Phase II trial of sequential therapy with fludarabine followed by cyclophosphamide, mitoxantrone, vincristine, and prednisone for low-grade follicular lymphomas.

Advanced follicular lymphomas, grades I and II, are indolent tumors but are not considered curable with standard therapy. Fludarabine has the highest single-agent response rates in this disease. However, fludarabine-based combination chemotherapy regimens have been associated with significant myelotoxicity. Data exist suggesting that the best way to combine partially non-cross-resistant agents may be to use them sequentially. Patients with bulky stage II, stage III, or stage IV follicular lymphoma (grade I or II) were entered on this protocol. Patients were treated with 3 cycles of fludarabine followed by 6-8 cycles of cyclophosphamide, mitoxantrone, vincristine, and prednisone (CNOP). Response was assessed after the 3(rd) cycle of fludarabine and after the 4(th), 6(th), and 8(th) cycles of CNOP. Twenty-seven patients were entered on the protocol. Median follow-up was 50 months. Eighteen patients (67%) attained a complete response (CR), and eight patients (30%) attained a partial response (PR), for an overall response rate of 97%. Median relapse-free survival was 34 months, and median overall survival was not reached for the entire cohort. While all patients who achieved only PR progressed, more than half of those in CR remain free of progression at 39-84 months of follow-up. The regimen was well tolerated. The sequential combination of fludarabine and CNOP appears to be active and well tolerated in patients with grade I and II follicular lymphoma. Patients who achieve CR fare best, and many remain disease-free long term. While these results are encouraging, the addition of other active agents such as rituximab to this regimen may further enhance efficacy and is under investigation.