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Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies
Ferrata Storti Foundation
Haematologica 2020 Volume 105(9):2205-2217
Julio Delgado,1,2,3 Ferran Nadeu,2,3 Dolors Colomer,2,3,4 and Elias Campo2,3,4
1Department of Hematology, Hospital Clínic, University of Barcelona, Barcelona; 2Centro de Investigación Biomédica en Red en Oncologia (CIBERONC), Madrid; 3Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona and 4Hematopathology Section, Hospital Clínic, University of Barcelona, Barcelona, Spain
ABSTRACT
Chronic lymphocytic leukemia is a well-defined lymphoid neoplasm with very heterogeneous biological and clinical behavior. The last decade has been remarkably fruitful in novel findings, elucidating multiple aspects of the pathogenesis of the disease including mechanisms of genetic susceptibility, insights into the relevance of immunogenetic fac- tors driving the disease, profiling of genomic alterations, epigenetic sub- types, global epigenomic tumor cell reprogramming, modulation of tumor cell and microenvironment interactions, and dynamics of clonal evolution from early steps in monoclonal B-cell lymphocytosis to progression and transformation into diffuse large B-cell lymphoma. All this knowledge has offered new perspectives that are being exploited therapeutically with novel, targeted agents and management strategies. In this review we pro- vide an overview of these novel advances and highlight questions and per- spectives that need further progress to translate this biological knowledge into the clinic and improve patients’ outcome.
History
Chronic lymphocytic leukemia (CLL) is a lymphoid malignancy characterized by the proliferation and accumulation of mature CD5+ B cells in the blood, bone marrow and lymphoid tissues. The diagnosis of CLL requires the presence of ≥5 x109/L mono- clonal B cells of typical phenotype in the blood. Patients with <5 x109/L circulating CLL-type cells may be diagnosed with small lymphocytic lymphoma if they also pres- ent with either lymphadenopathy, organomegaly or extramedullary disease; or with monoclonal B-cell lymphocytosis (MBL) if they do not.1 CLL is the most prevalent type of leukemia in adults in Western countries, with an age-adjusted incidence rate of 4.9 cases per 100,000 inhabitants per year. There is a stark difference between the incidence in men (6.8 cases per 100,000/year) and women (3.5 cases per 100,000/year) and also between Caucasians (7.3 and 3.8 cases per 100,000/year for men and women, respectively), African Americans (4.9 and 2.4 cases per 100,000/year for men and women, respectively) and Asian Americans (1.5 and 0.7 cases per 100,000/year for men and women, respectively).2 The disease may have a stable course but also become aggressive, with frequent relapses, or even transform into an aggressive lym- phoma, typically diffuse large B-cell lymphoma (DLBCL) (Richter transformation).
In the last decade, genomic and epigenomic studies have expanded our knowl- edge of the pathogenesis of CLL remarkably, unraveling a large number of novel alterations that might drive the evolution of the disease.3–7 Moreover, understand- ing the crosstalk between tumor cells and their microenvironment has been fun- damental in the development of new, targeted agents, which are transforming the way we manage the disease. In this review we provide an overview of these novel advances and how they relate to our understanding of the pathogenesis and cur- rent management of CLL.
Pathogenesis
Genetic predisposition
Family studies have consistently shown that first-degree relatives of patients with CLL have a 2- to 8-fold increased risk of developing the disease.8 Genome-
Correspondence:
ELIAS CAMPO
ecampo@clinic.cat
Received: April 29, 2020. Accepted: June 18, 2020. Pre-published: July 2, 2020.
doi:10.3324/haematol.2019.236000 ©2020 Ferrata Storti Foundation
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