Efficacy of Pharmacokinetics-Directed Busulfan, Cyclophosphamide, and Etoposide Conditioning and Autologous Stem Cell Transplantation for Lymphoma: Comparison of a Multicenter Phase II Study and CIBMTR Outcomes

Abstract

Busulfan, cyclophosphamide and etoposide (BuCyE) is a commonly used conditioning regimen for autologous stem-cell transplantation (ASCT). This multicenter, phase 2 study examined the safety and efficacy of BuCyE with individually-adjusted busulfan based on pre-conditioning pharmacokinetics. The study initially enrolled Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients 18–80 years, but was amended due to high early treatment-related mortality (TRM) in patients >65 years. BuCyE outcomes were compared with contemporaneous recipients of carmustine, etoposide, cytarabine and melphalan (BEAM) from the Center for International Blood and Marrow Transplant Research. Two hundred seven subjects with HL (n=66) or NHL (n=141) were enrolled from 32 centers in North America, and 203 underwent ASCT. Day 100 TRM for all subjects (n=203), patients >65 years (n=17), and patients ≤65 years (n=186) were 4.5%, 23.5% and 2.7%, respectively. The estimated 2-year PFS was 33% for HL, and 58%, 77% and 43% for diffuse large B-cell lymphoma (DLBCL; n=63), mantle cell lymphoma (MCL; n=29) and follicular lymphoma (FL; n=23), respectively. The estimated 2-year OS was 76% for HL, and 65%, 89% and 89% for DLBCL, MCL and FL, respectively. In the matched analysis, two-year TRM was 3.3% for BuCyE and 3.9% for BEAM, and there were no differences in outcomes for NHL. Patients with HL had lower 2-year PFS with BuCyE, 33% (95% CI: 21–46%) than BEAM, 59% (95% CI: 52–66%), with no difference in TRM or OS. BuCyE provided adequate disease control and safety in B-cell NHL patients ≤ 65 years, but produced worse PFS in HL patients when compared with BEAM.

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

“…Notably, BU TDM has not been consistently used in BuCyE conditioning for autologous HCT. Most publications show that weight-based BU dosing without BU TDM was used [54], although BU TDM can be used [70,73]. In patients with non-Hodgkin's lymphoma receiving BuCyE, improved OS with i.v.…”

Modified conditioning regimen with idarubicin followed by autologous hematopoietic stem cell transplantation for invasive B-cell non-Hodgkin’s lymphoma patients

“…With the aim of obtaining a higher anti-lymphoma activity and/or reducing the toxic effects, a number of studies suggested the possibility of improving the outcomes of NHL patients through modifying the conditioning regimens 8 – 10 . BuCyE (busulfan, cyclophosphamide, and etoposide) 11 , 12 and Benda-EAM (bendamustine, etoposide, cytarabine, and melphalan) 13 , 14 were approved to be effective and safe for NHL patients 15 , 16 . However, idarubicin, which was a widely used anthracycline drug for NHL patients, was rarely reported to be added in conditioning regimen.…”

Advances in the pathophysiology and treatment of relapsed/refractory Hodgkin’s lymphoma with an emphasis on targeted therapies and transplantation strategies

“…The two Phase III prospective randomized studies that established the role of ASCT in such patients used BEAM conditioning, 106 , 107 which remains one of the most commonly used regimens to date. Other common regimens include cyclo-phosphamide, carmustine and etoposide (CBV) with various dosing modifications 121 – 125 ; busulfan-based regimens such as busulfan and cyclophosphamide (BuCy), 126 busulfan and melphalan (BuMel), 127 busulfan, etoposide and cyclophosphamide (BuCyE) 128 , 129 a or triple alkylator regimen of busulfan, melphalan and thiotepa (BuMelTt). 130 , 131 total body irradiation (TBI) (or total lymphoid irradiation [TLI])-based regimens have also been used as conditioning regimens in previously nonirradiated patients 8 , 113 , 123 , 132 , 133 ; however, there has been a swift away from such regimens over time due to concerns for increased associated risk of secondary malignancies and long-term toxicity.…”