Chronic Lymphocytic Leukemia

1. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

2. INTRODUCTION
Definition:
• Chronic lymphocytic leukemia (CLL) is a clonal malignancy of mature b-lymphocytes,
characterized by progressive accumulation of small, functionally incompetent
lymphocytes in the peripheral blood, bone marrow, lymph nodes, and spleen.
• It is the most common leukemia in adults in western countries.
• Median age at diagnosis: ~70 years
• Often indolent, but may transform into more aggressive disease.

3. ETIOLOGY AND RISK FACTORS:
Genetic:
• Familial cases (~5–10%)
• Monozygotic twins and first-degree relatives have increased risk.
Environmental:
• Possibly associated with herbicides and pesticides (e.G., Agent orange), though data is limited.
Immunological:
• Dysregulation of immune surveillance may contribute.
Chromosomal abnormalities:
• Deletions of 13q (good prognosis)
• 11q, 17p (poor prognosis)
• Trisomy 12 (intermediate prognosis)

4. PATHOPHYSIOLOGY:
CLL arises from mature b-cells that have undergone antigen encounter and somatic hypermutation.
These b-cells:
• Express cd19, cd20 (weak), cd5, cd23
• Are monoclonal (identical light chain restriction: κ or λ)
CLL cells accumulate due to:
• Reduced apoptosis (not rapid proliferation)
• Increased expression of anti-apoptotic proteins (bcl2)
• Dysregulation of signaling pathways (e.G., BTK pathway)

5. CLINICAL FEATURES:
1. General features:
• Often asymptomatic (detected on routine CBC)
• Fatigue, malaise
• Weight loss, anorexia
• Fever, night sweats (less common unless advanced disease)

6. CLINICAL FEATURES:
2. Lymphoproliferative symptoms:
• Painless lymphadenopathy (commonest presentation)
• Splenomegaly
• Hepatomegaly

7. CLINICAL FEATURES:
3. Infectious complications:
• Due to hypogammaglobulinemia
• Frequent respiratory and urinary tract infections
• Encapsulated bacteria (e.G., Strep. Pneumoniae)

8. CLINICAL FEATURES:
4. Autoimmune phenomena:
• Autoimmune hemolytic anemia (aiha) – positive coombs test
• Immune thrombocytopenia (itp)
• Pure red cell aplasia (rare)

9. STAGING SYSTEMS:
RAI STAGING (US)
Stage Clinical Features Risk
0 Lymphocytosis only Low
I + Lymphadenopathy Intermediate
II + Splenomegaly/hepatomegaly Intermediate
III + Anemia (Hb <11 g/dL) High
IV + Thrombocytopenia (PLT
<100,000/µL)
High

10. STAGING SYSTEMS:
• BINET STAGING (EUROPE)
Stage Involvement Risk
A <3 lymphoid areas, no
anemia/thrombocytopenia
Low
B ≥3 lymphoid areas, no
anemia/thrombocytopenia
Intermediate
C Anemia and/or thrombocytopenia High

11. COMPLICATIONS:
• Infections (most common cause of death)
• Autoimmune cytopenias
• Richter’s transformation:
Sudden transformation to diffuse large b-cell lymphoma (DLBCL)
• Presents with rapid lymph node enlargement, B symptoms
• Secondary malignancies
Renal dysfunction, due to infiltration or cryoglobulinemia

12. LABORATORY DIAGNOSIS:
Investigation Findings
FBC Lymphocytosis >5,000/µL, mild anemia, thrombocytopenia (late)
Peripheral smear Small mature lymphocytes, smudge cells
Immunophenotyping (Flow cytometry) CD5+, CD19+, CD23+, weak CD20+, monoclonal κ/λ light chains
Bone marrow biopsy Hypercellular marrow with lymphocytic infiltration
Direct Coombs test May be positive in Autoimmune Haemolytic anaemia (AIHA)
Serum immunoglobulins Hypogammaglobulinemia (low IgG, IgA, IgM)
FISH / Cytogenetics To detect deletions: 13q (good), 17p/11q (poor), trisomy 12 (intermediate)
Beta-2 microglobulin Elevated in advanced disease – prognostic
LDH May be elevated in progressive or transformed disease

13. PERIPHERAL BLOOD FILM FOR CLL

14. BONE MARROW SMEAR

15. PROGNOSTIC MARKERS:
Marker Prognosis
(13q) Good
Trisomy 12 Intermediate
Del(11q), del(17p) Poor
TP53 mutation Poor
Unmutated IGHV gene Poor
ZAP-70 and CD38 positivity Poor

16. TREATMENT:
1. Indications for treatment (IWCLL criteria):
• Symptomatic disease (b symptoms, organomegaly, cytopenias)
• Progressive lymphocytosis
• Autoimmune complications unresponsive to steroids
• Symptomatic lymphadenopathy or splenomegaly

17. TREATMENT:
2. First-line therapy:
• Targeted therapy (preferred):
• Ibrutinib (BTK inhibitor)
• Acalabrutinib (BTK inhibitor)
• Venetoclax (BCL2 inhibitor) ± obinutuzumab
Chemoimmunotherapy (less favored now):
• FCR: fludarabine + cyclophosphamide + rituximab
• BR: bendamustine + rituximab (elderly)

18. TREATMENT:
3. Relapsed/refractory disease:
• Switch to targeted therapy (ibrutinib, venetoclax)
• Allogeneic stem cell transplant in selected young patients
4. Supportive care:
• IVIG replacement for recurrent infections due to hypogammaglobulinemia
• Antimicrobial prophylaxis (e.G., PJP prophylaxis with cotrimoxazole)
• Erythropoietin or transfusions for anemia

19. RICHTER’S TRANSFORMATION:
• Occurs in ~2–10% of CLL cases
• Most commonly transforms into diffuse large b-cell lymphoma (dlbcl)
• Poor prognosis
• Diagnosed via biopsy and high suv on pet-ct
• Requires aggressive chemotherapy (r-chop) ± stem cell transplant

20. SUMMARY TABLE:
Aspect CLL
Age >60 years
Cell of origin Mature B-cell
Immunophenotype CD5+, CD19+, CD23+, weak CD20
Smear feature Smudge cells
Common complications Infections, AIHA, Richter’s transformation
Common cytogenetic del(13q), trisomy 12, del(17p)
Treatment Observation, Ibrutinib, Venetoclax, FCR

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