The introduction of the PCR technique has provided a powerful tool to analyze the quality of complete responses in low grade follicular lymphomas. Complete remissions confirmed by PCR (""""""""molecular complete remissions"""""""") rarely occur with traditional chemotherapy regimens for low grade lymphomas. Preliminary studies conducted in our Institution have shown that a new strategy consisting of 3 alternating non-cross resistant chemotherapy combinations, is capable of inducing a high rate of molecular complete remissions in these disorders. The primary objective of project #1 is to use the molecular response as a surrogate endpoint to compare this new strategy against less intensive strategies. All low grade follicular lymphoma tissues will be phenotyped and genotyped. The peripheral blood and bone marrows will be examined by the PCR technique to detect bcl-2 or JH rearranged sequences before and' after therapy. Patients with Ann Arbor stage I-III will then be randomized to either the novel intensive alternating therapy or to standard management with total nodal radiation. Those with stage IV presentations will be randomized to either the same intensive alternating therapy or a new and effective but less toxic regimen consisting of Fludarabine, Mitoxantrone and Dexamethasone. Patients will be followed periodically with the standard clinical restaging techniques as well as with peripheral blood and bone marrow PCR. The primary endpoint of these trials will be the percentage of cases who achieve a molecular complete response at the end of 18 months. A secondary goal will be to more firmly establish the value of the PCR as a means of assessing response by correlating it with the clinical outcome. Rigorous evaluation of these therapeutic alternatives demands a large patient population with close and uniform disease monitoring as well as a cohesive group of investigators.
