It's a Great Day for
Learning About CLL

The ASH Education Sessions, always a meeting highlight, begin today. A session focusing on Chronic Lymphocytic Leukemia runs from 2:00 – 3:45 p.m. today and is repeated Sunday morning at 7:30 a.m.

Dr. Stephan Stilgenbauer will focus on genetic risk stratification of CLL. This area has seen an explosion of knowledge in recent years. Prognostic factors implying worse long-term outcome have included clinical characteristics such as older age and poor performance status, laboratory parameters such as elevated LDH and elevated beta-2 microglobulin levels, chromosomal abnormalities including 17p- and, 11q-, and unmutated VH genes. The VH gene mutational status has been shown to be a powerful indicator of prognosis in newly-diagnosed patients, including those with RAI stage 0-1 disease, but this test is cumbersome for commercial diagnostic laboratories. Surrogate measures of the VH mutational gene status have been proposed, including CD38 expression and ZAP-70 status. The usefulness of these markers as surrogates is controversial in CLL. Dr. Stilgenbauer sorts though this literature and focuses on prognostic markers retaining usefulness in multivariate models.

Drs. Ian Flinn and John Byrd focus on the treatment of CLL. Dr. Flinn reviews the literature covering the initial therapy of CLL. Two reports from randomized phase III trials reveal higher complete response rates for combination cyclophosphamide plus fludarabine (FC) compared to fludarabine (F) alone (20-23 percent vs. 6-9 percent), and longer PFS, but Dr. Flinn cautions about possible damage to hematopoietic stem cells using the combination and indicates that choosing which regimen to develop in combination with monoclonal antibodies is difficult. The addition of rituximab to FC or to F has resulted in improved response rates and improved progression-free survival in prospective trials. Retrospective studies also suggest improved survival with the addition of rituximab, which, if confirmed, would represent a major advance in CLL therapy.

Dr. Byrd tackles the difficult subject of treating fludarabine refractory CLL. He notes that virtually all CLL patients requiring therapy will eventually fall into this category. Clonal evolution appears to play a major role in the development of resistance. Mutations or deletions in the p53 gene are present in 5-10 percent of cases at diagnosis but nearly 50 percent of the time in fludarabine refractory patients. These mutations predict unresponsiveness to most available agents, including rituximab, alkylating agents, and other purine nucleoside analogues. However, combination therapy with the FCR regimen may overcome this resistance for some fludarabine refractory patients. Interestingly, alemtuzumab (campath 1-H) retains impressive single agent activity in CLL patients with p53 mutations or deletions. Dr. Byrd recommends therapy with campath if the patients do not have bulky adenopathy (nodes greater than 5 cm) or FCR for patients with bulky adenopathy. Several new agents are undergoing testing for this group of patients, and enrollment in clinical trials should be considered for all CLL patients.