How to differentiate between a leukemoid reaction and leukemia?

Differentiating Leukemoid Reaction from Leukemia

The critical distinction between leukemoid reaction and leukemia requires bone marrow examination with cytogenetics and molecular testing—specifically, the presence of BCR-ABL fusion gene (by RT-PCR or cytogenetics showing t(9;22)) definitively diagnoses chronic myeloid leukemia, while its absence with identification of an underlying cause (infection, malignancy, hemorrhage) confirms leukemoid reaction. 1, 2

Initial Clinical Assessment

Key Clinical Features to Evaluate

Leukemoid reaction typically presents with:

• White blood cell count >50,000 cells/μL in response to severe medical conditions 3, 2
• Identifiable underlying cause: severe infection (most common), non-hematopoietic malignancy, severe hemorrhage, acute hemolysis, or intoxication 2, 4
• Transient elevation that resolves when underlying condition is treated 3, 5

Chronic myeloid leukemia presents with:

• Leukocytosis with basophilia and immature granulocytes (metamyelocytes, myelocytes, promyelocytes) 1
• Splenomegaly in >50% of patients 1
• Often asymptomatic at diagnosis (40% of cases discovered incidentally) 1

Critical Peripheral Blood Findings

• Absolute basophilia ≥200/mm³ strongly suggests CML over leukemoid reaction 6
• In preleukemic CML, WBC may be normal or only mildly elevated (3.6-14.3 K/mm³), making diagnosis challenging 6

Definitive Diagnostic Algorithm

Step 1: Bone Marrow Examination (Mandatory)

Perform bone marrow aspirate and biopsy with:

• Examination of at least 500 nucleated cells 7
• Blast count assessment (≥20% blasts confirms acute leukemia) 1, 7
• Morphologic evaluation for dysplasia 1

Step 2: Cytogenetic Analysis (Essential)

Chromosome banding analysis (CBA) of marrow cell metaphases is required to:

• Detect t(9;22)(q34;q11.2) which confirms CML 1, 6
• Identify other recurrent cytogenetic abnormalities in AML: t(15;17), t(8;21), inv(16) 1
• If marrow cells cannot be obtained, substitute with interphase FISH using dual-color dual-fusion probes for BCR-ABL 1

Step 3: Molecular Testing (Confirmatory)

Qualitative RT-PCR on RNA from fresh bone marrow or blood:

• Detects BCR-ABL transcripts (e14a2, e13a2, or rarely e19a2, e1a2) confirming CML 1
• Absence of BCR-ABL excludes CML 6

Step 4: Immunophenotyping

Multiparameter flow cytometry to:

• Determine lineage involvement in acute leukemias 7
• Distinguish AML from acute lymphocytic leukemia 1
• Evaluate for aberrant antigen expression 1

Bone Marrow Morphologic Distinctions

Leukemoid Reaction Features:

• Straight microvessels on CD34 staining 6
• Only 13% small, hypolobated megakaryocytes 6
• Mean microvascular density: 5.0 ± 1.0 vessels/200× field 6
• No significant dysplasia 1

CML Features:

• Tortuous microvessels with abnormal branching on CD34 6
• 40-86% small, hypolobated "dwarf megakaryocytes" 1, 6
• Mean microvascular density: 10.0-12.5 vessels/200× field 6
• Blasts <5% in chronic phase 1
• Moderate to marked reticulin fibrosis in ~30% 1

AML Features:

• ≥20% blasts in marrow or peripheral blood 1
• Positive myeloperoxidase or nonspecific esterase staining 7
• May show multilineage dysplasia 1

Common Pitfalls to Avoid

• Do not rely solely on peripheral blood findings—bone marrow examination with cytogenetics is mandatory to exclude leukemia 1, 2
• Do not assume normal/mildly elevated WBC excludes CML—preleukemic CML can present with WBC as low as 3.6 K/mm³ 6
• Do not delay cytogenetic testing—this is the definitive test to distinguish leukemoid reaction from CML 1
• Do not confuse transient leukocytosis during treatment with disease progression—leukemoid reactions can occur during chemotherapy (e.g., azacitidine) and resolve spontaneously 5

Prognostic Considerations

Leukemoid reaction carries poor prognosis with high mortality, particularly when caused by:

• Infection (most common cause, 59% of cases) 4
• Paraneoplastic syndrome from non-hematopoietic malignancy 4
• Risk factors for death: lower hemoglobin, older age, increased segmented neutrophil count 4

The underlying cause determines outcome, not the leukocytosis itself—aggressive treatment of the precipitating condition is essential 3, 4.