CLADRIBINE AND MITOXANTRONE DOSE-ESCALATION IN INDOLENT NON-HODGKINS-LYMPHOMA

Purpose: Since cladribine (2-chlorodeoxyadenosine [2-CdA]) and mitoxan trone both exhibit major activity against indolent lymphoid malignanci es and have different mechanisms of action, we performed a dose-escala tion study of 2-CdA and mitoxantrone in patients with alkylator-failed indolent lymphoma to determine the maximum-tolerated dose (MTD) of th is combination and to make preliminary observations about efficacy. Pa tients and Methods: Twenty-three patients were treated every 28 to 35 days, in cohorts of at least three patients, with stepwise dose escala tions until dose-limiting toxicities (DLTs) were encountered. The init ial dose levels were 2-CdA 0.1 mg/kg/d by continuous infusion for 7 da ys, mitoxantrone 5 mg/m(2) intravenously (IV) on day 1, and prednisone 100 mg/d on days 1 to 5, Mitoxantrone was dose-escalated in increment s of 2.5 mg/m(2) IV on day 1. Results: The MTD of the combination was 2-CdA 0.1 mg/kg/d for 7 days, mitoxantrone 7.5 mg/m(2) IV on day 1, an d prednisone 100 mg/d on days 1 to 5. Myelosuppression and infection w ere the DLTs. The recommended phase II doses were 2-CdA 0.075 mg/kg/d for 7 days mitoxantrone 5 mg/m(2) IV on day 1; prednisone was omitted to decrease the risk of opportunistic infections, The overall response rate was 70%, with 22% complete responses (CRs) and 48% partial respo nses (PRs). The median duration of CR was 15 months and PR 5 months. C onclusion: These results demonstrate the feasibility and safety of com bining 2-CdA and mitoxantrone in the treatment of indolent lymphoma, a nd appear to confirm clinically the mechanistic synergism and rational e for this combination regimen, Prednisone exacerbated the risk of opp ortunistic infection and was omitted, The overall response rate was hi gh, including durable CRs, Further studies of this combination regimen are warranted in untreated and alkylator-failed indolent lymphoma.