Liposomal vincristine in relapsed non-Hodgkin's lymphomas: early results of an ongoing phase II trial.

OBJECTIVE: Vincristine is an active agent in lymphomas, but is often neurotoxic, and the resulting dose reductions have been associated with lower remission and survival rates in Hodgkin's disease. Liposomal vincristine (Onco-TCS) has prolonged half-life, reaches higher concentration in tumors and lymph nodes than in nerves, and administered at full doses appears to be less neurotoxic, and more active then free vincristine in mice bearing L-1210 and P-388 leukemias. We therefore explored its activity in relapsed non-Hodgkin's lymphomas (NHL) and acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Eligible patients had histologically proven relapse, age > or = 16 years, normal renal function, neutrophils > 500/microliter, platelets > 50,000/microliter, and no HIV infection, central nervous system disease, or serious neuropathy. Patients were treated with 2.0 mg/m2 of liposomal vincristine i.v. over 60 minutes q 14 days. Responders received up to 12 injections. RESULTS: Of the 51 registered patients, 35 are currently evaluable for response. Median age was 62 years (range 19-86), and 21 were male. The median number of prior regimens was 3 (range 1-10) and had included vincristine in all patients, of whom 51% were refractory to their last regimen. Serum LDH was high in 46%, and beta 2-microglobulin > 3.0 mg/l in 63% of patients. Of the 155 administered injections, 138 (89%) were at the 2.0 mg/m2 level. The median injected dose was 3.8 mg (range 2.6-4.8 mg), and median number of injections was 4 (range 1-12). Responses were seen in 14 of 34 (41%) patients with NHL (95% confidence intervals (95% CI) 25%-59%). Response rates were 10% for indolent, 71% for transformed, and 47% for aggressive NHL, but the 95% confidence intervals overlapped. Median progression-free survival was 5.5 months for responders. Grade 3-4 motor or sensory neuropathy was seen in 11, and caused termination of therapy in five patients. All five had prior neuropathy, two had previously received paclitaxel, one platinum, and two paclitaxel and platinum. Fever was detected in three patients, but there were no toxic deaths. CONCLUSIONS: Liposomal vincristine is active and well tolerated in this heavily pretreated population with relapsed NHL, but can be neurotoxic in a fraction of patients heavily exposed to prior neurotoxic agents. These data, if confirmed, would suggest a potential role for liposomal vincristine in the combination therapy of previously untreated patients with NHL.

Infusional vinorelbine in relapsed or refractory lymphomas.

Vinorelbine (Navelbine is a semisynthetic vinca alkaloid devoid of serious neurotoxicity. When given weekly vinorelbine has documented activity against many tumors, including lymphomas. Since weekly schedules cannot be easily incorporated in combination regimens, we tested an infusional schedule of vinorelbine given every 21 days in adults with relapsed or refractory lymphoma. Patients with inadequate organ or bone marrow reserve, HIV or other serious infection, central nervous system disease, or prior stem cell or bone marrow transplantation were ineligible. In the phase I part, patients received a constant intravenous bolus of 8 mg/m(2), followed by intravenous continuous infusion over 24 hours daily for four days increasing from 10, 12, to 14 mg/m(2) /d in successive three-patient cohorts. Cycles were repeated every 21 days, and the daily continuous infusion dose was adjusted for toxicity. Dose-limiting mucositis and neutropenia were reached at the continuous dose of 14 mg/m(2) /d. Consequently, for the Phase II trial the starting continuous infusion dose was 12 mg/m(2) /d. After the first 19 patients were entered in the phase II study, the starting infusion dose was reduced to 10 mg/m(2) /d because of frequent grade (3/4) myelosuppression and mucositis. Forty-four patients were entered in the phase II study, of whom 41 are evaluable. Median age was 61 years, 23 were males, with clinically aggressive non-Hodgkin's lymphoma (NHL) in 22, indolent NHL in 18, and Hodgkin's Disease in one patient. The median number of prior regimens was 3 (range 1-11). The lymphoma was refractory to the initial regimen in nine patients, and to the regimen immediately before vinorelbine in 20 patients. Serum LDH was high in 2(1/4)1, and serum beta(2) -microglobulin > 3.0 mg / L in 16/31 patients. Responses were observed in four of 22 patients with aggressive NHL (18%, 95% confidence interval 5%-40%), and in six of 18 with indolent NHL (33%, 95% confidence interval 13%-59%). Median progression-free survival was 6 months for responders. During the Phase II trial 114 vinorelbine courses were administered. Neutrophil nadir was < 1000/microl in 65% and < 100/microl in 35% of courses, respectively. Platelet nadir was < 100,000/microl in 30% and < 20,000/microl in 8% of courses, respectively. Grade (3/4) mucositis was seen in 18% of courses, and neutropenic fever in 13%, and was complicated by death in one patient. We conclude that this dosage and schedule of vinorelbine has modest activity in patients with relapsed or refractory NHL. Myelosuppression is frequent but reversible, but there is no significant neurotoxicity. The role of vinorelbine in combination regimens for patients with relapsed lymphomas, particularly those of indolent histology, should be further investigated.