Intravenous Busulfan Plus Melphalan Is a Highly Effective, Non-Toxic Preparative Regimen for Autologous Stem Cell Transplantation (ASCT) in Patients with Advanced Lymphoid Malignancies.

Bu130 mg/m² was infused daily for 4 days, either as a fixed dose per BSA (n=20), or to target an average daily AUC of 5,000 uMol-min ± 12% determined by a test dose of i.v. Bu at 32 mg/m² given 48 hours prior to the high dose regimen (n=82), followed by a rest day, followed by two daily Mel doses at 70mg/m². Stem cells were infused the following day. Dilantin was given for seizure prophylaxis.

102 patients (38 F/64 M) with non-Hodgkin's lymphoma (n=12), Hodgkin's lymphoma (n=49) and multiple myeloma (n=41) with median age 44 years (range 19-66) have been enrolled to date. The median number of prior chemotherapy regimens was 3 (range 1-6). At time of study entry, 88% of patients were in relapse (sensitive relapse n=70, refractory relapse n=19) and 12% were in second remission. The median CD34+ cell dose infused was 5.2 × 10⁶/kg (range 0.7-12.5). Median days to ANC ≥ 0.5 × 10⁹/L and platelet count ≥ 20 × 10⁹/L were 10 (range 8-44) and 9 (7-141), respectively. There was no grade IV or V toxicity. The most commonly observed toxicities were grade I or II nausea and vomiting (77%), mucositis (67%), and diarrhea (55%)., Reversible grade III liver enzyme abnormalities were observed in 4% of patients; one patient developed reversible VOD. With a median follow-up of 2.1 years (range 0.2-4.3), the cumulative incidence of treatment-related mortality (TRM) at 100 days, 1 year, and 2 years was 1.0%, 3.1%, and 4.3%, respectively. Among patients with non-Hodgkin's or Hodgkin's lymphoma, the overall response rate was 90%, with 1- and 2-year PFS rates of 63% and 58%, respectively; 1- and 2-year OS rates were 90% and 82% respectively (Figure 1). PFS was significantly better in patients with chemo-sensitive lymphoma, 61% vs. 42% at 2 years, p=.03. Among patients with multiple myeloma, the overall response rate was 58%, with 1- and 2-year PFS rates of 67% and 44%, respectively; 1- and 2-year OS rates were 90% and 82%, respectively. Survival rates were not significantly different between the chemo-sensitive and chemo-refractory multiple myeloma patients.

Intravenous busulfan-melphalan is well-tolerated, and the individualized PK-directed dosing of i.v. busulfan likely contributes to the low toxicity profile of this regimen. The high response rate and disease control in patients with advanced disease is encouraging, and should be explored in larger phase II studies.

Figure 1.

View largeDownload slide

Kaplan-Meier estimates for overall survival by chemo sensitivity in patients with Hodgkin's and non-Hodgkin's lymphoma (N=61).

Figure 1.

View largeDownload slide

Kaplan-Meier estimates for overall survival by chemo sensitivity in patients with Hodgkin's and non-Hodgkin's lymphoma (N=61).

Close modal

Andersson:Otsuka Pharmaceuticals: Consultancy.