How is lymphocytosis managed?

Management of Lymphocytosis

For lymphocytosis, the primary management decision hinges on whether this represents chronic lymphocytic leukemia (CLL) requiring treatment versus early-stage disease or monoclonal B-cell lymphocytosis (MBL) that warrants observation only.

Initial Diagnostic Approach

Confirm the diagnosis through:

• Sustained peripheral blood lymphocyte count >5 × 10⁹/L (5,000/μL) not explained by infections, steroids, or other secondary causes 1, 2
• Peripheral blood smear showing predominance of small, mature-appearing lymphocytes 3, 2
• Flow cytometry demonstrating the characteristic CLL immunophenotype: CD5+, CD19+, CD20+ (dim), CD23+, surface immunoglobulin (low), CD79b (low) 3, 2
• Physical examination with careful palpation of all lymph node areas, liver, and spleen 1, 2

Distinguish between MBL and CLL:

• MBL: Clonal B-cell count <5 × 10⁹/L without lymphadenopathy, organomegaly, or cytopenias 4
• CLL: Clonal B-cell count ≥5 × 10⁹/L with or without other disease manifestations 3

Risk Stratification for CLL

Perform staging using Binet or Rai classification 1:

Binet staging:

• Stage A: Hemoglobin ≥100 g/L, platelets ≥100 × 10⁹/L, <3 involved lymphoid sites
• Stage B: Hemoglobin ≥100 g/L, platelets ≥100 × 10⁹/L, ≥3 involved lymphoid sites
• Stage C: Hemoglobin <100 g/L or platelets <100 × 10⁹/L

Before treatment, obtain 1, 2:

• FISH for del(17p) and del(11q)
• TP53 mutation status
• IGHV mutational status
• Complete blood count, LDH, direct antiglobulin test, serum immunoglobulins
• Hepatitis B, C, CMV, and HIV serology

Management Algorithm

Early-Stage Disease (Binet A, Rai 0-I)

Watch-and-wait is the standard approach 1, 2:

• Blood cell counts and clinical examinations every 3 months during the first year 1
• After the first year, follow-up every 3-12 months depending on disease burden and dynamics 1
• Do not treat based on lymphocyte count alone 1, 2

Critical pitfall: Early treatment with chemotherapy does not improve survival in asymptomatic early-stage CLL 1

Indications to Initiate Treatment

Treatment should begin when at least one of the following criteria is met 1:

1. Progressive marrow failure: Hemoglobin <100 g/L or platelets <100 × 10⁹/L (note: stable thrombocytopenia <100 × 10⁹/L does not automatically require treatment) 1

2. Massive or progressive splenomegaly: ≥6 cm below left costal margin 1

3. Massive or progressive lymphadenopathy: ≥10 cm in longest diameter 1

4. Progressive lymphocytosis: 50% increase over 2 months OR lymphocyte doubling time <6 months (exclude infections and steroid administration as causes; patients with initial lymphocyte count <30 × 10⁹/L may require longer observation) 1, 3

5. Autoimmune cytopenias: Anemia or thrombocytopenia poorly responsive to corticosteroids 1

6. Symptomatic extranodal involvement: Skin, kidney, lung, or spine 1

7. Disease-related constitutional symptoms: After excluding other causes (infections, secondary malignancies, sleep disorders) 1

First-Line Treatment Selection

Treatment decisions should incorporate 1:

• IGHV and TP53 mutation status
• Patient age, comorbidities, performance status
• Drug availability and adherence potential

For patients WITHOUT del(17p) or TP53 mutations:

Preferred options 1:

• Continuous ibrutinib (Bruton tyrosine kinase inhibitor) until progression
• Time-limited venetoclax plus obinutuzumab
• Chemoimmunotherapy with fludarabine-based regimens (FCR, bendamustine plus rituximab)

For patients WITH del(17p) or TP53 mutations 1:

• Ibrutinib is the preferred first-line option 1
• Alternative: High-dose methylprednisolone plus rituximab, obinutuzumab/chlorambucil, or alemtuzumab with or without rituximab 1

Special Considerations for Novel Agents

Ibrutinib and idelalisib cause treatment-related lymphocytosis 1:

• Results from redistribution of leukemic cells from lymph nodes to peripheral blood 1
• Typically resolves within 8 months but may persist beyond 12 months 1
• This lymphocytosis does NOT indicate treatment failure or disease progression 1
• Continue treatment despite persistent lymphocytosis if lymph nodes and spleen are responding 1
• A new response category "PR with lymphocytosis" applies to patients with nodal response but persistent lymphocytosis 1

Ibrutinib-specific monitoring 1:

• Atrial fibrillation (grade ≥3) occurs in 6% of patients 1
• Major hemorrhage in 4% of patients; avoid concurrent warfarin 1
• Hypertension (grade ≥3) in 20% of patients; manage with antihypertensives 1
• Upon disease progression, transition to alternate therapy immediately as progression may accelerate after stopping ibrutinib 1

Idelalisib-specific monitoring 1:

• Fatal/serious hepatotoxicity, particularly in younger first-line patients 1
• Monitor transaminases closely; avoid concurrent hepatotoxic drugs 1
• Pneumocystis jirovecii pneumonia (PJP) and CMV prophylaxis required, especially in first 6 months 1

Monoclonal B-Cell Lymphocytosis (MBL)

For low-count MBL (<0.5 × 10⁹/L clonal B-cells) 4:

• Reassure patient this is not leukemia or lymphoma 1
• Routine monitoring not required; progression to CLL is rare 4

For high-count MBL (0.5-5.0 × 10⁹/L clonal B-cells) 4:

• Annual monitoring with complete blood count 4
• Progression to CLL requiring treatment occurs at 1-2% per year 4
• Increased risk of infections and second cancers similar to early-stage CLL 4