Tag Archives: mpn

Study shows early success of a novel drug in treating a rare and chronic blood cancer

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February 21, 2024

by The Mount Sinai Hospital

A novel treatment for polycythemia vera, a potentially fatal blood cancer, demonstrated the ability to control overproduction of red blood cells, the hallmark of this malignancy and many of its debilitating symptoms in a multi-center clinical trial led by the Icahn School of Medicine at Mount Sinai.

In the phase 2 study, the drug rusfertide limited excess production of red blood cells, the main manifestation of polycythemia vera, over the 28-week course of treatment. The results suggest it could replace therapeutic phlebotomy, a common form of treatment which has proven to be a burden for many patients. The results of the study were published today (Feb. 21) in The New England Journal of Medicine.

“Rusfertide appears to represent a significant step forward in treating polycythemia vera through its unique approach of limiting the amount of iron available for blood cell production,” says Marina Kremyanskaya, MD, Ph.D., Associate Professor of Medicine (Hematology and Medical Oncology) at Icahn Mount Sinai and lead author of the study.

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Clinical Review of Pegylated Interferons Suggests Formulation and Mechanism of Action May Improve Outcomes for MPN Patients

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Business Wire
BURLINGTON, Mass., February 21, 2024–(BUSINESS WIRE)–PharmaEssentia USA Corporation, a subsidiary of PharmaEssentia Corporation (TWSE: 6446), a global biopharmaceutical innovator based in Taiwan leveraging deep expertise and proven scientific principles to deliver new biologics in hematology, oncology and immunology, announced the publication of a manuscript reviewing the clinical safety, efficacy and practical management of treatment with two pegylated interferons – peginterferon alfa-2a and ropeginterferon alfa-2b-njft (marketed as BESREMi®). The manuscript, “Interferons in the Treatment of Myeloproliferative Neoplasms” was co-authored by 12 renowned myeloproliferative neoplasm (MPN) specialists and published in Therapeutic Advances in Hematology. Writing and editorial support were funded by PharmaEssentia, however authors retained full editorial control and provided final approval on all content.
“Interferons are immune modulators that have been used to treat MPNs for more than 35 years. Pegylated interferons are an important therapeutic option and have shown much promise across diseases, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF),” said Pankit Vachhani, M.D., study author and Associate Professor of Medicine in Hematology/Oncology at University of Alabama at Birmingham. “The manuscript serves as a tool for clinical practice by highlighting the advantages of pegylated interferons, as well as areas where more research is needed to further refine interferon therapies.”

Interferons in the treatment of myeloproliferative neoplasms

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Pankit Vachhani, John Mascarenhas , Prithviraj Bose , Gabriela Hobbs, Abdulraheem Yacoub, Jeanne M. Palmer , Aaron T. Gerds, Lucia Masarova, Andrew T. Kuykendall, Raajit K. Rampal, Ruben Mesa and Srdan Verstovsek

Abstract: Interferons are cytokines with immunomodulatory properties and disease-modifying effects that have been used to treat myeloproliferative neoplasms (MPNs) for more than 35 years. The initial use of interferons was limited due to difficulties with administration and a significant toxicity profile. Many of these shortcomings were addressed by covalently binding polyethylene glycol to the interferon structure, which increases the stability, prolongs activity, and reduces immunogenicity of the molecule. In the current therapeutic landscape, pegylated interferons are recommended for use in the treatment of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We review recent efficacy, molecular response, and safety data for the two available pegylated interferons, peginterferon alfa-2a (Pegasys) and ropeginterferon alfa-2b-njft (BESREMi). The practical management of interferonbased therapies is discussed, along with our opinions on whether to and how to switch from hydroxyurea to one of these therapies. Key topics and questions related to use of interferons, such as their safety and tolerability, the significance of variant allele frequency, advantages of early treatment, and what the future of interferon therapy may look like, will be examined. Pegylated interferons represent an important therapeutic option for patients with MPNs; however, more research is still required to further refine interferon therapy.

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Navigating Cytoreduction in MPNs: Benefits, Risks, and Considerations

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Jordyn Sava

In an interview with Targeted Oncology, Douglas Tremblay, MD, discussed the significance of cytoreductive therapy in mitigating thrombotic risk in myeloproliferative neoplasms.

According to Douglas Tremblay, MD, cytoreductive therapy has emerged with a pivotal role in mitigating thrombotic risk in the treatment landscape of myeloproliferative neoplasms (MPNs), specifically essential thrombocytopenia (ET) and polycythemia vera (PV).

Despite the evident benefits, each therapy carries unique adverse effects, requiring the careful consideration of patient-specific factors in treatment administration. Deciding when to initiate cytoreductive therapy in patients with chronic MPNs relies on accurate risk assessment, with parameters such as age and prior thrombotic events often guiding treatment decisions.

Frontline therapies, such as hydroxyurea and interferon, manage blood counts for patients with ET and PV, and newer options are emerging, according to Tremblay, assistant professor of medicine at the Icahn School of Medicine at Mount Sinai. However, the long-term implications focus on thrombosis prevention and disease progression.

Ongoing research endeavors aim to delve deeper into surrogate end points and novel therapeutic avenues, promising to further refine and revolutionize the management of MPNs.

In an interview with Targeted OncologyTM, Tremblay discussed the significance of cytoreductive therapy in mitigating thrombotic risk in MPNs, specifically ET and PV.

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Identification of Novel Risk Variants of Inflammatory Factors Related to Myeloproliferative Neoplasm: A Bidirectional Mendelian Randomization Study

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Yang Li, Ting Sun, Jia Chen, Lei Zhang

Abstract

Epidemiological and experimental evidence has linked chronic inflammation to the etiology of myeloproliferative neoplasm (MPN). However, it remains unclear whether genetic associations with specific inflammatory biomarkers are causal or due to bias. This study aimed to assess the effect of C-reactive protein (CRP) and systemic inflammatory regulators on MPN within a bidirectional Mendelian randomization design. Genetic associations with MPN were derived from a publicly available genome-wide association study (GWAS) comprising 1,086 cases and 407,155 controls of European ancestry. Additionally, data on inflammation were extracted from two GWASs focusing on CRP and cytokines. The causal relationships between exposure and outcome were explored using the inverse variance weighted (IVW) method. To confirm the final results, multiple sensitivity analyses, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO), were simultaneously employed. Our results suggest that lower levels of macrophage-migration inhibitory factor (IVW estimate odds ratio [OR IVW] per SD genetic cytokines change: 0.641; 95% confidence interval [CI]: 0.427–0.964; p = 0.032) and higher levels of interleukin-2 receptor α (lL2Rα, 1.377, 95% CI: 1.006–1.883; p = 0.046) are associated with an increased risk of MPN. Genetically predicted MPN is related to increased levels of RANTES (IVW estimate β: 0.043, 95% CI: 0.002–0.084; p = 0.039) and interleukin-10 (IVW estimate β: 0.030, 95% CI: 0.001–0.060; p = 0.041). This study provides evidence for a causal relationship between CRP, systemic inflammatory regulators, and MPN, and new insights into the etiology, prevention, and prognosis of MPN.

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Depression in patients with hematologic malignancies: The current landscape and future directions

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Thomas M. Kuczmarski, Lizabeth Roemer, Oreofe O. Odejide

February 13, 2024

Abstract

Patients with hematologic malignancies experience high rates of depression. These patients are vulnerable to depression throughout the disease trajectory, from diagnosis to survivorship, and at the end of life. In addition to the distressing nature of depression, it has substantial downstream effects including poor quality of life, increased risk of treatment complications, and worse survival. Therefore, systematic screening for depression and integration of robust psychological interventions for affected patients is crucial. Although depression has been historically studied mostly in patients with solid malignancies, research focusing on patients with hematologic malignancies is growing. In this article, we describe what is known about depression in patients with hematologic malignancies, including its assessment, prevalence, risk factors, and implications. We also describe interventions to ameliorate depression in this population. Future research is needed to test effective and scalable interventions to reduce the burden of depression among patients with blood cancers.

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MPN Symptoms Mimic Other Conditions, Open Communication Is Key

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Brielle Benyon

Myeloproliferative neoplasm (MPN) symptoms can often appear as another condition, making it essential that patients find a cancer care team that they trust and can have open communication with, according to Patrick Buxton.

Buxton, who is a clinical nurse manager at Fred Hutchinson Cancer Center in Seattle and a 2023 MPN Hero, explained that certain side effects like constant fatigue could mimic conditions such as depression. That is why it is important for patients to work with their oncology team to establish a baseline of lab results and symptoms and keep them up to date on how they are feeling.

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Study Supports Further Exploration of Tamoxifen in MPNs

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Sabrina Serani

Findings from a phase 2 study support the further investigation of tamoxifen (Soltamox), a selective estrogen receptor modulator (SERM), as a treatment option in patients with myeloproliferative neoplasms (MPNs), with extra consideration for thrombotic risk.1

A total of 38 patients with MPNs with mutated JAK2V617F, CALRins5, or CALRdel52 peripheral blood allele burden greater than 20% were recruited, and 32 patients completed 24 weeks of treatment. A greater than 50% reduction in mutant allele burden at 24 weeks was observed in 3 patients, and a 25% or greater reduction in mutant allele burden at 24 weeks was observed in 5 patients.

An exploratory analysis of hematopoietic stem/progenitor cell (HSPC) transcriptome identified a difference between responders and non-responders. Investigators observed that in responder HSPCs, there was a high baseline expression of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling and oxidative phosphorylation genes, which tamoxifen appeared to downregulate.

“The perfect segregation of the HSPC transcriptome from responders and non-responders at baseline could serve in the future as a platform for the stratification of patients based on their likelihood to respond to tamoxifen and for the identification of predictive biomarkers of response, if prospectively validated,” study authors wrote in findings published in Nature Communications.

“These results suggest that the metabolic effects of SERMs in cancer might be underappreciated and propose ways to modulate pathogenic JAK-STAT signaling through metabolic rewiring. These results warrant further investigation of tamoxifen as potential therapeutic for MPN in larger studies, after careful consideration of the risk of thrombosis,” study authors wrote.

Patients with essential thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (MF), post-PV MF, and post-ET MF were included in the study. The primary end point was a mutant allele burden reduction of greater than 50% at 24 weeks. The secondary end points included mutant allele burden reduction between 25% and 50% at 24 weeks, a greater than 50% reduction at 12 weeks, thrombotic events, toxicities, and hematological response.

Thrombotic adverse events (AEs) potentially related to tamoxifen were reported in 2 patients, and 1 patient discontinued treatment due to this AE. Investigators identified that the thrombotic events only occurred in non-responders, so identifying responders before initiating treatment should help reduce risks to patients.

Regarding safety, 11 additional patients discontinued study treatment due to toxicity. A grade 1 intracranial hemorrhage unrelated to tamoxifen was reported. No patient deaths were reported. Complete symptoms response was observed in 19% of patients, while 71.4% of patients had a partial symptom response, and 9.5% of patients had no response.

The results of this study warrant further exploration into tamoxifen as a treatment option for MPNs and further investigation of SERMs with lower thrombotic risks.

REFERENCES:
1. Fang Z, Corbizi Fattori G, McKerrell T, et al. Tamoxifen for the treatment of myeloproliferative neoplasms: A phase II clinical trial and exploratory analysis. Nat Commun. 2023;14(1):7725. Published 2023 Nov 25. doi:10.1038/s41467-023-43175-5

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Dr Vincelette on MYC Expression in Myelofibrosis

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Nicole D. Vincelette, PhD

Nicole D. Vincelette, PhD, postdoctoral fellow, Moffitt Cancer Center, discusses findings from a study investigating the role of MYC expression and S100A9-mediated inflammation in a subgroup of triple-negative myeloproliferative neoplasms (MPNs).

To determine how MYC expression drives MPNs, such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis, Vincelette and colleagues conducted a study in which they generated a mouse model that overexpresses MYC in the stem cell compartment. This analysis demonstrated that MYC overexpression was associated with the mice developing a myelofibrosis-like phenotype, which included anemia, atypical megakaryocytes, splenomegaly, bone marrow fibrosis, liver fibrosis, spleen fibrosis. The mice also experienced adverse clinical outcomes, such as reduced overall survival (OS), compared with wild-type mice, Vincelette says.

Since the MYC-overexpressed mice developed myelofibrosis, the next step of this research was to investigate how MYC drives myelofibrosis, Vincelette explains. Investigators performed single-cell RNA sequencing to compare the bone marrow cells from MYC-overexpressed and wild-type mice. MYC overexpression correlated with upregulation of the S100A9 protein, which contributes to inflammation and innate immunity, according to Vincelette. Therefore, MYC drives the development of myelofibrosis through S100A9-mediated chronic inflammation. To validate the role of S100A9 downstream of MYC in myelofibrosis, investigators created a mouse model with S100A9 knockout in the presence of MYC overexpression, Vincelette notes. The S100A9 knockout protected against the development of myelofibrosis phenotype in that mouse model, Vincelette emphasizes.

By generating a mouse model that overexpresses S100A9, investigators also determined that S100A9 overexpression alone contributes to the development of myelofibrosis phenotypes, Vincelette says. When investigators treated the MYC-overexpressing mice with the S100A9 inhibitor tasquinimod (ABR-215050), the agent only partially abrogated the myelofibrosis phenotype, meaning the mice had reduced atypical megakaryocytes and splenomegaly. Additionally, the mice developed anemia and no OS difference occurred between tasquinimod and vehicle treatment, potentially because of off-target drug effects, Vincelette concludes.

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The role of inherited genetic variants in rare blood cancer

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January 17, 2024

Researchers from the University of Cambridge, Wellcome Sanger Institute, and collaborators have shown how inherited genetic variants can influence the risk of developing a rare blood cancer.

Large-scale genetic analysis has helped researchers uncover the relationship between cancer-driving genetic mutations and inherited genetic variants in a rare type of blood cancer.

The team combined datasets to understand the impact of cancer-driving spontaneous mutations and inherited genetic variation on the risk of developing myeloproliferative neoplasms (MPN).

Published in Nature Genetics, the study describes how inherited genetic variants can influence whether a spontaneous mutation in a particular gene increases the risk of developing this rare blood cancer.

The analysis will have an impact on current clinical predictions of disease development in individuals.

More research is needed to understand the mechanisms behind how the inherited genetic variants influence the probability of developing rare blood cancer.

In the future, the work could aid drug development interventions that reduce the risk of disease.

Myeloproliferative neoplasms

MPNs are a group of rare and chronic blood cancers, with around 4,000 cases in the UK each year. These occur when the bone marrow overproduces blood cells, resulting in blood clots and bleeding.

MPNs can also progress into other forms of blood cancer.

Genetic risk score

There is a large amount of natural variation between individuals’ blood cells which can affect the amount of blood cells a person has and their traits. This is because different genes can influence blood cell features in an individual.

Researchers take known information about these genes during routine blood tests and analyse the variation to give a genetic risk score. This is how likely that individual is to develop a disease over their lifetime.

MPNs have been linked to random somatic mutations in a gene called JAK2; however, mutated JAK2 is commonly found in the global population. The vast majority of these individuals do not have or go on to develop MPN.

Previous studies identified over a dozen associated inherited genetic variants that increase the risk of MPN. However, these studies do not explain why most individuals do not go on to develop MPN.

Inherited genetic variants can influence risk

The new study combined information on the known somatic driver mutations in MPN inherited genetic variants, and genetic risk scores from individuals with MPN.

They found that the inherited genetic variants that cause natural blood cell variation in the population also impact whether a JAK2 somatic mutation will cause MPN. The team also discovered that individuals with an inherited risk of having a higher blood cell count could display MPN features in the absence of cancer-driving mutations, mimicking disease.

Dr Jing Guo, from the University of Cambridge and the Wellcome Sanger Institute and first author of the study, said: “Our large-scale statistical study has helped fill the knowledge gaps in how variants in DNA, both inherited and somatic, interact to influence complex disease risk.

“By combining these three different types of datasets we were able to get a more complete picture of how these variants combine to cause blood disorders.”

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