Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm. The American Cancer Society estimated that in 2012, the number of newly diagnosed CML cases would be 5,430, with 610 deaths.1 The discovery of the tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment and prognosis of CML, making imperative early recognition of the disease. Timely diagnosis will ensure that patients receive early treatment, significantly improving their prognosis.
CML is caused by a cytogenetic abnormality that is thought to be acquired and involves a balanced translocation between chromosome 9 and chromosome 22. The BCR gene on chromosome 22 fuses with the ABL1 gene on chromosome 9, resulting in the abnormal fusion gene BCR-ABL1 located on chromosome 22 (Figure 1). The fusion gene produces a protein with tyrosine kinase activity that causes cells to proliferate. The resultant abnormal chromosome 22 [t(9;22) (q34;q11)] is also known as the Philadelphia (Ph) chromosome. It is identified in 95% of patients with CML and can be detected in all myeloid cells, including granulocytes, erythrocytes, monocytes, and B lymphocytes.2
CML typically occurs in patients between the ages of 50 and 70 years, with a slight male predominance. Most patients with CML have no identifiable risk factors. A history of high-dose radiation exposure has been linked to the development of CML.3
CML manifests with fatigue, low-grade fever, night sweats, abdominal fullness, and marked sternal tenderness. Rarely, patients are asymptomatic, and the diagnosis is based on a routine CBC. Physical examination reveals pallor and splenomegaly.
The three phases of CML are the chronic phase, the accelerated phase, and blast crisis.4 Patients usually present in the chronic phase. As the disease progresses, patients become more anemic and the size of the spleen increases.
The chronic phase of CML is characterized by a marked leukocytosis resulting from an increase in the number of granulocytic cells. A smear of the peripheral blood will show a left shift in granulocytes, with many immature granulocytes. An absolute basophilia and thrombocytosis are also present. Bone marrow aspiration and biopsy performed during the chronic phase of CML will show a markedly hypercellular bone marrow (Figure 2) with a left-shifted granulocytic hyperplasia and basophilia. The blast count will be less than 5%. Megakaryocytes are small and hypolobated. In the accelerated phase, the blast count in the bone marrow ranges from 10% to 20%. Marked basophilia is demonstrated in the peripheral blood and bone marrow. Blast crisis is characterized by a blast count of greater than 20% in the bone marrow. The blast cells are usually myeloblasts, but they can also be lymphoblasts, erythroblasts, or undifferentiated blast cells. Flow cytometric analysis of bone marrow helps identify the increased numbers of blast cells in the bone marrow. This analysis also determines if the blast cells are myeloblasts; lymphoblasts; or biphenotypic blast cells, ie, cells with features of both myeloblasts and lymphoblasts.
Cytogenetic studies performed on peripheral blood or bone marrow will identify the presence of the Ph chromosome.2 In a small proportion of patients, the Ph chromosome is cryptic and cannot be detected by routine cytogenetic studies. When performed during the accelerated phase or blast crisis, such studies reveal clonal evolution of the cytogenetic abnormalities. For patients in whom a Ph chromosome cannot be identified on routine cytogenetic studies, polymerase chain reaction (PCR) studies and/or a fluorescent in situ hybridization (FISH) study is necessary to identify a BCR/ABL1 molecular fusion, thereby confirming a diagnosis of CML.
The differential diagnosis of CML includes chronic neutrophilic leukemia and chronic myelomonocytic leukemia. Marked leukocytosis with greater than 80% neutrophils and band forms in a patient without a Ph chromosome is suggestive of a chronic neutrophilic leukemia. A persistent peripheral blood monocytosis and a clonal cytogenetic abnormality without a Ph chromosome is suggestive of chronic myelomonocytic leukemia. A de novo acute lymphoblastic leukemia in a patient with a Ph chromosome can be difficult to differentiate from CML in lymphoblastic blast crisis in a patient with no previous history of CML.5
CURRENT TREATMENT OPTIONS
Tyrosine kinase inhibitors (TKIs) comprise the standard therapy for CML. These agents have changed the overall prognosis of the disease because of their ability to induce a durable response in most patients. Prior to the discovery of TKIs, therapies, such as as hydroxyurea, interferon alfa, combination chemotherapy, and splenic irradiation, were palliative. With the discovery of TKIs, long-term disease control has become a therapeutic goal. TKIs act by blocking the locus with a tyrosine kinase function at the BCR-ABL1 transcript, thereby inhibiting abnormal tyrosine kinase activity.6 The drugs normalize peripheral blood counts, eliminate the Ph chromosome-positive clone, and eradicate the BCR-ABL1 transcript at the molecular level. The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN) describe the criteria for obtaining hematologic, cytogenetic, and molecular remission.7 Several first- and second-generation TKIs are currently being used in the treatment of CML. Each drug type is classified according to its specific target in the BCR-ABL1 transcript. Selection of the appropriate TKI is based on patient disease characteristics and drug tolerability.
Imatinib mesylate, also known as STI571, was approved by the FDA in 2001 as the first TKI to demonstrate efficacy against advanced-stage CML. Imatinib blocks the binding of adenosine triphosphate to the ABL tyrosine kinase domain. In 2002, imatinib was approved for first-line treatment in newly diagnosed cases based on the results of a randomized trial that compared the efficacy of imatinib to that of interferon alfa (INF) plus cytarabine, a combination that had previously been used as treatment for chronic-phase CML. Results of the study showed that both groups achieved a hematologic response, with improvement of the WBC count, but the imatinib-treated group experienced a higher overall rate of complete hematologic response (95.3% vs 55.5%) that was more rapidly obtained when compared with the INF-treated group (1 month vs 2.5 months). In addition, the complete cytogenetic response rate was better in the imatinib-treated group (76.2% vs 14.5%).8 Moreover, fewer side effects were noted in the imatinib-treated group. Based on these findings, the recommended effective standard dose of imatinib was determined to be 400 mg/day. Although higher doses, ie, 600 to 800 mg/day, have produced more rapid response rates, greater toxicities resulting in higher incidences of dose reduction, interruption, or discontinuation have limited their use as up-front treatment.6,9,10 In addition, higher dose levels have not demonstrated greater benefit in long-term disease control. Therefore, current guidelines do not recommend high-dose imatinib for newly diagnosed CML.
Adverse effects commonly associated with imatinib therapy include nausea and diarrhea, fluid retention, hepatotoxicity, cardiotoxicity, and cytopenias. Some patients may require antiemetics and/or diuretics for symptomatic relief of nausea and fluid retention, respectively. Prior to initiation of therapy, a baseline evaluation should include a CBC, comprehensive metabolic panel, and liver function tests. Additionally, an echocardiogram should be performed to assess left ventricular ejection fraction. Continued monitoring of side effects and laboratory data at regular intervals is required to assess for toxicities and/or cytopenias and to avoid severe neutropenia or thrombocytopenia that could result in complications, such as life-threatening infections or bleeding. Dose reductions may be required in patients who experience severe hematologic and nonhematologic side effects.
Frequent monitoring of disease status by cytogenetic analysis and/or PCR is essential to evaluate for signs of progression that may necessitate dose escalation or a change in therapy. Higher doses of imatinib (600-800 mg/day) may be indicated in patients who have a suboptimal response to the standard dose or who have residual molecular disease. Studies have shown that 12% of patients in early chronic phase, 32% of those in late chronic phase, and 62% of patients in accelerated phase will develop a resistant mutation in the BCR-ABL1 gene within 2 years of starting treatment.6 Patients should be evaluated for point mutations in the ABL kinase domain if they are resistant to imatinib therapy; fail to achieve complete hematologic response at 3 months, minor cytogenetic response at 6 months, or major cytogenetic response at 12 months; or have any sign of loss of response, such as hematologic relapse, cytogenetic relapse, or 1 log increase in BCR-ABL1 transcript, or loss of major molecular response.7
Second-generation TKIs have been developed to target point mutations in the BCR-ABL1 gene. Two newer TKIs, dasatinib and nilotinib, were originally approved for imatinib-resistant patients and those with accelerated-phase CML. Both drugs have been found to be more potent than imatinib against cells expressing “normal” (wild-type) BCR-ABL1 and are active against all imatinib-resistant mutants tested, except for the T315I mutation, which is highly resistant to all TKIs.6,11
Approved by the FDA in June 2006 for imatinib-resistant CML, dasatinib is active at the BCR-ABL1, SRC, c-KIT, and platelet-derived growth factor loci and is a highly potent dual SRC/ABL inhibitor. Dasatinib binds to both the active and inactive conformation of the ABL kinase domain. In vitro, its effect is 325 times more potent than that of imatinib.6 When compared with imatinib in a randomized trial of newly diagnosed chronic-phase CML patients, dasatinib-treated patients showed higher rates of complete cytogenetic and major molecular responses at 12 months.12 In the 24-month follow-up study, dasatinib-treated patients had more rapid and better major molecular responses than imatinib recipients (64% vs 46%, respectively) and fewer progressions to advanced stages of CML.13 The toxicity profiles were similar for all groups in both trials. In October 2010, dasatinib 100 mg/day was approved as a first-line therapy for newly diagnosed chronic-phase CML. Potential side effects associated with dasatinib therapy are similar to those of imatinib. Patients who present with any signs or symptoms of fluid overload should have a chest radiograph and/or echocardiogram. Dasatinib should be withheld until the effusion resolves. Additional treatment with corticosteroids may be indicated depending on the severity of the effusion. Peripheral blood counts should be monitored regularly for evidence of cytopenias. Thrombocytopenia and bleeding complications are more pronounced with dasatinib than with imatinib. Therefore, patients with a history of GI bleeding should not be considered for front-line therapy with dasatinib. If severe bleeding occurs, dasatinib should be discontinued.9,14
Nilotinib is a second-generation TKI initially approved for imatinib-resistant or newly diagnosed CML in October 2007. A highly selective inhibitor of BCR-ABL kinase, nilotinib is 30 times more potent than imatinib.6,11 Similar to dasatinib, nilotinib induced more rapid, durable response rates when compared with imatinib.9,14,15 These results led to approval in June 2010 of nilotinib 300 mg twice daily as front-line therapy for CML. Like other TKIs, side effects of nilotinib include cytopenias and liver function abnormalities. In addition, prolongation of the QTc interval is noted with nilotinib therapy. Therefore, patients receiving nilotinib should avoid other drugs that cause QTc prolongation or that are CYP3A4 inhibitors or hepatotoxic.7,10 Electrolyte abnormalities should be evaluated and corrected prior to therapy and monitored during treatment. An ECG must be obtained prior to initiation of therapy and repeated periodically. Any change in dose requires repeat ECG within 7 days of change.10 As is the case with other TKIs, CBCs should be monitored regularly in patients taking nilotinib.
- Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm characterized by the abnormal proliferation of granulocytic cells in the bone marrow.
- The onset of CML is insidious, and patients typically present in the chronic phase with bone pain and splenomegaly.
- Laboratory findings during the chronic phase include a CBC with marked leukocytosis due to proliferation of left-shifted granulocytic cells, a markedly hypercellular bone marrow with a granulocytic hyperplasia, a blast count less than 5%, and identification of the Philadelphia chromosome in myeloid cells.
- CML can progress to the accelerated phase and blast crisis.
- Tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib, and nilotinib, are currently the standard therapy for CML and have markedly improved the prognosis of patients with this disease.
Promising new therapies that target BCR-ABL tyrosine kinase and point mutations are currently being studied. Such drugs include bosutinib, ponatinib, and omacetaxine mepesuccinate. Bosutinib is a dual inhibitor of both the ABL and SRC kinases. It has been found to be effective in all phases of CML and more effective in vitro than imatinib for CML in chronic phase. The toxicity profile is similar to that of the other TKIs, with GI side effects being the most common adverse event.11,16 Ponatinib is an oral multikinase inhibitor with activity against wild-type and mutated ABL, including the T315I mutation. Finally, omacetaxine mepesuccinate is a cephalotaxine ester that has demonstrated activity against the T315I mutation.9,16 Ongoing studies are currently assessing the efficacy and tolerability of these newer agents.
CML is a chronic myeloproliferative disorder that typically occurs in patients between the ages of 50 and 70 years and is characterized by a marked proliferation of left-shifted granulocytic cells in the bone marrow and peripheral blood. The Philadelphia chromosome t[9;22][q34;q11] is identified in the myeloid cells of 95% of patients with CML. The discovery of TKIs, which inhibit the abnormal tyrosine kinase activity that occurs due to the presence of the Ph chromosome, has revolutionized the treatment and prognosis of CML. The excellent prognosis of patients treated with TKIs increases the importance of early diagnosis and referral to a hematologist so that patients can receive prompt treatment. When compared with imatinib, the second-generation TKIs dasatinib and nilotinib have shown superior results in inducing and maintaining cytogenetic and molecular responses. However, imatinib is the only TKI that has demonstrated improvement in long-term survival. Additionally, TKI therapy has played a significant role in eliminating the need for allogeneic stem cell transplantation. Thus far, only limited data are available regarding the ability to discontinue TKI therapy in patients who have achieved a molecular remission. One study evaluated the ability to maintain a molecular remission achieved with imatinib for at least 2 years after stopping the drug. Results showed that 59% of patients relapsed in 12 months and 41% maintained a molecular remission. However, all patients who relapsed responded to the reintroduction of imatinib. These results suggest that CML may be curable for patients who respond to imatinib (or other TKIs) and that discontinuation of treatment, even after a prolonged molecular remission, is not advised.17 Continued long-term follow-up is necessary to assess long-term and progression-free survival with the second-generation TKIs. In addition, effective monitoring and management of side effects may improve quality of life and reduce the incidence of dose interruption and discontinuation. Patient adherence to therapy also contributes to overall treatment success. Therefore, selection of the appropriate TKI should be based on such patient characteristics as age, comorbidities, and tolerability to improve treatment outcomes.
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