In a 57-year-old man with leukocytosis, neutrophilia, and normal alkaline phosphatase, what is the most likely diagnosis and recommended treatment?

Diagnosis and Management of Leukocytosis with Neutrophilia

Most Likely Diagnosis

This laboratory pattern (WBC 12,900/µL, neutrophils 9,200/µL, alkaline phosphatase 44 U/L) is most consistent with a reactive leukocytosis rather than a primary hematologic malignancy, though further evaluation is required to exclude chronic myeloid leukemia (CML) and other myeloproliferative disorders. 1

Interpretation of Laboratory Findings

White Blood Cell Count Analysis

• The WBC of 12,900/µL represents mild leukocytosis (normal range 4,500–11,000/µL), which is far below the threshold for leukostatic emergency (>100,000/µL). 2
• The absolute neutrophil count of 9,200/µL indicates neutrophilia (normal range approximately 1,500–7,500/µL), which has a likelihood ratio of 3.7 for bacterial infection when WBC ≥14,000/µL. 2
• This degree of leukocytosis is commonly seen with infection, stress, medications, smoking, obesity, or chronic inflammatory conditions rather than malignancy. 1

Alkaline Phosphatase Interpretation

• The alkaline phosphatase of 44 U/L is LOW (normal range 45–115 U/L), which is a critical distinguishing feature. 3
• Low leukocyte alkaline phosphatase (LAP) score is characteristic of CML, whereas reactive leukocytosis typically shows elevated LAP. 4
• However, LAP is not required for normal neutrophil bactericidal activity, so a low value does not indicate functional neutrophil deficiency. 5

Differential Diagnosis Algorithm

High-Priority Exclusions (Require Immediate Testing)

1. Chronic Myeloid Leukemia (CML)

• CML typically presents with higher WBC counts (often >100,000/µL) but can present with moderate leukocytosis. 2
• Key distinguishing features of CML include: basophilia, eosinophilia, splenomegaly, elevated vitamin B12, and elevated uric acid. 4
• The low alkaline phosphatase raises concern for CML, as this is a characteristic finding. 3, 4
• Order BCR-ABL testing (quantitative PCR) and peripheral blood FISH for Philadelphia chromosome to definitively exclude CML. 3

2. Other Myeloproliferative Disorders

• Chronic neutrophilic leukemia (CNL) typically shows higher LAP scores (opposite of this case) and sustained mature neutrophilic leukocytosis with hepatosplenomegaly. 4
• Obtain peripheral blood smear to look for immature forms, blast cells, dysplastic features, or toxic granulations. 2, 1

Reactive Causes (More Likely Given Moderate Elevation)

3. Infection

• Bacterial infection is the most common cause of neutrophilic leukocytosis. 1
• Assess for fever, localizing symptoms, and signs of infection. 3
• Obtain blood cultures if febrile (temperature ≥38.3°C or ≥38.0°C sustained ≥1 hour). 6

4. Stress-Related Leukocytosis

• Surgery, exercise, trauma, emotional stress can double WBC within hours due to demargination of neutrophils. 1

5. Medications

• Review all medications, particularly corticosteroids, lithium, and G-CSF. 7

6. Other Nonmalignant Causes

• Smoking, obesity, asplenia, chronic inflammatory conditions (e.g., inflammatory bowel disease, rheumatoid arthritis). 1

Immediate Diagnostic Work-Up

Essential First-Line Tests:

1. Complete blood count with manual differential to assess for left shift (bands ≥1,500/mm³ or ≥6% increases likelihood of bacterial infection). 2
2. Peripheral blood smear to evaluate cell morphology, maturity, and presence of blasts or dysplastic features. 2, 1
3. BCR-ABL quantitative PCR to exclude CML (given the low alkaline phosphatase). 3
4. Comprehensive metabolic panel to assess for organ dysfunction. 7
5. Lactate dehydrogenase (LDH) and uric acid (elevated in hematologic malignancies). 7

If Initial Testing Suggests Malignancy:

• Bone marrow aspiration and biopsy with cytogenetics if peripheral smear shows blasts, immature forms, or dysplastic features. 3, 7
• Immediate hematology/oncology referral if splenomegaly, lymphadenopathy, or constitutional symptoms (fever, weight loss, bruising, fatigue) are present. 2, 1

Treatment Approach

If CML is Confirmed

• Initiate tyrosine kinase inhibitor (TKI) therapy: imatinib 400 mg daily is first-line for chronic-phase CML. 3
• Monitor BCR-ABL transcript levels every 3 months by quantitative PCR. 3
• Bone marrow cytogenetics at 6 and 12 months to assess cytogenetic response. 3

If Reactive Leukocytosis

• Treat the underlying cause (e.g., antibiotics for bacterial infection, discontinue offending medications, manage inflammatory conditions). 1
• No specific treatment for leukocytosis itself unless WBC >100,000/µL (which would require hydroxyurea, hydration, and consideration of leukapheresis). 2

If Infection is Suspected

• Empiric antibiotics are NOT indicated for asymptomatic leukocytosis without fever or localizing symptoms. 6
• If fever develops (≥38.3°C or ≥38.0°C sustained ≥1 hour), initiate empiric broad-spectrum antibiotics within 2 hours. 6

Monitoring Plan

If Malignancy is Excluded:

• Repeat CBC in 2–4 weeks to establish whether leukocytosis is transient or persistent. 7
• Weekly CBC monitoring if neutrophil count trends downward toward neutropenia (ANC <1,500/µL). 7

Red Flags Requiring Urgent Re-Evaluation:

• Development of fever, night sweats, weight loss, or fatigue. 1
• Progressive leukocytosis (WBC doubling or exceeding 50,000/µL). 8
• New splenomegaly or lymphadenopathy on examination. 2
• Appearance of blasts or immature cells on peripheral smear. 2

Critical Pitfalls to Avoid

• Do not dismiss low alkaline phosphatase as insignificant; it is a key clue to CML and warrants BCR-ABL testing. 3, 4
• Do not delay BCR-ABL testing if CML is suspected, as early diagnosis and treatment significantly improve outcomes. 3
• Do not assume reactive leukocytosis without obtaining a peripheral smear to exclude malignancy. 2, 1
• Do not initiate empiric antibiotics for asymptomatic leukocytosis without evidence of infection. 6
• Do not overlook medication review, as drug-induced leukocytosis is common and reversible. 7