2003. Although IV BU was assumed to be pharmacokinetically less variable compared to oral BU, there is a three-to-four-fold difference in the area under the blood concentration-time curve (AUC) of the serum BU concentration among patients receiving the same IV dose. 4,5 BU is eliminated by glutathione S-transferase (GST)-catalyzed conjugation with glutathione in the liver, and GSTA1 is the major isoform catalyzing BU conjugation. 6 GSTA1 gene polymorphism is known to be related to BU pha...