B-CLL: is the enigma of disease heterogeneity about to be revealed?

B-chronic lymphocytic leukemia (B-CLL) can be a relatively easy management problem since a majority of these patients initially come to the hematologist with minimal-to-low tumor burden. But there is a compelling need for accurate prognostic parameters because at least 20%-30% of these patients will ultimately progress and require therapy. We are now in an era where exciting therapeutic options exist for the B-CLL patient. Thus, there is a therapeutic advantage to more accurately predict patients who are high risk and which early stage patients will progress quickly. Current accepted prognostic features include classification in the Rai or Binet staging system, lymphocyte-doubling time, marrow infiltration patterns, and select cytogenetic abnormalities. While these have proved useful, they remain imperfect for use in an individual patient. Two recent pivotal papers by the Hamblin and Chiorazzi groups have defined immunoglobulin (Ig) mutational status and CD38 expression level as 2 new important prognostic markers. In this issue, 3 papers studying relatively large cohorts of B-CLL patients further study the association of these 2 novel biologic parameters with other biologic features to further our understanding of critical prognostic elements in B-CLL. In summary, these articles (1) affirm the value of Ig mutation status as an independent prognostic factor for B-CLL, (2) demonstrate that the incidence of high-risk genetic aberrations is significantly higher in patient tumor cells that express unmutated Ig V_H region genes than in those that express mutated Ig genes, and (3) identify 17p− and/or mutant p53 as a new independent prognostic factor in multivariate analysis.

Oscier and colleagues (page 1177) have added important new information regarding survivorship of B-CLL patients in relationship to the mutational status of the leukemic B-cell clone. Specifically, they have determined that unmutated IgV_H genes are associated with trisomy 12 and deletion 11q23, two previously known unfavorable genetic alterations. Conversely, they showed that clones with mutated IgV_H genes were associated with the more favorable genetic defect 13q14.

Kröber and colleagues (page 1410) present from a large cohort convincing data, which demonstrate that the high-risk 17p− and 11q− genomic aberrations were seen almost exclusively in patients with unmutated IgV_H genes. Conversely and consistent with work by Oscier and colleagues, the clinically favorable 13q− abnormality was over represented in the patients with mutated Ig genes. These data continue to affirm the growing body of information that IgV_H mutational status of the CLL B-cell clone is linked to disease outcome. In addition, the finding of more frequent deleterious genetic defects in the unmutated IgV_H-type clones suggests that these clones are more likely to undergo critical genetic transformation events. Future analysis of gene methylation patterns and chromosomal stability parameters in sequential fashion in these clones will be of interest. This latter study may lend insight into CLL B cell clones that are prone to undergo clonal evolution.

All 3 papers, using different approaches, affirm the unfavorable clinical outcome for patients with 17p/p53 mutation and/or loss. Using an alternative assay of p53 function, that is, responsiveness to ionizing radiation, Lin and colleagues (page 1404) demonstrated that all of the patients studied with dysfunctionalp53 belonged to the unmutated IgV_H subgroup. Moreover, dysfunctional p53 was a highly significant predictor of poor outcome. Of interest, when patients with functionalp53 were studied, the prognostic power of Ig mutation status was lost. If the clinical use of this test is indeed feasible, there may be a powerful prognostic test now available.

The association of CD38 expression levels with genetic aberrations and Ig mutation status and its utility as a prognostic factor was also evaluated in the 3 papers. All 3 groups confirm the association between CD38 expression and relative lack of IgV_H region mutations. Lin and colleagues were able to demonstrate that patients with more than 20% CD38⁺ leukemic cells exhibited significant shorter survival times than those with fewer than 20% CD38⁺ cells. But Oscier et al using a cutoff of 30% CD38 and Kröber et al using a cutoff of 7% failed to demonstrate that CD38 had independent prognostic significance. Since we know that CD38 levels on leukemic B cell clones may change with time and that mixed levels of CD38 expression are commonly observed in leukemic cells (Kröber et al), understanding the precise role that this molecule plays in this disease is problematic. Nevertheless, the association with Ig mutation status and prior reports in the literature demonstrating prognostic value for CD38 in B-CLL validates further functional studies (ie, adhesion, signaling capacity) of this molecule.

We are now blessed with a surfeit of laboratory tools to more accurately dissect the transformed programs in B-CLL clones. This collection of papers substantiates that, by further understanding critical features of CLL B cell clones, we can further discern disease outcome in B-CLL. This of course is not the final answer to the puzzle of disease heterogeneity but encourages us to keep trying.