Emili Montserrat

The prognostic significance of lymphocyte doubling time (LDT) in chronic lymphocytic leukemia (CLL) was identified when the biology of the disease was poorly understood and therapy was not effective. We assessed the clinical and biological significance of LDT in 848 CLL patients in a real-life setting and the context of new biomarkers and effective therapy. A short LDT (≤12 months) was enriched for adverse biomarkers. Patients with a rapid LDT did need therapy shortly after diagnosis (median 23 months vs. not reached; p < 0.001) and had a poorer overall survival (median 95 months vs. not reached p < 0.001). LDT, IGHV mutational status, Beta-2 microglobulin, and Rai clinical stage were independent predictors for time to first treatment in the whole series and in Binet stage A patients. No correlation was observed between LDT and response to chemoimmunotherapy. However, a short LDT along with age ≥65 years, high-risk FISH (del(17p), del(11q)), unmutated IGHV, increased Beta-2 microglobulin, and TP53 mutations predicted short survival. Moreover, the prognostic significance of LDT was independent of the CLL-IPI and the Barcelona/Brno prognostic model. LDT remains an important outcome marker in the modern CLL era and should be incorporated into the clinical assessment and stratification of CLL patients.

Because chronic lymphocytic leukemia is a heterogeneous disease, there are considerable efforts underway to develop increasingly accurate and precise analytics with which to estimate the probability of future events such as the need for and probability of response to therapy, progression‐free survival, and survival. These analytics typically are constructed from clinical and laboratory variables. These variables often are combined into scores or staging systems, some of which are prognostic (therapy‐independent), whereas others are predictive (therapy‐dependent). Predictive variables differ with different therapies. Because response to therapy is a necessary condition for the improvement of survival, predictive biomarkers are extremely important. However, despite some progress to identify new predictive biomarkers, del(17p)/TP53 mutation remains the only widely accepted variable used to guide therapy. New laboratory techniques and analytical tools may contribute to improvements in the precision and accuracy of outcome indicators. However, there are inherent limitations when applying cohort‐based estimates to individuals within the cohort. The accuracy and precision of prediction also are limited by measurement error and chance. Ultimately, estimating outcomes requires a careful balance between clinical experience, imperfect prediction, and uncertainty.

Chronic lymphocytic leukemia (CLL), the most frequent type of leukemia in western countries, is characterized by the progressive accumulation in blood, bone marrow and lymphoid tissues of monoclonal B lymphocytes with a characteristic immunophenotype. Despite advances in therapy and improved outcome, in most instances CLL is an incurable disorder. Signaling via the B-cell receptor (BCR), the upregulation of anti-apoptotic proteins, and the cross-talk between CLL cells and microenvironment constitute key factors in the pathogenesis of CLL. Currently, inhibitors of kinases like BTK or PI3K blocking BCR signaling, and molecules that mimic the BH3 domain to compete with BCL-2 are established tools in the treatment of CLL. As the complex biology of CLL is rapidly unfolding, the number of small molecules targeting CLL molecular pathways is increasing and it is likely that they will further improve the outcome of patients with this form of leukemia.

Rai and Binet staging systems are important to predict the outcome of patients with chronic lymphocytic leukemia (CLL) but do not reflect the biologic diversity of the disease nor predict response to therapy, which ultimately shape patients' outcome. We devised a biomarkers‐only CLL prognostic system based on the two most important prognostic parameters in CLL (i.e., IGHV mutational status and fluorescence in situ hybridization [FISH] cytogenetics), separating three different risk groups: (1) low‐risk (mutated IGHV + no adverse FISH cytogenetics [del(17p), del(11q)]); (2) intermediate‐risk (either unmutated IGHV or adverse FISH cytogenetics) and (3) high‐risk (unmutated IGHV + adverse FISH cytogenetics). In 524 unselected subjects with CLL, the 10‐year overall survival was 82% (95% CI 76%‐88%), 52% (45%‐62%), and 27% (17%‐42%) for the low‐, intermediate‐, and high‐risk groups, respectively. Patients with low‐risk comprised around 50% of the series and had a life expectancy comparable to the general population. The prognostic model was fully validated in two independent cohorts, including 417 patients representative of general CLL population and 337 patients with Binet stage A CLL. The model had a similar discriminatory value as the CLL‐IPI. Moreover, it applied to all patients with CLL independently of age, and separated patients with different risk within Rai or Binet clinical stages. The biomarkers‐only CLL prognostic system presented here simplifies the CLL‐IPI and could be useful in daily practice and to stratify patients in clinical trials.