Phase I/II and pharmacokinetic study of cladribine with 2-h infusion in Japanese patients with relapsed indolent B-cell lymphoma mostly pretreated with rituximab.
ABSTRACT We conducted a phase I/II study to investigate the toxicity, pharmacokinetics, and efficacy profiles of cladribine with 2-h intravenous infusion for five consecutive days every four weeks in Japanese patients with relapsed indolent B-cell lymphoma. This was a dose-escalation study to confirm the safety of the doses which have been recommended for Caucasian patients (phase I), and to further evaluate the efficacy and safety (phase II). In the phase I portion for nine patients, no dose-limiting toxicities were observed at levels 1 (0.09 mg/kg/day, n = 3) and 2 (0.12 mg/kg/day, n = 6). No appreciable accumulation of plasma cladribine concentration was suggested. We enrolled a total of 20 patients, and an additional 14 patients in the phase II portion at level 2 (0.12 mg/kg/day). Eighteen patients, including 13 with follicular lymphoma, were eligible for efficacy evaluation, and 15 (83%) were pretreated with rituximab. The overall response rate was 50% (9/18; 80% confidence interval, 35-65%), with 11% (2/18) complete response. With a median follow-up of 296 days, the estimated median time to progression for 18 eligible patients was 382 days. The most frequent adverse events were hematologic toxicities, including grade 4 neutropenia. Non-hematologic toxicities were mild. In conclusion, cladribine with 2-h intravenous infusion for five consecutive days every four weeks is effective with acceptable toxicities for Japanese patients with relapsed indolent B-cell lymphoma, including those pretreated with rituximab.
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ABSTRACT: BACKGROUND Cladribine (2-chlorodeoxyadenosine) is a purine nucleoside analog with cytotoxic activity against both resting and proliferating cells. Clinical studies with cladribine have reported antitumor activity against various hematologic malignancies.METHODS The authors studied responses to cladribine among patients with low and intermediate grade non-Hodgkin's lymphoma that had been refractory to or relapsed after prior chemotherapy. Cladribine was given intravenously over 2 hours at a dose of 0.14 mg/kg daily for 5 consecutive days, repeated every 4 weeks.RESULTSTwenty-eight patients (16 males, 12 females) with a median age of 58 years (range, 41-75 years) were accrued. Twenty-three patients had low grade and 5 had intermediate grade lymphoma. Stage IV disease was present in 22 (79%), and 17 (61%) had systemic B-symptoms. The majority (57%) had received 2 or more prior chemotherapy regimens (median, 2; range, 1-5); 6 had had prior fludarabine therapy. Major responses were documented in 32% (9 of 28 patients), with 4 complete remissions (CR) and 5 partial remissions (PR) after a median of 4 cycles (range, 1-9). One CR occurred in one patient with intermediate grade diffuse large cell lymphoma, and three of six patients who had had prior fludarabine therapy experienced CR or PR with cladribine. Severe hematologic toxicities included reversible neutropenia, protracted thrombocytopenia, and lymphopenia. Other reported adverse effects included mild-to-moderate fatigue, nausea, and diarrhea.CONCLUSIONS Cladribine is an active single agent in the treatment of patients with refractory or relapsed advanced stage indolent lymphoma, with major responses in one third of patients. Cancer 1998;83:2370-2376. © 1998 American Cancer Society.Cancer 11/1998; 83(11):2370 - 2376. · 5.20 Impact Factor
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ABSTRACT: The objective of this study was to compare the efficacy of 3 regimens, cladribine alone, cladribine and cyclophosphamide combination, or cyclophosphamide, vincristine, and prednisone combination in previously untreated patients with low-grade B-cell non-Hodgkin lymphoma (LGNHL). For this 3-arm, phase 3 study, 197 patients were randomly allocated to receive 6 monthly courses of cladribine alone, cladribine and cyclophosphamide combination, or cyclophosphamide, vincristine, and prednisone combination. Patients for whom all clinical data were available and 162 patients who completed scheduled chemotherapy were analyzed for the endpoints of this study. Compared with cyclophosphamide, vincristine, and prednisone combination regimen, cladribine alone or cladribine and cyclophosphamide combination induced higher probability of overall response (odds ratio [OR] = 4.0; 95% confidence interval [CI], 1.7-9,3; P = .002, and OR = 8.5; 95% CI, 3.2-22.7; P < .0001, respectively), complete remission (OR = 5.8; 95% CI, 1.8-18.5; P = .003; and OR = 14; 95% CI, 4.4-44; P < .0001, respectively), progression-free survival (log-rank test P < .0001), but not overall survival. After incorporating the International Prognostic Index in multivariate analysis, treatment with cladribine-containing regimens remained an independent prognostic factor for progression-free survival (chi(2) = 35.94; hazard ratio = 2.38; P < .0002). Incidences of infections were similar in the randomized groups, whereas cladribine and cyclophosphamide combination, but not cladribine alone, induced more frequent neutropenia, anemia, and thrombocytopenia compared with cyclophosphamide, vincristine, and prednisone combination (P < .05 for each). This resulted in a higher frequency of prolongation of intervals between cladribine and cyclophosphamide combination and cyclophosphamide, vincristine, and prednisone combination cycles (P < .05), but dose reductions due to hematological or other toxicity did not differ significantly in cladribine alone, cladribine and cyclophosphamide combination, and cyclophosphamide, vincristine, and prednisone combination groups. For patients with LGNHL, first-line cladribine alone or cladribine and cyclophosphamide combination regimens both provided similar treatment responses, acceptable toxicity, and better response rates than cyclophosphamide, vincristine, and prednisone combination.Cancer 08/2008; 113(2):367-75. · 5.20 Impact Factor
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ABSTRACT: Cladribine (2-chlorodeoxyadenosine) (2-CdA) has been shown to be effective in mantle-cell (MCL) and low-grade lymphomas (lgNHL). The aim of this multicentre study was to evaluate the rate and duration of remissions and to examine the toxicity of the combination of reduced-dose 2-CdA and mitoxantrone (CdM) in MCL and lgNHL as first-line therapy or for patients in their relapse. A total of 285 courses, median of five courses per patient, were administered to 62 evaluable patients (42 previously untreated, 20 relapsed) with 5 mg/m(2) 2-CdA per day given as an intermittent 2-h infusion over 3 consecutive days combined with 8 mg/m(2) mitoxantrone on days 1 and 2 for the untreated patients or 12 mg/m(2) mitoxantrone on day 1 for patients in their first relapse for a maximum of six cycles every four weeks. 32 follicular, 18 MCL, 9 lymphoplasmacytoid, 2 marginal zone and 1 unclassified low-grade B-cell lymphoma were involved in the study. 56 of the 62 patients responded to CdM resulting in an overall response rate of 90% (95% confidence interval (CI), 80-96%) with a complete remission (CR) rate of 44% (95% CI, 31-57%) and a median duration of remission of 25 months (range 6-42+). The overall survival rate at 48 months was 80%. For 42 previously untreated patients, the overall response rate was 88% (95% CI, 74-96%) with a CR rate of 38% (95% CI, 24-54%), whereas the response rate for the group of 20 previously treated patients was similar with a 95% overall response (95% CI, 75-100%) and a CR rate of 55% (95% CI, 32-77%). In MCL, CdM showed a high activity, achieving a response rate of 100% (95% CI, 81-100%) with a CR rate of 44% and a median duration of remission of 24 months (range 6-35+). Myelosuppression was the major toxicity with 23% grade 3 granulocytopenia and 50% grade 4. Thrombocytopenia was less commonly observed, with only 8% grades 3 and 4. These results demonstrate that the combination of reduced-dose 2-CdA and mitoxantrone is a highly active regimen in the treatment of low-grade lymphomas, and in particular of MCL.European Journal of Cancer 10/2002; 38(13):1739-46. · 5.06 Impact Factor