What are the typical laboratory and physical findings in a patient with Chronic Myeloid Leukemia (CML)?

Laboratory and Physical Findings in Chronic Myeloid Leukemia

The hallmark laboratory finding in CML is marked leukocytosis with left-shifted granulocytosis, basophilia, and the presence of the Philadelphia chromosome (BCR-ABL1 fusion gene), while splenomegaly is the most consistent physical finding, detected in 40-50% of cases at diagnosis. 1

Clinical Presentation

Symptom Profile

• Approximately 50% of CML patients diagnosed in Europe are completely asymptomatic, with disease discovered incidentally on routine blood work 1
• When symptomatic, patients present with fatigue, weight loss, malaise, and left upper quadrant fullness or pain resulting from anemia and splenomegaly 1
• Rare manifestations include bleeding (from thrombocytopenia/platelet dysfunction), thrombosis (from marked leukocytosis/thrombocytosis), gouty arthritis (elevated uric acid), retinal hemorrhages, and upper GI ulceration (from basophilia-related elevated histamine) 1
• Leukostatic symptoms (priapism, dyspnea, drowsiness, confusion) are uncommon in chronic phase despite WBC counts often exceeding 100 × 10⁹/L 1

Physical Examination Findings

Organomegaly

• Splenomegaly is present in 40-50% of cases and represents the most consistent physical sign 1
• Hepatomegaly occurs less commonly than splenomegaly 1
• Extramedullary infiltration (excluding liver and spleen) is rare in chronic phase 1

Advanced Disease Signs

• Headaches, bone pain, arthralgias, splenic infarction pain, and fever become more frequent with disease transformation to accelerated or blast phase 1

Laboratory Findings

Peripheral Blood Abnormalities

Complete Blood Count:

• Leukocytosis with WBC counts frequently exceeding 100 × 10⁹/L 1
• Left-shifted granulocytosis with immature forms: metamyelocytes, myelocytes, promyelocytes predominate 1
• Basophilia is characteristic and pathognomonic 1
• Eosinophilia may be prominent 1
• Blasts must be <10% in blood for chronic phase diagnosis (per European LeukemiaNet criteria) 1
• Thrombocytosis is frequent at presentation 1
• Severe anemia is rare at diagnosis 1

Chronic Phase Criteria (must meet all):

• WBC variable but typically elevated
• <15% blasts in blood and bone marrow 1
• Basophils <20% 1
• Platelet count typically elevated but must be 100-1000 × 10⁹/L 2
• No extramedullary disease 1

Bone Marrow Findings

Morphologic Features:

• Increased cellularity due to myeloid proliferation in all maturation stages with predominance of mature forms 1
• Blasts <15% (per ELN recommendations for chronic phase) 1
• Small, hypolobated "dwarf" megakaryocytes with hypolobulated nuclei are characteristic 1
• Basophilia is common 1
• Moderate to marked reticulin fibrosis in approximately 30% of cases 1
• Pseudo-Gaucher cells and sea-blue histiocytes are usually observed 1
• No substantial dysplastic features 1

Molecular and Cytogenetic Findings

Diagnostic Confirmation (required):

• Philadelphia chromosome t(9;22)(q34;q11.2) detected by conventional cytogenetics 1
• BCR-ABL1 fusion gene confirmed by RT-PCR 1
• Qualitative RT-PCR identifies transcript type: e14a2 or e13a2 (also known as b3a2 and b2a2), indicating P210 protein 1
• Rarely e19a2 (P230) or e1a2 (P190) transcripts 1

Baseline Testing Requirements:

• Chromosome banding analysis (CBA) of bone marrow metaphases is mandatory to detect additional chromosomal abnormalities 1
• Interphase FISH can substitute for CBA only if metaphases cannot be obtained 1
• Quantitative RT-PCR (qRT-PCR) is not required at baseline but will be necessary for monitoring 1

Biochemical Abnormalities

• Elevated uric acid levels (may cause gouty arthritis) 1
• Elevated histamine levels from basophilia (may cause GI ulceration) 1

Atypical Presentations

Aleukemic CML

• Extremely rare presentation without significant leukocytosis or thrombocytosis 3
• Only 26.7% exhibit neutrophilia, 56.7% have basophilia, 13.3% show eosinophilia at diagnosis 3
• Frequently misdiagnosed (45.2% initially missed) until cytogenetic/FISH results available 3
• Over half have history of concurrent hematopoietic or non-hematopoietic malignancies 3

Preleukemic Phase

• Normal to mildly elevated WBC (3.6-14.3 K/mm³) with 50-73% granulocytes and 0% blasts 4
• Absolute basophilia ≥200/mm³ present in only 57% of cases 4
• Increased microvascular density (10.0 vessels/200× field) with tortuous, abnormally branching vessels on CD34 staining 4
• 40% small, hypolobated megakaryocytes (intermediate between leukemoid reaction at 13% and typical CML-CP at 86%) 4

Diagnostic Algorithm

Step 1: Peripheral Blood Evaluation

• Obtain CBC with differential looking specifically for leukocytosis, left-shifted granulocytosis, basophilia, and thrombocytosis 1

Step 2: Physical Examination

• Assess for splenomegaly by palpation (present in 40-50%) and hepatomegaly 1

Step 3: Confirmatory Testing

• Bone marrow aspiration and biopsy with cytology 1
• Chromosome banding analysis (CBA) of bone marrow metaphases to detect t(9;22) 1
• Qualitative RT-PCR on fresh blood or marrow to confirm BCR-ABL1 and identify transcript type 1

Step 4: Baseline Assessment

• Blood counts and differential 1
• Bone marrow cytology and karyotype 1
• Qualitative RT-PCR (not quantitative at baseline) 1

Common Diagnostic Pitfalls

• Missing aleukemic CML: Maintain high suspicion in patients with absolute basophilia even without marked leukocytosis, especially those with concurrent malignancies 3
• Confusing with leukemoid reaction: CML shows characteristic small hypolobated megakaryocytes, increased microvascular density with tortuous vessels, and absolute basophilia, which are absent in reactive conditions 4
• Relying solely on FISH: Conventional cytogenetics (CBA) is mandatory to detect additional chromosomal abnormalities that affect prognosis 1
• Overlooking preleukemic phase: Consider CML even with normal WBC if basophilia and characteristic bone marrow findings are present 4