Category Archives: Research

High Levels of C5a Are Associated With Reduced Macular Sensitivity in Patients With Myeloproliferative Neoplasms

Posted on by

February 2025

Kathrine Gotfredsen; Andreas Abou-Taha; Charlotte Liisborg; Marie Krogh Nielsen; Morten Kranker Larsen; Vibe Skov; Lasse Kjær; Hans Karl Hasselbalch; Torben Lykke Sørensen

Abstract

Purpose: Previous findings indicate that patients with myeloproliferative neoplasms (MPN) exhibit elevated levels of inflammatory biomarkers and have a high prevalence of AMD. In this study, we aim to determine whether drusen and systemic inflammation in patients with MPN affect macular sensitivity in the same manner as in patients with AMD.

Methods: The study was conducted as a prospective cross-sectional study. A total of 139 study eyes of 71 patients were included in this study. We measured macular sensitivity using microperimetry and extracted blood samples to evaluate systemic inflammation markers.

Results: Multilevel linear mixed-effect analysis did not show any difference in macular sensitivity when comparing eyes of MPN patients with AMD to those without drusen (β = −0.254, P = 0.657). However, higher levels of the complement system fragment C5a were significantly correlated with decreased total macular sensitivity (β = −0.561, P = 0.027), irrespective of the presence of drusen.

Conclusions: We found that high levels of the systemic inflammation marker C5a are associated with reduced macular sensitivity, regardless of the presence of visible degenerative changes in the macular area. These findings suggest an early contribution of the complement system to macular sensitivity.

Read more

 

Forget about ‘robot uprisings’, AI is a force for good

Posted on by

7th Feb 2025 – Dr Sammy Eden

Professor Daniel Royston is a haematopathologist at Oxford University Hospitals NHS Trust who is using AI to help improve the diagnosis and treatment of blood cancer. Here he writes about the benefits of AI in his research.

An artificial intelligence imagines what a Blood Cancer UK researcher working with AI might look like

AI imagines what a Blood Cancer UK researcher using AI in their work might look like. This image was AI generated for illustrative purposes.

AI is ever present in our world today

The majority of us use AI regardless of whether we realise it, and whether we like it or not. From social media platforms such as Instagram and Facebook, to Google Maps, to computer tools such as Spell Check and virtual assistants like Siri and Alexa. AI has been around for decades, but the rate of development and growth of AI is now surprising us all.

There is a lot of speculation and uncertainty around the use and impact of artificial intelligence or AI. I want to illustrate that when used responsibly, AI is truly a force for good in the healthcare space. But of course, I would say that… because I’m currently harnessing AI to help beat blood cancer.

Read more

Cardiovascular Risk Factors Increase Thrombosis, Mortality in Patients With Myelofibrosis, Other MPNs

Posted on by

January 27, 2025

Author(s): Luke Halpern, Assistant Editor

 

Cardiovascular risk factors (CVRFs) that increase thrombosis and overall mortality are more prevalent in patients with myeloproliferative neoplasms (MPNs), and especially those with myelofibrosis (MF), who have increased rates of hyperlipidemia and hypertension compared with patients with essential thrombocythemia (ET) or polycythemia vera (PV), according to study results published in Blood: Vessels, Thrombosis, and Hemostasis.1

Thrombosis is a potentially serious complication of myelofibrosis. | Image Credit: © Artur | stock.adobe.com

Managing thrombosis risk in patients with MF are pillars of optimal treatment, along with controlling bleeding. Studies have indicated that thrombosis is common across a variety of MPNs, including MF, ET, and PV, and more common in those patients when compared with the general population. CVRFs such as hypertension, hyperlipidemia, type 2 diabetes, and obesity have known effects on thrombosis in the general population, but data is unclear on the impact of CVRFs on patients with MF or other MPNs.2,3

For patients with MF, it is critical for pharmacists and treatment providers to recognize the prevalence of thrombosis and its potential risk factors, including CVRFs. In this current study, the investigators conducted a retrospective cohort analysis of 1005 patients with MPNs to evaluate the impact of CVRFs on real-world patient outcomes. Additionally, study authors investigated the likelihood of MPN transition to conditions such as MF or acute leukemia.1,2,3

Across the study sample, 215 patients had MF, 28 had pre-MF, 415 had ET, and 313 had PV. Patients with MF were found to be more likely to harbor at least 1 CVRF compared with those with ET, PV, and the general patient population (46% vs 34% in the general MPN population), according to the investigators. The most common CVRFs observed in the overall patient population were hypertension (21%), hyperlipidemia (16%), and having a body mass index (BMI) greater than or equal to 30 (12%). For patients with MF, these incidences were 31%, 22%, and 11% respectively.1

Read more

Spleen volume assessment in Ph-negative chronic myeloproliferative neoplasms: a real-life study comparing ultrasonography vs. magnetic resonance imaging scans

Posted on by

January 21, 2025

Novella Pugliese, Carlo Cavaliere, Luca Basso, Laura De Fazio, Rosalia Malafronte, Claudia Giordano, Annamaria Vincenzi, Silvia Varricchio, Massimo Mascolo, Vincenzo Martinelli, Marco Picardi, Marco Salvatore & Fabrizio Pane

Abstract

Splenomegaly is a quite common clinical feature of Philadelphia (Ph) negative chronic myeloproliferative neoplasms (MPNs) and its presence may, in some cases, drives treatment decision. Most importantly, palpable splenomegaly is a minor criterion for both pre-fibrotic/early primary myelofibrosis and primary myelofibrosis (PMF) diagnosis, even if clinical assessment by physical examination is poorly reliable and accurate. On the other hand, despite the International Working Group-Myeloproliferative Neoplasms Research and Treatment and European LeukemiaNet guidelines defined spleen response criteria by palpation, they also recognized the highly subjective nature of spleen size assessment by physical examination, and recommended objective confirmation of volume reduction via computed tomography or magnetic resonance imaging (MRI). In particular, spleen volume (SV) reduction of at least 35% via MRI is typically the primary endpoint in PMF and in some polycythemia vera clinical trials. Nevertheless, this technique seems inconvenient in routine clinical practice. To simplify serial monitoring of spleen size by using ultrasonography (US), we retrospectively analyzed medical records of 39 newly diagnosed MPN patients who underwent spleen ultrasonography as well as MRI. The median SV assessed by US was 600 ml (range 200–5000 ml) while median SV evaluated by MRI was 553.1 ml (range 172–5140 ml), revealing a strong linear relationship between methods, with a correlation coefficient of r = 0.96 (95% CI 0.92–0.98, P < 0.0001). Our findings support the role of US into pre-screening assessments for clinical trials and practice, offering a pragmatic solution for evaluating SV in MPN patients and ultimately improving patient care and clinical decision-making in this complex disease landscape.

Read more

 

Basophilia at Diagnosis Associated With Worse Outcomes in Several MPNs

Posted on by

January 20, 2025

The significance of basophilia across essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) has not been previously characterized. This led Lisa Yuen, MD, and colleagues to conduct a retrospective study examining a broad cohort of myeloproliferative neoplasms (MPNs) to determine basophilia’s associations with clinical and molecular features and patient outcomes. The researchers found that a more aggressive disease phenotype and poorer clinical outcomes were associated with higher levels among patients with MPNs. The findings were reported in the American Journal of Hematology.

The investigators analyzed data from 195 patients who were diagnosed with an MPN between 2008 and 2019. All cases were classified according to the revised 4th edition World Health Organization classification.

The researchers defined basophilia as a relative or absolute increase in peripheral blood or bone marrow aspirate within 6 months of the patient’s first diagnostic biopsy.

Basophilia was present in 22% of patients. The investigators noted a lower incidence of basophilia in patients with ET and PV compared with patients with pre-fibrotic PMF, fibrotic PMF, post-ET MF, post-PV MF, or MPN-unclassifiable (8% vs 35%; P<0.001). Among the patients without basophilia at baseline, the researchers found that 12% subsequently developed basophilia within a median of 19.6 months after the initial MPN diagnosis. Patients with basophilia were also significantly older (P<0.001) and had higher white blood cell count (P<0.001) and reticulin grade (P<0.001), lower hemoglobin levels (P=0.01), and lower platelet counts (P<0.001) than patients without basophilia.

Basophilia was also associated with more frequent abnormal cytogenetics (P<0.001), higher mean total of mutations detected by next-generation sequencing (P<0.001), and more frequent JAK2 (P<0.001), SF3B1 (P=0.0083), and SRSF2 (P=0.0159) mutations, but less frequent calreticulin mutations (P=0.0018). At a median follow-up of 63 months, overall survival (OS) and leukemia-free survival (LFS) were significantly shorter in the basophilia group (54 months and 46 months, respectively; P<0.001). The median OS and LFS remained shorter in the basophilia group when patients with ET and PV were excluded (P=0.003 and P=0.002, respectively).

“These results suggest that basophilia could represent an additional prognostic marker in patients with MPNs, by highlighting patients who may have shorter survival and higher risk of progression to blast phase than would be predicted by current risk modeling,” the researchers concluded.

Read more

Impact of Recent Translational and Therapeutic Developments on Clinical Course of BCR::ABL1-Positive and -Negative Myeloproliferative Neoplasms

Posted on by

January 2025

Tariq I Mughal, John Mascarenhas, Raajit K Rampal, Prithviraj Bose, Thomas Lion, Helen Ajufo, Abdulraheem Yacoub, Soheil Meshinchi, Lucia Masarova, Ruben Mesa, Catriona Jamieson, Tiziano Barbui, Giuseppe Saglio, Richard A Van Etten

Abstract

Despite the study of BCR::ABL1-positive and -negative myeloproliferative neoplasms (MPNs) providing seminal insights into cancer biology, tumor evolution and precision oncology over the past half century, significant challenges remain. MPNs are clonal hematopoietic stem cell-derived neoplasms with heterogenous clinical phenotypes and a clonal architecture which impacts the often-complex underlying genetics and microenvironment. The major driving molecular abnormalities have been well characterized, but debate on their role as disease-initiating molecular lesions continues. The introduction of the ABL1 tyrosine kinase inhibitors have been extremely successful in the treatment of chronic myeloid leukemia with most patients having a near-normal life expectancy. Similar success has, however, not been achieved for BCR::ABL1-negative MPNs in terms of disease course modification and most patients remain incurable. In both disease categories, genomic instability seems to increase the risk of disease progression to accelerated/blast phase, which is resistant/refractory to conventional treatment and associated with a poor prognosis. To address some of these issues, the late John Goldman and Tariq Mughal founded a scientific and clinical platform in 2006, the Post-American Society of Hematology (ASH) MPN workshop, to appraise novel cancer biology, candidate therapeutic targets, treatments and other clinical challenges and pay tribute to all the many scientists and clinicians around the world instrumental to the progress made and continuing advances being made. This paper summarizes some of the recent data discussed at the 18th edition of the workshop and includes reference to some data presented or published after the workshop, including the 26th John Goldman CML conference.

Read more

N-acetylcysteine inhibits thrombosis in a murine model of myeloproliferative neoplasm

Posted on by

Brianna M Craver 1, Gajalakshmi Ramanathan 1, Summer Hoang 1, Xinyue Chang 1, Laura F Mendez Luque 1, Stefan Brooks 1, Hew Yeng Lai 1, Angela G Fleischman

January 2020

Abstract

Thrombosis is a major cause of mortality in patients with myeloproliferative neoplasms (MPNs), though there is currently little to offer patients with MPN beyond aspirin and cytoreductive therapies such as hydroxyurea for primary prevention. Thrombogenesis in MPN involves multiple cellular mechanisms, including platelet activation and neutrophil-extracellular trap formation; therefore, an antithrombotic agent that targets one or more of these processes would be of therapeutic benefit in MPN. Here, we treated the JAK2V617F knockin mouse model of polycythemia vera with N-acetylcysteine (NAC), a sulfhydryl-containing compound with broad effects on glutathione replenishment, free radical scavenging, and reducing disulfide bonds, to investigate its antithrombotic effects in the context of MPN. Strikingly, NAC treatment extended the lifespan of JAK2V617F mice without impacting blood counts or splenomegaly. Using an acute pulmonary thrombosis model in vivo, we found that NAC reduced thrombus formation to a similar extent as the irreversible platelet inhibitor aspirin. In vitro analysis of platelet activation revealed that NAC reduced thrombin-induced platelet-leukocyte aggregate formation in JAK2V617F mice. Furthermore, NAC reduced neutrophil extracellular trap formation in primary human neutrophils from patients with MPN as well as healthy controls. These results provide evidence that N-acetylcysteine inhibits thrombosis in JAK2V617F mice and provide a pre-clinical rationale for investigating NAC as a therapeutic to reduce thrombotic risk in MPN.

Read more

 

 

In Charleston, West Virginia, Tracking MPN Symptoms Becomes a Priority

Posted on by

January 17, 2025

Author(s): Mary Caffrey

When patients with myeloproliferative neoplasms (MPNs) must travel 2 hours for appointments with a cancer care team, capturing all their symptoms to ensure proper treatment is vital.

So, when Charleston Area Medical Center (AMC) Vandalia Health, located in Charleston, West Virginia, signed on to be part of the Association of Cancer Care Centers (ACCC) MPN Quality Improvement Program, systematic and accurate recording of patients’ symptoms was a priority. In a 12-month period, the cancer program serves 78 patients with polycythemia vera, 111 patients with essential thrombocythemia, and 48 patients with primary myelofibrosis.

Charleston AMC serves a large area in southern West Virginia, including some heavily rural areas. Its team includes general medical oncologists and hematologists who treat all types of cancers, 5 patient navigators, and 2 financial navigators who deal with insurance coverage, transportation issues, and other barriers to access. There is 1 social worker as well as nurses and other team members. Complementing the team are outside partners who help Charleston AMC meet multiple social needs.

As with ACCC Quality Improvement Program participants from Perlmutter Cancer Center at NYU Langone Health and Kent Hospital in Rhode Island, the multidisciplinary team in Charleston West Virginia, first took part in a webinar on MPN patient management.1

The ACCC Quality Improvement program was supported by Incyte.

The Charleston AMC team learned about the MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS),2 a validated MPN patient-reported outcome tool that is recommended in the National Comprehensive Cancer Network Guidelines. Patients complete the assessment when they arrive at their appointments, giving providers an overview of symptoms that can be tracked over time.

Read more

RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia

Posted on by

Published January 16, 2025

Tim Kong, Angelo B. A. Laranjeira, Christopher T. Letson, LaYow Yu, Shuyang Lin, Jared S. Fowles, Daniel A. C. Fisher, Sherwin Ng, Wei Yang, Fan He, Minyoung Youn, et al.

Abstract

Myeloid malignancies are heterogenous disorders characterized by distinct molecular drivers but share convergence of oncogenic signaling pathways and propagation by ripe pro-inflammatory niches. Here, we establish a comprehensive transcriptional atlas across the spectrum of myeloproliferative neoplasms (MPN) and secondary acute myeloid leukemia (sAML) through RNA-sequencing of 158 primary samples encompassing CD34+ hematopoietic stem/progenitor cells and CD14+ monocytes. Supported by mass cytometry (CyTOF) profiling, we reveal aberrant networks of PI3K/AKT/mTOR signalling and NFκB-mediated hyper-inflammation. Combining ATAC-Seq, CUT&Tag, RNA-seq, and CyTOF, we demonstrate that targeting of ribosomal protein S6 kinase A1 (RSK1) suppresses NFκB activation and diminishes pro-inflammatory mediators including tumor necrosis factor (TNF) associated with MPN disease severity and transformation. We further evaluate a therapeutic approach utilizing a first-in-class RSK inhibitor, PMD-026, currently in Phase 2 development for breast cancer, for use in myeloid malignancies. Treatment with PMD-026 suppressed disease burden across seven syngeneic and patient-derived xenograft leukemia mouse models spanning the spectrum of driver and disease-modifying mutations. These findings uncover a therapeutic avenue for a conserved dependency across MPN and sAML.

Read more

Baseline Basophilia Associated With Aggressive MPN and Poor Outcomes

Posted on by
Andrea S. Blevins Primeau, PhD, MBA
Publish Date

A more aggressive disease phenotype and poorer clinical outcomes were associated with higher baseline basophil levels among patients with myeloproliferative neoplasms (MPNs), according to the results of a retrospective study published in the American Journal of Hematology.

In the study, researchers analyzed data from 195 patients who were diagnosed with an MPN between 2008 and 2019 at a single center. Cases of chronic myeloid leukemia, chronic eosinophilic leukemia, and chronic neutrophilic leukemia were excluded. Basophilia was defined as a relative or absolute increase in peripheral blood or bone marrow aspirate within 6 months of the patient’s first diagnostic biopsy.

Of the 195 patients, 40.5% had essential thrombocythemia (ET), 23.1% had overt fibrotic phase primary myelofibrosis (PMF), 10.8% had post-ET myelofibrosis (MF), 8.2% had pre-fibrotic PMF, 8.2% had MPN-unclassifiable (MPN-U), 7.2% had polycythemia vera (PV), and 2.1% had post-PV MF.

Basophilia were present among 22% of patients. The lowest level of basophilia was present among patients with ET and PV at 8% compared with 35% among patients with pre-PMF, F-PMF, post-ET MF, post-PV MF, or MPN-U (P <.0001). There were 9% of patients who demonstrated basophilia in the bone marrow, but not the blood.

Of the patients without basophilia at baseline, researchers found that 12% developed basophilia within a median of 19.6 months after diagnosis. Older age (P <.001), higher white blood cell count (P <.001), higher reticulin grade (P =.0007), lower hemoglobin levels (P =.01), and lower platelet counts (P <.001) were significantly associated with basophilia.

Read more