Great expectations? Conditioning with busulfan, melphalan and thiotepa in recurrent Hodgkin lymphoma

Autologous stem cell transplant is a long-established curative treatment for chemotherapy-sensitive recurrent Hodgkin lymphoma (HL) [1,2], and is predicated on the concept that dose escalation of established drugs, particularly alkylating agents, can overcome disease resistance [3]. Commonly used conditioning regimens such as CBV (cyclophosphamide, BCNU, etoposide) or BEAM (BCNU, etoposide, cytarabine, melphalan) combine alkylating agents such as cyclophosphamide, melphalan and carmustine (BCNU) that have limited overlapping toxicities with cytarabine and/or etoposide [1]. These combinations have a record of safety and relative efficacy in lymphoid neoplasms. With contemporary improvements in supportive care, the major cause of treatment-related failure in this population remains disease relapse. Many previous efforts to improve cure rates have proven ineffective. Further escalation of nitrosoureas can induce pulmonary and hepatic toxicities, and the nitrogen mustards can result in severe mucositis and occasional cardiac or renal toxicity [4]. Incorporating radiation as part of the conditioning regimen has demonstrated encouraging results [5], however has not found widespread acceptance due to increased acute toxicities, practical limitations [6] and concerns over secondary malignancies. Tandem autologous transplant may have benefits in patients with high-risk disease, but is not widely utilized in the United States [7]. Allogeneic transplant in patients with high-risk disease similarly remains controversial because of concerns over late toxicities [8].

In an attempt to improve upon the rates of disease progression, the group from Seattle began to explore triple alkylator based busulfan, melphalan and thiotepa (Bu/Mel/Tt) more than 20 years ago [9,10]. With ablation of the marrow as the dose limiting toxicity of all three drugs, it was hoped that dose escalation with stem cell rescue would improve cure rates without the BCNU-associated interstitial pneumonitis. After initial studies in patients with solid tumors [10], they retrospectively compared Bu/Mel/Tt and BEAM in patients with non-Hodgkin lymphoma (NHL) [11]. Although they observed a lower risk of late disease recurrence in the Bu/Mel/Tt group, this was felt to be due to differences in risk features between the two cohorts. Bu/Mel/Tt was associated with more grade 3 or 4 toxicities and with treatment-related deaths that included severe interstitial pneumonitis and veno-occlusive disease (VOD). With similar efficacy compared to BEAM, the increased toxicity precluded the continued use of Bu/Mel/Tt by the Seattle group. More recently Ganguly et al. came to the same conclusion while using intravenous (IV) rather than oral busulfan [12].

Within this historical context the current issue of Leukemia and Lymphoma presents an analysis by Bains and colleagues, who retrospectively investigated 100 patients with relapsed/refractory HL conditioned with Bu/Mel/Tt while comparing it to “other” regimens prior to autologous transplant [13]. Unlike previous studies, regimens such as BEAM and CBV were grouped together with Cy/E/TBI (cytoxan, etoposide and total body irradtion) and single-agent melphalan. Of the 40 patients receiving one of the “other” regimens, 21 received CBV and 14 received Cy/E/TBI, comprising close to 90% of the non-Bu/Mel/Tt group. Only four patients received BEAM. Consistent with prior studies, the Bu/Mel/Tt regimen resulted in a higher incidence of mucositis than the other combinations without an increase in treatment-related mortality, which may be attributed to the improvements in current supportive care. The authors reported a higher 5-year progression-free survival (PFS) and overall survival (OS) in the Bu/Mel/Tt cohort (PFS 66% vs. 37% other, OS 73% vs. 44% other). These results, however, are confounded by the fact that different regimens with varying utilization and toxicity profiles were combined as the one comparative cohort, and that few in the comparator arm received BEAM, likely a superior regimen [7,14]. It is therefore difficult to draw conclusions based on this analysis regarding the efficacy of Bu/Mel/Tt compared with that of other regimens widely in use. Recently, targeted agents such as brentuximab have shifted the focus away from intensification of therapy for recurrent HL, but are likely to be soon incorporated in front-line therapy. As initial strategies gain efficacy it is likely that those patients with recurrent disease will comprise a small group who are highly refractory and in whom more intensive conditioning regimens may offer clinical benefit and should continue to be further investigated.

Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.