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

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Abstract
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.

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