The risk of essential thrombocytopenia (ET), polycythemia vera (PV), and prefibrotic primary myelofibrosis (PrePMF) developing into overt myelofibrosis (MF) increases with age, the accumulation of mutations, and the activation of proliferative pathways, which identifies new targets for therapeutic intervention.
The findings, based on an analysis of the mutational landscape of more than 1700 genes and the gene expression of various cells from patients with myeloproliferative neoplasms (MPNs), was published in Clinical Cancer Research.1
ET, PV, PMF, and MF are all part of a group of diseases MPNs, in which a mutation in the bone marrow causes too many red blood cells, white blood cells, or platelets.2 In addition to being the most common MPNs, ET, PV, and PMF share the presence of mutations in either Janus kinase 2 (JAK2), calreticulin (CALR), and/or MPL.3 ET and PV are less aggressive forms of MPN, but they still can progress to MF. According to the Leukemia & Lymphoma Society, Pre-PMF will likely progress to PMF, “suggesting that more regular observations for pre-fibrotic PMF patients is warranted.”3
Jean-Jacques Kiladjian, Francisca Ferrer Marin, Haifa Kathrin Al-Ali, Alberto Alvarez-Larrán, Eloise Beggiato, Maria Bieniaszewska, Massimo Breccia, Veronika Buxhofer-Ausch, Olga Cerna, Ana-Manuela Crisan, Catalin Doru Danaila, Valerio De Stefano, Konstanze Döhner, Victoria Empson, Joanna Gora-Tybor, Martin Griesshammer, Sebastian Grosicki, Paola Guglielmelli, Valentin García-Gutierrez, Florian H. Heidel, Arpád Illés, Ciprian Tomuleasa, Chloe James, Steffen Koschmieder, Maria-Theresa Krauth, Kurt Krejcy, Mihaela-Cornelia Lazaroiu, Jiri Mayer, Zsolt György Nagy, Franck-Emmanuel Nicolini, Francesca Palandri, Vassiliki Pappa, Andreas Johannes Reiter, Tomasz Sacha, Stefanie Schlager, Stefan Schmidt, Evangelos Terpos, Martin Unger, Albert Wölfler, Blanca Xicoy Cirici & Christoph Klade
Abstract
Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). Current ET treatments aim to normalize hematological parameters and reduce the thrombotic risk, but they do not modify the natural history of the disease and hence, have no impact on disease progression. Ropeginterferon alfa-2b (trade name BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval, has demonstrated a robust and sustained efficacy in polycythemia vera (PV) patients. Given the similarities in disease pathophysiology and treatment goals, ropeginterferon alfa-2b holds promise as a treatment option for ET. The ROP-ET trial is a prospective, multicenter, single-arm phase III study that includes patients with ET who are intolerant or resistant to, and/or are ineligible for current therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman, leaving these patients with limited treatment options. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. Secondary endpoints include improvements in symptoms and quality of life, molecular response and the safety profile of ropeginterferon alfa-2b. Over a 3-year period the trial assesses longer term outcomes, particularly the effects on allele burden and clinical outcomes, such as disease-related symptoms, vascular events and disease progression. No prospective clinical trial data exist for ropeginterferon alfa-2b in the planned ET study population and this study will provide new findings that may contribute to advancing the treatment landscape for ET patients with limited alternatives.
A review published in the American Journal of Hematology details current aspects of diagnosis, risk stratification, and management of essential thrombocythemia (ET). The review was written by Ayalew Tefferi, MD, of Mayo Clinic in Rochester, Minnesota; Alessandro Maria Vannucchi, MD, of the University of Florence in Florence, Italy; and Tiziano Barbui, MD, of Papa Giovanni XXIII Hospital in Bergamo, Italy.
Regarding ET diagnosis, Tefferi and colleagues highlighted criteria from the International Consensus Classification. This system involves multiple criteria for ET diagnosis, such as thrombocytosis (with a platelet count ≥450×109/L), exclusion of other myeloid neoplasms, and other features, such as possible mutation of JAK2, CALR, or MPL. However, the authors noted, up to 20% of patients having ET might be negative for mutations in all 3 of these genes.
According to data from the Surveillance, Epidemiology, and End Results Registry in the US, the 5-year survival rate among 8768 patients with ET was 88.7%. The median survival time for this population was 12.1 years.
Among risk factors related to survival with ET, the authors considered age to be most important. Additional risk factors identified for survival vary by the risk model being used. The triple A survival risk model, for example, includes absolute neutrophil count and absolute lymphocyte count, in addition to age, and stratifies patients into 4 risk groups with median survival times ranging from 8 years in the high-risk group to 47 years in the low-risk group. The authors emphasized age, presence of a thrombosis history, and presence of JAK2 mutation as risk factors for thrombosis with ET.
In describing their treatment approach to ET, the authors indicated they began with consideration of thrombosis risk stratification, with some treatment options within thrombosis risk groups based on cardiovascular risk.
JNJ-88549968 is under clinical development by Johnson & Johnson and currently in Phase I for Essential Thrombocythemia. According to GlobalData, Phase I drugs for Essential Thrombocythemia does not have sufficient historical data to build an indication benchmark PTSR for Phase I. GlobalData uses proprietary data and analytics to create drugs-specific PTSR and LoA in the JNJ-88549968 LoA Report.
GlobalData tracks drug-specific phase transition and likelihood of approval scores, in addition to indication benchmarks based off 18 years of historical drug development data. Attributes of the drug, company and its clinical trials play a fundamental role in drug-specific PTSR and likelihood of approval.
JNJ-88549968 overview
JNJ-88549968 is under development for the treatment of calreticulin (CALR)-mutated myeloproliferative neoplasms, essential thrombocythemia, neoplasms, leukemia and myelofibrosis. The therapeutic candidate is a bispecific antibody acts by targeting calreticulin and CD3.
Julien Grenier, Wassim El Nemer, and Maria De Grandis
Abstract
Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) characterized by clonal erythrocytosis and thrombocytosis, respectively. The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. Despite a debated notion that red blood cells (RBCs) play a passive and minor role in thrombosis, there has been increasing evidence over the past decades that RBCs may play a biological and clinical role in PV and ET pathophysiology. This review summarizes the main mechanisms that suggest the involvement of PV and ET RBCs in thrombosis, including quantitative and qualitative RBC abnormalities reported in these pathologies. Among these abnormalities, we discuss increased RBC counts and hematocrit, that modulate blood rheology by increasing viscosity, as well as qualitative changes, such as deformability, aggregation, expression of adhesion proteins and phosphatidylserine and release of extracellular microvesicles. While the direct relationship between a high red cell count and thrombosis is well-known, the intrinsic defects of RBCs from PV and ET patients are new contributors that need to be investigated in depth in order to elucidate their role and pave the way for new therapeutical strategies.
MPN Advocacy & Education International partnered with MPN specialists to offer insights on patient concerns and updates on drug treatments during this pandemic. The videos are now available on our YouTube channel, click here to subscribe.
These videos are made possible by a grant from Bristol Myers Squibb
Naveen Pemmaraju, MD-MD Anderson Cancer Center
Mark Heaney, MD, PhD-Columbia University Medical Center
Ellen Ritchie, MD-Weill Cornell Medicine
Linda Smith-Resar, MD-Johns Hopkins
Dr. Resar’s presentation will be posted as soon as it is available.
My wife was diagnosed with ET (Essential Thrombocythemia) in 2007. Since then, her health issues have varied. For several months, she will do very well with little to no problems, and then an episode that has included an ER visit on occasion, will throw us into action mode. Even our children know what is expected of them. We all becoming a caregiving team.
Caregiving has many layers. It requires endurance, listening skills, humility, open mindedness, flexibility, wisdom, empathy, managerial skills, problem solving skills, healthy choices, rest, outlets, support and in many ways, the needs similar to those we care for, except that we have to be willing to be the strength BEHIND the patient.
Endurance. There will be days when the one you are caring for requires everything you’ve got. It is easy to get burnt out. You may find yourself doing it all and feeling a bit resentful, at times. My suggestion is to get a backup caregiver. So many people offer help and we graciously decline with a thank you and assurance that we are okay. I now say, thank you and how can you help? Getting help doesn’t mean you are shrugging your responsibilities or care less about your loved one. It is a wise decision when times are tough. Sometimes just having someone grocery shop is a great gift.
Humility. Caregiving is not about you. I’ve learned to keep my place and learn from my wife and those that administer her medical care. I don’t have all the answers. My role is vital but there is no room for an ego.
Managerial skills. I never dreamed the managerial skills I learned in my career would come in handy for caregiving. Managing appointments, medical needs, insurance companies, children, household needs, and day to day care for the patient can be overwhelming without a system. When times are tough we run a tight ship with each of us knowing our role and responsibilities. Delegating is a way of life. We’ve learned to adjust quickly and as needed.
Keeping EVERYONE healthy. Parenting and caregiving for an adult are very similar. If we aren’t healthy, everyone suffers. Proper nutrition, exercise, rest, and finding outlets and support are essential. Recognize when you need a break and take it.
The Rewards. I’ve never felt closer to my wife. Our family is stronger and we know we can rely on one another. I’ve learned a lot about ET, but equally about life and love.
