Category Archives: Research

Triple-Negative Myelofibrosis: Disease Features, Response to Treatment and Outcomes

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Luis E. Aguirre, Akriti Jain, Somedeb Ball, Najla Al Ali, Virginia O. Volpe, Sara Tinsley-Vance, David Sallman, Kendra Sweet, Jeffrey Lancet, Eric Padrom, Seongseok Yun, Andrew Kuykendall, Rami Komrokji

Abstract

Background

Myelofibrosis is the most aggressive subtype among classical BCR::ABL1 negative myeloproliferative neoplasms. About 90% of cases are driven by constitutive activation of 1 of 3 genes impacting the JAK/STAT pathway: JAK2, CALR, and MPL. Triple-negative myelofibrosis (TN-MF) accounts for only 5-10% of cases and carries the worst outcomes. Little has been described about this subset of disease. Given the marked heterogeneity surrounding disease biology, clonal architecture, clinical presentation, and poor outcomes in TN-MF, identification of features of interest and assessment of treatment response are areas in need of further investigation.

Patients and methods

We collected and evaluated baseline clinical and molecular parameters from 626 patients with a diagnosis of myelofibrosis who presented to the H. Lee Moffitt Cancer Center in Tampa (Florida, US) between 2003-2021 and compared them based on presence or absence of the three classical phenotypic driver mutations.

Results

A small proportion of patients (6%) harbored TN-MF which correlated with inferior outcomes, marked by a 4-year reduction in overall survival time compared to the non-TN cohort (mOS 37.4 months vs. 85.7 months; p=.009) and higher rates of leukemic transformation. More pronounced thrombocytopenia and anemia, lower LDH, EPO levels, as well as lower percentage of marrow blasts at baseline were more commonly seen in TN-MF (p<0.05). Similarly, patients with TN-MF had higher risk disease per DIPSS+ and GIPSS. Mutations impacting RNA splicing, epigenetic modification and signaling, specifically SRSF2, SETBP1, IDH2, CBL and GNAS, were more commonly seen among those lacking a classical phenotypic driver. The prevalence of co-mutant ASXL1/SRSF2 clones was significantly higher in TN-MF as was trisomy 8. TN patients had fewer responses (46.2% vs 63.4%) and shorter duration of response to ruxolitinib.

Conclusion

TN-MF is invariably associated with significantly decreased survival and more aggressive clinical behavior with higher rates of leukemic transformation and shorter duration of response to ruxolitinib. Mutations impacting RNA splicing, epigenetic modification and signaling (SRSF2, SETBP1, IDH2, CBL and GNAS) are more common in TN-MF, which likely drive its aggressive course and may account for suboptimal responses to JAK inhibition.

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Patients With Myelofibrosis Are at Higher Risk for Poor Cardiovascular Outcomes After Heart Failure Hospitalization

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Grace Taylor

03/05/2024

Patients with myeloproliferative neoplasms (MPN) are at high risk of cardiovascular (CV) disease, including heart failure (HF). Those with myelofibrosis in particular have a higher chance of experiencing HF. In a study presented at the 2023 ASH Annual Meeting & Exposition, Orly Leiva, New York University Grossman School of Medicine, Boston, Massachusetts, and colleagues examined CV outcomes for patients with MPN (essential thrombocythemia [ET], polycythemia vera [PV], or MF) who were hospitalized for HF.

The authors completed a retrospective analysis using data from the National Readmission Database (NRD). They used ICD-10 codes to identify adult patients with a history of MPN who had a primary diagnosis of HF from 2017 and 2018 (N = 4632). Of these patients, 2639 had ET, 1109 had PV, and 884 had MF.

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About 1 in 5 Hematologic Cancer Patients Had Severe COVID-19, Despite Vaccination

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Leah Lawrence

In a study of more than 6000 patients with hematologic cancers, 21% developed severe COVID-19, despite being vaccinated. Researchers reported these results in JAMA Network Open.

The study included 6122 patients from the national Veterans Health Administration who had hematologic cancers. All patients had been vaccinated against COVID-19 but had a confirmed case of COVID-19 between January 1, 2021, and September 30, 2022.

The patients had chronic lymphocytic leukemia (CLL; n=1206) or other non-Hodgkin lymphomas (NHLs; n=1731), plasmacytoid neoplasms (n=1014), myeloproliferative neoplasms (MPNs; n=1144), myelodysplastic syndromes (MDS; n=518), chronic myeloid leukemia (CML; n=180), acute myeloid leukemia (AML; n=172), or Hodgkin lymphoma (n=157).

A total of 1301 paints (21.3%) had severe COVID-19, which was defined as dying within 28 days of SARS-CoV-2 infection, requiring mechanical ventilation, or requiring hospitalization with the use of dexamethasone, evidence of hypoxemia, or the use of supplemental oxygen.

The proportion of patients with severe COVID-19 was similar among those with lymphoid malignancies (21.6%) and those with myeloid malignancies (20.5%). The rate of severe COVID-19 was highest in patient with MDS (28.2%) and lowest in patients with Hodgkin lymphoma (12.1%).

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Non-Driver Gene Mutations Have Adverse Prognostic Impact in Primary Myelofibrosis

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Lauren Dembeck, PhD

A study published in the American Journal of Hematology has confirmed the adverse prognostic impacts of numerous non-driver gene mutations in primary myelofibrosis (PMF).

Researchers analyzed the impact of non-driver somatic mutations in patients with PMF treated at 60 institutions in Spain. Targeted next-generation sequencing (NGS) sequencing evaluating up to 56 non-myeloproliferative neoplasm driver genes was conducted. Of those, the team focused on 20 genes consistently analyzed across NGS panels. Only pathogenic or likely-pathogenic genetic variants with a variant allele frequency (VAF) higher than 1% were considered mutations.

A total of 312 patients with PMF according to World Health Organization criteria at the time of diagnosis and with availability of NGS data were included in the analysis. The median age of the cohort was 68 years. At a median follow-up duration of 4 years, 9% of patients had progressed to acute myeloid leukemia, and 47% had died.

Overall, 72% of patients had non-driver mutations, with 47% having 2 or more mutations (range, 0-7). The most frequent mutations detected were in ASXL1 (34%), TET2 (22%), SRSF2 (17%), U2AF1 Q157 (9%), CBL (8%), EZH2 (7%), TP53 (6%), DNMT3A (6%), and SETBP1 (5%).

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Years After Genetic Finding, Drugs Targeting CALR-Mutant Myeloproliferative Neoplasms Enter Trials

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Feb 29, 2024 | Catherine Shaffer

NEW YORK – More than a decade after mutations in the CALR gene were first linked to the development of myeloproliferative neoplasms, CALR-targeted drug candidates are advancing to Phase I clinical trials.

If these drugs reach the market, they could provide a treatment option for a group of patients with myelofibrosis and essential thrombocythemia who typically must wait until their condition turns serious to attempt a risky stem cell transplant.

About 300,000 patients in the US have myeloproliferative neoplasms. Kapila Vigas, CEO of the MPN Research Foundation, said patients can have very different presentations of the disease, and it can take “years or decades” to get a diagnosis. Although myeloproliferative neoplasms are classified as chronic cancers that patients can live with for many years with blood count monitoring, Vigas said some patients can abruptly progress, and their condition can become serious.

“That uncertainty is really concerning to patients,” Vigas said. “We think from a psychosocial perspective, it’s worse than an acute cancer because while cancer may be more serious, it’s predictable, and there’s a plan and a protocol, whereas when you’re diagnosed with [a myeloproliferative neoplasm] watch and wait is almost a first-line approach. It just adds to the anxiety.”

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Broad next generation integrated sequencing of myelofibrosis identifies disease-specific and age-related genomic alterations

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Malathi Kandarpa; Dan Robinson; Yi-Mi Wu; Tingting Qin; Kristen Pettit; Qing Li; Gary Luker; Maureen Sartor; Arul Chinnaiyan; Moshe Talpaz
Purpose: Myeloproliferative neoplasms (MPNs) are characterized by the overproduction of differentiated myeloid cells. Mutations in JAK2, CALR and MPL are considered drivers of Bcr-Abl-ve MPNs, including essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic primary myelofibrosis (prePMF) and overt myelofibrosis (MF). However, how these driver mutations lead to phenotypically distinct and/or overlapping diseases is unclear. Experimental Design: To compare the genetic landscape of MF to ET/PV/PrePMF, we sequenced 1711 genes for mutations along with whole transcriptome RNA-seq of 137 MPN patients. Results: In addition to driver mutations, 234 and 74 genes were found to be mutated in overt MF (N=106) and ET/PV/PrePMF (N=31), respectively. Overt MF had more mutations compared to ET/PV/prePMF (5 vs 4 per subject, P=0.006). Genes frequently mutated in MF included high-risk genes (ASXL1, SRSF2, EZH2, IDH1/2 and U2AF1), and Ras pathway genes. Mutations in NRAS, KRAS, SRSF2, EZH2, IDH2 and NF1, were exclusive to MF. Advancing age, higher DIPSS and poor overall survival (OS) correlated with increased variants in MF. Ras mutations were associated with higher leukocytes and platelets, and poor OS. The comparison of gene expression showed upregulation of proliferation and inflammatory pathways in MF. Notably, ADGRL4, DNASE1L3, PLEKHGB4, HSPG2, MAMDC2 and DPYSL3 were differentially expressed in hematopoietic stem and differentiated cells. Conclusions: Our results illustrate that evolution of MF from ET/PV/PrePMF likely advances with age, accumulation of mutations, and activation of proliferative pathways. The genes and pathways identified by integrated genomics approach provide insight into disease transformation and progression, and potential targets for therapeutic intervention.

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The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Results from a Randomized Phase I Pilot Study for Feasibility and Adherence

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Laura F. Mendez Luque1,2, Julio Avelar-Barragan3, Hellen Nguyen1, Jenny Nguyen1, Eli M. Soyfer1, Jiarui Liu1, Jane H. Chen1, Nitya Mehrotra1, Xin (Helen) Huang1, Heidi E. Kosiorek4, Amylou Dueck4, Alexander Himstead1, Elena Heide1, Melinda Lem1, Kenza El Alaoui1, Eduard Mas1, Robyn M. Scherber5, Ruben A. Mesa6, Katrine L. Whiteson3, Andrew Odegaard1, Angela G. Fleischman1

ABSTRACT

Purpose: Chronic inflammation is integral to Myeloproliferative Neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low- risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among MPN patients.

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Tixagevimab plus cilgavimab offers COVID-19 protection for haematological cancer patients

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Author: Lynda Williams

medwireNews: Tixagevimab and cilgavimab immunoprophylaxis may help protect patients with haematological malignancies from COVID-19 infection and hospitalisation, suggests a research letter published in JAMA Oncology.

The cohort study reports the outcomes of 204 patients who were eligible for immunoprophylaxis with the two fully human SARS-CoV-2-neutralising monoclonal antibodies due to an increased risk of inadequate response to COVID-19 vaccination.

The patients were enrolled between June and September 2022 and followed-up for 6 months, during which time Omicron variants were prevalent in Italy, write Marco Salvini (ASST Sette Laghi, Varese, Italy) and co-authors.

Overall, 130 patients were given a single pre-exposure prophylactic dose of tixageviamb 150 mg and cilgavimab 150 mg, while 74 patients did not receive the treatment.

The majority of patients in the treatment and control arms had lymphoproliferative disorders or multiple myeloma (77 vs 81%), followed by myeloproliferative neoplasms (19 vs 12%) and acute leukaemia (4 vs 7%). Most patients in the two groups were undergoing active treatment (95 vs 92%), with immunotherapy, targeted therapy, chemotherapy, autologous stem cell transplantation or other treatments.

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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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