What is the appropriate evaluation and management for a patient with chronic mild leukocytosis on peripheral blood smear without blasts or schistocytes?

Evaluation and Management of Chronic Mild Leukocytosis Without Blasts or Schistocytes

For chronic mild leukocytosis without blasts or schistocytes, first exclude reactive causes through targeted history (infections, inflammatory conditions, solid tumors) and basic laboratory testing, then proceed to bone marrow evaluation only if monocytosis ≥1.0×10⁹/L persists beyond 3 months or if dysplastic features are present on peripheral smear. 1, 2

Initial Clinical Assessment

The evaluation begins with specific historical elements that distinguish reactive from clonal causes:

• Infectious exposures: tuberculosis, endocarditis, parasitic infections, HIV, hepatitis C, CMV, and ehrlichiosis (which presents with leukopenia, thrombocytopenia, and elevated transaminases) 2
• Inflammatory conditions: systemic lupus erythematosus, adult-onset Still's disease, inflammatory bowel disease, and rheumatoid arthritis 2
• Solid tumors: any known malignancy can cause reactive leukocytosis 1
• Constitutional symptoms: fever, weight loss, night sweats suggest clonal disorder 1

Physical examination must specifically assess:

• Spleen size: measure distance from costal margin (splenomegaly suggests myeloproliferative process) 1, 2
• Cutaneous lesions: may indicate CMML 1
• Lymphadenopathy: suggests lymphoproliferative disorder 3

Laboratory Evaluation Strategy

Peripheral Blood Smear Analysis

Critical finding: The absence of blasts is reassuring but does not exclude clonal disorders. 4

Examine the smear for:

• Absolute monocyte count: calculate from CBC differential; monocytosis is defined as >1.0×10⁹/L 1, 2
• Dysgranulopoiesis: nuclear hypolobation (pseudo-Pelger-Huët), cytoplasmic hypogranulation 1
• Promonocytes and neutrophil precursors: suggest CMML 1
• Morphology: monomorphic lymphocytes suggest lymphoproliferative neoplasm; polymorphic populations indicate reactive process 5

Basic Laboratory Testing

Before proceeding to invasive testing, obtain: 6

• Complete metabolic panel including LDH, calcium, albumin
• Hepatitis B and C serology (especially if transfusion history)
• HIV testing
• Inflammatory markers if autoimmune condition suspected

Decision Point: When to Proceed to Bone Marrow Evaluation

Bone marrow aspiration and biopsy are indicated when: 1, 6, 2

1. Persistent monocytosis ≥1.0×10⁹/L for >3 months despite excluding reactive causes
2. Any dysplastic features on peripheral smear (even without monocytosis)
3. Concurrent cytopenias (hemoglobin <12 g/dL, platelets <100×10⁹/L)
4. Unexplained splenomegaly on examination

Bone Marrow Evaluation Components

When bone marrow is indicated, the workup must include: 1

Morphologic assessment:

• Cellularity and dysplasia in erythroid, granulocytic, and megakaryocytic lineages
• Blast percentage (must include myeloblasts, monoblasts, and promonocytes)
• Granulocytic hyperplasia
• Bone marrow fibrosis (Gomori's silver stain)

Cytogenetic analysis:

• Conventional karyotyping to detect clonal abnormalities and exclude t(9;22) and t(5;12) 1
• Most frequent abnormalities in CMML: chromosome 7 abnormalities, trisomy 8, complex karyotype 1

Molecular testing:

• BCR-ABL1 fusion gene to definitively exclude chronic myeloid leukemia 1
• PDGFRA and PDGFRB rearrangement if eosinophilia present 1
• Consider TET2, SRSF2, ASXL1, and RAS mutations if CMML suspected (93% of CMML patients carry at least one somatic mutation) 1, 2

Flow cytometry immunophenotyping:

• Detect monocytic aberrancies (abnormal CD11b/HLA-DR, CD36/CD14, overexpression of CD56) 1
• Distinguish monomorphic from polymorphic lymphocyte populations 5

Management Based on Findings

If Reactive Cause Identified

Treat the underlying condition and monitor with serial CBCs every 3 months until resolution 6

If CMML Diagnosed

The WHO 2008 diagnostic criteria for CMML require: 1

1. Persistent peripheral blood monocytosis >1×10⁹/L
2. No Philadelphia chromosome or BCR-ABL1 fusion gene
3. No PDGFRA or PDGFRB rearrangement
4. <20% blasts in peripheral blood and bone marrow
5. Dysplasia in ≥1 cell line, clonal cytogenetic abnormality, or persistent monocytosis >3 months with no other cause

Distinguish MD-CMML (WBC <13×10⁹/L) from MP-CMML (WBC ≥13×10⁹/L): 1, 2

• MD-CMML with <10% bone marrow blasts: supportive care with erythropoietic stimulating agents for anemia 2
• MD-CMML with ≥10% bone marrow blasts: add hypomethylating agents (azacitidine or decitabine) 2
• MP-CMML: hydroxyurea as first-line cytoreductive therapy 2
• Curative option: allogeneic stem cell transplantation for selected patients <65 years 2

If No Definitive Diagnosis After Initial Workup

For patients with mild dysplasia only, normal karyotype, and <15% ring sideroblasts: 1

• Observe for 6 months before making MDS diagnosis
• Repeat bone marrow examination at 6 months 1, 6
• Serial CBCs every 3 months 6

Critical Pitfalls to Avoid

1. Failing to calculate absolute monocyte count: Always calculate from total WBC × monocyte percentage; relative monocytosis is meaningless 2

2. Premature bone marrow biopsy: If monocyte count <1.0×10⁹/L and no dysplasia, exclude reactive causes first 1, 2

3. Missing infectious causes: Specifically test for ehrlichiosis (look for morulae in monocytes), CMV, and tuberculosis before concluding clonal disorder 2

4. Inadequate blast counting: Minimum 500-cell differential required for reliable blast percentage determination 4

5. Ignoring sustained mild abnormalities: Monocytosis persisting >3-4 months warrants hematology referral even if mild 2

6. Incomplete molecular testing: Failure to exclude BCR-ABL1 can miss chronic myeloid leukemia with atypical presentation 1