Abstract
Busulfan and cyclophosphamide (BuCy) is a frequently used myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT). Theoretical considerations and pharmacological data indicate that application of busulfan prior to subsequent cyclophosphamide (BuCy) may trigger liver toxicity. Reversing the order of application to cyclophosphamide-busulfan (CyBu) might be preferable, a hypothesis supported by animal data and retrospective studies. We performed a prospective randomized trial to determine impact of order of application of Bu and Cy before allo-HCT in 70 patients with hematological malignancy, 33 patients received BuCy and 37 CyBu for conditioning. In the short term, there were minimal differences in liver toxicity favoring CyBu over BuCy, significant only for alanine amino transferase at day 30 (p = 0.03). With longer follow-up at 4 years, non-relapse mortality (6% versus 27%, p = 0.05) was lower and survival (63% versus 43%, p = 0.06) was higher with CyBu compared to BuCy. Other outcomes, such as engraftment (p = 0.21), acute and chronic graft-versus-host disease (p = 0.40; 0.36), and relapse (p = 0.79), were similar in both groups. We prospectively show evidence that the order of application of Cy and Bu in myeloablative conditioning in allo-HCT patients has impact on outcome.
Highlights
The combination of busulfan and cyclophosphamide (BuCy) is a frequently used established myeloablative conditioning regimen before allogeneic cell transplantation
Interactions between busulfan (Bu) and cyclophosphamide (Cy) are well described [5, 6]; studies have shown that Bu affects the hepatic metabolism of Cy and may increase liver toxicity when given in this order [7, 8]
This is a prospective multicenter (University Hospitals Basel, Zurich, and Geneva) open label 1:1 randomized controlled trial (RCT), comparing the order of application of busulfan followed by cyclophosphamide (BuCy, standard group) versus cyclophosphamide followed by busulfan (CyBu, experimental group) as myeloablative conditioning regimen prior to allo-HCT done between 2013 and 2017
Summary
The combination of busulfan and cyclophosphamide (BuCy) is a frequently used established myeloablative conditioning regimen before allogeneic cell transplantation (allo-HCT). Interactions between busulfan (Bu) and cyclophosphamide (Cy) are well described [5, 6]; studies have shown that Bu affects the hepatic metabolism of Cy and may increase liver toxicity when given in this order [7, 8]. The pathophysiology behind this interference is possibly a decrease in levels of glutathione, which is a major player in the breakdown of metabolites of Cy in the hepatocyte [9, 10]. With the introduction of intravenous Bu, associated with reduced liver complications and mortality [7], these considerations influencing the order of application no longer apply
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