ABSTRACT
A diagnosis of typical chronic lymphocytic leukemia (CLL) requires the presence of ≥5000 clonal B-lymphocytes/µL, the coexistence of CD19, CD20, CD5, and CD23, the restriction of light chain immunoglobulin, and the lack of expression of antigens CD22 and CD79b. Atypical CLL (aCLL) can be distinguished from typical CLL morphologically and immunophenotypically. Morphologically atypical CLL cells have been defined mainly as large, atypical forms, prolymphocytes, or cleaved cells. However, current aCLL diagnostics rely more on immunophenotypic characteristics rather than atypical morphology. Immunophenotypically, atypical CLL differs from classic CLL in the lack of expression of one or fewer surface antigens, most commonly CD5 and CD23, and the patient does not meet the criteria for a diagnosis of any other B-cell lymphoid malignancy. Morphologically atypical CLL has more aggressive clinical behavior and worse prognosis than classic CLL. Patients with aCLL are more likely to display markers associated with poor prognosis, including trisomy 12, unmutated IGVH, and CD38 expression, compared with classic CLL. However, no standard or commonly accepted criteria exist for differentiating aCLL from classic CLL and the clinical significance of aCLL is still under debate. This review summarizes the current state of knowledge on the morphological, immunophenotypic, and genetic abnormalities of aCLL.
ABSTRACT
OPINION STATEMENT: The better understanding of the biology of chronic lymphocytic leukemia (CLL) gained over the past decade has led to the development and introduction of several targeted drugs, with an demonstrable improvement in the prognosis for this currently incurable condition. Currently, Bruton's tyrosine kinase (BTK) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, venetoclax, and CD20 monoclonal antibodies are the key elements in the treatment of both previously untreated and relapsed/refractory CLL patients. Ibrutinib was the first BTK inhibitor approved for clinical use, and showed excellent efficacy and an acceptable safety profile. Following this, the better-tolerated second-generation irreversible BTK inhibitors acalabrutinib and zanubrutinib have been introduced for the treatment of lymphoid malignancies, and acalabrutinib was approved for CLL. When used as single drugs, BTK inhibitors are given continuously until unacceptable toxicity or disease progression; however, when combined with venetoclax and/or CD20 antibodies, they induce deeper response and can be given for a limited time. Recently, promising new reversible BTK inhibitors pirtobrutinib and nemtabrutinib were discovered, and these seem to be more active and better tolerated than their irreversible predecessors. However, they are in an early phase of development and are not currently approved for CLL. The phosphatidylinositol 3-kinase (PI3K) inhibitors idelalisib and duvelisib are highly effective in patients with relapsed CLL, including high-risk disease. The major limitations for their use are adverse events, mostly of autoimmune origin (hepatitis, enteritis/colitis, and pneumonitis). Otherwise, cellular therapies like allogeneic hematopoietic stem cell transplantation and chimeric antigen receptor (CAR) T cells and bispecific monoclonal antibodies offer promise for patients who have failed BTK inhibitors and venetoclax treatment. In the coming years, it is likely that novel targeted therapies will replace immunochemotherapy regimens in most patients.
