New prognostic markers are now available to the clinician and investigator.[6,7] The use of these markers to stratify patients in clinical trials, to help assess the need for therapy, and to help select the type of therapy continues to evolve. Prospective trials to verify and establish the role of these prognostic markers are ongoing. No large multivariable analyses exist as yet to test the relative power of these individual prognostic variables. Prognostic indices are under evaluation and will require prospective validation.
Immunoglobulin variable region heavy chain gene (IgVH) mutation.[10,11,12,13,14] The finding of significant numbers of mutations in this region is associated with a median survival in excess of 20 to 25 years. The absence of mutations is associated with a median survival of 8 to 10 years.
ZAP-70. ZAP-70 has been proposed as a surrogate for the mutational status.[15,16,17,18] ZAP-70 positivity for previously untreated and asymptomatic patients (>30%) is associated with a more unfavorable median survival (6-10 years), while a negative ZAP-70 is associated with a median survival of more than 15 years. A prospective evaluation of these markers in a randomized study of fludarabine-based chemotherapy (E2997 [NCT00003764]) failed to show any difference in response rates, response duration, progression-free survival, or overall survival (OS).
Chromosomal abnormalities by fluorescent in situ hybridization (FISH). FISH chromosomal abnormalities were associated with prognosis in retrospective and prospective studies and clonal evolution has been seen over time.[20,21,22,23] 13q- is favorable (with a 17-year median OS in a prospective study). Trisomy 12 and 11q- have less favorable prognoses (with a 9- to 11-year median OS in a prospective study). In particular, 17p- is associated with mutated TP53 and with poor response rates and short duration of response to the standard therapeutic options. 17p- is associated with the most unfavorable prognosis (with a 7-year median OS in one prospective trial).[19,23,24] The combination of adverse cytogenetics such as 11q- or 17p- (suggesting a worse prognosis) with ZAP-70 negativity (suggesting a better prognosis) in the same patients resulted in a poor prognosis. These findings emphasize the need for prospective studies of combinations of these prognostic markers.
CD38 immunophenotype.[11,25] CD38 positivity (>30%) correlates with a worse prognosis, but there is a 30% false-positive rate and a 50% false-negative rate using IgVH mutational status as the gold standard for prognosis.