CHRONIC LYMPHOCYTIC-LEUKEMIA - CORRELATION OF RESPONSE AND SURVIVAL

Chronic lymphocytic leukemia (CLL) is considered to be an incurable hematologic malignancy using conventional therapy. Complete remissions (CR) were unusual with conventional approaches such as chlorambucil with or without prednisone or cyclophosphamide, vincristine, and prednisone (CVP). Pathologic complete remissions including negative bone marrow biopsies were seldom mentioned in the literature. Two parameter flow cytometry has demonstrated that CLL cells co-express CD5 and pan-B cell antigens such as CD19 and CD20. In addition, immunoglobulin gene rearrangement occurs predictably in B-cell CLL and can be used as a further marker of completeness of remission. The National Cancer Institute (NCI) has published criteria for complete remission which allow persistent lymphoid nodules to be present on the bone marrow biopsy and the patient can be considered in complete remission. Our group has considered these patients to have a nodular CR (Nod CR) to separate them from having a true remission on bone marrow biopsy (CR-bx). Thus bone marrow biopsy criteria, two parameter flow cytometry, and immunoglobulin gene rearrangement are now available for routine clinical application to re-define completeness of remission in CLL. With the use of fludarabine monophosphate (Fludara), complete and partial responses are obtained in 50-55% of previously treated patients with CLL and 75-80% of patients with previously untreated CLL. There was a strong correlation of probability of response with degree of previous therapy, stage of disease, age, hemoglobin level, platelet count, serum albumin and beta 2-microglobulin, and bone marrow infiltration with lymphocytes. Patients can be identified as being at high/low risk of achieving a complete or partial response. Analysis of previously untreated patients with CLL demonstrates that patients who achieve a true CR/CR-bx have a 90% chance of five-year survival versus 75% for those with a CR-Nod. Relatively few partial responders were available for comparison. There is a significantly longer survival for CR-bx and Nod-CRs than in the previously treated group. However, in previously treated patients with CLL there is no difference in survival according to whether the patient had a CR-bx, Nod-CR, or PR using NCI criteria. Studies of two parameter flow cytometry demonstrate that there is a much longer time-to-progression for patients who have <5% CD5+, CD19+ co-expressing cells in their bone marrow aspirate. Patients with persistent nodules have a longer time-to-progression than those with interstitial aggregates. Those who have true pathologic bone marrow biopsy CRs have a longer time-to-progression. However, this does not translate into a survival advantage. New methods are available to quantitate the degree of cytoreduction which is achieved in CLL with therapy. These measures of minimal residual disease will be useful in planning an analysis of clinical trials for autologous bone marrow transplantation and maintenance programs in CLL.