Prognosis at diagnosis: integrating molecular biologic insights into clinical practice for patients with CLL

Abstract

Heterogeneity in the clinical behavior of patients with chronic lymphocytic leukemia (CLL) makes it difficult for physicians to accurately identify which patients may benefit from an early or more aggressive treatment strategy and to provide patients with relevant prognostic information. Given the potential efficacy of newer therapies and the desire to treat patients at "optimum" times, it is more important than ever to develop sensitive stratification parameters to identify patients with poor prognosis. The evolution of risk stratification models has advanced from clinical staging and use of basic laboratory parameters to include relevant biologic and genetic features. This article will review the dramatic progress in prognostication for CLL and will propose statistical modeling techniques to evaluate the utility of these new measures in predictive models to help determine the optimal combination of markers to improve prognostication for individual patients. This discussion will also elaborate which markers and tools should be used The B-cell malignancies share a common cell lineage but a wide range of clinical, laboratory, molecular, and genetic features. Once grouped together as "subtypes" under the broad term of nonHodgkin lymphoma, the classification systems for these diseases have gone through extensive refinement to better distinguish their clinical and biologic characteristics. 1,2 Traditional teaching labeled diseases that were fatal in weeks to months if untreated as "aggressive" and those that progressed over months to years as "indolent."Through a major, collaborative, international effort, the World Health Organization (WHO) published a consensus classification system that distinguished lymphoid disorders on the basis of a combination of clinical syndromes, morphology, immunophenotype, and genetic features. 2 The WHO classification added the concept that each disorder represented a separate and distinct disease with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma grouped into a single entity (CLL). 2 Although this categorization no longer distinguishes these diseases as indolent or aggressive, the low-grade B-cell disorders are still evaluated along these lines. 3 These disorders are often considered chronic diseases of the elderly, and patients are thought likely to die of unrelated causes. These assumptions are incorrect and, to a certain extent, have hampered progress in this field.For CLL, the median age of diagnosis is 65 to 68 years old. 4 Some patients experience a slowly progressive clinical course, but most will eventually progress and have fatal outcomes. 4,5 Importantly, significant subsets of patients with early stage CLL become active, 4,[6][7][8] are refractory to treatment, 7 experience infectious or autoimmune complications, and have more rapidly fatal outcomes than anticipated.This clinical heterogeneity emphasizes the problem of considering CLL indolent and, in the era of more efficacious therapy, highlights the need to improve our ability to identify patients wit...

The effect of immunoglobulin VH gene mutation status and other prognostic factors on the incidence of major infections in patients with chronic lymphocytic leukemia

“…18 However, it cannot distinguish rapidly progressing patients from patients whose disease remains quiescent for a long period. 2 The prognostic significance of IgV H mutation status has been confirmed repeatedly by many independent groups 3,5,29 and in our own work. 30 Patients with CLL with malignant cells that have unmutated IgV H genes have a shorter overall and treatment-free survival and have a worse response to therapy.…”

“…2 High levels of CD38 and ZAP-70 expression 3,4 and unmutated IgV H genes 3,5 are associated with aggressive disease. Trisomy 12, complex karyotype, and deletions of chromosomic regions 11q and 17p are associated with reduced overall survival.…”

Flow cytometry for ZAP‐70: New colors for chronic lymphocytic leukemia

“…Indeed prognostic markers in CLL have attracted a great deal of interest in recent years. Using a Pubmed search for ''CLL'' and ''Prognosis,'' Shanafelt and colleagues found up to 100 publications per year devoted to this topic (2). So how come one would find a whole issue of the journal devoted to this one marker?…”

T/B ratio does not reflect levels of ZAP70 expression in clonal CLL B‐cells due to ZAP70 overexpression in patient T‐cells

“…ZAP70 is thus thought to be one of the most promising phenotypic markers because of its correlation with the IGHV mutational status as well as other cytogenetic prognostic markers (1,3,9,10). Different techniques for ZAP70 FCM detection have been published since the first publication in 2003 and different consensus protocols have been established.…”