Cisplatin, fludarabine, and cytarabine: a novel, pharmacologically designed salvage therapy for patients with refractory, histologically aggressive or mantle cell non-Hodgkin's lymphoma

Abstract

Background: Based on in vitro synergism, the combination of cytarabine (ara-C) and cisplatin is the basis of many salvage regimens for patients with aggressive non-Hodgkin lymphoma (NHL). However, patients with previously refractory disease are significantly less likely to respond, stimulating the search for novel salvage regimens. In vitro, fludarabine enhances the cytotoxicity of both ara-C and cisplatin, increasing ara-C incorporation into DNA and inhibiting repair of platinum/DNA adducts, suggesting that the combination of cisplatin, fludarabine, and ara-C (PFA) may have clinical utility.

Methods: A Phase-II study of a 96 hour continuous infusion of cisplatin with two timed-sequential couplets of fludarabine and ara-C together with granulocyte colony stimulating factor was performed in 45 patients with previously refractory, histologically aggressive or mantle cell NHL.

Results: Patients had predominantly diffuse large cell and/or immunoblastic NHL or its variants (80%), or they had mantle cell lymphoma (18%). Overall, 93% of patients had previously refractory disease, with a median International Prognostic Index score of 3. A median of 2 cycles per patient were delivered (range, 1-4 cycles) with significant myelosuppression; there were medians of 2 days of neutropenia < 0.5 x 10(9)/L (range, 0-12 days) and 3 days of thrombocytopenia < 20 x 10(9)/L (range, 0-24 days). This was more severe in older patients and was cumulative with successive cycles. Thirty-five percent of cycles were complicated by infections, nausea and emesis were prominent, but other nonhematologic toxicity was mild. Peripheral blood progenitor cells were mobilized adequately after the first cycle, but collections were impaired after more prolonged therapy. The overall response rate was 48% (7% of patients had complete responses, and 41% of patients had partial responses), with one toxic death due to tumor-lysis syndrome. Patients with mantle cell lymphoma were more likely to respond than patients with other histologies (88% vs. 39%, respectively; P = 0.019), although three of eight patients had relapsed rather than refractory disease. The median remission duration was 4 months, with 28% of potentially eligible patients able to proceed to subsequent high dose therapy. The actuarial 2 year survival rates were 20% +/- 6% overall and 50 +/- 18% for patients with mantle cell lymphoma.

Conclusions: Given the adverse outlook for these patients, the results are promising, particularly for patients with mantle cell lymphoma, and suggest that the addition of fludarabine as a potential biochemical modulator may enhance the activity of cisplatin and ara-C. This is associated with significant cumulative (but manageable) myelosuppression. This paradigm, in which a nucleoside analogue is used to inhibit the repair of platinum/DNA adducts, also may be applicable for the treatment of patients with other types of platinum-sensitive tumors.