Intravenous (i.v.) Busulfan (Bu) Plus Melphalan (Mel) Is a Well-Tolerated Preparative Regimen for Stem Cell Transplantation (SCT) in Patients (pts) with Advanced Lymphoid Malignancies.

High dose chemotherapy and SCT is an accepted treatment option for pts with relapsed lymphoid malignancies. However, relapse remains a significant issue for pts with advanced disease. A double alkylating regimen of Bu and Mel has been suggested as an effective and myeloablative pre-transplant conditioning regimen. Historically, oral Bu was used and the combination resulted in considerable mucositis and VOD. Recently, an i.v. formulation of Bu has been developed that has less pharmacokinetic (PK) variability. We are investigating the safety and efficacy of i.v. Bu-Mel in pts with lymphoid malignancies undergoing auto- or allo-SCT.

Patients and Methods: The conditioning regimen consists of i.v. Bu 130 mg/m² over 3 hr daily for 4 days, either as a fixed dose per BSA, or to target an average daily AUC of 5,000 μMol-min ± 12% determined by a test dose of i.v. Bu at 32 mg/m² given 48 hours prior to the high dose regimen. After the four daily Bu doses, there is a rest day, followed by two daily doses of Mel at 70mg/m². Stem cells are infused the following day. Dilantin is administered for seizure prophylaxis. GVHD prophylaxis consists of tacrolimus and mini-dose methotrexate for pts receiving allo-SCT.

Results: 14 pts (10 M/4 F) with median age 32 years (range 20–65) have been enrolled to date: MM (n=3), NHL (n=3), HD (n=8). The median number of prior chemotherapy regimens was 3 (range 2–8). At time of study entry, 2 pts were in CR2, 5 were in first relapse, and 7 had primary- or relapsed refractory disease. The median CD34+ cell dose infused was 4.88 x 10⁶/kg (range 2.3–7.7). Median time to ANC ≥ 0.5 x 10⁹/L was 9 days for auto-SCT pts (n=11), and 14 days for allo-SCT pts (n=3). Median time to platelet count ≥ 20 x 10⁹/L was 9 days for auto-SCT pts, and 14.5 days for allo-SCT pts. All allo-SCT pts had 100% donor chimerism by day 30. 11 pts had i.v. Bu delivered per test dose guidance; 3 pts received fixed dose Bu at 130 mg/m². The median daily systemic Bu exposure was 5292 μMol-min (range 4113–6734) in the dose-adjusted population. Median Bu clearance was slightly lower than reported in other studies at 99 ml/min/m² (range 69–116). 7 of 11 pts were within ± 12% of the exposure target; 3 pts had AUCs above 6,000 μMol-min per dose. 3 of 11 evaluable pts have achieved complete remissions and 5 a partial response. With follow-up time of 7 to 117 days, there has been 1 death from disease progression (day 117). Grade II-IV acute GVHD was noted in 2 of 3 allo-SCT pts. The treatment was well tolerated, with grade I or II mucositis as the most common regimen-related toxicity. 2 auto-SCT pts developed grade III toxicity (mucositis and gastritis), and 1 allo-SCT pt developed grade III reversible acute renal failure. Grade II reversible hyperbilirubinemia was noted in 1 allo-SCT pt. No grade IV toxicity has been observed.

Conclusion: Intravenous Bu-Mel is well tolerated with prompt neutrophil and platelet engraftment. Individualized PK-directed dosing of i.v. Bu is feasible, and likely contributes to the low toxicity profile of this regimen. It is too early to assess efficacy.