What is the initial approach to diagnosing and managing chronic neutrophilic leukocytosis?

Diagnostic Approach to Chronic Neutrophilic Leukocytosis

The initial workup for chronic neutrophilic leukocytosis must include bone marrow aspiration and biopsy for morphologic and cytogenetic evaluation, along with quantitative RT-PCR to establish the presence of BCR-ABL1 transcripts to rule out chronic myeloid leukemia (CML). 1

Initial Evaluation

History and Physical Examination

• Assess for symptoms of underlying conditions:
  • Fever, bone pain (may indicate CML progression)
  • Hepatosplenomegaly (palpate for spleen and liver enlargement)
  • Bleeding or bruising (may indicate platelet dysfunction)
  • Weight loss, night sweats, fatigue (B symptoms)

Laboratory Testing

1. Complete blood count with differential

   • Quantify neutrophil count and assess for other cytopenias
   • Examine peripheral blood smear for immature cells and dysplastic features

2. Chemistry profile

   • Including LDH, bilirubin, and liver function tests

3. Bone marrow studies (critical for diagnosis)

   • Aspirate and biopsy for morphologic evaluation
   • Cytogenetic analysis to detect Philadelphia chromosome or other abnormalities
   • Flow cytometry to assess blast percentage and immunophenotype

4. Molecular testing

   • Quantitative RT-PCR for BCR-ABL1 transcripts (essential to rule out CML)
   • If bone marrow evaluation is not feasible, FISH on peripheral blood with dual probes for BCR and ABL1 genes is acceptable 1

Differential Diagnosis

1. Chronic Myeloid Leukemia (CML)

• Characterized by presence of Philadelphia chromosome (t(9;22)) and BCR-ABL1 fusion gene
• Often presents with neutrophilia, basophilia, and splenomegaly
• Requires specific TKI therapy (imatinib, nilotinib, dasatinib) 1

2. Chronic Neutrophilic Leukemia (CNL)

• Rare BCR-ABL1-negative myeloproliferative neoplasm
• Diagnostic criteria: leukocytosis ≥25 × 10^9/L, neutrophils ≥80% with <10% circulating precursors, absence of dysplasia, and presence of activating CSF3R mutation 2
• Often associated with hepatosplenomegaly

3. Atypical Chronic Myeloid Leukemia (aCML)

• Myelodysplastic/myeloproliferative overlap disorder
• Features dysplastic neutrophilia and circulating myeloid precursors
• Diagnostic criteria include leukocytosis ≥13 × 10^9/L, dysgranulopoiesis, circulating myeloid precursors ≥10%, and at least one cytopenia 2

4. Leukemoid Reaction

• Defined as persistent neutrophilic leukocytosis above 50,000 cells/μL due to non-leukemic causes 3
• Major causes: severe infections, intoxications, malignancies, severe hemorrhage, acute hemolysis

5. Monoclonal Gammopathy Association

• Some cases of neutrophilia may be associated with monoclonal gammopathy of undetermined significance (MGUS) 4
• Serum protein electrophoresis should be considered in the workup

Diagnostic Algorithm

1. Rule out reactive causes

   • Infection workup (blood cultures, imaging as indicated)
   • Medication review (corticosteroids, growth factors)
   • Evaluate for underlying malignancy
   • Check for evidence of hemorrhage or hemolysis

2. Perform definitive testing

   • Bone marrow aspiration and biopsy
   • Cytogenetic analysis (karyotype)
   • FISH for BCR-ABL1 and other relevant translocations
   • Molecular testing for BCR-ABL1 transcripts
   • If BCR-ABL1 negative, test for CSF3R, ASXL1, SETBP1 mutations

3. Interpret findings

   • BCR-ABL1 positive → CML diagnosis
   • BCR-ABL1 negative with CSF3R mutation → Consider CNL
   • BCR-ABL1 negative with dysplasia and myeloid precursors → Consider aCML
   • No genetic abnormalities and no evidence of clonal disorder → Consider leukemoid reaction

Management Approach

Management depends on the specific diagnosis:

1. For CML:

   • Tyrosine kinase inhibitors (imatinib, nilotinib, dasatinib) based on patient factors 1
   • Regular monitoring with quantitative PCR for BCR-ABL1 transcripts

2. For CNL/aCML:

   • Risk stratification using established models
   • Symptom-directed therapy (hydroxyurea, interferon, JAK inhibitors)
   • Consider allogeneic stem cell transplantation in eligible patients 2

3. For leukemoid reaction:

   • Treat underlying cause
   • Monitor blood counts until resolution

Pitfalls to Avoid

• Failing to perform bone marrow examination and cytogenetic studies
• Misdiagnosing CML as a leukemoid reaction
• Not testing for BCR-ABL1 transcripts in all cases of unexplained neutrophilia
• Overlooking rare variants of BCR-ABL1 transcripts (e.g., e1a2, e19a2) 1
• Neglecting to consider monoclonal gammopathy in the workup

Regular follow-up with repeat blood counts is essential, with frequency determined by the specific diagnosis and clinical stability of the patient.