Chronic myeloid leukemia (CML) is a hematopoietic stem cell malignancy with an age-adjusted incidence rate of 1.5 per 100,000 individuals per year within the United States, accounting for 15% of all adult leukemias [1
]. The median age of diagnosis is 66, but CML may occur in all age groups [1
]. CML typically progresses through three sequential phases: chronic phase (CP), accelerated phase (AP), and terminal blast crisis (BC). Most often, patients are diagnosed during CP.
At the cellular level, CML is characterized by the presence of the Philadelphia (Ph) chromosome [3
]. This genetic abnormality results from a reciprocal translocation between chromosomes 9 and 22, leading to the formation of the pathogenic tyrosine kinase signal transduction protein, BCR-ABL [4
]. BCR-ABL is also found in some patients with acute lymphoblastic leukemia (Ph+ ALL).
If untreated, the prognosis for patients with CML is poor. Under these conditions the disease usually progresses from CP to BC within 3-5 years [2
]. Even with the benefit of imatinib mesylate treatment, some patients with CML progress to BC [7
]. Therefore, there is a strong medical need for effective treatments for this malignancy.
The treatment of CML was revolutionized by the use of tyrosine kinase inhibitors (TKIs) directed against BCR-ABL, the first developed being imatinib (Gleevec®
). Currently, imatinib remains the only FDA-approved first-line treatment option for this disease [8
]. Imatinib has been shown to benefit most patients; however, resistance and intolerance to this agent have emerged as clinical concerns. These problems may either prevent a patient from attaining a sufficient clinical response (suboptimal response), or may cause a patient to lose an existing one (relapse). In the pivotal phase III study of imatinib, 23% of patients faced initial, inherent (primary) resistance, and a further 4% of patients presented with intolerance to the agent [9
]. After 7 years of follow-up, it was found that 40% of patients discontinued imatinib due to adverse events, lack of efficacy, bone marrow transplant, death, protocol violation, withdrawal of consent, loss of follow-up, or administrative reasons [11
]. A large European retrospective survey found that 45% of all patients treated with imatinib displayed resistance or intolerance [12
Reasons for imatinib resistance are multifactorial. The most understood mechanism is mutation of BCR-ABL, preventing imatinib from binding effectively to the protein [8
]. It is thought to be the most important mechanism underlying secondary resistance. Other mechanisms include decreased intracellular levels of imatinib (caused by changed expression of drug efflux or influx proteins), increased levels of BCR-ABL (via gene amplification or over expression), or pathologic alteration of downstream intracellular pathways (e.g., SRC family kinases; SFKs).
Effective second-line treatments for imatinib-resistant or -intolerant patients with CML are now available. Dasatinib (Sprycel®
) and nilotinib (Tasigna®
) are both second-line TKIs approved for patients with CP or AP CML resistant or intolerant to imatinib. The drugs are similar in their ability to overcome resistance to imatinib therapy, but there are subtle differences in indications and side effect profiles that are worth mentioning. Nilotinib is associated with prolongation of the QT interval and therefore a screening EKG is recommended prior to starting therapy [13
]. In addition, nilotinib administration requires the patient to fast prior to taking the twice daily dose. Dasatinib does not have a fasting or screening EKG requirement, but is associated with a higher incidence of pleural effusions [14
]. Dasatinib is also indicated for the treatment of patients with BC CML or Ph+ ALL and who are resistant or intolerant to imatinib. It is important to note there are no direct comparisons of efficacy of nilotinib and dasatinib in CML.
Although both second-line TKIs are well tolerated, side effects do occur during treatment. Management of side effects is essential to ensure that patients continue treatment and have the best possible chance of a positive long-term outcome. In this review, we will focus on the the occurrence and appropriate management of pleural effusions during dasatinib therapy.