Prognostic Indicators

In 1981 and in 1989, the International Workshop on CLL (IWCLL) recommended the combined use of the Rai and Binet systems (51,55). This recommendation has not been widely implemented, and clinicians use one or the other in their practice, as the combination is too cumbersome. In reality, the Americans continue to use the Rai system and the Europeans the Binet system. As noted above, in 1987, the five stages in the original Rai system were reduced to three in recognition of the three survival curves, which were different from each other (54). The high-risk group, which combines Rai stages III and IV, is similar to Binet's worst prognosis group, stage C. Binet's stage A and Rai's lowest group 0 are, however, not as similar. In 1988, Rai and Sawitsky (56) described the staging system of Jaksic and Vitale proposed in 1981 (57), which attempts to estimate the total tumor mass (TTM) of leukemic cells in CLL. The TTM score was further reviewed in 1999 by Rai and Han (59). The TTM is the sum of the square root of the ALC plus the diameter in centimeters of the largest lymph node plus the number of centimeters the spleen is below the left costal margin. Scores below and above 9.0 were associated with median

Fig. 34. Overall survival according to the A, B, C staging within Rai's staging system (second interim analysis). Stage III excludes C-CHOP cases. (From ref. 52, Binet, 1988, Fig. 8. With permission from Harwood Academic Publishers, Inc.)

survivals of101 and 39 mo, respectively. In 1973 Zippin et al. (59) performed a statistical analysis of 839 CLL patients diagnosed between 1955 and 1964 in 24 hospitals participating in the End Results Program of the NCI. They reported that the overall 5-yr survival was 44%, and the relative 5-yr survival decreased with increasing age. Five-year survival was greater in women (50%) than in men (41%). They also noted an unusual plateau or peak in the WBC, with increasing survival peaking in the WBC interval 25,000-49,000 cells/^L and then decreasing.

In an attempt to improve on these clinical staging systems, a host of prognostic factors have been studied. In 1982 Rozman et al. (60) showed the prognostic value of the ALC in Rai stage I and II and in Binet stage A and B. Survival is shortened in both clinical stages when the ALC is greater than 50 x 109 cells/L. In 1987 Lee et al. (61), using a regression model as well as uric acid and lactate dehydrogenase (LDH) levels, were able to separate risk groups within a given clinical Rai stage, but this approach does not appear to have been widely used (61). In 1987 Mandelli et al. (62) drew attention to the ALC (> 60 x 109 cells/L) and the size of a given lymph node and spleen and likewise were able to improve on the present staging systems. It is of interest that they defined their first stage as a benign monoclonal lymphocytosis. Using plastic embedding methods, in 1974 Gray et al. (63) were one of the first groups to investigate bone marrow pattern and cellularity using the ratio of percent lymphocytes in the marrow over the ALC. As predicted, patients with marked marrow infiltration had a shortened survival. Notably, these investigators also described the large cell in CLL as "having a large nucleus, an increased quantity of cytoplasm, increased nuclear indentation, and most notably a single, prominent nucleolus with a dense nucleolar chromatin ring."

A long list of prognostic indicators were reviewed by Molica in 2001 (64) and Montserrat and Rozman in 1988 (53). Some of these indicators are clinical stage, lymphocyte count (ALC), lymphocyte morphology, size, immunophenotype, molecular cytogenetics, lymphocyte doubling time, bone marrow histology, response to chemotherapy, autoimmune disease, other medical problems, and a number of serum factors. In addition to cytogenetics, CD38 expression and Ig gene sequence have emerged as potential prognostic indicators that will be clinically useful. Immunophenotyping has for the most part played a role in both establishing B-cell monoclonality and contributing significantly to the differential diagnosis of CLL. Zwiebel and Cheson in 1998 (65) noted that the usefulness of many prognostic factors remains uncertain unless they are evaluated in prospective randomized studies.

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