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

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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 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 hours daily for 4 days, either as a fixed dose per BSA, or to target an average daily AUC of 5000 mMol-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 4 daily Bu doses, there is a rest day, followed by 2 daily doses of Mel at 70 mg/m². Stem cells are infused the following day. Dilantin is administered for seizure prophylaxis. GVHD prophylaxis consists of tacrolimus and methotrexate for pts receiving allo-SCT. Results: Twenty-five pts (17 M/8 F) with median age 40 years (range 19–65): MM (n = 5), NHL (n = 5), HD (n = 13), ALL (n = 2). Median number of prior chemotherapy regimens was 3 (range 1–8). At study entry, 2 pts were in CR1; 23 were in relapse: refractory (n = 3), chemo-sensitive first relapse (n = 9), and beyond first relapse (n = 11). Engraftment, GVHD, and toxicity data are shown in Table 1. Grades I or II mucositis was the most common regimen-related toxicity. Of note, there were no cases of VOD; reversible hyperbilirubinemia, grade II (n = 2) and grade III (n = 1), was observed in 3 pts receiving allo-SCT. All allo-SCT pts had 100% donor chimerism by day 30. Twenty pts had i.v. Bu delivered per test dose guidance; 5 pts received fixed dose Bu at 130 mg/m². The median daily systemic Bu exposure was 4867 μMol-min. Conclusions Intravenous Bu-Mel is well tolerated and enables 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. Longer follow-up is needed to assess disease control (Table 1).

Table 1. Engraftment, GVHD, and Regimen Toxicities

	Auto-SCT	Allo-SCT
No. Patients	18	7
Median CD34+ cell dose × 106/kg (range)	5.20(2.49–10.48)	4.89(2.27–13.31)
Median days to ANC >0.5 × 109/L (range)	10(9–11)	11(9–19)
Median days to platelet >20 × 109/L (range)	9(8–30)	12(10–19)
No. patients with grade II–IV acute GVHD	0	2
No. patients with grade III toxicity	2	2
Type grade III toxicity	mucositis	renal failure, hyperbilirubinemia
No. Patients with grade IV toxicity	0	0
No. Deaths with 8 month follow-up	0	2
Cause of death		disease progression, GVHD