Clinical Implications and the Development of Novel Therapeutics

CLINICAL IMPLICATIONS AND THE DEVELOPMENT OF NOVEL THERAPEUTICS

Currently used clinical staging systems defined by Rai and by Binet help clini-cians to monitor disease progression and decide when to treat patients. Because of difficulties distinguishing patients with poor prognosis at the onset of dis-ease using these staging systems, the generally used practice is to wait to start therapy until the patient’s clini-cal course becomes evident (“wait and watch” mode). However, the molecular and cellular markers that reflect intrin-sic properties of leukemic cells present at the disease onset can help to distin-guish patients that will follow worse clinical courses, regardless of their Rai and Binet risk categories at diagnosis. Although determination of IgVH gene mutation status is not yet routinely avail-able, measurement of CD38 and ZAP-70 has become more widely available. Thus, although the wait-and-watch mode is still being followed in current clinical practice, it may be substituted for by new more aggressive strategies in the future. The new prognostic markers indicate that 30–50 percent of the patients have features portending a poor outcome, and therefore an early start of therapy may be justified in such poor-prognosis groups. This strategy is plausible, considering that continued proliferation and expansion of the neoplastic clone facilitates accumula-tion of ominous cytogenetic abnormali-ties. However, before any recommended guidelines can be proposed, clinical trials must test the use of early intervention in patients in poor-prognosis groups.

New knowledge about the biology of B-CLL can provide clues for novel therapeu-tic targets. For example, since B-CLL cells must interact with the stroma in bone mar-row or other peripheral lymphoid tissues to survive, furthering our knowledge of these interactions may generate new objec-tives for innovative therapies. Another compelling set of options may derive from specific inhibition of the BCR or CD38 sig-naling pathways or other pathways in which ZAP-70 is crucial. Likewise, the pos-sibility of using cell-cycle-specific drugs is worth being explored in clinical trials, given the documented active turnover of B-CLL cells. Finally, because up to 20 per-cent of patients with the worst prognostic markers have stereotypic antigen re-ceptors, these common structures may be feasible as vulnerable points of attack. As the antigens that engage these receptors become more precisely defined, it may be possible to use these to develop an arsenal of specific therapies.