What is the appropriate diagnosis and treatment for lymphocytosis?

Lymphocytosis: Diagnosis and Treatment

Immediate Diagnostic Priority

The first step is to determine if lymphocytosis represents chronic lymphocytic leukemia (CLL) versus a reactive process—this requires flow cytometry to identify monoclonal B-cell populations expressing CD5, CD19, CD20, and CD23 with light chain restriction. 1, 2

Diagnostic Workup

Essential Initial Testing

• Complete blood count with differential to quantify absolute lymphocyte count (ALC) 1, 3
• Peripheral blood flow cytometry to distinguish monoclonal (malignant) from polyclonal (reactive) lymphocytosis 1
• Blood film review to assess lymphocyte morphology and identify atypical features 3

Key Diagnostic Thresholds

• ALC >10,000/μL strongly suggests CLL (all patients in one study with counts this high had monoclonal B-cell disease) 4
• ALC <10,000/μL may represent either early CLL or reactive T-lymphocytosis 4
• Sustained lymphocytosis without demonstrating monoclonality is insufficient for CLL diagnosis 4

If CLL is Confirmed: Mandatory Pre-Treatment Testing

• FISH panel for del(17p), del(11q), trisomy 12, and del(13q14.1) 1, 2
• TP53 mutation analysis (separate from FISH, as mutations can occur without deletion) 1, 2
• IGHV mutation status (unmutated predicts shorter time to treatment and worse outcomes) 1, 2
• Hepatitis B surface antigen and core antibody, hepatitis C, CMV, and HIV serology 1, 5
• Direct antiglobulin test and serum immunoglobulins 1

Clinical Staging

Use either Rai or Binet staging systems based on physical examination findings and basic laboratory values—imaging is not required for staging 1

Treatment Indications for CLL

Treatment should NOT be initiated based on lymphocyte count alone or early-stage disease without symptoms. 1, 2 The absolute lymphocyte count should never be the sole indicator for treatment, as leukostasis symptoms rarely occur in CLL 1, 2.

When to Treat: Active Disease Criteria

Initiate treatment only when at least ONE of the following is documented: 1, 2

1. Progressive marrow failure: Development or worsening of anemia (Hb <100 g/L) and/or thrombocytopenia (platelets <100 × 10⁹/L) 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 (calculated by linear regression of counts obtained every 2 weeks over 2-3 months) 1

   • Critical caveat: For initial ALC <30 × 10⁹/L, do not use doubling time as the sole criterion 1
   • Must exclude infections, steroid administration, and other secondary causes before attributing to CLL progression 1, 2

5. Autoimmune cytopenias poorly responsive to corticosteroids 1

6. Constitutional symptoms (any one of): 1

   • Unintentional weight loss ≥10% in 6 months
   • Significant fatigue (ECOG PS ≥2, inability to work)
   • Fever >38°C for ≥2 weeks without infection
   • Night sweats >1 month without infection

Who Should NOT Be Treated

• Binet stage A or B without active disease criteria 1
• Rai stage 0, I, or II without active disease criteria 1
• Hypogammaglobulinemia or paraproteinemia alone 1

Treatment Selection for CLL

First-Line Treatment Algorithm

Treatment decisions must incorporate IGHV mutation status, TP53 aberrations, patient fitness, and comorbidities. 1, 2

For Patients WITHOUT del(17p) or TP53 Mutation:

Preferred option: Venetoclax plus obinutuzumab for 12 months (time-limited, chemotherapy-free) 1, 2

Alternative options based on patient factors:

• Continuous ibrutinib (BTK inhibitor) until progression 1
• Fludarabine, cyclophosphamide, rituximab (FCR) for young, fit patients with mutated IGHV 1
• Bendamustine plus rituximab for older or less fit patients 1

For Patients WITH del(17p) or TP53 Mutation:

Mandatory: Continuous BTK inhibitor therapy OR venetoclax-based regimens (these patients do not respond to standard chemotherapy) 1, 2

Premedication Requirements

• Before each rituximab infusion: Administer premedication to reduce infusion reactions 5
• Monitor closely during first infusion: 80% of fatal infusion reactions occur with the first dose 5

Infection Prophylaxis Considerations

• Patients <65 years on fludarabine-based first-line therapy: No routine anti-infective prophylaxis required 1
• Patients on alemtuzumab or allogeneic transplant: Monitor for CMV infection 1

Critical Pitfalls to Avoid

1. Do not diagnose CLL without flow cytometry confirmation of monoclonal B-cells 1, 4
2. Do not treat based on lymphocyte count alone 1, 2
3. Do not start treatment without obtaining IGHV and TP53 status first—these fundamentally alter treatment selection 1, 2
4. Do not attribute progressive lymphocytosis to CLL without excluding infections, steroids, and other causes 1, 2
5. Do not use standard chemotherapy in patients with del(17p) or TP53 mutations—they are refractory and require targeted agents 1, 2
6. Do not forget HBV screening before rituximab—reactivation can be fatal 1, 5

Reactive Lymphocytosis

If flow cytometry shows polyclonal T-lymphocytosis (no monoclonal population), this is typically reactive rather than neoplastic 4. Common causes include:

• Acute infections (viral, bacterial, fungal) 6
• Physical or mental stress 6
• Trauma (associated with higher injury severity and mortality) 7
• Autoimmune conditions 6

Management: Treat the underlying condition; no specific therapy for lymphocytosis itself 3, 6