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.
Prognostication is an essential component of the treatment of patients with chronic lymphocytic leukemia. Prognostication requires a sound balance between accuracy and precision (never perfect) and uncertainty (inherent to medical practice).
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.
The previous edition of the consensus guidelines of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL), published in 2008, has found broad acceptance by physicians and investigators ...caring for patients with CLL. Recent advances including the discovery of the genomic landscape of the disease, the development of genetic tests with prognostic relevance, and the detection of minimal residual disease (MRD), coupled with the increased availability of novel targeted agents with impressive efficacy, prompted an international panel to provide updated evidence- and expert opinion–based recommendations. These recommendations include a revised version of the iwCLL response criteria, an update on the use of MRD status for clinical evaluation, and recommendations regarding the assessment and prophylaxis of viral diseases during management of CLL.
Chronic lymphocytic leukemia (CLL) cells proliferate in pseudofollicles within the lymphatic tissues, where signals from the microenvironment and BCR signaling drive the expansion of the CLL clone. ...Mobilization of tissue-resident cells into the blood removes CLL cells from this nurturing milieu and sensitizes them to cytotoxic drugs. This concept recently gained momentum after the clinical activity of kinase inhibitors that target BCR signaling (spleen tyrosine kinase, Bruton tyrosine kinase, PI3Kδ inhibitors) was established. Besides antiproliferative activity, these drugs cause CLL cell redistribution with rapid lymph node shrinkage, along with a transient surge in lymphocytosis, before inducing objective remissions. Inactivation of critical CLL homing mechanism (chemokine receptors, adhesion molecules), thwarting tissue retention and recirculation into the tissues, appears to be the basis for this striking clinical activity. This effect of BCR-signaling inhibitors resembles redistribution of CLL cells after glucocorticoids, described as early as in the 1940s. As such, we are witnessing a renaissance of the concept of leukemia cell redistribution in modern CLL therapy. Here, we review the molecular basis of CLL cell trafficking, homing, and redistribution and similarities between old and new drugs affecting these processes. In addition, we outline how these discoveries are changing our understanding of CLL biology and therapy.
The individual prognosis of patients with chronic lymphocytic leukemia (CLL) is extremely variable. Although clinical stages remain the basis for assessing prognosis in CLL, a number of biological ...markers, particularly serum markers, cytogenetic abnormalities, IgVH mutations, CD38 and ZAP-70 expression in leukemic cells offer important, independent prognostic information. Before being incorporated into daily practice, however, these markers require standardization and validation in large, prospective trials. Meanwhile, treatment of patients with CLL not included in clinical studies should be decided on the basis of classical NCI/CLL Working Group criteria. An important area of research in CLL prognostication is the identification of markers useful for predicting response to therapy and its duration. Among them, del(17p), reflecting P53 abnormalities, is particularly important. Also relevant is del(11q), which points to ATM defects. There is also some correlation between IgVH mutational status, ZAP-70 and CD38 expression and response to therapy and its duration, although these relationships need further investigation. Finally, there is increasing evidence that response to therapy, particularly in those cases in which minimal residual disease is eradicated, is associated with longer survival.
Standardized criteria for diagnosis and response assessment are needed to interpret and compare clinical trials and for approval of new therapeutic agents by regulatory agencies. Therefore, a ...National Cancer Institute–sponsored Working Group (NCI-WG) on chronic lymphocytic leukemia (CLL) published guidelines for the design and conduct of clinical trials for patients with CLL in 1988, which were updated in 1996. During the past decade, considerable progress has been achieved in defining new prognostic markers, diagnostic parameters, and treatment options. This prompted the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) to provide updated recommendations for the management of CLL in clinical trials and general practice.
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.
PDF
