Chronic Myeloid Leukemia: Evaluation and Diagnosis
The criteria for diagnosing AP-CML has not been agreed upon by various groups, but the modified MD Anderson Cancer Center (MDACC) criteria are used in the majority of clinical trials evaluating the efficacy of TKIs in preventing progression to advanced phases of CML. MDACC criteria define AP-CML as the presence of one of the following: 15% to 29% blasts in the peripheral blood or bone marrow, ≥ 30% peripheral blasts plus promyelocytes, ≥ 20% basophils in the blood or bone marrow, platelet count ≤ 100 × 103/μL unrelated to therapy, and clonal cytogenetic evolution in Ph-positive metaphases (Table).7
BP-CML is typically defined using the criteria developed by the International Bone Marrow Transplant Registry (IBMTR): ≥ 30% blasts in the peripheral blood and/or the bone marrow or the presence of extramedullary disease.8 Although not typically used in clinical trials, the revised World Health Organization (WHO) criteria for BP-CML include ≥ 20% blasts in the peripheral blood or bone marrow, extramedullary blast proliferation, and large foci or clusters of blasts in the bone marrow biopsy (Table).9 The defining feature of CML is the presence of the Ph chromosome abnormality. In a small subset of patients, additional chromosomal abnormalities (ACA) in the Ph-positive cells may be identified at diagnosis. Some reports indicate that the presence of “major route” ACA (trisomy 8, isochromosome 17q, a second Ph chromosome, or trisomy 19) at diagnosis may negatively impact prognosis, but other reports contradict these findings.10,11
The typical BCR breakpoint in CML is the major breakpoint cluster region (M-BCR), which results in a 210-kDa protein (p210). Alternate breakpoints that are less frequently identified are the minor BCR (mBCR or p190), which is more commonly found in Ph-positive acute lymphoblastic leukemia (ALL), and the micro BCR (µBCR or p230), which is much less common and is often characterized by chronic neutrophilia.12 Identifying which BCR-ABL1 transcript is present in each patient using qualitative PCR is crucial in order to ensure proper monitoring during treatment.
The most sensitive method for detecting BCR-ABL1 mRNA transcripts is the quantitative real-time PCR (RQ-PCR) assay, which is typically done on peripheral blood. RQ-PCR is capable of detecting a single CML cell in the presence of ≥ 100,000 normal cells. This test should be done during the initial diagnostic workup in order to confirm the presence of BCR-ABL1 transcripts, and it is used as a standard method for monitoring response to TKI therapy.13 The International Scale (IS) is a standardized approach to reporting RQ-PCR results that was developed to allow comparison of results across various laboratories and has become the gold standard for reporting BCR-ABL1 transcript values.14
Determining Risk Scores
Calculating a patient’s Sokal score or EURO risk score at diagnosis remains an important component of the diagnostic workup in CP-CML, as this information has prognostic and therapeutic implications (an online calculator is available through European LeukemiaNet [ELN]). The risk for disease progression to the accelerated or blast phases is higher in patients with intermediate- or high-risk scores compared to those with a low-risk score at diagnosis. The risk of progression in intermediate- or high-risk patients is lower when a second-generation TKI (dasatinib, nilotinib, or bosutinib) is used as frontline therapy compared to imatinib, and therefore, the National Comprehensive Cancer Network (NCCN) CML Panel recommends starting with a second-generation TKI in these patients.15-19
