Chronic lymphocytic leukemia

Indolent B-cell leukemia of older adults, characterized by chronic lymphocytosis and immune dysfunction. Small lymphocytic lymphoma (SLL) is the term for the same clonal malignancy when it presents primarily in lymph nodes rather than blood.

• Most common adult leukemia in Western countries. Frequently encountered as an incidental lymphocytosis, yet important for its classic exam hallmarks (e.g., smudge cells) and unique management (often observation until progression). Also notable for potential transformation to an aggressive lymphoma (Richter syndrome).

• Often asymptomatic at diagnosis; routine labs may show very high WBC (e.g., >50,000) with lymphocytosis. Physical exam can be unremarkable or reveal painless lymphadenopathy and splenomegaly.
• Typical patient is elderly (median age ~65–70). Some patients develop nonspecific symptoms like fatigue or weight loss. B symptoms (fever, night sweats, unintentional weight loss) are usually absent until advanced disease or transformation.
• Recurrent infections are common later due to hypogammaglobulinemia (impaired immunoglobulin production). Autoimmune complications can occur (e.g., warm autoimmune hemolytic anemia).

1. Confirm the diagnosis with flow cytometry of peripheral blood showing a clonal B-cell population co-expressing CD5 and CD23 (characteristic immunophenotype of CLL).
2. Stage the disease (e.g., Rai or Binet systems): early stage (lymphocytosis only) vs. advanced (extensive lymphadenopathy, organomegaly, anemia or thrombocytopenia). Staging guides prognosis but not treatment decisions.
3. Assess prognostic markers: perform FISH for cytogenetics (e.g., del(13q) is favorable, while del(17p) or TP53 mutation portends poor prognosis) and determine IGHV mutation status (mutated IGHV = more indolent disease).
4. Treatment is indicated only for active disease (e.g., significant symptoms, rapidly progressive lymphocytosis, bulky lymphadenopathy, or cytopenias from marrow infiltration). Watchful waiting is standard for low-risk, asymptomatic CLL.
5. If treatment is needed, targeted therapies are first-line (see Treatment below). Also address supportive care: e.g., periodic IVIG infusions for severe hypogammaglobulinemia with infections, and manage autoimmune hemolysis with steroids.

1. Early-stage or low-risk CLL (e.g., Rai stage 0) is managed with observation ("watch and wait") – no treatment unless the disease progresses or symptoms appear.
2. For active or advanced disease, first-line therapy involves targeted agents rather than traditional chemo. Bruton tyrosine kinase (BTK) inhibitors like ibrutinib or acalabrutinib, or the BCL-2 inhibitor venetoclax, are used often in combination with an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).
3. Intensive chemoimmunotherapy (e.g., FCR regimen – fludarabine, cyclophosphamide, rituximab) can induce remissions in fit younger patients (particularly with IGHV-mutated disease) but is now largely supplanted by targeted therapies due to better safety and outcomes.
4. Manage complications: e.g., autoimmune hemolytic anemia is treated with corticosteroids; severe infections may warrant IVIG; consider allogeneic stem cell transplant or CAR T-cell therapy in refractory CLL cases.

• Mnemonic: CLL = Crushed Little Lymphocytes – referring to the classic smudge cells (fragile lymphocytes broken during smear preparation).
• CLL/SLL cells aberrantly co-express CD5 (normally a T-cell antigen) along with B-cell markers (CD19, CD20) and CD23 – a key immunophenotypic clue distinguishing CLL from other leukemias/lymphomas.
• Cytogenetics predict prognosis: del(13q) is most common and confers a favorable outcome, whereas del(17p) (loss of TP53) is associated with chemotherapy resistance and worse prognosis.

• New-onset B symptoms (fever, drenching night sweats, weight loss) or a rapidly enlarging lymph node in a CLL patient – raises concern for Richter transformation to an aggressive lymphoma.
• Unexplained rapid drop in hemoglobin in CLL → evaluate for autoimmune hemolytic anemia (Coombs-positive hemolysis, which CLL can trigger) and treat promptly (e.g., steroids).

1. Unexplained lymphocytosis (especially in an older adult) or persistent lymphadenopathy → suspect CLL.
2. Confirm CLL with flow cytometry on blood showing clonal B cells (CD19+) with co-expression of CD5 and CD23.
3. Evaluate disease extent: thorough exam for lymph nodes and organomegaly; use Rai/Binet staging to stratify risk (e.g., lymphocytosis only vs. lymphadenopathy vs. anemia/thrombocytopenia).
4. If early stage and asymptomatic → observe (no immediate treatment, regular follow-up).
5. If symptomatic or advanced (bulky nodes, cytopenias, or symptoms) → treat with appropriate therapy (targeted agents ± anti-CD20 antibody).

• Older adult with a very high WBC count (e.g., 100,000) composed mostly of lymphocytes and many smudge cells on peripheral smear → Chronic lymphocytic leukemia (often asymptomatic at presentation).
• Patient with known CLL who develops sudden B symptoms (fevers, night sweats, weight loss) and rapid growth of a single lymph node → suspect Richter transformation (CLL evolving into an aggressive large B-cell lymphoma).