Chronic Lymphocytic Leukemia¶
Chapter 112 | Harrison's 22e · Part 4 – Oncology: Hematologic Malignancies · Chapter 112
Key Clinical Points¶
- CLL is defined by an absolute lymphocyte count ≥5 × 10⁹/L with monoclonal B-cell proliferation.
- Median age at diagnosis is 71 years; incidence rate is 4.6/100,000 in the US.
- Prevalence has increased due to improved therapies and an aging population (survival rates rose from 70% in 1980 to 92% in 2015).
- NOTCH1 mutations (10–13%) correlate with poor response to CD20 therapy and risk of Richter's transformation.
- SF3B1 mutations (8–14%) affect RNA splicing and are linked to specific cytogenetic abnormalities.
- ATM mutations (8–11%) can lead to resistance to venetoclax; TP53 mutations are associated with poor response to DNA-damaging therapy.
- Targeted therapies include BTK inhibitors (ibrutinib, acalabrutinib), BCL-2 inhibitors (venetoclax), and PI3K inhibitors (idelalisib).
- MRD negativity after treatment is a key predictor of improved survival outcomes.
1. DEFINITION & OVERVIEW¶
• Definition: Chronic lymphocytic leukemia (CLL) is a monoclonal proliferation of mature B lymphocytes defined by an absolute lymphocyte count ≥5 × 10⁹/L.
• Precursor State: Monoclonal B-cell expansion without cytopenias or organomegaly (MBL).
• Clinical Course: Highly variable, ranging from asymptomatic indolent forms to aggressive transformations.
• Progression Risk: 1–2% annual progression risk from MBL.
2. EPIDEMIOLOGY¶
• Demographics: Primarily a disease of older adults. ◦ Median age at diagnosis: 71 years. ◦ Male-to-female ratio: 2:1 (equal after age 80).
• Incidence & Prevalence: ◦ Age-adjusted incidence: 4.6/100,000 in the US. ◦ Survival rates increased from 70% (1980) to 92% (2015).
• Ethnicity: ◦ Most common in Caucasians. ◦ Less frequent in Hispanics and African Americans. ◦ Rare in Asians.
• Environmental Factors: ◦ No definitive links to radiation exposure. ◦ Agent Orange exposure associated with service-connected status.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
• Molecular Heterogeneity: Influences prognosis and treatment response.
• Recurrent Mutations (Table 112-1): ◦ SF3B1: 8–14% frequency; affects RNA splicing, linked to specific cytogenetic abnormalities. ◦ NOTCH1: 10–13% frequency; mutations in the PEST domain cause constitutive signaling and are associated with Richter's transformation. ◦ ATM: 8–11% frequency; mutations can lead to resistance to venetoclax. ◦ XPO1, POT1, EGR2: <5% frequency each.
• Genetic Impact (Figure 112-2): ◦ TP53 mutations: Associated with poor response to DNA-damaging therapy. ◦ SF3B1 mutations: Linked to specific cytogenetic abnormalities.
4. CLINICAL MANIFESTATIONS¶
• Presentation: ◦ Asymptomatic: 20–30% of cases at diagnosis. ◦ Symptomatic manifestations (70–80% will eventually require treatment): ◦ Fatigue (most common). ◦ Lymphadenopathy (70–80%). ◦ Splenomegaly (50–60%). ◦ Autoimmune phenomena: e.g., hemolytic anemia, thrombocytopenia.
• Natural History: ◦ 10–20% of patients never require therapy. ◦ Median survival: 10 years with modern therapies.
5. DIAGNOSTIC APPROACH¶
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Initial Diagnosis: • Confirm absolute lymphocyte count ≥5 × 10⁹/L. • Identify monoclonal B-cell population (Table 112-2: CD5+, CD19+, CD20+ [dim], CD23+). • Exclude other lymphoproliferative disorders.
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Staging (Table 112-3): • Rai System: ◦ Stage 0 (Low risk): Lymphocytosis only. ◦ Stage I/II (Intermediate risk): Lymphocytosis with lymphadenopathy, with or without splenomegaly or hepatomegaly. ◦ Stage III/IV (High risk): Lymphocytosis with anemia or thrombocytopenia due to bone marrow involvement. • Binet System: Categorized as A, B, or C.
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Risk Stratification (Table 112-4): • Calculate International Prognostic Index (IPI) based on: ◦ TP53 status: Deleted or mutated → 4 points. ◦ β-Microglobulin concentration: >3.5 mg/L → 2 points. ◦ Age: >65 years → 1 point. • Interpretation of Risk Score: ◦ 0–1: Low risk (93.2% 5-year survival). ◦ 4–6: High risk (63.3% 5-year survival).
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Decision to Initiate Therapy (Table 112-5): Identify triggers for treatment initiation: • Marrow Failure: worsening of anemia or thrombocytopenia not due to autoimmune destruction. • Splenomegaly: Massive (≥6 cm below costal margin), progressive, or symptomatic. • Lymphadenopathy: Massive (≥10 cm), progressive, or symptomatic. • Rapid Progression: Lymphocytosis increase ≥50% over a 2-month period OR lymphocyte doubling time <6 months. • Autoimmune Issues: Anemia or thrombocytopenia not responsive to standard therapy. • Extranodal Involvement: Symptomatic or functional involvement. • Constitutional Symptoms: One or more of the following: ◦ Unintentional weight loss ≥10% over 6 months. ◦ Significant fatigue. ◦ Fevers ≥100.5°F for 2+ weeks without infection. ◦ Night sweats for >1 month without infection.
6. MANAGEMENT & TREATMENT¶
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Initial Strategy: • Watchful waiting for asymptomatic patients with low-risk features.
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First-line Therapies: • BTK inhibitors: ibrutinib, acalabrutinib. • BCL-2 inhibitors: venetoclax. • PI3K inhibitors: idelalisib.
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Advanced/High-Risk Options: • CAR-T cell therapy: for high-risk relapsed/refractory disease. • Bispecific antibodies: blinatumomab.
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Response Assessment (Table 112-6): • Complete Response (CR) Criteria: ◦ Lymphocyte count: <4000/μL. ◦ Lymph nodes: None >1.5 cm. ◦ Spleen/Liver size: Not palpable. ◦ Bone marrow: Normocellular, <30% lymphocytes, no B lymphoid nodules. ◦ Peripheral blood counts: ◦ Platelet count >100,000/μL. ◦ Hemoglobin >11 g/dL. ◦ Neutrophils >1500/μL. • Partial Response (PR) / Stable Disease (SD): ◦ Defined by ≥50% decrease from baseline in lymphocyte count, lymph node size, or spleen/liver size. • Progression (PD): ◦ Increase ≥50% from baseline in any of the above metrics.
7. KEY PEARLS & HIGH-YIELD POINTS¶
• Morphology: Smudge cells (basket cells) are a hallmark of CLL due to fragile cell membranes.
• Immunophenotype Comparison (Table 112-2): ◦ CLL: CD5+, CD19+, CD20+ (dim), CD23+. ◦ Mantle Cell Lymphoma: CD5+, CD19+, CD20+ (mod/bright), Cyclin D1+.
• Prognostic Cytogenetics: ◦ 17p deletion: Worst prognosis. ◦ 13q deletion: Best prognosis.
• Treatment Goal: Achieving MRD negativity after treatment correlates with improved survival outcomes.
Reference Tables¶
TABLE 112-1 Recurrent Mutations in¶
Harrison's 22e, p.851
| GENE | FREQUENCY OF MUTATIONS (% |
|---|---|
| SF3B1 | 8–14 |
| NOTCH1 | 10–13 |
| ATM | 8–11 |
| XPO1 | <5 |
| POT1 | <5 |
| EGR2 | <5 |
TABLE 112-2 Typical Immunophenotype of CLL Compared with Other B-Cell Malignancies¶
Harrison's 22e, p.852
| DISEASE | CD5 | CD10 | CD19 | CD20 | CD23 | CYCLIN D1 | SURFACE IG |
|---|---|---|---|---|---|---|---|
| CLL | + | − | + | + (dim) | + | − | + (dim) |
| + | − | + | + (mod/bright) | − | + | ||
| Marginal zone lymphoma | −/+ | − | + | + (mod/bright) | −/+ | − | + (mod/bright) |
| − | + | + | + | + | − |
TABLE 112-4 CLL International Prognostic Index Risk Score VARIABLE TP53 status IGHV mutational status β -Microglobulin…¶
Harrison's 22e, p.854
| Risk Score | ||
|---|---|---|
| VARIABLE | ADVERSE FACTOR | RISK SCORE |
| TP53 status | Deleted or mutated | 4 |
| Unmutated | ||
| β-Microglobulin 2 concentration |
>3.5 mg/L | 2 |
| Rai I–IV or Binet B–C | ||
| Age | >65 years | 1 |
| Implications of Risk Score | ||
| RISK SCORE | RISK CLASSIFICATION | 5-YEAR SURVIVAL (TRAINING SET DATA) |
| 0-1 | Low | 93.2% |
| Intermediate | ||
| 4-6 | High | 63.3% |
| Very high |
TABLE 112-5 Criteria for the Initiation of Therapy Symptoms Indicating Need for Therapy in CLL Evidence of progressive…¶
Harrison's 22e, p.854
- Symptoms Indicating Need for Therapy in CLL
- Evidence of progressive marrow failure (worsening of anemia or
thrombocytopenia not due to autoimmune destruction) - Massive (≥6 cm below costal margin), progressive, or symptomatic splenomegaly
- Massive (≥10 cm), progressive, or symptomatic lymphadenopathy
Progressive lymphocytosis with an increase of ≥50% over a 2-month period or
lymphocyte doubling time <6 months - Autoimmune anemia or thrombocytopenia not responsive to standard therapy
Symptomatic or functional extranodal involvement - Constitutional symptoms (one or more of the following: unintentional weight loss
≥10% over 6 months, significant fatigue, fevers ≥100.5°F for 2+ weeks without
infection, night sweats for >1 month without infection)
TABLE 112-3 Staging of CLL Rai Staging System Low risk (stage 0) Intermediate risk (stage I/II) High risk (stage…¶
Harrison's 22e, p.854
| Rai Staging System | |
|---|---|
| Low risk (stage 0) | Lymphocytosis only |
| Intermediate risk (stage I/II) | Lymphocytosis with lymphadenopathy, with or without splenomegaly or hepatomegaly |
| High risk (stage III/IV) | Lymphocytosis with anemia or thrombocytopenia due to bone marrow involvement |
| Binet Staging System |
TABLE 112-6 Response Criteria in CLL CR¶
Harrison's 22e, p.856
| LYMPHOCYTE COUNT |
LYMPH NODESa | SPLEEN/LIVER SIZEb | BONE MARROWc | PERIPHERAL BLOOD COUNTS | |
|---|---|---|---|---|---|
| CR | <4000/μL | None >1.5 cm | Not palpable | Normocellular, <30% lymphocytes, no B lymphoid nodules |
• Platelet count >100,000/μL • Hemoglobin >11 g/dL • Neutrophils >1500/μL |
| Decrease ≥50% from baseline |
Decrease ≥50% from baseline |
Decrease ≥50% from baseline |
Infiltrate ≤50% of baseline | ||
| Stable disease | Not meeting CR/ PR/PD criteria |
Not meeting CR/PR/ PD criteria |
Not meeting CR/PR/PD criteria |
Not meeting CR/PR/PD criteria |
Not meeting CR/PR/PD criteria |
| Increase ≥50% | Increase ≥50% | Increase ≥50% |