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Difficulty: MediumHematology and Oncology

A 5252-year-old man comes to the physician due to progressive fatigue, unintentional weight loss, and a feeling of early satiety over the past 33 months. He has no other medical conditions and takes no medications. His temperature is 37.2∘C37.2^\circ\text{C} (99.0∘F99.0^\circ\text{F}), blood pressure is 128/78 mmHg128/78\text{ mmHg}, and pulse is 82/min82/\text{min}. Physical examination reveals a palpable spleen edge 8 cm8\text{ cm} below the left costal margin. There is no palpable cervical, axillary, or inguinal lymphadenopathy. Laboratory studies show the following:

TestResult
Hemoglobin10.4 g/dL10.4\text{ g/dL}
Leukocyte count85,000/mm385,000/\text{mm}^3
Platelet count420,000/mm3420,000/\text{mm}^3

A peripheral blood smear demonstrates a full spectrum of granulocytic cells, including 5%5\% myeloblasts, 10%10\% promyelocytes, 15%15\% myelocytes, 10%10\% metamyelocytes, 15%15\% bands, 35%35\% neutrophils, 6%6\% eosinophils, and 4%4\% basophils. The leukocyte alkaline phosphatase score is markedly decreased. Which of the following is the most appropriate next step in the evaluation or management of this patient?

  1. Fluorescence in situ hybridization testing for the BCR-ABL1 fusion geneAnswer
  2. B
    Initiation of induction chemotherapy with cytarabine and an anthracycline
  3. C
    Empiric administration of broad-spectrum intravenous antibiotics
  4. D
    Measurement of serum JAK2 V617F mutation
  5. E
    Flow cytometry of peripheral blood for CD5 and CD23 surface markers

Answer

The most appropriate next step is fluorescence in situ hybridization (FISH) testing for the BCR-ABL1 fusion gene to confirm the diagnosis of Chronic Myeloid Leukemia.
This patient's clinical presentation (fatigue, early satiety, massive splenomegaly) combined with his laboratory findings (profound leukocytosis with a full spectrum of granulocytic differentiation, absolute basophilia, and a low leukocyte alkaline phosphatase score) is highly characteristic of Chronic Myeloid Leukemia (CML). The low leukocyte alkaline phosphatase (LAP) score is historically significant as it helps distinguish CML from a leukemoid reaction, which would typically show an elevated LAP score in response to severe infection or stress. To definitively diagnose CML, the presence of the Philadelphia chromosome (a reciprocal translocation between chromosomes 9 and 22) or its product, the BCR-ABL1 fusion gene, must be confirmed. This is most appropriately accomplished through fluorescence in situ hybridization (FISH), karyotyping, or quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR) of the peripheral blood or bone marrow.

Step-by-Step Solution

1
Analyze the patient's systemic symptoms and physical exam findings.
The patient presents with B-symptoms (fatigue, weight loss) and massive splenomegaly causing early satiety, which are classic signs of a myeloproliferative disorder.
Splenomegaly in this context represents extramedullary hematopoiesis or massive cellular infiltration, prompting a careful review of the complete blood count.
2
Evaluate the laboratory results and peripheral blood smear.
Labs reveal marked leukocytosis (85,000/mm385,000/\text{mm}^3) with a full spectrum of developing granulocytes, absolute basophilia (4%4\%), and a decreased leukocyte alkaline phosphatase (LAP) score.
The low LAP score and presence of basophilia are critical in differentiating Chronic Myeloid Leukemia (CML) from a leukemoid reaction (which typically features an elevated LAP score and lacks basophilia).
3
Determine the required test to establish a definitive diagnosis based on the suspected etiology.
The suspected diagnosis is CML, which is driven by the Philadelphia chromosome (t(9;22)t(9;22)). This requires cytogenetic confirmation.
Identifying the BCR-ABL1 fusion gene via FISH or quantitative polymerase chain reaction (qPCR) confirms the diagnosis of CML and provides a target for tyrosine kinase inhibitor therapy.

Key Concept

Chronic Myeloid Leukemia (CML) presents with dramatic leukocytosis, splenomegaly, and a low leukocyte alkaline phosphatase score, and is definitively diagnosed by detecting the BCR-ABL1 fusion gene.
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Topics

Hematology and Oncology

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