CLL is a slow-progressing cancer in which mature clonal B lymphocytes accumulate in the bone marrow, blood, and other lymphoid tissues.

• Complications associated with CLL include recurrent infection and autoimmune diseases, risk of secondary malignancy, and transformation to diffuse large B-cell lymphoma (DLBCL).⁴

The cause of CLL is unknown. Gene-expression profiling and phenotypic studies suggest that CLL is potentially derived from CD5+ B cells.⁵

Vast genetic and epigenetic heterogeneity among patients and within individual patient samples has been observed; this likely contributes to the variability in clinical course among patients with CLL.⁶

• The most recurrent genomic lesions that have been identified are deletions of chromosome 13q, 17p, and 11q, and trisomy of chromosome 12.⁶
• Unmutated IgVH is associated with more aggressive disease, poor prognosis, and decreased survival.⁷

The most relevant prognostic parameters are IgVH mutational status, serum β2-microglobulin, and the presence of del(17p) and/or TP53 mutations. Typically, high-risk CLL is defined in part by a genetic aberration of the TP53 gene (ie, del(17p) or TP53 mutation).⁸

Many patients are incidentally diagnosed with asymptomatic CLL when lymphocytes are detected in the peripheral blood during evaluation for other illnesses or in a routine physical exam.⁹

A diagnosis of CLL is based on the updated International Workshop on CLL (iwCLL) criteria:⁸

• There is a presence of at least 5 x 109 (5000/μL) B lymphocytes in the peripheral blood sustained for 3 months.
  • Clonality of circulating B lymphocytes must be confirmed by flow cytometry.
  • Cells are characteristically small, mature lymphocytes with a narrow border of cytoplasm and a dense nucleus lacking discernible nucleoli and having partially aggregated chromatin.
  • Gumprecht nuclear shadows, or smudge cells, found as cellular debris, are additional morphologic features commonly associated with CLL
• CLL cells co-express the surface antigen CD5 together with the B-cell antigens CD19, CD20, and CD23.
• Each leukemic cell clone is restricted to expression of either kappa or lambda immunoglobulin light chains, indicating monoclonality.
• Additional tests are not essential to diagnose CLL, but may help predict the prognosis or assess the tumor burden, including: molecular genetics, mutational status of IgVH and variable heavy stereotypes, immunophenotypic markers, serum markers, and marrow examination.

Two staging systems, the Rai and Binet systems, are currently used worldwide in the evaluation of patients with CLL both in routine practice and clinical trial settings.¹⁰

Within the last few decades, numerous advances in the treatment of CLL have been made, including the introduction of novel classes of targeted small molecules such as BCL2 inhibitors, BTK inhibitors, or PI3K inhibitors. Randomized clinical trials have demonstrated improved progression free survival with these therapeutics over chemoimmunotherapy in both the first-line and relapsed/refractory setting. These chemotherapy-free regimens have especially helped to improved outcomes in high-risk subgroups, albeit still with reduced activity relative to patients without these high-risk characteristics.¹¹

CLL is a chronic disease; therefore, most patients will relapse on or after treatment with these drugs and will require multiple lines of therapy, especially high-risk subgroups. The major treatment challenge has now shifted from having few therapeutic choices to how best to sequence and combine available agents.^11,12

While allogenic stem cell transplant (Allo-SCT) remains the only potentially curative option, it is a risky procedure only suitable for more fit patients.¹⁴

Clinical trials are ongoing investigating second-generation targeted agents as well as combination approaches and novel treatment strategies including small molecules with novel targets, CAR T cells targeting different antigens, CAR natural killer cells, or bispecific antibodies.^12,13,17