Bethesda Handbook of Clinical Oncology, 2nd Edition
Muzaffar H. Qazilbash
Jorge E. Cortes
M.D. Anderson Cancer Center, University of Texas, Houston, Texas
Every year, approximately 5,000 to 7,000 individuals are diagnosed with chronic myeloid leukemia (CML) in the United States. The annual incidence of CML is one to two cases per 100,000 individuals. The median age at presentation reported from large cohort studies is 45 to 55 years. More than 80% of patients are diagnosed in the chronic phase, often incidentally during routine tests. CML rarely occurs in children (2% to 3% of childhood leukemias).
The hallmark of CML is the Philadelphia chromosome (Ph-chromosome), a reciprocal translocation between the long arms of chromosomes 9 and 22 [i.e., t(9;22)]. The translocation results in the transfer of the Abelson (ABL) gene to an area of chromosome 22 termed the breakpoint cluster region (BCR), producing the BCR-ABL fusion gene. This fusion gene gives rise to a chimeric protein, p210BCR-ABL, with tyrosine kinase activity, which is believed to play a pathogenic role in this disease.
STAGING AND PROGNOSIS
CML typically progresses over time from its chronic phase to an accelerated phase and then to a blast phase (see Table 25.1).
- Blast crisis: An abrupt transition to a blast phase is called blast crisis. Features of a blast crisis include fever, malaise, progressive and painful splenomegaly and/or hepatomegaly, bone pain, worsening anemia and thrombocytopenia, and thrombotic or bleeding complications.
- Prognosis: The chronic phasetypically lasts 3 to 4 years, with the annual rate of progression to a blast phase being 5% to 10% in the first 2 years and 20% in the subsequent years. The prognosis for patient in the chronic phase is 5 to 6 years, with some patients surviving as long as 10 years. For patients in the accelerated phase, survival is usually less than 1 year, and for blast phase, the survival is a few months. A shorter chronic phase may be predicted by characteristic features at diagnosis, such as older age, male sex, increased lactate dehydrogenase (LDH) level, multiple cytogenetic abnormalities, high percentage of immature myeloid cells, basophilia, eosinophilia, thrombocytosis, and anemia. A useful predictive model using these multiple risk factors is the Sokal risk index. A recently modified version of this index that predicts patients who do best with chemotherapy or interferon (IFN)-α is illustrated in Table 25.2.
TABLE 25.1. Chronic Myeloid Leukemia Stages and Prognosis
TABLE 25.2. Modified Sokal Risk Index
DIAGNOSIS AND CLINICAL FEATURES
- Patients in the early chronic phase may have no symptoms
- Weight loss
- Dyspnea on exertion.
The most common finding is splenomegaly; the spleen can be massive (in about 10% of patients, the spleen is not enlarged even on splenic scan).
CML is characterized by the following laboratory studies:
- Increased white blood cell (WBC) count (usually >25 × 103per µL)
- Increased platelet count in approximately 50% of cases
- Myeloid cells at all stages of maturation in the peripheral smear (the percentage of immature myeloid cells in the blood or bone marrow can indicate the phase of the disease, as described earlier)
- Marked marrow myeloid hyperplasia
- Leukocyte alkaline phosphatase (LAP) activity of CML neutrophils is markedly diminished from the 20% reactivity of normal neutrophils (or leukoerythroblastic reaction)
- Diagnosis is confirmed through detection of the t(9;22) abnormality on cytogenetic analysis or through the polymerase chain reaction (PCR) detection of the BCL-ABL fusion in WBCs from peripheral blood [about 10% of patients will be negative for the t(9;22) on standard karyotypic analysis].
- Leukoerythroblastic reaction in response to infection or malignancy (see Table 26.1 in Chapter 26 for features to distinguish CML from other myeloproliferative disorders)
- Chronic myelomonocytic leukemia (CMML)
- Atypical CML
- Idiopathic myelofibrosis
- Essential thrombocytosis
- Polycythemia rubra vera.
The treatment options for CML can be divided into:
- Stem cell transplantation (SCT)
- IFN-α with or without cytarabine
- Imatinib mesylate
- Other experimental agents
Stem Cell Transplantation
Allogeneic SCT is curative in select patients with CML and is most effective when performed during the chronic phase of disease. Conventional myeloablative hematopoietic stem cell transplantation (HSCT) carries risks of morbidity and mortality from regimen-related toxicities; its use has been restricted to relatively young patients in good medical condition. In patients older than 50 years with a matched sibling donor, nonmyeloablative SCT has shown promising results in clinical trials. A matched unrelated donor (MUD) may be found in an additional 10% of patients without a matched related donor; however, MUD SCT has a significantly higher transplant-related mortality and morbidity. Allogeneic SCT is currently being studied as a curative option for patients with imatinib-resistant chronic phase or for consolidation after treatment with imatinib in patients with accelerated or blast phase CML.
As such, this remains the treatment of choice for patients younger than 50 years with a matched sibling donor (about 20% of patients). In patients older than 50 years with a matched donor and with comorbidities, nonmyeloablative SCT may be considered.
Imatinib has revolutionized the treatment and prognosis of CML. Several studies in patients with chronic-phase CML have shown high rates of complete cytogenetic responses. The impact of such therapy on long-term prognosis awaits further maturation of the data. However, if the early results continue to persist, with long-term follow-up of the high rates of complete and durable cytogenetic responses as well as low transformation and mortality rates, and if no new unexpected frequent long-term imatinib toxicities arise, then imatinib will soon be established as the most effective treatment for CML (see Table 25.3).
TABLE 25.3. Suggested Regimens, Toxicities, and Response Rates
Hydroxyurea is an excellent debulking agent and allows for the rapid control of the blood count, inducing hematologic responses in 50% to 80% of patients. Cytogenetic responses are rare, and hydroxyurea does not appear to change the natural history of CML. Hydroxyurea is very effective in initial cytoreduction as an adjunct to other more definitive therapies and to control disease in preparation for allogeneic SCT. However, it should not be considered as a definitive therapy for CML.
Interferon-α with and without ChemoTHERAPY
Single-agent IFN-α is active in CML. Response rates with single-agent IFN-α include a complete hematologic response (CHR) of 40% to 80%, a cytogenetic response of 15% to 58%, a major cytogenetic response (Ph of 35%) of 30% to 50%, and a complete cytogenetic response (Ph of 0%) of 5% to 25%. The median survival ranges from 60 to 90 months. Achieving a complete cytogenetic response is associated with 10-year survival rates of 70% to 80%.
Combining chemotherapy with IFN-α may allow a greater reduction in the burden of abnormal clonal cells: IFN-α in combination with cytarabine produces greater long-term survival and more major cytogenetic responses compared with IFN-α alone. However, a randomized trial comparing interferon-α and low-dose cytarabine to imatinib showed a statistically significant improvement in major and complete cytogenetic responses and freedom from progression to accelerated and blast phases in the imatinib group.
Treatment of Blast Phase Chronic Myelogenous Leukemia
Curative treatment is usually unsuccessful in this phase. Approximately 30% of cases with a blast phase having lymphoid features [terminal deoxynucleotidyl transferase (Tdt) or CD10 positive] may respond to regimens used for acute lymphoblastic leukemia. In a phase I and II study in 75 patients with blast phase CML, imatinib mesylate produced a response rate of 52% and a median survival of 6.5 months, both superior to the historic controls treated with standard cytarabine combinations.
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