Busulfan/melphalan (bu/mel) is now a well recognised conditioning regimen and is being explored as an alternative to BEAM in patients undergoing an autograft for relapsed low grade non-Hodgkin lymphoma, mantle cell lymphoma and Hodgkin lymphoma, and in selected patients with poor prognosis myeloma. There is no head to head comparison between BEAM and bu/mel. However the evidence available shows that patients with advanced disease, including chemotherapy refractory disease, do poorly after BEAM autografting with an expected 10-year OS of only 10% to 20% following SCT in patients with primary refractory HL and a 5-year OS of 10% in NHL patients.rr
In the efforts to develop more effective and less toxic high-dose chemotherapy regimens, it has been assumed that alkylating agents, which form the backbone of most pretransplant regimens, can ‘‘break through’’ (limited) resistance to chemotherapy based on their multiple intracellular mechanistic targets. Neither busulfan or melphalan needs to be activated, and they both display linear pharmacokinetics in the dose range(s) to be utilised. Further, the good central nervous system (CNS) penetration for both agents and their relative non-overlapping clinical toxicity profiles make this combination an effective, high-dose chemotherapy regimen.
Earlier studies used oral busulfan with melphalan, which is associated with variable absorption and first-pass metabolism through the liver. More recently, once daily intravenous dosing has been used, and with the advent of pharmacokinetic monitoring, there is good evidence that this is markedly better tolerated and associated with better outcomes. Once-daily i.v. busulfan administration has been reported to be safe, and to have linear pharmacokinetics (PKs) with highly reproducible intra- and interpatient systemic exposure. PK monitoring it allows identification of an optimised therapeutic interval represented by the busulfan area under the plasma concentration-versus-time curve (AUC).
The Royal Melbourne Hospital have reported their experience in follicular lymphoma and mantle cell lymphoma. In 22 patients with non-bulky follicular lymphoma, they observed 86% overall survival and 72% event-free survival after a median follow-up of 56.5 months (note using oral busulfan).r In an ALLG study, 37 patients with relapsed poor prognosis follicular lymphoma transplanted between 1995 and 1999 (again using oral busulfan, also followed by interferon), overall survival at 7 years was 49% however 22% remain alive at a median of 9.3 years post-transplant having never relapsed and another six patients remain alive in durable remission after salvage therapy. rMedian progression free survival was 3.4 years. Most transplants were complicated by moderately severe mucositis. Two patients died of transplant-related causes.
The Melbourne group reported 13 patients with previously untreated mantle cell lymphoma who received R-hyperCVAD as initial treatment followed by a bu/mel autograft. With a median follow-up from diagnosis of 36 months, overall and event-free survival was 92%.r
Blanes and colleagues reported a matched control analysis comparing conditioning with bu/mel to melphalan 200 mg/m2 in patients with newly diagnosed multiple myeloma.r No differences were observed in overall response or complete response between both groups. After a median follow-up of 50 and 63 months, progression free survival was 33 months following bu/mel conditioning versus melphalan alone.
The largest published experience with IV busulfan-melphalan is by the MD Anderson group.r Busulfan target was performed to an average daily area under the curve of 5000 umol-min. They reported on 102 patients, 49 with HL, 12 with NHL and 41 with MM. Importantly, 89/102 patients had residual disease at the time of transplant (refractory n=19, chemosensitive but detectable disease n=70). The 2 years overall survival and progression-free survival rates were 85% and 57% respectively for Hodgkin's lymphoma, 67% and 64% for NHL and 82% and 42% for multiple myeloma. No grade toxicity was noted. The most commonly observed toxicities were grade I or II nausea and vomiting (77%), mucositis (67%) and diarrhoea (55%). Only one case of mild-moderate VOD was diagnosed. The cumulative incidences of treatment-related mortality (TRM) at 100 days. 1 year and 2 years were 1%, 3% and 3% respectively. PFS was significantly better in patients with chemosensitive lymphoma (61%) vs. chemo-refractory lymphoma (42%) at 2 years (p=.03).