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Drugs offer new hope for patients with CML who are resistant to Imatinib: as seen in the Clinical Journal of Oncology Nursing.

Imatinib mesylate, an inhibitor of Bcr-Abl tyrosine kinases, has revolutionized the treatment of chronic myelogenous leukemia (CML), showing marked improvements in survival in all three phases of the disease: chronic, accelerated, and blast crisis (see Figure 1). Almost all patients diagnosed with CML now receive imatinib, which produces complete cytogenetic responses in more than 80% of patients in the chronic phase of the disease. However, about 10% of the patients who initially respond to imatinib eventually develop resistance and relapse.
Figure 1. Characteristics of Chronic Myelogenous Leukemia

Chronic Phase

* Peripheral blood leucocytosis is reflected in numerical
increase in all stages of myeloid differentiation.

* Basophilia frequently is pronounced.

* Bone marrow aspirates show hypercellularity and and
increased myeloid to erythroid ratio (> 25:1). Philadelphia
chromosome is present in all myeloid cells.

Accelerated Phase

* A blast cell population emerges.

* Accelerated phase requires at least one of the following.

--Rising leucocyte count during adequate treatment

--Platelet count < 100 or > 1,000 x 10.sup.9/L

--> 15% blasts in peripheral blood

--> 20% basophils and eosinophils in peripheral blood

Blast Crisis Phase

* > 30% blasts and promyelocytes exist in peripheral blood or marrow.
marrow erythropoiesis and megakaryopoiesis are reduced.

Imatinib Resistance

The mechanisms of imatinib resistance are not yet fully understood. However, researchers recognize that patients in the accelerated and blast phases have higher rates of resistance than patients in the chronic phase. In addition, patients who do not achieve a major reduction of Philadelphia chromosomes in 6-12 months of therapy appear to have less durable remissions. Mutations in the Bcr-Abl tyrosine kinase may account for the development of imatinib resistance.

Managing patients with imatinib-resistant CML has been a serious challenge for healthcare providers, but recent pharmacologic developments offer real hope. Scientists have created two other agents, dasatinib and nilotinib, that offer alternatives for resistant disease. These second-generation tyrosine kinase inhibitors (see Table 1 for targets) form tighter molecular bonds, overcoming imatinib resistance in many patients and producing durable hematologic and cytogenetic remissions.

Implications for Nursing

Nurses caring for patients who receive imatinib, dasatinib, or nilotinib (in clinical trials) should be aware of the agents' adverse events (see Table 1). For all three, the side-effect profile is usually mild, and the agents are well tolerated by most patients. Side effects include myelosuppression, edema, gastrointestinal symptoms, headache, and rash. Unforeseen toxicities may still emerge as the newer agents are tested and used more widely, and "new molecular-targeted therapies require hypervigilant observation and concise and accurate evaluation" (Ault, 2007, p. 126).

Oncology nurses should be prepared to provide patient education and instructions for these oral agents. For example, imatinib should be taken with food and a large glass of water, and patients should remain upright for 30 minutes to prevent reflux and vomiting. Dasatinib is taken twice per day, with or without food.

Imatinib should not be taken with acetaminophen, grapefruit products, or alcohol. In addition, it may interact with warfarin, erythromycin, and phenytoin. Dasatinib has similar interactions (although not with acetaminophen). It also requires stomach acid for adequate absorption. Therefore, antacids should not be used within two hours of taking dasatinib, and long-acting proton-pump inhibitors should be avoided. (See full prescribing information for all products for complete dosage and administration considerations.)

Ault, P. (2007). Overview of second-generation tyrosine kinase inhibitors for patients with imatinib-resistant chronic myelogenous leukemia. Clinical Journal of Oncology Nursing, 11, 125-129.

Kantarjian, H., Giles, F., Wunderle, L., Bhalla, K., O'Brien, S., Wassmann, B., et al. (2006). Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. New England Journal of Medicine, 354, 2542-2551.

Talpaz, M., Shah, N.P., Kantarjian, H., Donato, N., Nicoll, J., Paquette, R., et al. (2006). Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. New England Journal of Medicine, 354, 2531-2541.

"Five-Minute In-Service" is a monthly feature that offers readers a concise recap of full-length articles published recently in the Clinical Journal of Oncology Nursing (CJON) and Oncology Nursing Forum. This edition summarizes "Overview of Second-Generation Tyrosine Kinase Inhibitors for Patients With Imatinib-Resistant Chronic Myelogenous Leukemia" by Patricia Ault, RN, MS, ACCNP, NP-C, FNP-C, which was featured in the February 2007 issue of CJON. Questions regarding the information presented in this Five-Minute In-Service should be directed to the CJON editor at Photocopying of this article for educational purposes and group discussion is permitted.

Pamela Oestreicher, PhD, ONS Scientific Writer

RELATED ARTICLE: Key Definitions.

Chronic myelogenous leukemia (CML): clonal hematopoietic stem cell disorder accounting for 15%--20% of all cases of adult leukemia

Cytogenetic response: a goal of treatment; refers to the elimination of cells that have the Philadelphia chromosome mutation

Dasatinib: Sprycel[R], Bristol-Myers Squibb; a tyrosine kinase approved in 2006 to treat patients with CML who are resistant to or intolerant of imatinib

Hematologic response: a goal of treatment; refers to normalization of the white blood cell count

Imatinib mesylate: Gleevec[R], Novartis; a tyrosine kinase inhibitor approved in 2001 to treat CML; now standard of care

Nilotinib: Tasigna(TM), AMN107, Novartis; a tyrosine kinase under investigation to treat patients with CML who are resistant to or intolerant of imatinib

Philadelphia chromosome: the origin of almost all cases of CML and some cases of acute lymphocytic leukemia; when mutated, it produces an abnormal protein (Bcr-Abl) that causes overproduction of immature white blood cells.
Table 1. Tyrosine Kinase Inhibitors of Bcr-Abl in Chronic
Myelogenous Leukemia

Characteristic     Imatinib

Targets            Bcr-Abl tyrosine kinases

Response rates     Complete cytogenetic response
                   occurred in more than 80%
                   of patients in early chronic
                   phase; in accelerated and blast
                   phases, 76% and 34% had
                   hematologic remissions.

Adverse events     Nausea, vomiting, myelosuppression,
                   edema, headache,
                   indigestion, rash, muscle
                   cramps, bone pain, liver toxicity

Characteristic     Dasatinib

Targets            Bcr-Abl (a), SRC kinase, c-KIT,
                   EPHA2, platelet-derived growth
                   factor receptor (PDGFR) [beta]

Response rates     Complete hematologic response
                   occurred in 37 of 40 patients in
                   chronic phase and 31 of 44 patients
                   in other phases. Major cytogenetic
                   response occurred in 45%
                   in accelerated and 25% in blast
                   crisis. Responses were maintained
                   in 95% of patients with chronic
                   phase and 82% of those with accelerated
                   phase. All patients with
                   blast crisis relapsed within six
                   months (Talpaz et al., 2006).

Adverse events     Thrombocytopenia, gastrointestinal
                   bleeding, tumor lysis
                   syndrome, arthralgias, pyrexia,
                   fatigue, peripheral edema, headache,
                   diarrhea, mild prolongation
                   of QT interval

Characteristic     Nilotinib

Targets            Inhibits Bcr-Abl (b), SRC kinase,
                   KIT, PDGFR

Response rates     13 of 33 patients in blast crisis
                   had a hematologic response;
                   9 had a cytogenetic response.
                   33 of 46 patients in accelerated
                   phase had a hematologic
                   response; 22 had a cytogenetic
                   response. 11 of 12 patients in
                   chronic phase had a complete
                   hematologic remission (Kantarjian
                   et al., 2006).

Adverse events     Myelosuppression, transient
                   indirect hyperbilirubinemia, rash

(a) Including 14 of 15 mutant forms

(b) Including 32 of 33 mutant forms

Note. Based on inf
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Title Annotation:FIVE MINUTE INSERVICE; chronic myelogenous leukemia
Author:Oestreicher, Pamela
Publication:ONS Connect
Geographic Code:1USA
Date:Jul 1, 2007
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