Superior Survival in Non-Hodgkin Lymphoma Following Autologous Stem Cell Transplantation with Intravenous Busulfan, Cyclophosphamide, and Etoposide.
Authors: Dean Robert , Rybicki Lisa , Pohlman Brad , Sweetenham John William , Smith Stephen , Copelan Edward , Sobecks Ronald , Kalaycio Matt , Andresen Steven , Sungren Shawnda , Bolwell Brian J. 
Published: April 2020

Abstract
Preparative regimens for autologous stem cell transplantation (ASCT) are distinguished mainly by their toxicities, not differences in their antitumor efficacy. Erratic gastrointestinal absorption confers a narrow therapeutic range for oral busulfan-based regimens, whereas the bioavailability and pharmacokinetic (PK) profile of intravenous (IV) busulfan are highly predictable. In a pilot study, we observed better relapse-free survival among lymphoma patients over 50 years old who underwent ASCT after high-dose busulfan, cyclophosphamide, and etoposide (BuCyVP) with IV busulfan in place of oral busulfan. This analysis describes outcomes of ASCT for 604 adult patients with non-Hodgkin lymphoma (NHL) who received IV busulfan (N=136) or oral busulfan (N=468) as part of conditioning with BuCyVP from 1996 through 2007 at the Cleveland Clinic. Oral busulfan was used in the preparative regimen through 10/2004 in patients older than 50 years and through 5/2006 in patients age 50 years or younger; after these dates, IV busulfan was used. The regimen consisted of busulfan (1 mg/kg PO or 0.8 mg/kg IV) Q6 hours x 14 doses; etoposide 60 mg/kg IV over 36 hours; and cyclophosphamide 60 mg/kg IV daily for 2 consecutive days. Busulfan levels were not measured. Patients who received IV rather than oral busulfan were older (median 58 vs. 51 years), had less advanced stage, had diffuse large B-cell NHL (DLBCL) or high-risk IPI scores less frequently, were more heavily pretreated (3 or more regimens in 40% vs. 25%), and received chemotherapy for stem cell mobilization more frequently. Prior radiotherapy, disease status at transplant, and CD34+ cell dose were similar between groups. Mean scores using the Oral Mucositis Assessment Scale (OMAS) during ASCT indicated more severe mucositis with oral busulfan than with IV busulfan (0.90 versus 0.54, P&lt;0.001). Although the times to neutrophil and platelet engraftment were equivalent, median length of stay was 1 day shorter for IV versus oral busulfan (P&lt;0.001). Median follow-up was 69 months versus 15 months for oral and IV busulfan recipients, respectively. Overall survival (OS) and relapse-free survival (RFS) were superior in patients receiving IV versus oral busulfan (median OS not observed versus 72 months, P=0.03; median RFS not observed compared with 31 months, P=0.005). Nonrelapse causes accounted for 65/225 deaths (29%) among oral busulfan recipients and 3/24 deaths (12.5%) among IV busulfan recipients. In multivariable Cox proportional hazards analysis using stepwise selection, IV versus oral busulfan was associated with superior OS (P=0.002) and RFS (P=0.001), and a lower risk of relapse (P=0.013). Other factors significantly associated with improved OS and RFS in multivariable analysis included younger age (OS: P&lt;0.001; RFS: P=0.004), B-cell versus T-cell NHL histology (OS and RFS: P&lt;0.001), less extensive prior therapy (OS and RFS: P&lt;0.001), and chemotherapy-sensitive disease before ASCT (OS and RFS: P&lt;0.001). Relapse was also associated with NHL subtype (T-cell versus others, P&lt;0.001), extent of prior therapy (P&lt;0.001), and disease status (P&lt;0.001). In summary, IV busulfan in conditioning with BuCyVP for ASCT is associated with superior non-relapse mortality, RFS, and OS compared with oral busulfan in patients with NHL. These findings suggest that IV busulfan is not only less toxic but also a more effective anticancer agent than oral busulfan. Alternate dosing schedules and PK-directed dosing may enable the activity of IV busulfan to be optimized further in ASCT for NHL.
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