Release Date: September 29, 2017
Expiration Date: September 29, 2018
Media: Internet - based
Community Practice Connections™: Expert Insights on the Management of Myeloproliferative Neoplasms: Evidence-based Approaches and Emerging Strategies to Address Challenges in Care features a summary of clinical evidence guiding best practices for the treatment of patients with myeloproliferative neoplasms (MPNs), including essential thrombocythemia, polycythemia vera, and myelofibrosis. This activity focuses on the important molecular and clinical features for diagnosis of these disorders, the nuances of risk stratification, current treatment approaches, as well as new potentially practice-changing approaches that may further advance the field, which are currently being evaluated in clinical trials. Interactive clinical vignettes are followed by short video interviews with leading experts in the management of patients with MPNs. The video interviews address decision points in the clinical vignettes, as well as questions commonly faced in the community oncology practice setting.
Acknowledgement of Commercial Support
This activity is supported by an educational grant from Incyte Corporation.
CME/CE Activity Table of Contents
Module 1: Essential thrombocythemia
Module 2: Polycythemia vera
Module 3: Post-polycythemia vera myelofibrosis
Instructions for This Activity and Receiving Credit
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Each presentation may contain an interactive question(s). You may move forward through the presentation; however, you may not go back to change answers or review videos/content until you finish the presentation.
At the end of the activity, “educational content/video files” will be available for your reference.
In order to receive a cme/ce certificate, participants must complete the activity.
Complete the posttest and pass with a score of 70% or higher, complete the evaluation and then click on request for credit. Participants may immediately download a cme/ce certificate upon completion of these steps.
This educational program is directed toward medical oncologists, surgical oncologists, and radiation oncologists interested in the treatment of hematological disorders. Nurse practitioners, physician assistants, nurses, and other healthcare professionals involved in the treatment and management of patients with hematological disorders are also invited to participate.
At the conclusion of this activity, you should be better prepared to:
Explain mechanistic approaches to manage myeloproliferative neoplasms and their biologic rationale
Discuss phenotypic drivers of myeloproliferative neoplasms and the implications for practice of new markers and diagnostic criteria
Evaluate emerging clinical data regarding new agents and evolving strategies for myeloproliferative neoplasms
Apply an evidence-based approach to optimize outcomes in the treatment of myeloproliferative neoplasms
Faculty, Staff, and Planners' Disclosures
Ruben A. Mesa, MD, FACP
Chair, Division of Hematology & Medical Oncology
Deputy Director, Mayo Clinic Cancer Center
Professor of Medicine
Disclosure: Grant Research Support: Incyte, Gilead, CTI BioPharma, NS Pharma, Promedior Consultant: Novartis, AOP
Daniel J. DeAngelo, MD, PhD
Associate Professor of Medicine
Harvard Medical School
Institute Physician, Adult Leukemia Program
Dana-Farber Cancer Institute
Disclosure: Consultant: Novartis, Amgen, Incyte Corporation, Pfizer, Takeda Pharmaceutical Company, Shire
John Mascarenhas, MD
Director, Adult Leukemia Program
Leader, Myeloproliferative Disorders Clinical Research Program
Tisch Cancer Institute, Division of Hematology/Oncology
Associate Professor of Medicine
Icahn School of Medicine at Mount Sinai
New York, NY
Disclosure: Grant Research Support: Incyte Corporation, Janssen Pharmaceutical, CTI BioPharma, Merck & Co., Roche Holding AG, Promedior Consultant: Novartis (DSMB), Incyte Corporation (Clinical Steering Contributing Trials)
Michael J. Mauro, MD
Leader, Myeloproliferative Neoplasms Program
Clinical Director, Leukemia Service
Memorial Sloan Kettering Cancer Center
Professor of Medicine, Weill Cornell Medical College
New York, NY
Disclosure: No relevant financial relationships with commercial interests.
The staff of PER® have no relevant financial relationships with commercial interests to disclose.
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As a sponsor accredited by the ACCME, it is the policy of PER® to ensure fair balance, independence, objectivity, and scientific rigor in all of its CME/CE activities. In compliance with ACCME guidelines, PER® requires everyone who is in a position to control the content of a CME/CE activity to disclose all relevant financial relationships with commercial interests. The ACCME defines “relevant financial relationships” as financial relationships in any amount occurring within the past 12 months that creates a COI.
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Off-Label Disclosure and Disclaimer
This CME/CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME/CE activity is for continuing medical and nursing education purposes only, and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER®.
PER Pulse Recap™
PER Pulse Recap (1 of 3)
This first of 3 PER Pulse™
Recaps reviews the pathogenesis of MPNs.
Below are some highlights from Dr. Mauro’s lecture:
There are 3 primary driver mutations in MPNs, each of which impacts survival:
The JAK2 V617F driver mutation was discovered in 2005 and is present in ~95% of all PV cases and in ~50% to 60% of all ET and myelofibrosis cases.
This mutation produces ligand-independent JAK2 signaling that increases proliferation and differentiation of hematopoietic progenitor cells and is a negative prognostic factor.
The MPL515 mutation in the thrombopoietin receptor is the least frequent of the driver mutations, being present in 3% to 6% of ET cases and 8% to 10% of myelofibrosis cases and absent altogether in PV.
The MPL515 mutation leads to constitutive activation of the Mpl protein and is a negative prognostic factor.
The CALR mutation is another driver mutation. It is present in <10% of ET cases, ~15% of myelofibrosis cases, but absent in PV.
The CALR mutation produces mutant calreticulin. Although the exact pathogenic mechanism has not been resolved, mutated calreticulin does appear to bind to Mpl and activate the JAK/STAT pathway. Its presence is a favorable prognostic factor.
Patients with triple-negative disease (negative for JAK2, MPL515, and CALR mutations), who account for 10% to 25% of all cases, have the worst prognosis.
In addition, there are several nondriver mutations that are also present in MPNs, including ASXL1, EZH2, SRSF2, and IDH1-2. The presence of any of these mutations negatively impacts survival.
PER Pulse Recap (2 of 3)
This second of 3 PER Pulse™
Recaps reviews the diagnosis and risk stratification of MPNs.
Below are some highlights from Dr. DeAngelo’s lecture:
A diagnosis of PV requires (1) elevated hemoglobin, elevated hematocrit, or increased red cell mass; (2) bone marrow findings of hypercellularity with panmyelosis, including pleomorphic mature megakaryocytes; and (3) either JAK2 mutation or subnormal erythropoietin level.
The definition of a complete response to PV therapy includes all of the following: hematocrit <45% (without phlebotomy), platelet count ≤400 x 109/L, white blood cell count ≤10 x 109/L, normal spleen size on imaging, and no disease-related symptoms.
Patients with PV are stratified into low-risk disease (age <60 and no history of thrombosis) and high-risk disease (age ≥60 or previous thrombosis).
The European LeukemiaNet has the following indications for cytoreductive therapy with hydroxyurea or interferon: (1) high-risk disease, (2) frequent phlebotomy requirement, (3) platelets >1500 x 109/L, and (4) progressive leukocytosis.
A diagnosis of ET requires (1) elevated platelet count, (2) bone marrow findings of abnormal megakaryocyte proliferation, (3) exclusion of diagnoses of other related disorders, and (4) presence of a specific mutation (JAK2, CALR, or MPL), presence of a clonal marker, or absence of evidence for reactive thrombocytosis.
In patients with ET, the risk of thrombosis is stratified into high risk (age ≥60 or previous thrombosis), low risk (age <60, no history of thrombosis, and platelet count <1 million), and low risk with extreme thrombocytosis (in which platelet count >1 million), which may have even lower thrombotic risk.
A diagnosis of post-PV or post-ET myelofibrosis requires previous diagnosis of PV or ET and grade 2 or 3 bone marrow fibrosis on a 0-3 scale or grade 3 or 4 fibrosis on a 0-4 scale. In addition, 2 of the remaining criteria are required: anemia, leukoerythroblastosis, worsening splenomegaly, constitutional symptoms, and increased serum lactose dehydrogenase level (post-ET disease only).
The Dynamic International Prognostic Scoring System for Primary Myelofibrosis (DIPSS) Plus uses 8 risk factors to predict survival: age >65, hemoglobin <10 g/dL, leukocytes >25 x 109/L, circulating blasts ≥1%, constitutional symptoms, red blood cell transfusion dependency, platelet count <100 x 109/L, and unfavorable karyotype.
Patients with myelofibrosis have a median survival time of 5.75 years.
Seven mutations have been identified that predict poor prognosis among patients with myelofibrosis: ASXL1, SRSF2, CBL, KIT, RUNX1, SH2B3, and CEBPA. Patients with these mutations have a median survival of only 3.6 years.
PER Pulse Recap (3 of 3)
This third of 3 PER Pulse™
Recaps describes evolving therapeutic options for patients with MPNs.
Below are some highlights from Dr. Mascarenhas’ lecture:
The phase III ARETA trial of anagrelide versus placebo in ET demonstrated that anagrelide produced superior 1-year event-free survival (87% vs 69%; HR, 0.356; P = .0008).
In an interim analysis of the randomized MPD-RC 112 trial in patients with high-risk PV or ET treated with either hydroxyurea or weekly pegylated interferon (IFN), no significant differences in either overall response rate or molecular response were observed between arms. Pegylated IFN appeared to have more safety concerns, however.
The phase III PROUD-PV study demonstrated noninferiority of biweekly ropeginterferon alfa-2b compared with hydroxyurea in complete hematologic response rate (43.1% vs 45.6%; P = .0028). In addition, ropeginterferon showed evidence of a more favorable safety profile than hydroxyurea among patients with PV.
Pacritinib, a JAK inhibitor, was compared with best available therapy (including ruxolitinib) in the phase III PERSIST-2 trial in patients with myelofibrosis and thrombocytopenia. Results suggest that pacritinib administered twice daily was superior in both spleen volume and symptom reduction compared with best available therapy, but this was not true for once-daily pacritinib.
Momelotinib, another JAK inhibitor, was compared with ruxolitinib in the phase III Simplify 1 trial in patients with myelofibrosis. Momelotinib met the primary noninferiority endpoint of spleen volume reduction at 24 weeks (26.5% vs 29.0%; P = .011), but it did not meet the secondary endpoint of total symptom score reduction.
PRM-151, or recombinant human pentraxin-2, is an endogenous regulator of tissue repair that has been shown to prevent and reverse fibrosis in preclinical models. In a phase I and extension study of PRM-151 alone or in combination with ruxolitinib, 9 of 13 patients achieved at least a 50% reduction in symptoms at 72 weeks and 9 of 10 evaluable patients had spleen reductions.
Other agents that have demonstrated activity in MPNs are idasanutlin, an MDM2 inhibitor; LCL161, a second mitochondrial-derived activator of caspases (SMAC) mimetic; sotatercept, an activin inhibitor; and imetelstat, a telomerase inhibitor.
For additional commentary about this topic and the Expert Insights on the Management of Myeloproliferative Neoplasms: Evidence-Based Approaches and Emerging Strategies to Address Challenges in Care
symposium, please visit www.gotoper.com