An Initiative to Equip Health-System Pharmacists to Select and Manage Drug Therapy for the Disease

Transcription

1 An Initiative to Equip Health-System Pharmacists to Select and Manage Drug Therapy for the Disease What Health-System Pharmacists Should Know About CML Chronic myelogenous leukemia (CML, also known as chronic myeloid, myelocytic, or granulocytic leukemia) is a hematopoietic stem cell disease for which the prognosis once was poor, with a 5-year survival rate less than 20% and a median survival time less than 3 years. 1 The prognosis and survival in patients with CML have improved markedly since the introduction of the first oral tyrosine kinase inhibitor, imatinib mesylate, in The majority of patients with CML now survive for more than 5 years after diagnosis. 2,3 Approximately 22,475 Americans have CML. 4 In 2009, about 5,050 new cases of CML and 470 deaths from the malignancy were expected in the United States. 5 CML accounts for about 10% to 15% of all leukemias. 5 The lifetime risk for CML is roughly 1 in CML primarily affects adults; it is rare in children. The average age at the time of diagnosis is 66 years. 5 The likelihood of the disease is higher in men than in women and in whites than in African Americans. 5 Almost all patients with CML have the Philadelphia chromosome, an abnormally shortened chromosome 22 formed as a result of reciprocal translocation of chromosomal material between chromosomes 9 and 22 [t(9;22)]. 6 This translocation results in the formation of the fusion BCR-ABL oncogene and the production of an aberrant BCR-ABL tyrosine kinase protein that causes rapid proliferation of CML cells. 7 The three phases of CML are based primarily on the number of myeloblasts (i.e., blast cells, which are immature white blood cells) in the blood or bone marrow, with important implications for prognosis and treatment. Most patients with CML are diagnosed in the chronic phase, which is characterized by less than 10% blasts in the blood or bone marrow, mild or no symptoms, and a good response to treatment. 5 The accelerated phase is characterized by more than Faculty Christopher A. Fausel, Pharm.D., BCPS, BCOP Co-chair, CML Initiative Clinical Director, Oncology Pharmacy Services Indiana University Simon Cancer Center Indianapolis, Indiana R. Donald Harvey III, Pharm.D., FCCP, BCPS, BCOP Co-chair, CML Initiative Assistant Professor Department of Hematology/Medical Oncology Director, Phase I Unit Winship Cancer Institute Emory University Atlanta, Georgia Ashley Morris Engemann, Pharm.D., BCOP Clinical Associate Department of Medicine Duke University Medical Center Durham, North Carolina Amy Hatfield Seung, Pharm.D., BCOP Pharmacy Clinical Specialist, Hematologic Malignancies Director, PGY2 Oncology Residency Program Sidney Kimmel Comprehensive Cancer Center Johns Hopkins Hospital Assistant Clinical Professor University of Maryland School of Pharmacy Baltimore, Maryland Joseph S. Bubalo, Pharm.D., BCPS, BCOP Oncology Clinical Pharmacy Specialist Assistant Professor of Medicine, Division of Hematology and Medical Oncology Oregon Health Sciences University Hospitals & Clinics Portland, Oregon Downloaded from Page 1

2 10% but fewer than 20% blasts in the blood or bone marrow. Patients may exhibit symptoms (e.g., fever, poor appetite, weight loss, splenomegaly), and they tend to have a less favorable response to treatment than patients in the chronic phase. The survival is usually less than 1 year without treatment. 7 The blast phase (also called acute phase or blast crisis) is characterized by more than 20% blasts in the blood or bone marrow and aggressive disease, with the spread of blast cells to tissues and organs beyond the bone marrow. Patients often are symptomatic and survive only a few months if they are not treated. 7 Imatinib mesylate, a selective inhibitor of BCR-ABL tyrosine kinase, is recommended in practice guidelines from the National Comprehensive Cancer Network (NCCN) as standard first-line therapy for CML in the chronic phase. 6 In the past, interferon-a was used for this purpose, but imatinib is now preferred because of greater efficacy, including improved overall survival. 8 Resistance can develop to imatinib as a result of mutations of BCR-ABL among other mechanisms. Some patients cannot tolerate imatinib because of adverse effects (e.g., edema, myelosuppression). Two second-generation oral tyrosine kinase inhibitors, dasatinib and nilotinib, with greater potency in inhibiting BCR-ABL have been developed since imatinib mesylate was introduced. 6 These new agents currently are recommended by NCCN as second-line therapy for patients who develop resistance to or are unable to tolerate imatinib, but research is under way to explore the use of these second-generation agents as first-line therapy. Why Focus on CML? Many health-system pharmacists who do not practice in oncology settings do not have practical knowledge of cancer chemotherapies because of a lack of involvement in the dispensing and administration of oral and intravenous chemotherapy. Oral chemotherapy using tyrosine kinase inhibitors on a long-term basis in the ambulatory setting is now the standard of care for patients with chronic myelogenous leukemia (CML). Pharmacists need to understand the natural history of, molecular basis for, and treatment of CML and the proper use of oral tyrosine kinase inhibitors, including potential drug interactions with and adverse effects from these agents. Knowledge of drug therapy monitoring methods, dose-adjustment strategies, and options for managing toxicity and interactions will enable pharmacists to take an active role in the management of drug therapy for patients with CML References 1. Miller KB, Grodman HM. Leukemia. In: Lenhard RE Jr, Osteen RT, Gansler T, eds. Clinical oncology. Atlanta, GA: The American Cancer Society; 2001: Druker BJ, Guilhot F, O Brien SG et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006; 355: Hochhaus, O Brien SG, Guilhot F et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009; 23: The Leukemia & Lymphoma Society. Chronic myelogenous leukemia. id=8501#response (accessed 2010 Apr 13). American Cancer Society. Detailed guide: leukemia chronic myeloid. (accessed 2010 Apr 13). National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: chronic myelogenous leukemia. v (accessed 2010 Apr 13). National Cancer Institute. Chronic myelogenous leukemia treatment (PDQ ). HealthProfessional (accessed 2010 Apr 13). Guilhot F, Drucker B, Larson RA et al. High rates of durable response are achieved with imatinib after treatment with interferon alpha plus cytarabine: results from the International Randomized Study of Interferon and STI571 (IRIS) trial. Haematologica. 2009; 94: Downloaded from Page 2

3 Take the Initiative ASHP Advantage with the support of Novartis Oncology has developed an educational initiative to equip health-system pharmacists to select and manage drug therapy in patients with CML. The initiative comprises a live educational activity on CML with interactive case studies to be conducted in 17 different locations in cooperation with ASHP state affiliates. Audience response questions are integrated into the case studies, allowing participants to apply the information to different patient scenarios. The activity title and content are as follows: Chronic Myelogenous Leukemia: Considerations for Selecting and Managing Therapy What is a live webinar? A live webinar brings the presentation to you at your desk at work or in your home, or through a staff inservice program. You listen to the speaker make a presentation in real time using a telephone connection while you view slides that highlight key concepts on a computer screen. You have the opportunity to ask questions using your keyboard at the end of the program. 1) Introduction a) Epidemiology b) Natural history c) Molecular pathophysiology d) Historical treatment options (busulfan, hydroxyurea, stem cell transplantation) 2) Imatinib a) Molecular pharmacology b) Toxicity profile c) Drug-drug interactions d) Clinical trial data (IRIS trial) for newly diagnosed patients e) Data in accelerated phase/chronic phase 3) Second-generation tyrosine kinase inhibitors (dasatinib and nilotinib) a) Pharmacodynamics compared with imatinib b) Toxicity profile compared with imatinib c) Drug-drug interactions d) Data in chronic phase, accelerated phase/blast crisis (second-line use) e) Role as a third-line agent f) Comparative costs of dasatinib, nilotinib, and imatinib 4) Stem cell transplantation (brief overview of how its role has changed) 5) Future directions The live educational activity will be repeated three times as a live webinar that will also be archived as a web-based activity. The Web-based activity may be completed at any time. Choose the webinar date and time most convenient for you: Tuesday, April 27 12:00-1:00 pm (EDT) Tuesday, May 18 1:00-2:00 pm (EDT) Wednesday, June 23 2:00-3:00 pm (EDT) The activity has been developed by a group of nationally-recognized oncology experts. One hour (0.1 CEU) of continuing pharmacy education (CPE) credit will be offered. To obtain further details, including a schedule of dates and locations for the live educational activities and to register, go to Register today! Downloaded from Page 3

4 CE Information The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity provides 1 hour (0.1 CEU) of continuing pharmacy education credit (ACPE Activity # L01P and H01P). Attendees must complete a Continuing Pharmacy Education Request online and may immediately print their official statements of continuing pharmacy education credit at the ASHP Learning Center ( following the activity. For complete information on the educational activities included in this initiative and to sign up to receive updates, visit There is no fee for participation in these activities. Please share this e-newsletter with colleagues who might be interested in this topic. Planned and conducted by ASHP Advantage and supported by an educational grant from Novartis Oncology. Making a Difference ASHP Advantage is interested to know how educational activities affect pharmacy practice and patient outcomes, and what educational needs might remain after an activity. Therefore, participants in the live educational activity will be asked how information gleaned from the activity might be applied in clinical practice and what educational needs remain. Participants in the live webinars will receive a brief survey from ASHP Advantage with questions designed to ascertain the impact of information obtained from the webinar on clinical practice and identify any unmet educational needs. Please complete the evaluation or survey to provide us with feedback about changes in practice and unmet educational needs. The aggregate information will be used to plan future educational activities. Emerging News New European LeukemiaNet Recommendations for CML Management In December 2009, the European LeukemiaNet, a consortium of European physicians and researchers whose mission is to develop and strengthen scientific and technological excellence in leukemia research and treatment, updated its 2006 recommendations for the management of CML. The new recommendations focus on the three currently available BCR-ABL tyrosine kinase inhibitors and are based on a comprehensive review of recently reported results of therapeutic interventions and monitoring procedures using various definitions of responses. Imatinib 400 mg/day is recommended as standard first-line therapy in patients with chronic-phase CML, which is consistent with current NCCN guidelines. The drug should be continued indefinitely in optimal responders. An imatinib dosage increase or use of dasatinib or nilotinib instead of imatinib might be considered for suboptimal responders to standard-dose imatinib. Dasatinib or nilotinib is recommended for patients with imatinib failure. Mutational analysis is recommended for all patients who demonstrate imatinib failure. The choice between the two second-generation agents may Downloaded from Page 4

5 be based on mutational analysis because the development of BCR-ABL mutations is a recognized cause of resistance to second-generation tyrosine kinase inhibitors as well as imatinib. The type of mutation associated with resistance to secondgeneration agents appears to differ, with F317l mutations commonly associated with dasatinib resistance, and E255K/V and Y253H mutations commonly associated with nilotinib resistance. The T315l mutation is associated with resistance to all three currently available tyrosine kinase inhibitors. Successful treatment with a tyrosine kinase inhibitor should not be discontinued. The dosage should not be reduced to less than the standard dose unless substantial adverse effects are present. Allogeneic hematopoietic stem-cell transplantation is recommended for patients who present in the accelerated phase or blast phase or display the T315l mutation. Transplantation also may be used in patients with a suboptimal response to second-line dasatinib or nilotinib therapy. Reference: Baccarani M, Cortes J, Pane F et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009; 27: Importance of Adherence in Response to Imatinib The prevalence, predictors, and consequences of CML patient nonadherence to imatinib were assessed in a prospective, noninterventional study known as ADAGIO conducted in Belgium and published in May Observations of adherence were made in 169 patients at two times 90 days apart using clinical interviews by physicians of patients or third persons (e.g., family members); visual analogue scale ratings by physicians, patients, and third persons; and pill counts. One third of the patients were judged nonadherent. Only 14.2% of patients were adherent with 100% of prescribed imatinib doses. Nonadherence was more common in patients with a suboptimal response than in patients with an optimal response to imatinib. Knowledge of the disease and treatment, a large number of medications taken daily, secondary school or higher education, and self-efficacy in long-term medication behavior correlated with adherence. Advanced age, a long time since CML diagnosis, living alone, male sex, long duration of imatinib therapy, imatinib dose of 600 mg/day or higher, high degree of chronic care received, and high self-reported functional status and quality of life correlated with nonadherence. A medication event monitoring system comprising a prescription vial with an electronic device in the cap to automatically record each time the vial is opened was used to measure adherence in a study described in a poster presentation at the 51 st American Society of Hematology Annual Meeting and Exposition in December Adherence to imatinib therapy was evaluated over a 3-month period in 87 consecutive patients with chronic-phase CML. The patients had received the drug as first-line therapy for a median duration of 59.7 months prior to study enrollment and were in complete cytogenetic response. The median adherence rate was 97.6%, but the adherence rate was 90% or less in a subset of 23 (26%) patients. The 6-year probabilities of major molecular response and complete molecular response were significantly lower in this subset of patients than in patients with an adherence rate exceeding 90%. Adherence was an independent predictor of major molecular response and complete molecular response. The findings of these studies suggest that adherence plays an instrumental role in the success of imatinib therapy in patients with CML. Some of the factors that promote adherence and contribute to nonadherence are modifiable, particularly knowledge of the disease and treatment. Pharmacists can promote adherence through patient and caregiver education. References: Noens L, van Lierde MA, De Bock R et al. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood. 2009; 113: Bazeos A, Khorashad J, Mahon FX et al. Long term adherence to imatinib therapy is the critical factor for achieving molecular responses in chronic myeloid leukemia patients. Presented at the 51 st American Society of Hematology Annual Meeting and Exposition. December 7, Available at: (accessed 2010 Mar 16). Downloaded from Page 5

6 New Research Sheds Light on Mechanism for Imatinib Resistance Researchers at the National Institute of Arthritis and Musculoskeletal and Skin Diseases and University of Southern California recently determined that a B-cell-specific enzyme, activation-induced cytidine deaminase (AID), is associated with imatinib resistance and progression to blast crisis in patients with CML. These findings were published in September The AID protein causes BCR-ABL mutations that result in imatinib resistance, and AID is expressed in high concentrations in blast cells. This finding may facilitate the development of therapies to overcome imatinib resistance and improve survival in patients with CML. Reference: Klemm L, Duy C, Iacobucci I et al. The B cell mutator AID promotes B lymphoid blast crisis and drug resistance in chronic myeloid leukemia. Cancer Cell. 2009; 16: Available at FDA Grants Nilotinib Priority Review for Newly-Diagnosed CML in the Chronic Phase Nilotinib was approved by the Food and Drug Administration (FDA) in 2007 for the treatment of chronic- and accelerated-phase CML in adults resistant to or intolerant of imatinib. In February 2010, FDA granted nilotinib priority review for the treatment of adults with newly-diagnosed CML in the chronic phase. This priority review reduces the standard review time from 10 months to 6 months. Data presented by Giuseppe Saglio and colleagues in a late-breaking session at the 51st American Society of Hematology Annual Meeting and Exposition in December 2009 provided some of the impetus for this accelerated review. These data were obtained from Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients, a phase III, randomized, open-label study known as ENESTnd. This study compared the efficacy and safety of imatinib 400 mg once daily (the current standard of care) with two dosing regimens of nilotinib in 846 patients with newly-diagnosed CML in the chronic phase. Nilotinib 300 mg twice daily and 400 mg twice daily both induced significantly higher rates of and shorter times to major molecular response and complete cytogenetic response over a 12-month period compared with imatinib. The rate of progression to advanced disease was lower with nilotinib than imatinib, and both agents were well-tolerated. These findings support the use of nilotinib for newly-diagnosed patients. Dasatinib also may prove useful for first-line treatment of CML. In a study published in January 2010 of 50 newly-diagnosed patients with early, chronic-phase CML who were followed for at least 3 months, high rates of major molecular response and complete cytogenetic response were achieved with dasatinib 100 mg once daily or 50 mg twice daily. Additional clinical trials of dasatinib and nilotinib for treatment of newly-diagnosed early, chronic-phase CML are under way. References: Saglio G, Kim DW, Issaragrisil S et al. Nilotinib demonstrates superior efficacy compared with imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase: results from the international randomized phase III ENESTnd trial. Presented at the 51st American Society of Hematology Annual Meeting and Exposition. New Orleans, LA: December 8, Abstract LBA-1. Available at ash.confex.com/ash/2009/webprogram/paper25663.html. Cortes JE, Jones D, O Brien S et al. Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia. J Clin Oncol. 2010; 28: Available at Downloaded from Page 6

7 Key to CML Progression Identified Researchers at the Ohio State University have linked the progression of CML to the loss of a microrna molecule known as mir-328 from immature white blood cells. Their findings were published in March The mir-328 molecule appears to ordinarily function as a decoy by binding to a protein that prevents white blood cells from maturing. The presence of mir-328 allows normal maturation, and loss of the molecule impedes maturation, resulting in progression to blast crisis. This finding improves understanding of CML progression and may help elucidate treatment strategies. Reference: Eiring AM, Harb JG, Neviani P et al. mir-328 functions as an RNA decoy to modulate hnrnp E2 regulation of mrna translation in leukemic blasts. Cell. 2010; 140: Available at m=140%5bvolume%5d%20and%20652%5bpage%5d%20and%202010%5bpdat%5d. Upcoming Meeting The American Society of Clinical Oncology (ASCO) Annual Meeting, the premier event for sharing late-breaking clinical research findings in the oncology community, will be held June 4-8, 2010, in Chicago. Abstracts of live and poster presentations will be released to the public on the ASCO Web site ( on May 20. Look for highlights of the ASCO presentations pertaining to CML in future e-newsletters from ASHP Advantage, which will be sent to registrants for the live educational activities or webinars and can be accessed at the initiative Web site. Downloaded from Page 7