Chronic Lymphocytic Leukemia (CLL) is a type of cancer characterized by the accumulation of mature B lymphocytes, a type of white blood cell. These cells normally help combat infections. CLL is the most common lymphoproliferative disorder. While often presenting with typical features, CLL can also manifest with “atypical” characteristics, which deviate from the standard presentation and distinguish it from classical CLL.
Defining Atypical CLL: What Makes It Different?
Atypical CLL is distinguished from classic CLL by specific morphological and immunophenotypic characteristics. Morphologically, atypical CLL cells can appear as large, atypical forms, prolymphocytes, or cleaved cells. Unlike typical CLL cells, which are small with round nuclei and clumped chromatin, atypical lymphocytes might be enlarged with irregular nuclear contours and more abundant cytoplasm. The presence of prolymphocytes, or larger atypical cells, is a key morphological feature.
Immunophenotypically, atypical CLL often shows variations from the typical CLL profile, which usually includes the co-expression of CD19, CD20, CD5, and CD23 antigens on leukemic cells. Atypical CLL may lack the expression of one or more of these surface antigens, most commonly CD5 and CD23, such as in CD5-negative CLL. Atypical immunophenotypes can also be characterized by higher expression of CD20, FMC7, CD79b, CD49d, and an intermediate-high expression of membrane surface immunoglobulin compared to typical cases.
Genetic abnormalities also contribute to the definition of atypical CLL and its behavior. Patients with atypical CLL are more likely to display markers associated with a less favorable outlook, such as trisomy 12, unmutated immunoglobulin heavy chain variable (IGHV), and CD38 expression. Trisomy 12 is the second most frequent chromosomal aberration detected in CLL and is often associated with atypical morphology. Deletions in chromosome 17p and/or TP53 mutations are also considered indicators of atypical CLL and are associated with a poor prognosis.
Diagnosing Atypical CLL
The diagnostic process for atypical CLL involves a combination of laboratory tests to identify its distinguishing features. A complete blood count (CBC) and morphological evaluation of a blood smear are initial steps, revealing leukocytosis with lymphocytosis. Peripheral blood smear analysis helps observe cell morphology, such as the presence of prolymphocytes or other atypical lymphocyte forms.
Flow cytometry is a primary tool used to assess the immunophenotype of the leukemic cells. This test confirms the presence of a clonal B-cell population and evaluates the expression of specific markers like CD5, CD19, CD20, and CD23. It also helps identify variations, such as the absence of CD5 or CD23 expression, which are indicative of atypical CLL.
Cytogenetic and molecular tests are performed to detect genetic abnormalities. Fluorescence in situ hybridization (FISH) is commonly used to identify chromosomal deletions, such as del(17p). Gene sequencing, particularly for TP53 mutations, is also employed, as these genetic changes are associated with a less favorable disease course and can influence treatment decisions.
Prognosis and Clinical Course
A diagnosis of atypical CLL generally indicates a more aggressive disease course compared to typical CLL. The specific atypical features, particularly certain genetic markers or immunophenotypic variations, correlate with a faster progression. Morphologically atypical CLL often exhibits more aggressive clinical behavior and a less favorable prognosis. Patients with atypical CLL may present at higher clinical stages and often require immediate treatment.
Genetic abnormalities, such as trisomy 12, unmutated IGHV, and CD38 expression, are common in atypical CLL and indicate a less favorable outlook. Deletions in chromosome 17p and TP53 mutations are recognized as significant adverse prognostic factors, often leading to decreased survival and a reduced response to standard chemotherapy. The prognosis for atypical CLL is highly individualized, depending on the specific combination of atypical features present in each patient.
Treatment Strategies for Atypical CLL
Treatment approaches for atypical CLL often differ from those for typical CLL due to its more aggressive nature and potential resistance to standard therapies. Targeted therapies have transformed CLL care and are frequently utilized. These include Bruton’s tyrosine kinase (BTK) inhibitors, which offer effective options.
Another class of targeted agents includes BCL-2 inhibitors, like venetoclax, which can be used alone or in combination with immunotherapy. For patients who relapse after treatment with BTK and BCL-2 inhibitors, novel strategies are being explored, including non-covalent BTK inhibitors and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In select cases, more intensive approaches such as allogeneic stem cell transplantation may be considered. Treatment decisions are personalized, taking into account the specific atypical features and overall patient factors.