Cladribine in combination with mitoxantrone and cyclophosphamide(CMC) in the treatment of heavily pre-treated patients with advanced indolent lymphoid malignancies.

The aim of our study was to determine the effectiveness and toxicity of combined chemotherapy consisting of cladribine (2-chloro-deoxyadenosine, 2-CdA), mitoxantrone and cyclophosphamide (CMC regimen) in the treatment of refractory or relapsed indolent lymphoproliferative disorders. The treatment course consisted of 2-CdA given at a dose of 0.12 mg/kg/24 h in a 2-h intravenous infusion for 5 (CMC5) or 3 (CMC3) consecutive days, mitoxantrone 10 mg/m2 on day 1 and cyclophosphamide 650 mg/m2/iv on day 1. Thirty-three patients (19 with B-CLL and 14 with LG-NHL) entered the study and all of them were eligible. Twenty patients (60.6%) were recurrent after prior therapy and 13 (39.4%) had refractory disease. All patients received 5 or more cycles of chemotherapy before CMC treatment. Twenty-one patients were treated with CMC5 regimen and 12 with CMC3 regimen. The overall response rate, including CR and PR, was 48.6% (95% CI 32-66). There were no differences in the frequency of responses between the CMC3 and CMC5 treated groups (p>0.05). One patient with B-CLL and three patients with lymphocytic lymphoma achieved CR (12.1%). Among 12 patients (36.4%) who achieved PR there were 6 CLL patients, and 6 lymphoma patients. The major toxicity was myelosuppression. Severe neutropenia was seen in 11/33 (33.3%) patients, more frequently in patients who received CMC5 than in the patients who received CMC3, both in the CLL (50.0% and 28.5%, respectively) and in the LG-NHL group (22.2% and 0%, respectively). The rate of thrombocytopenia was similar in both groups. Infections and fever of unknown origin complicated the treatment with CMC5 more often than with CMC3: five episodes were seen in 3 patients treated with CMC3 when compared to 15 episodes in 12 patients treated with CMC5. In conclusion, the CMC programme is an active combined regimen in heavily pre-treated CLL and LG-NHL patients. However, its toxicity is significant and we suggest a shortening of 2-CdA infusion from 5 to 3 d in further studies. Whether a combination of 2-CdA with cyclophosphamide and mitoxantrone would result in improved outcome as compared to 2-CdA alone, is being investigated in a prospective, randomised trial.