Tag Archives: essential thrombocythemia

Phase 3 Trial of Bomedemstat in Essential Thrombocythemia Begins Enrollment

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By Sabrina Serani
Fact checked by Jordyn Sava

A pivotal phase 3 trial (NCT06456346) has initiated to evaluate bomedemstat (MK-3543; IMG-7289), an investigational agent for the treatment of patients with essential thrombocythemia (ET) who have previously not received cytoreductive therapy.1

“The standard of care in essential thrombocythemia has remained unchanged for decades, and patients are in need of new options that have the potential to not only improve disease control, but also improve their quality of life,” said Gregory Lubiniecki, MD, vice president, global clinical development, Merck Research Laboratories, in a press release. “We are rapidly advancing our clinical development programs with the goal of helping to address these unmet needs and bring more options to patients living with myeloproliferative neoplasms.”

The Shorespan-007 trial will compare the orally available LSD1 inhibitor bomedemstat with standard-of-care hydroxyurea in patients with treatment-naive ET, the most common myeloproliferative neoplasm. LSD1 is an enzyme that is potentially important for regulating the proliferation of hematopoietic stem cells, as well as the maturation of progenitor cells.

The study’s primary end point is durable clinicohematologic response rate, and secondary end points include duration of hematologic remission, event-free survival, incidence of adverse events, and disease progression rate. Additionally, investigators will be patient-reported outcomes, including fatigue and symptoms.

The FDA previously granted orphan drug and fast track designations to bomedemstat in ET and myelofibrosis, as well as orphan drug designation in acute myeloid leukemia.

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Essential Thrombocythemia Trial Launched Evaluating Bomedemstat

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By Alex Biese
Fact checked by Ashley Chan

A second phase 3 clinical trial has been launched for the investigational oral drug bomedemstat as a potential new treatment for patients with essential thrombocythemia.

The Shorespan-007 clinical trial, according to a news release from bomedemstat manufacturer Merck, will investigate the use of the drug among patients with essential thrombocythemia who have not previously received cytoreductive therapy.

The global trial, which is currently recruiting, will compare bomedemstat to the current standard of care chemotherapy, hydroxyurea. The trial, with 300 participants, is expected to be concluded in May 2029, according to its listing on clinicaltrials.gov.

Essential thrombocythemia, part of a group of blood cancers known as myeloproliferative neoplasms (MPNs), is a rare disease in which the bone marrow produces too many platelets, according to The Leukemia & Lymphoma Society. This disease, The Leukemia & Lymphoma Society explained, can cause blood clots to form in a patient’s blood vessels, in turn resulting in serious health issues such as stroke, heart attack or pulmonary embolism.

“The standard of care in essential thrombocythemia has remained unchanged for decades, and patients are in need of new options that have the potential to not only improve disease control but also improve their quality of life,” said Dr. Gregory Lubiniecki, vice president of global clinical development for Merck Research Laboratories, in the company’s news release. “We are rapidly advancing our clinical development programs with the goal of helping to address these unmet needs and bring more options to patients living with myeloproliferative neoplasms.”

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Merck Announces Phase 3 Trial Initiation for Bomedemstat, an Investigational Candidate for the Treatment of Certain Patients With Essential Thrombocythemia

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August 27, 2024 6:45 am ET

The initiation of a second Phase 3 clinical trial for bomedemstat demonstrates company’s commitment to advancing research in myeloproliferative neoplasms (MPNs)

RAHWAY, N.J.–(BUSINESS WIRE)– Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the initiation of Shorespan-007, a pivotal Phase 3 clinical trial evaluating bomedemstat, an investigational orally available lysine-specific demethylase 1 (LSD1) inhibitor, for the treatment of patients with essential thrombocythemia (ET) who have previously not received cytoreductive therapy. Essential thrombocythemia is a chronic, rare blood disorder and is the most common type of myeloproliferative neoplasm. Global recruitment of the Shorespan-007 trial has begun, with patients now enrolling.

“The standard of care in essential thrombocythemia has remained unchanged for decades, and patients are in need of new options that have the potential to not only improve disease control, but also improve their quality of life,” said Dr. Gregory Lubiniecki, vice president, global clinical development, Merck Research Laboratories. “We are rapidly advancing our clinical development programs with the goal of helping to address these unmet needs and bring more options to patients living with myeloproliferative neoplasms.”

Shorespan-007 is a Phase 3, randomized, double-blind, active comparator-controlled clinical trial ( NCT06456346 ) evaluating bomedemstat compared to the current standard of care chemotherapy, hydroxyurea, for treatment of patients with ET who have previously not received cytoreductive therapy. The trial will enroll approximately 300 patients globally. The primary endpoint of the study is durable clinicohematologic response rate (CHR). Key secondary endpoints include Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) individual fatigue symptom item score, Patient-reported Outcomes Measurement Information System (PROMIS) Fatigue SF-7a total fatigue score and MFSAF v4.0 total symptom score. Additional secondary endpoints include duration of hematologic remission, event-free survival and disease progression rate.

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Which Factors Predict Thrombotic Events in Essential Thrombocythemia?

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August 13, 2024

The risk for essential thrombocythemia-related events in patients with the disease can be predicted using currently available clinical data, researchers wrote in a letter to the editor appearing in Blood Cancer Journal.

“Although considered the most indolent myeloproliferative neoplasm (MPN), essential thrombocythemia (ET) is linked to burdensome vasomotor symptoms and potentially fatal complications that include thrombosis, hemorrhage, and disease progression to myelofibrosis and aggressive myeloid neoplasms,” Ghaith Abu-Zeinah, MD, a hematologist and oncologist at the Richard T. Silver Myeloproliferative Neoplasms Center at Weill Cornell Medicine, New York, and colleagues wrote. “Prognostic measures to identify those at greatest risk for thrombosis, progression, and death in ET [events] are important for timely risk-adapted intervention with available treatments, and for development of interventional trials to improve event-free survival [EFS]. But predicting risks of events in ET has been difficult because ET is an uncommon and clinically heterogeneous chronic disease.”

Predicting excess mortality and disease progression related to ET presents challenges because such events often occur decades after a patient is diagnosed, the researchers continued.

“Thus, retrospective analysis of large cohorts with sufficiently long follow-up is required to identify prognostic measures to stratify risk in patients with ET,” they wrote.

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Are thrombosis, progression, and survival in ET predictable?

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June 25, 2024

Ghaith Abu-Zeinah, Katie Erdos, Neville Lee, Ahamed Lebbe, Imane Bouhali, Mohammed Khalid, Richard T. Silver & Joseph M. Scandura

Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm (MPN) that originates from a hematopoietic stem cell harboring a mutated JAK2, CALR, or MPL gene, or none of these three mutations (10–15% are “triple negative”). Although considered the most indolent MPN, ET is linked to burdensome vasomotor symptoms, and potentially fatal complications that include thrombosis, hemorrhage, and disease progression to myelofibrosis and aggressive myeloid neoplasms. Prognostic measures to identify those at greatest risk for thrombosis, progression, and death in ET (events) are important for timely risk-adapted intervention with available treatments, and for development of interventional trials to improve event-free survival (EFS). But predicting risks of events in ET has been difficult because ET is an uncommon and clinically heterogenous chronic disease. Predicting progression and excess mortality is even more challenging because these events typically occur decades after ET diagnosis [1]. Thus, retrospective analysis of large cohorts with sufficiently long follow-up is required to identify prognostic measures to stratify risk in patients with ET.

Prognostic models have been developed to assess the risk of thrombosis (IPSET-thrombosis [2]) or overall survival (OS) in ET (IPSET-survival [3], MIPSS-ET [4], and triple A [AAA] [5]). This journal recently published two large retrospective ET cohorts: Gangat et al. at the Mayo Clinic (Mayo) [6] and Loscocco et al. at the Florence Center Research and Innovation of Myeloproliferative Neoplasms (CRIMM) [7]. Both studies confirmed previously identified risk factors for thrombosis, progression and/or death in ET that include older age (Age ≥ 60), male sex, elevated white blood cell count (WBC > 11 × 109/L), elevated absolute neutrophil count (ANC ≥ 8 × 109/L), and low absolute lymphocyte count (ALC < 1.7 × 109/L) at the time of presentation. We evaluated these parameters and current risk models in our cohort of 328 adult patients with ET treated at the Weill Cornell Medicine (WCM) Silver MPN Center over a median follow-up of 6 years [8]. This cohort was rigorously defined according to the 2022 World Health Organization diagnostic criteria and therefore all patients had a diagnostic bone marrow biopsy and had alternative diagnoses scrupulously ruled out. The methods of data collection, retrieval, and analysis used were previously described [9], and cohort characteristics are included in Supplementary Table 1.

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Prospective Analysis Highlights Patterns of Progression to Myelofibrosis Following Essential Thrombocythemia Diagnosis

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June 17, 2024

Author(s): Caroline Seymour

Most patients with essential thrombocythemia (95.7%; 1184/1237) included in an analysis of the prospective, observational MOST study (NCT02953704) did not experience disease progression to myelofibrosis, but those who did were found to have had longer duration of disease, higher white blood cell counts, and lower hemoglobin levels at enrollment, according to findings presented at the 2024 EHA Congress.1

Of the 4.3% (n = 53) of patients who progressed to myelofibrosis, a pathologic diagnosis of the disease or grade 2 or greater fibrosis was the most common indicator (49.1%; n = 26) of disease progression, followed by new or worsening splenomegaly coupled with a combination of high white blood cell counts and low hemoglobin levels and platelet counts (22.6%; n = 12). Additional indicators were death from myelofibrosis, myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML; 11.3%; n = 6) and circulating blasts above 1% with new or worsening splenomegaly (5.7%; n = 3); patients also met at least 2 progression criteria (11.3%; n = 6).

“These findings and further analyses of MOST data will add insight into disease progression in patients with essential thrombocythemia and facilitate clinical management of this patient population,” lead study author Ruben A. Mesa, MD, FACP, president and executive director of Atrium Health Levine Cancer Institute and Atrium Health Wake Forest Baptist Comprehensive Cancer Center, and vice dean of cancer programs at Wake Forest University School of Medicine in Charlotte, North Carolina, and coauthors wrote in the poster.

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A Grand Time in Grand Rapids

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MPN Advocacy & Education International held an in-person patient/caregiver event in Grand Rapids, Michigan on April 25th. The room buzzed with excitement and camaraderie as patients and caregivers had the opportunity to engage with each other and MPN experts on a wide range of topics. 

Dr. Anas Al-Janadi gave an overview of the history of MPNs and defined where we are in our current understanding of the disease and what the future may hold. While exciting discoveries were made that supported the development of drug therapies for MPN patients; such as the JAK2 mutation in 2005 and later the MPL and CALR mutations, the MPN community is still working to better understand the reasons for disease progression and ways to reduce symptom burden.

Dr. Kristin Pettit, on the heels of her wedding (Congrats, Dr. Pettit), discussed the challenges MPN patients have flying, having elective or emergency surgeries, symptom management, and some critical women’s issues. Each topic had the following take-aways: check with your doctor and practice good self-care. Dr. Pettit emphasized hydration, healthy eating, exercise and reducing stress.

Dr. Aaron Gerds shared a play-by-play of diagnosing and treating MPNs. He began by situating ET, PV, and MF on the greater spectrum of Myeloid Neoplasms. Dr. Gerds, along with the other experts that presented, stressed the importance of a good clinical examination including a thorough history and a hands-on physical examination. Gerds went on to describe the testing required to make a proper MPN diagnosis, such as; blood counts, chemistries, infectious disease, bone marrow biopsy, and molecular testing. Afterwards, he walked us through the process of navigating individual risk and treatment options using the National Comprehensive Cancer Network (NCCN) Guidelines for Myelofibrosis. 

Justin Grinell, owner and head trainer of State of Fitness, reminded us that our health is not our fault, but it is our responsibility. He shared some ways to move toward a healthy lifestyle by incorporating an 11 min movement break in our day. To take just 11 minutes each day doing something active at your own Zone 2 (when your heart rate is 180 minus your age) can have an accumulative positive effect on not just your body but on your brain as well. Be sure to look for Justin this summer during our Healthy Summer Series webinars where you can join Justin for a quick lunch-time workout. 

Finally, Dr. Craig Kessler implored patients to ask questions. Ask your doctor questions about the treatment plan they create for you. Ask what component of MPN symptoms they are focusing on, and how the treatment they recommend will address that component (anemia, blood counts, spleen reduction, etc.). He stressed getting your COVID-19 vaccine and boosters. He also made clear that your questions matter and not to be afraid to ask.

We want to thank the specialists for sharing their valuable information and spending their time away from their respective institutions. We also want to thank our patients and their family members and friends for joining us and asking such thought-provoking questions. We hope that you will have a chance to join us at our next MPN Advocacy and Education International in-person event in Asheville, NC on Thursday August 22nd. To learn more, please visit www.mpnadvocacy.com/events-list.

Disease-, Age-, Genomic-Specific Factors Increase Risk of ET, PV, PrePMF Developing Into Overt MF

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Laura Joszt, MA

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

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ROP-ET: a prospective phase III trial investigating the efficacy and safety of ropeginterferon alfa-2b in essential thrombocythemia patients with limited treatment options

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Published: 

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.

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Review Details Current State of Essential Thrombocythemia Diagnosis and Care

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Vicki Moore, PhD

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.

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