Maximum Tolerated Dose of Lomustine in Combination with Etoposide, Cytarabine and Melphalan in a Short Conditioning Regimen in the Transplantation of Hematopoietic Stem Cells in Patients with Lymphoma

The maximum tolerated dose (MTD) of lomustine when used in combination with etoposide, ara-C, and melphalan (LEAM) in a conditioning regimen prior to autologous hematopoietic stem cell transplantation (HSCT) for lymphoma is unknown. We performed a phase 1 clinical trial with traditional 3+3 design to determine the MTD of lomustine administered on D-4 followed by etoposide (1 g/m2 D-3), ara-C (4g/m2 D-2), and melphalan (140 mg/m2 D -1). Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic or infectious toxicity, delayed engraftment beyond D+30 or death from any cause. The initial dose of lomustine was 200 mg/m2 (L200 cohort), increased by 200 mg/m2 at each subsequent cohort (L400, etc). Because L400 exceeded MTD, a third cohort was created with 300 mg/m2 of lomustine (L300). Fourteen subjectes entered the trial being 9 with Hodgkin lymphoma, 2 with mantle cell lymphoma, 1 with diffuse large B-cell lymphoma, 1 with follicular lymphoma and 1 with peripheral T-cell lymphoma. Subjects were either in PR (n=6) or CR (n=8) after the most recent salvage theapy. Median age of subjects was 36 years. Six patients were treated with L200 (1 DLT, death by sepsis), two patients were treated with L400 (2 DLT, grade 4 gastrointestinal toxicity) and 6 patients were treated at an intermediate dose of 300 mg/m2 (L300, 1 DLT, neurological grade 4, reversible) and L300 was declared the MTD. A median number of 6.91 CD34 cells/kg (range 1.37-18.8) were infused. The average duration of neutropenia (neutrophils <500/mm3) was 7.8 days, lower than the historical control of 13 days with cyclophosphamide, BCNU, and etoposide (CBV) conditioning. Neutrophils and platelet engraftment occurred on average at day 10 and 12 respectively. We concluded that 300mg/m2 is the MTD of lomustine  in combination with etoposide, ara-C and melphalan (LEAM) conditioning in autologous-HSCT in patients with lymphoma. More detailed toxicity profile and anti-lymphoma activity will be obtained from ongoing expansion of the L300 cohort. LEAM is a simple conditioning regimen with rapid dosing, consequent short period of neutropenia and acceptable toxicity.