Peer Review Directed by: SM Medical Education Activities for Clinicians Since 1980 University of California Irvine, School of Medicine Peer Review Directed by Offices of CME at: Education Initiative in Oncology Profiles in CML: Case-Based Approaches to Managing Resistance PENN CME University of Pennsylvania, School of Medicine A CME/CE On-Demand Webcast www.clinicianschannel.com/cmlwebcast Syllabus Table of Contents Introduction... 3 Program Information... 4 Faculty Biographies... 5 Profiles in CML: Overview of Practice Challenges Moshe Talpaz, MD.... 7 Profiles in CML: Case 1 Neil P. Shah, MD, PhD... 8 Profiles in CML: Case 2 Michael J. Mauro, MD... 9 Suggested Readings...10 This independent CME/CE activity is supported by an educational grant from Bristol-Myers Squibb. Copyright 2009. Projects In Knowledge, Inc. All rights reserved. Projects In Knowledge, Overlook at Great Notch, 150 Clove Road, Little Falls, NJ 07424 www.projectsinknowledge.com 1875
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Introduction Profiles in CML: Case-Based Over the past 10 years, mortality from chronic myeloid leukemia (CML) has decreased from 2400 deaths in 1997 to 490 deaths in 2007. This decrease has been due largely to the development of BCR-ABL tyrosine kinase inhibitors (TKIs) that block the activity of the mutant BCR-ABL protein responsible for the disease. Although the first of these BCR-ABL inhibitors, imatinib, has become standard therapy for newly diagnosed patients, many patients develop resistance-conferring mutations that result in loss of response to the drug. More than 100 BCR-ABL mutations have been identified that confer varying degrees of loss of sensitivity to imatinib. Two newer BCR-ABL TKIs, dasatinib and nilotinib, are effective against most tumors bearing these mutations. Determining whether to increase imatinib dosage or switch to another agent in the case of imatinib failure or suboptimal response and, if switching agents, which of the two newer inhibitors is the most appropriate second-line therapy for an individual patient is based on several factors. These include the level of the patient s response to imatinib, the specific BCR-ABL mutations present, and preexisting risk factors, such as bleeding disorders, diabetes, and cardiac, pancreatic, and liver disease. In this webcast, experts in the treatment of CML discuss BCR-ABL inhibitors and weigh available choices among therapeutic options in determining the best therapy for two actual patients. We welcome you to this timely and informative webcast and hope that it is useful to you in incorporating new treatment options into your own practice. Page 3 of 10
Program Information Target Audience This CME/CE activity is designed for medical oncologists, hematologists/oncologists, hematologists, leukemia specialists, and other healthcare professionals who are involved in the management of patients with CML. Activity Goal The goal of this activity is to provide clinicians with a case-based approach that facilitates competence and performance through a better understanding of BCR-ABL kinase inhibitors, methodology (hematologic, cytogenetic, and molecular responses) for early identification and monitoring of treatment failure/suboptimal responses/resistance, and treatment strategies that include alternative second-generation BCR-ABL kinase inhibitors. Learning Objectives By understanding the disease progression process in CML and assay methodology, measure the hematologic, cytogenetic, and molecular responses of patients undergoing first-line treatment for CML. Based on BCR-ABL mutation analysis in CML patients who develop resistance to first-line treatment and on the mechanism of action, efficacy, and safety of current and emerging alternative BCR-ABL kinase inhibitors, implement optimal, personalized CML treatment strategies to maximize patient response. CME Information: Physicians Statement of Accreditation Projects In Knowledge is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Credit Designation Projects In Knowledge designates this educational activity for a maximum of 1.25 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity. CE Information: Pharmacists Projects In Knowledge is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity has been planned and implemented in accordance with the ACPE Criteria for Quality and Interpretive Guidelines. The ACPE Universal Program Number assigned to the program, for 1.25 contact hour (0.125 CEU) is 052-000-09-010-H01-P. CME Information: Nurses Projects In Knowledge, Inc. (PIK) is an approved provider of continuing nursing education by the Delaware Nurses Association, an accredited approver by the American Nurses Credentialing Center s Commission on Accreditation. PIK Provider Code: 08-09-03. Projects In Knowledge is also an approved provider by the California Board of Registered Nursing, Provider Number CEP-15227. This activity is approved for 1.41 nursing contact hours. Disclaimer: Accreditation refers to educational content only and does not imply ANCC, DNA, CBRN, or PIK endorsement of any product. Disclosure Information The Disclosure Policy of Projects In Knowledge requires that presenters comply with the Standards for Commercial Support. All faculty are required to disclose any personal interest or relationship they or their spouse/partner have with the supporters of this activity or any commercial interest that is discussed in their presentation. Any discussions of unlabeled/unapproved uses of drugs or devices will also be disclosed in the course materials. For complete prescribing information on the products discussed during this CME/CE activity, please see your current Physicians Desk Reference (PDR). Faculty Disclosures Complete faculty disclosure information is available at www.clinicianschannel.com/cmlwebcast Peer Reviewer has no significant relationships to disclose. Projects In Knowledge's staff members have no significant relationships to disclose. Conflicts of interest are thoroughly vetted by the Executive Committee of Projects In Knowledge. All conflicts are resolved prior to the beginning of the activity by the Trust In Knowledge peer review process. The opinions expressed in this activity are those of the faculty and do not necessarily reflect those of Projects In Knowledge. This CME/CE activity is provided by Projects In Knowledge solely as an educational service. Specific patient care decisions are the responsibility of the clinician caring for the patient. Projects In Knowledge is a registered trademark of Projects In Knowledge, Inc. This independent CME/CE activity is supported by an educational grant from Bristol-Myers Squibb. Page 4 of 10
CHAIR Profiles in CML: Case-Based Faculty Biographies Moshe Talpaz, m d Professor Department of Internal Medicine Hematology/Oncology University of Michigan Comprehensive Cancer Center Ann Arbor, Michigan Moshe Talpaz, MD, Associate Chief, Division of Hematology/ Oncology, University of Michigan, is a leading clinical investigator in hematologic malignancies. Dr. Talpaz focuses on the treatment of chronic myeloid leukemia (CML) and brings special expertise in immunotherapy, cytokines, and biologic response modifiers. Internationally known for his role in the development of targeted cancer therapeutics, Dr. Talpaz pioneered the study of interferon in CML, which was the first-line therapy for CML until the introduction of imatinib. A pivotal member of the team that developed imatinib, Dr. Talpaz was instrumental in bringing to market one of the most effective targeted treatments used to date in cancer care. As a leader in the development of novel therapeutics, Dr. Talpaz has unique experience in the building of phase I clinical trial programs. In addition to expanding the University of Michigan s program in hematologic malignancies, he will be establishing a phase I therapeutics program at the Cancer Center. Dr. Talpaz joined the University of Michigan in 2006, from M.D. Anderson Cancer Center in Houston, where he was professor of medicine and held the David Bruton Chair for Cancer Research. He has authored or co-authored nearly 400 articles in top national journals and textbooks, and is a member of the American Society of Hematology and the NCCN Chronic Myelogenous Leukemia Guidelines Panel. Page 5 of 10
Faculty Biographies FACULTY Michael J. Mauro, m d Associate Professor Center for Hematologic Malignancies, Knight Cancer Institute Oregon Health & Science University Portland, Oregon Michael J. Mauro, MD, Associate Professor, Division of Hematology-Oncology, Oregon Health & Science University, Portland, Oregon, has extensive clinical and research experience in the treatment of chronic myeloid leukemia (CML) and other myeloproliferative disorders. His current research focus is on the monitoring and management of minimal residual disease, optimizing response to therapy in patients with CML, and the patient decision-making process in choosing between stem cell transplant and nontransplant therapy. At present, he is directing several clinical trials of novel agents, including vaccines and second- and thirdgeneration targeted therapies in patients with CML and Ph+ acute lymphocytic leukemia. Dr. Mauro received his undergraduate and graduate medical degrees from Dartmouth College and Dartmouth Medical School. He then went on to complete an internship and residency in internal medicine at New York Hospital-Cornell University Medical Center and a fellowship in hematology/ oncology at Weill Medical College of Cornell University Medical Center-New York-Presbyterian Hospital in New York. He is an associate editor for the Journal of Hematology & Oncology, and has published widely on the use of BCR-ABL kinase inhibitors, interferon alpha, and stem cell transplantation in the treatment of patients with CML. Among other honors, Dr. Mauro received First Prize, New York Society for the Study of Blood Research Award, for his work in thrombotic thrombcytopenic purpura. His current professional activities include serving as vice president of the Oregon Chapter, Leukemia & Lymphoma Society, and chairman of the Oregon Cancer Institute Data Safety Monitoring Committee. FACULTY Neil P. Shah, m d, phd Assistant Professor Division of Hematology/Oncology University of California San Francisco School of Medicine San Francisco, California Neil P. Shah, MD, PhD, Assistant Professor, Department of Hematology & Oncology at the University of California, San Francisco (UCSF) School of Medicine, is an expert in developing molecularly targeted therapies for chronic myeloid leukemia and other hematologic malignancies. Dr. Shah has played a critical role in the development of several tyrosine kinase inhibitors, including dasatinib. His most recent honors include the Leukemia & Lymphoma Society Career Development Award for Special Fellows (2004 2007) and the Doris Duke Charitable Foundation Clinical Scientist Development Award (2006 2009). Dr. Shah is interested in improving targeted treatments of human hematologic malignancies. Through his work in recent years, Dr. Shah has sought to understand the molecular mechanisms of disease response, resistance, and persistence in human CML, with the hope of developing therapies that can cooperate with the antiproliferative effects of kinase inhibitors. Dr. Shah received his Bachelor of Science degree from the University of California, Berkeley, and pursued further education at the University of California, Los Angeles (UCLA). He obtained a PhD in microbiology and molecular genetics in 1992 and performed his doctoral dissertation on the molecular basis of CML. He then obtained an MD from the UCLA School of Medicine, where he also completed a Residency in internal medicine and a Fellowship in hematology and oncology in 2003. He performed postdoctoral research in the laboratory of Charles Sawyers. From 2003 to 2006 Dr. Shah was Associate Physician and visiting assistant professor, in the Division of Hematology and Oncology at the David Geffen School of Medicine at UCLA. Since 2006, Dr. Shah has held the position of assistant professor, Division of Hematology and Oncology, UCSF School of Medicine. Page 6 of 10
Profiles in CML: Overview of Practice Challenges Moshe Talpaz, MD Chronic myeloid leukemia (CML) is an abnormal clonal hematopoietic stem cell disorder characterized by increased cell proliferation and decreased apoptosis and adhesion. CML is linked to a single cytogenetic abnormality, the Philadelphia chromosome, which is formed by a reciprocal translocation between chromosomes 9 and 22. The resulting fusion gene, BCR-ABL, codes for an abnormal tyrosine kinase. The BCR portion of this protein interferes with the regulatory component of ABL kinase activity, resulting in kinase activity that is constitutively activated. Left untreated, CML progresses through three phases chronic phase, accelerated phase, and blast crisis characterized by increasing refractoriness to therapy and worsening clinical features and laboratory findings. Although the majority of patients present in chronic phase and then progress to accelerated phase, 25% to 40% of patients progress directly from chronic phase to the terminal blast crisis without evidence of a transitional accelerated phase. Although the incidence of CML has remained constant at 4300 to 4570 cases over the past 10 years, mortality has been greatly reduced from 2400 deaths in 1997 to fewer than 500 in 2007. This reduction has been due primarily to the availability of new BCR-ABL tyrosine kinase inhibitors. The first of these, imatinib, has resulted in a 7-year overall survival rate of 86%, and a 94% survival rate if only CML-related deaths are considered. However, the development of BCR-ABL specific resistance-conferring mutations occurs over time in approximately 50% of patients, necessitating alternative treatment strategies. Two novel BCR-ABL tyrosine kinase inhibitors, dasatinib and nilotinib, have been developed that are active against most BCR-ABL mutations. The use of these three agents is discussed in the following case presentations. Page 7 of 10
Profiles in CML: Case 1 Neil P. Shah, MD, PhD Imatinib, a BCR-ABL selective tyrosine kinase inhibitor, has established itself as standard therapy for patients with newly diagnosed chronic myeloid leukemia (CML). Although responses in individuals with chronic phase disease are typically durable, a proportion of patients suffer relapsing disease. Additionally, patients with advanced disease most often develop resistance to the drug within a period of months to a few years. Currently, more than 90 BCR-ABL mutations associated with varying degrees of clinical resistance to imatinib have been identified at varying frequency, among them the E255K mutation. This case presentation discusses the factors involved in determining therapy for imatinib-resistant patients with this commonly detected mutation. Two second-generation BCR-ABL tyrosine kinase inhibitors, dasatinib and nilotinib, have been approved for the treatment of imatinib-resistant CML. Dasatinib is effective against a wide range of imatinib-resistant BCR-ABL mutations, including E255K, with an overall survival in imatinib-resistant/intolerant patients of 96% at 12 months and 91% at 24 months. Although nilotinib is also effective against a variety of imatinib-resistant mutations in vitro, the sensitivity of various mutations to nilotinib varies substantially, with some, such as E255K, associated with significantly relative resistance in vitro and less-favorable clinical response rates and progression-free survival. Given the reduced sensitivity of this patient s mutation to nilotinib, dasatinib is the most appropriate second-line treatment. In summary, while both dasatinib and nilotinib are beneficial in treating most imatinib-resistant patients, individuals with select mutations that are more sensitive to a specific second-line agent should be treated preferentially with that drug. Page 8 of 10
Profiles in CML: Case 2 Michael J. Mauro, MD Although imatinib is considered standard therapy for newly diagnosed patients with chronic myeloid leukemia (CML), not all patients respond to therapy and of these, many develop mutations believed to confer resistance. Various analyses of IRIS trial data have demonstrated the value of log reductions in qpcr at 3 months in predicting a subsequent major molecular response, as well as the predictive value of percent Ph+ cells at 6 months in determining both complete cytogenetic response at 12 months and event-free survival at 42 months. Investigators have also shown that patients with suboptimal response (35% 95% Ph+) or failure to respond (>95% Ph+) to imatinib early in treatment (6 12 months) have similar outcomes, with a significantly inferior likelihood of achieving remission and/or remaining progression-free compared with patients with more optimal response. Development of BCR-ABL kinase domain mutations is observed in >50% of cases of clinical resistance to imatinib. More than 100 BCR-ABL mutations conferring varying degrees of resistance to imatinib have been identified, with the mutation at position 315 resulting in resistance to the two other available BCR-ABL tyrosine kinase inhibitors, dasatinib and nilotinib, as well. In addition to these mutations, other mechanisms, including BCR-ABL amplification, Ph+ clonal evolution, decreased drug exposure, and mutations in other genes, may also result in loss of response. Both dasatinib and nilotinib provide effective salvage therapy in the case of imatinib failure. Factors to be considered in choosing between the two include the specific mutation profile of each case as well as specific patient comorbidities in light of known toxicities. Several new BCR-ABL tyrosine kinase inhibitors are currently being explored that promise to expand future treatment options for patients with CML. When to increase imatinib dosage versus switching to another agent, factors to consider in choosing salvage therapy, and when/ whether to proceed to stem cell transplantation are discussed in this case presentation. Page 9 of 10
Suggested Readings Branford S, Rudzki Z, Walsh S, et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood. 2003;102:276-283. Giles FJ, Cortes J, Jones D, et al. MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood. 2007;109:500-502. Hochhaus A, Kantarjian HM, Baccarini M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109:2303-2309. Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood. 2006;108:28-37. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome positive ALL. N Engl J Med. 2006:354:2542-2551. Khorashad JS, Anand M, Marin D, et al. The presence of a BCR-ABL mutant allele in CML does not always explain clinical resistance to imatinib. Leukemia. 2006;20:658-663. Koptyra M, Falinski R, Nowicki MO, et al. BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood. 2006;108:319-327. Skorski T. BCR/ABL regulates response to DNA damage: the role in resistance to genotoxic treatment and in genomic instability. Oncogene. 2002;21:8591-8604. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531-2541. www.clinicianschannel.com/pik/1875/1875_cmlpracticetools.pdf Page 10 of 10