CML Phases: Detailed Criteria, Genetic Markers, and Lab Findings

Chronic myeloid leukemia (CML) progresses through distinct phases, each with specific clinical and laboratory characteristics. Recognizing these phases is crucial for prognosis and treatment decisions.

Understanding the criteria that define each phase, along with associated genetic markers and lab findings, aids in accurate diagnosis and disease monitoring.

Chronic Phase Criteria

The chronic phase of CML is the earliest and most stable stage, often with an indolent course and relatively preserved hematopoietic function. Patients typically exhibit leukocytosis with a predominance of mature granulocytes—neutrophils, eosinophils, and basophils—without significant disruption of normal blood cell production. The bone marrow remains hypercellular but still produces functional red blood cells and platelets, preventing severe cytopenias. Clinically, individuals may be asymptomatic or present with fatigue, weight loss, or splenomegaly due to extramedullary hematopoiesis.

The World Health Organization (WHO) defines this phase by fewer than 10% blasts in the bone marrow and peripheral blood. Basophilia is often present but remains below 20%, as levels beyond this suggest disease progression. The Philadelphia chromosome (t(9;22)(q34;q11)) and its associated BCR-ABL1 fusion gene are universally detected in CML, confirmed through quantitative polymerase chain reaction (qPCR) or fluorescence in situ hybridization (FISH).

Hematologic stability is a hallmark, with platelet counts often within or slightly above normal, though thrombocytosis can occur. Anemia, if present, is usually mild. The leukocyte alkaline phosphatase (LAP) score is typically low, reflecting the abnormal function of granulocytes. Despite an elevated white blood cell count, infections are uncommon due to the preserved function of mature myeloid cells.

Accelerated Phase Criteria

The transition from chronic to accelerated phase signals increasing disease instability, marked by worsening cytogenetic abnormalities and rising blast proliferation. Patients may experience higher white blood cell counts that become refractory to tyrosine kinase inhibitor (TKI) therapy. Bone marrow fibrosis increases, leading to more pronounced anemia and thrombocytopenia. Splenomegaly often worsens, sometimes causing discomfort or early satiety.

The WHO classifies the accelerated phase by 10–19% blasts in the bone marrow or peripheral blood. Persistent thrombocytopenia (<100,000/µL) unrelated to therapy or thrombocytosis (>1,000,000/µL) unresponsive to treatment indicates progression. Basophilia exceeding 20% is another defining feature, as excessive basophil proliferation is linked to aggressive disease. Additional chromosomal abnormalities, including trisomy 8, isochromosome 17q, or an extra Philadelphia chromosome, indicate genomic instability and a poorer prognosis.

Clinically, patients often exhibit increased fatigue, night sweats, and weight loss due to heightened leukemic cell activity. Resistance to first-line TKIs, such as imatinib, necessitates stronger second- or third-generation inhibitors like dasatinib, nilotinib, or ponatinib. Molecular monitoring of BCR-ABL1 transcript levels with qPCR is critical, as rising levels often precede overt progression. A failure to achieve major molecular response despite optimal therapy underscores the need for prompt treatment adjustments.

Blast Phase Criteria

The blast phase of CML is the most aggressive stage, marked by a rapid expansion of immature myeloid or lymphoid precursor cells that disrupt normal hematopoiesis. This transformation resembles acute leukemia, with blasts dominating the bone marrow and peripheral blood, leading to profound cytopenias. Patients often experience severe anemia, recurrent infections, and spontaneous bleeding due to thrombocytopenia. Organ infiltration by blasts, particularly in the liver and spleen, can worsen hepatosplenomegaly, causing significant discomfort.

The WHO defines blast phase CML by 20% or more blasts in the bone marrow or peripheral blood. Extramedullary blast proliferation, such as myeloid sarcomas or infiltration into lymph nodes, skin, or the central nervous system, also qualifies a patient for this classification. A rising burden of chromosomal abnormalities, particularly complex karyotypic changes, further indicates disease progression.

Therapeutic response in this phase is often poor, with significant resistance to TKIs necessitating alternative strategies. While second- and third-generation TKIs like ponatinib may provide temporary control, many patients require intensive chemotherapy similar to acute leukemia regimens. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option but requires reducing blast burden before transplantation. Without effective intervention, median survival in blast phase CML is typically less than one year.

Genetic Markers

The genetic hallmark of CML is the Philadelphia chromosome, resulting from the reciprocal translocation t(9;22)(q34;q11). This rearrangement generates the BCR-ABL1 fusion gene, which encodes a constitutively active tyrosine kinase driving uncontrolled myeloid proliferation. The fusion gene exists in different transcript variants, primarily p210BCR-ABL1, which is most common, and less frequently p190BCR-ABL1, typically seen in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) but occasionally detected in CML. The transcript type influences disease behavior, therapy response, and prognosis.

Molecular diagnostics play a central role in detecting and monitoring BCR-ABL1 expression. Quantitative polymerase chain reaction (qPCR) is the gold standard for assessing minimal residual disease, allowing precise transcript measurement over time. A reduction in BCR-ABL1 transcripts to 0.1% or lower on the International Scale (IS) correlates with a major molecular response (MMR), a key treatment milestone. Fluorescence in situ hybridization (FISH) is an alternative method for detecting the Philadelphia chromosome when conventional karyotyping is inconclusive, particularly in cases with cryptic translocations.

Common Laboratory Findings

Laboratory evaluation in CML provides critical insights into disease progression and treatment response. Routine blood tests often reveal leukocytosis with a marked left shift, where immature granulocytes such as promyelocytes, myelocytes, and metamyelocytes appear in circulation. While blasts remain below 10% in the chronic phase, their proportion increases as the disease advances. Differential counts frequently show basophilia and eosinophilia, markers of disease activity. Platelet counts vary, with thrombocytosis common in early stages and thrombocytopenia more prevalent as bone marrow failure ensues.

Biochemical abnormalities may emerge with increasing tumor burden. Elevated lactate dehydrogenase (LDH) reflects high cellular turnover, while uric acid may rise due to enhanced nucleic acid metabolism, predisposing patients to hyperuricemia and tumor lysis syndrome. Bone marrow aspirates reveal hypercellularity with granulocytic hyperplasia, and as progression occurs, increased fibrosis may be noted. The leukocyte alkaline phosphatase (LAP) score is typically low in CML, distinguishing it from reactive leukocytosis seen in infections or inflammatory conditions. Regular monitoring of these parameters is essential for assessing disease trajectory and guiding treatment.