First-Line Use of Second-Generation Tyrosine Kinase Inhibitors in Patients With Chronic Myeloid Leukemia

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Chronic myeloid leukemia (CML), a hematopoietic stem cell disease, is characterized by a reciprocal chromosomal translocation between chromosomes 9 and 22, resulting in the formation of the Philadelphia chromosome (Ph+).1 The bcr-abl oncogene, a fusion protein with tyrosine kinase activity, results from this translocation, and leads to the development of CML.1,2 Treatment of patients with Ph+ CML in chronic phase with the tyrosine kinase inhibitor (TKI) class of oral agents—imatinib, nilotinib, and dasatinib, which selectively bind to the bcr-abl kinase domain—generally leads to complete cytogenetic remission with minimal adverse events.3-6

Imatinib, a first-generation TKI, has been the standard of care for patients with Ph+ CML for the past decade.3,7 However, the development of resistance mechanisms to imatinib, in addition to poorly tolerated adverse events in some patients, has resulted in a new unmet need.3 Results of 2 randomized phase III studies of 2 more potent second-generation TKIs, nilotinib5 and dasatinib,6 recently demonstrated significantly better response compared with imatinib in the treatment of newly diagnosed Ph+ CML patients. Notable results included higher rates of complete cytogenetic remission, faster time to remission, and reduced rates of disease progression.3,5,6 Based on these studies, the United States Food and Drug Administration (FDA) granted a new indication for nilotinib in newly diagnosed patients in June 2010 and a priority review of data supporting the use of dasatinib in newly diagnosed patients with Ph+ CML in chronic phase.8,9 The first-line indication for nilotinib, and potentially that of dasatinib, presents the opportunity for a new standard of care in the treatment of Ph+ CML.5,9

Oncology nurses play a pivotal role in monitoring patients with Ph+ CML, from those who are newly diagnosed to others who may have been receiving TKI treatment for years. Indications, dosing, and characteristics of second generation oral TKIs, including potential drug-drug interactions and adverse events, and how best to manage them, are explored in this article. Two case studies of representative patients are also presented to provide an understanding of treatment considerations for Ph+ CML.

If left untreated, CML usually progresses through 3 clinically recognized phases: chronic, accelerated, and blast.1,10 Although patients most commonly progress through all 3 stages, 20% to 25% progress directly from the chronic phase to the blast phase.10 The time course for disease progression is also quite varied.10

The cytogenetic hallmark of CML is the Ph+, created by a reciprocal translocation between chromosomes 9 and 22 (t[9;22][q34;q11]).10 The conjugation of the breakpoint cluster region (bcr) gene on chromosome 22 and the Abelson (abl) kinase gene on chromosome 9 creates the bcr-abl oncogene. This codes for a deregulated tyrosine kinase, leading to uncontrolled cell proliferation, reduced apoptosis, and malignant expansion of pluripotent stem cells in the bone marrow.10 Oral TKIs—imatinib, nilotinib, and dasatinib—selectively inhibit bcr-abl through different binding mechanisms.3

Epidemiology and Risk Factors
There are few known risk factors for CML. In most cases, no cause can be found, and CML cannot be prevented by lifestyle changes. The only known environmental risk factor is exposure to high-dose radiation (ie, an atomic bomb blast or nuclear reactor accident).11

Incidence and prevalence: Approximately 11% of all adult leukemias are CML.12 The risk of CML increases with age (Figure 1)13 and occurs to a slightly greater degree in males than in females.11 Median age of onset of CML is 67 years;1 however, CML can occur in any age group.13

FIGURE 1. Age-Specific Incidence Rates for Chronic Myeloid Leukemia, 2002-2006

Although median age of onset of CML is 67 years, the disease can occur in any age group. Incidence increases with age. Source: Horner 201013

Morbidity/mortality: An estimated 5050 cases of CML were diagnosed in the US in 2009 and 470 patients died of their disease.12 In 2009, approximately 22,473 people in the US were living with CML.14 Patients with chronic-phase CML that remains untreated will eventually progress to more aggressive phases within 3 to 5 years.1,15

Approximately 40% of patients with CML may be asymptomatic at the time of diagnosis; in these patients, an abnormal blood count may be the only finding that suggests a diagnosis of CML.15 Signs and symptoms of CML develop gradually and may include fatigue, anorexia, or weight loss.15 Approximately 90% of patients are diagnosed during the indolent chronic phase.10 The most common finding on physical examination at diagnosis is splenomegaly, which is present in up to one-half of patients.15 The National Comprehensive Cancer Network (NCCN) Guidelines recommend that initial evaluation of adult patients with chronic-phase CML include1:

  • History and physical examination, including spleen size palpitation
  • Complete blood count with differential, including platelet counts
  • Chemistry profile
  • Bone marrow aspirate and biopsy

Bone marrow aspirate and biopsy are preferred in the initial evaluation to confirm CML diagnosis because of the ability to detect chromosomal abnormalities that may not be found in peripheral blood.1 Bone marrow also provides a basis for a morphology review.1 However, cytogenetic testing using fluorescence in situ hybridization (FISH) or quantitative reverse-transcriptase polymerase chain reaction (QRT-PCR) assay may be used to confirm a CML diagnosis in the event bone marrow cannot be attained.1 QRT-PCR, which measures bcr-abl transcript levels, has shown strong correlations between peripheral blood and bone marrow results, demonstrating it as an accurate means of confirming diagnosis.1

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