Advances in the Treatment and Management of Patients With CML: A Nurse's Perspective CE Patricia S. Ault, MSN, RN

[1] Imatinib, which targets a constitutively active tyrosine kinase encoded by the chimeric BCR-ABL1 oncogene, was approved for use in 2001 and has been shown to induce durable responses and an overall survival rate of 89% at 5 years.[2]

Imatinib is currently accepted as standard treatment for patients with CML in the front-line setting. Two newer tyrosine kinase inhibitors (TKIs), dasatinib and nilotinib, have been found to be active in patients with imatinib-intolerant or imatinib-resistant disease[3,4] and are both approved in this setting. Recently, these agents have both demonstrated efficacy in the front-line setting,[5,6] and the US Food and Drug Administration approved nilotinib for the first-line treatment of adult patients with newly diagnosed Philadelphia chromosome-positive CML in the chronic phase. A similar indication for dasatinib may soon be approved. Thus, the changing landscape of CML treatment requires that nursing professionals maintain awareness of how to monitor patients for resistance to first-line therapy with TKIs and how to recognize and manage potential adverse effects of these agents. On behalf of MedscapeCME, Emma Hitt, PhD, spoke with Patricia Ault, MSN, RN, a nurse practitioner in the Leukemia Department at the University of Texas M.D. Anderson Cancer Center, in Houston, about these issues and their clinical implications for nursing practice.

Medscape: What are the current treatment options for first-line and relapsed CML, and what considerations are used when selecting treatment?

Ms. Ault: Imatinib has been the standard first-line treatment for years. Primary hematologic resistance to imatinib therapy is rare in newly diagnosed patients, but primary cytogenetic resistance -- failure to achieve any level of cytogenetic response at 6 months, major cytogenetic response at 12 months, or complete cytogenetic response at 18 months -- is present in 15% to 25% of patients.[7] Dose escalation of imatinib from 400 mg to up to 800 mg per day can be an appropriate treatment option and may help some patients achieve cytogenetic responses. However, imatinib dose escalation may be insufficient in patients with primary resistance to imatinib, hematologic disease recurrence, or emergent BCR-ABL kinase domain mutations. In these cases, dasatinib or nilotinib may provide effective treatment options.[7,8]

Medscape: Studies have compared imatinib directly with nilotinib or dasatinib in the front-line setting. Can you discuss the findings from these trials?

Ms. Ault: A recent study compared nilotinib with imatinib in first-line chronic-phase CML, and this pivotal trial formed the basis for the approval of nilotinib use in the front-line setting.[5] A total of 846 patients received either nilotinib, at a dose of 300 mg (n = 282) or 400 mg (n = 281) twice daily, or imatinib at a dose of 400 mg once daily (n = 283). The rates of major molecular response at 12 months for nilotinib were 44% for the 300-mg dose and 43% for the 400-mg dose groups compared with only 22% for imatinib (P < .001 for both comparisons). Likewise, the rates of complete cytogenetic response at 12 months were 80% for the 300-mg dose and 78% for the 400-mg dose group compared with 65% for imatinib (P < .001 for both comparisons). Nilotinib also significantly improved time to progression to accelerated phase or blast crisis. Nilotinib was associated with fewer gastrointestinal and fluid-retention events but more dermatologic events, elevated liver enzymes, and headache than imatinib.

Phase 3 trial of dasatinib published in the same month also demonstrated superiority for dasatinib compared with imatinib in patients with newly diagnosed chronic-phase CML.[6] A total of 519 patients were randomized to receive dasatinib 100 mg once daily (n = 259) or imatinib at a dose of 400 mg once daily (n = 260). At 12 months, the rate of complete cytogenetic response was 77% with dasatinib compared with 66% with imatinib (P = .007). The rate of major molecular response was higher with dasatinib than with imatinib (46% vs 28%; P < .0001). Both of these studies demonstrate superiority for nilotinib and dasatinib over the standard imatinib and will likely influence clinical practice.

Medscape: In addition to nilotinib and dasatinib, what other agents are important for nurses to know about?

Ms. Ault: Omacetaxine (formerly known as homoharringtonine) and other investigational agents have been associated with a reduction in the T315I clone, which is important because imatinib, dasatinib, and nilotinib are not effective when that mutation is present. Omacetaxine recently demonstrated efficacy in a phase 2/3 trial of patients who no longer responded to imatinib; almost 80% of the patients had failed 2 or more TKIs.[9] A complete hematologic response was achieved in 86% of patients in chronic phase, in 22% of those in accelerated phase, and in 20% of those in blast phase. A cytogenetic response was achieved in 41% of those in chronic phase compared with 6% of those in accelerated phase, and in no patients in the blast phase.

This agent has recently been considered for approval, but the Oncologic Drugs Advisory Committee to the US Food and Drug Administration voted 7 to 1 to require that a validated in vitro companion diagnostic test for theT315I mutation be submitted to the agency before approval of the drug.

Medscape: How can nurses monitor patients for the development of resistance to imatinib?

Ms. Ault: An increase in PCR [polymerase chain reaction] by a 3-log suggests a mutation, but the only way to confirm resistance is to perform a bone marrow biopsy. Often clinicians try to avoid taking a bone marrow sample, but unless this is done, it is not possible to identify the mutation and properly treat the disease.

An absence of molecular remission is the first indicator of resistance, a loss of cytogenetic remission is the second indicator, and the last indicator is a loss of hematologic response. The point is to look for these indicators, first of all by testing the bone marrow for mutations that could cause resistance.

Medscape: Do doctors test for this, or is this something nurses should consider?

Ms. Ault: Physicians should stay keenly aware of the need to obtain a bone marrow sample, but if a patient calls and reports new symptoms to the nurse, he or she would want to think first about resistance testing. The physician is usually not the first person to identify the problem because nurses screen these calls and, at that time, may also gain a very important insight regarding the patient's adherence. The more knowledgeable the nurse is, the more appropriately he or she can handle the situation.

Medscape: What are the mutations that influence the development of resistance to specific agents?

Ms. Ault: More than 70 mutations leading to 50 amino acid substitutions have been described to date in patients with CML resistant to imatinib therapy.[10] A useful schematic of these mutations showing the sensitivity to imatinib, dasatinib, and nilotinib was published in 2008 by Baccarani and colleagues (Table).[10] <click here

Table. Sensitivity of BCR/ABL Kinase Domain Mutations to TKIs (values are given as IC50)[10]

Determining the sensitivity to the tyrosine kinase inhibitors (in terms of inhibitory concentration [IC]50) means that the clinical strategy can be modified in treatment-resistant patients, for example, by choosing to increase the dose of imatinib, replace it with a second-generation tyrosine kinase inhibitor or, in the case of the pan-resistantT315I mutation, enroll the patient into a stem cell transplant program.

Medscape: What should nurses know about the safety profiles of these agents?

Ms. Ault: The NCCN [National Comprehensive Cancer Network] guidelines suggest withholding medication for grade 3 or higher side effects and restarting in 2 weeks at a reduced dose. In addition, nurses should remain aware of specific side effects associated with specific agents. For example, dasatinib has been linked to bleeding.[11] A study of 138 patients with CML found that any grade bleeding was present in 32 patients (23%) and was present at a level of grade 3 or higher in 9 patients (7%). Bleeding was more common in patients treated in the accelerated and blast phases than in the chronic phase (P = .02). Of the bleeding episodes, 81% were associated with the gastrointestinal tract. Risk factors for bleeding included thrombocytopenia and advanced-phase CML. Management consisted of interrupting dasatinib treatment for a range of 3 to 51 days, and about three fourths of the patients received a transfusion.[11]

Imatinib, dasatinib, and nilotinib each have potential cardiotoxic effects.[12] Imatinib is more likely than nilotinib or dasatinib to be associated with severe congestive heart failure and left ventricular dysfunction, especially at doses of more than 600 mg/day. By contrast, both dasatinib and nilotinib are more likely to be associated with QT prolongation than imatinib. In addition, dasatinib and imatinib are associated with pericardial effusion, whereas nilotinib is not. Given these issues, it is imperative that nurses remain vigilant about potentially cross-reactive medicines and that patients are monitored carefully for cardiac conditions with an EKG [electrocardiogram] before and after treatment and are assessed by a cardiologist. Nurses should adhere to the NCCN guidelines to ensure the safest use of these agents with respect to cardiotoxicity.

The take-home message is that expanded treatment options for patients with CML means that therapy should be selected based on both efficacy and specific side effects, which should be considered and monitored throughout the course of treatment.

Most grade 1/2 side effects are manageable, and the patient can continue taking medication without dose interruption. Some common side effects are rashes, nausea, vomiting, and generalized fatigue. Specifically, nilotinib is associated with elevation of pancreatic and liver enzymes. With dasatinib, there may be a higher incidence of GI [gastrointestinal] bleeding. All of the agents cause anemia and thrombocytopenia. Pleural and pericardial effusion is also an important side effect that requires monitoring. All 3 agents may cause thyroid dysfunction, and patients should be assessed for signs of hypothyroidism. Renal insufficiency can occur with all agents and require monitoring. Headache is specific to all 3 drugs but, perhaps, most predominant with nilotinib.

NCCN guidelines provide recommendations for the management and care of patients with all phases of CML. These include obtaining a regular complete blood count, liver enzymes, renal function, blood urea nitrogen, creatinine, and glucose (which can be elevated with nilotinib). The side effects, especially with nilotinib and dasatinib, may be transient and seem to dissipate within a few months.

Medscape: What are the issues that nurses need to discuss with patients about CML treatment?

Ms. Ault: In addition to managing side effects, the most important thing that a nurse should do is to discuss and emphasize the importance of adherence. In order for treatment to work, it must be taken every day. There can be no "drug holidays." Recent European studies showed that patients who did not adhere to therapy lost their molecular response, and relapse was soon to follow.[13,14] It is important for nurses to develop a good relationship with patients so that they can encourage them to adhere to treatment and assess any potential problems that may prevent patients from adhering to treatment.

Supported by an independent educational grant from Novartis.