INTRODUCTION
Chronic myeloid leukemia (CML),a hematopoietic stem cell disease, is characterizedby a reciprocal chromosomaltranslocation between chromosomes 9and 22, resulting in the formation of thePhiladelphia chromosome (Ph+).1 Thebcr-abl oncogene, a fusion protein withtyrosine kinase activity, results from thistranslocation, and leads to the developmentof CML.1,2 Treatment of patients withPh+ CML in chronic phase with thetyrosine kinase inhibitor (TKI) class of oralagents—imatinib, nilotinib, and dasatinib,which selectively bind to the bcr-abl kinasedomain—generally leads to completecytogenetic remission with minimaladverse events.3-6

Imatinib, a first-generation TKI, has beenthe standard of care for patients with Ph+CML for the past decade.3,7 However, thedevelopment of resistance mechanisms toimatinib, in addition to poorly toleratedadverse events in some patients, has resultedin a new unmet need.3 Results of 2 randomizedphase III studies of 2 more potentsecond-generation TKIs, nilotinib5 anddasatinib,6 recently demonstrated significantlybetter response compared withimatinib in the treatment of newly diagnosedPh+ CML patients. Notable results includedhigher rates of complete cytogenetic remission,faster time to remission, and reducedrates of disease progression.3,5,6 Based on these studies, theUnited States Food and Drug Administration (FDA) granteda new indication for nilotinib in newly diagnosed patientsin June 2010 and a priority review of data supporting theuse of dasatinib in newly diagnosed patients with Ph+ CMLin chronic phase.8,9 The first-line indication for nilotinib,and potentially that of dasatinib, presents the opportunity fora new standard of care in the treatment of Ph+ CML.5,9

Oncology nurses play a pivotal role in monitoring patientswith Ph+ CML, from those who are newly diagnosed toothers who may have been receiving TKI treatment foryears. Indications, dosing, and characteristics of second generationoral TKIs, including potential drug-druginteractions and adverse events, and how best to managethem, are explored in this article. Two case studies ofrepresentative patients are also presented to provide anunderstanding of treatment considerations for Ph+ CML.

DISEASE-STATE OVERVIEW
If left untreated, CML usually progresses through3 clinically recognized phases: chronic, accelerated, andblast.1,10 Although patients most commonly progressthrough all 3 stages, 20% to 25% progress directly fromthe chronic phase to the blast phase.10 The time course fordisease progression is also quite varied.10


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Pathophysiology
The cytogenetic hallmark of CML is the Ph+, created bya reciprocal translocation between chromosomes 9 and 22(t[9;22][q34;q11]).10 The conjugation of the breakpointcluster region (bcr) gene on chromosome 22 and theAbelson (abl) kinase gene on chromosome 9 creates thebcr-abl oncogene. This codes for a deregulated tyrosinekinase, leading to uncontrolled cell proliferation, reducedapoptosis, and malignant expansion of pluripotent stemcells in the bone marrow.10 Oral TKIs—imatinib, nilotinib,and dasatinib—selectively inhibit bcr-abl through differentbinding 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 bylifestyle changes. The only known environmental riskfactor is exposure to high-dose radiation (ie, an atomicbomb blast or nuclear reactor accident).11

Incidence and prevalence: Approximately 11% of alladult leukemias are CML.12 The risk of CML increaseswith age (Figure 1)13 and occurs to a slightly greater degreein males than in females.11 Median age of onset of CML is67 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 CMLwere diagnosed in the US in 2009 and 470 patients diedof their disease.12 In 2009, approximately 22,473 people inthe US were living with CML.14 Patients with chronic-phaseCML that remains untreated will eventually progressto more aggressive phases within 3 to 5 years.1,15

DIAGNOSIS
Approximately 40% of patients with CML may be asymptomaticat the time of diagnosis; in these patients, anabnormal blood count may be the only finding that suggestsa diagnosis of CML.15 Signs and symptoms of CML developgradually and may include fatigue, anorexia, or weightloss.15 Approximately 90% of patients are diagnosed duringthe indolent chronic phase.10 The most common findingon physical examination at diagnosis is splenomegaly, whichis present in up to one-half of patients.15 The NationalComprehensive Cancer Network (NCCN) Guidelinesrecommend that initial evaluation of adult patients withchronic-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 theinitial evaluation to confirm CML diagnosis because of theability to detect chromosomal abnormalities that may notbe found in peripheral blood.1 Bone marrow also providesa basis for a morphology review.1 However, cytogenetictesting using fluorescence in situ hybridization (FISH)or quantitative reverse-transcriptase polymerase chainreaction (QRT-PCR) assay may be used to confirm a CMLdiagnosis in the event bone marrow cannot be attained.1QRT-PCR, which measures bcr-abl transcript levels, hasshown strong correlations between peripheral bloodand bone marrow results, demonstrating it as an accuratemeans of confirming diagnosis.1