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

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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.

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Getting Closer to Disease Modification in Polycythemia Vera

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February 2025 Vol 11 No 1

Dr. Lucia Masarova

Polycythemia vera was first recognized by French physician Louis H. Vaquez in 1892 and was known then as maladie de Vaquez.1 The name poly-cyt-[h]emia originates from the Greek and Latin, and literally means many-cells-in the blood. In 1951, Dr. William Dameshek included polycythemia vera in the category of classic Philadelphia chromosome–negative myeloproliferative disorders (now classified as myeloproliferative neoplasms, MPNs; myelo refers to the bone marrow, proliferative refers to rapid growth of blood cells, and neoplasm describes abnormal and excessive growth). It is the only one among the 3 classic MPNs that exhibits erythrocytosis, the increased production of red blood cells. Polycythemia vera is a condition associated with overproduction of all blood cells, including white cells and platelets.

Polycythemia vera is a chronic, incurable disease of the hematopoietic stem cells, the primary cells that can develop into different types of blood cells and are responsible for the production of blood cells during a human’s entire life. It is a clonal disease, meaning it occurs when a mutated hematopoietic stem cell starts making clones—cells with the same genetic mutation. Most affected patients can live a relatively normal and long life.

A breakthrough discovery of a genetic “driver” of polycythemia vera was made in 2005—a mutation in the JAK2 gene was found in 95% of cases, typically JAK2V617F, a mutation that leads to the constitutive activation of the JAK-STAT protein pathway causing unregulated overproduction of hematopoietic cells. This discovery led to improved understanding of the biology, pathogenesis, and long-term behavior of the disease and initiated numerous efforts to develop novel therapies focused on the inhibition of the JAK-STAT pathway.

The abnormal function of the immune system and the subsequent increased inflammation, powerfully driven by the JAK-STAT pathway as the major regulator of inflammatory signaling, contribute to disease progression and an impaired quality of life. Despite the relatively slow progression of the disease course in most patients, the disease possesses its challenges and risks, including a lifetime risk of developing thrombosis (blood clots); the evolution into myelofibrosis, a chronic type of leukemia; or development into acute leukemia. Both blood clots and leukemia are consequences that can shorten life expectancy significantly.

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Patients With Cytopenic Primary Myelofibrosis Face Unique Therapeutic Challenges, Poor Prognosis

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February 12, 2025

Author(s): Luke Halpern, Assistant Editor

Patients with primary myelofibrosis (PMF) harboring the cytopenic phenotype called cytopenic (CyP) PMF face greater unmet needs and worsened prognosis compared with other myeloproliferative neoplasms (MPNs), including polycythemia vera (PV) and essential thrombocytopenia (ET), according to an analysis of data from the European multicenter collaborative ERNEST registry.1

Myelofibrosis that advances to blast phase worsens outcomes for patients affected. | Image Credit: © tonaquatic – stock.adobe.com

Disease behavior of MF can vary widely based on clinical phenotype. Two distinct subgroups comprise MF: proliferative MF and cytopenic MF, which is also called myelodepletive MF. For patients with cytopenic MF, disease presentation can encompass lower blood counts—specifically thrombocytopenia and anemia—additional somatic mutations, and a worse prognosis compared with proliferative MF.2

Additionally, approved Janus kinase (JAK) inhibitors that can improve constitutional symptoms of MF carry risks of worsening anemia and thrombocytopenia in CyP MF, making treatment uniquely challenging for patients. Severe anemia is known to further worsen patient prognosis, and measures to relieve disease burden, such as transfusions, can lead to disease progression into blast phase (BP) MF. Given the poor outcomes MF patients with CyP face, describing the clinical characteristics and outcomes of this population is critical.1,3

The current investigators analyzed data gathered from the European multicenter collaborative ERNEST registry, with a focus on the clinical outcomes and characteristics of MF patients with CyP. In total, 559 patients comprised the study population; a CyP was defined by the presence of at least 1 cytopenia at diagnosis, including sex-adjusted anemia, thrombocytopenia, or leukopenia. Patients who showed none of these characteristics were considered MyP.1

Median follow-up was 5.4 years. A CyP was identified in 275 patients (49.2%); these patients were more likely to be older, less frequently JAK2V617F-mutated, and included in higher risk categories. In total, 392 patients (70.1%) died, including 59.9% of MyP patients and 80.7% of CyP patients, and the incidence rate of death among patients with both anemia and thrombocytopenia was the highest among the subgroups analyzed.1

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Allogeneic Hematopoietic Stem Cell Transplantation May Resolve Osteosclerosis in MF

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Özge Özkaya, MSc, PhD
Publish Date

Allogeneic hematopoietic stem cell transplantation leads to extensive skeletal homeostasis reconstruction and subsequent resolution of osteosclerosis in patients with myelofibrosis (MF), according to a new study published in the peer-reviewed journal Nature Communications.

For the study, a team of German researchers outlined the skeletal characteristics of patients with MF before and after allogeneic hematopoietic stem cell transplantation using clinical high-resolution imaging, laboratory analyses, and bone marrow biopsy studies.

The team reported that even though the bone microarchitecture was not impaired at peripheral skeletal sites, there was a marked increase in bone mineral density at the lumbar spine and proximal femur.

This, the researchers said, is histologically related to severe bone marrow fibrosis and osteosclerosis.

Following allogeneic hematopoietic stem cell transplantation, the bone marrow fibrosis was fully normalized.

The team also reported that the regression of fibrosis was accompanied by vanishing osteosclerosis together with restored osteoclastic resorption activity and whole-body calcium homeostasis.

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Lactate is a Key Regulator of Immune Escape, Bone Marrow Fibrosis in Myelofibrosis

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February 11, 2025

Author(s):

Luke Halpern, Assistant Editor

New study results published in the Journal of Translational Medicine reveal that circulating lactate is a key regulator of immune escape and bone marrow (BM) fibrotic transformation in patients with myelofibrosis (MF), with a marked increase in lactate concentration and lactate import channel monocarboxylate transporter 1 (MCT1) expression in the site of blood cell production. The investigators suggest that MCT1 blocking could be used as a novel antifibrotic strategy in patients with MF.1

An enlarged image of fibrous scar tissue, dense collagen network
Myelofibrosis can cause fibrosis in bone marrow. | Image Credit: © Jasmine – stock.adobe.com

According to the study authors, the pathophysiology of MF is significantly influenced by alterations in the BM microenvironment, and these changes are often associated with the metabolic reprogramming of cancer cells in patients. Glycolysis is a hallmark aspect of the changes that occur in cancer cells; prior evidence from investigational models strongly suggests that lactate production is associated with tumor microenvironment (TME) progression in patients with certain types of cancer.1-3

Prior observations also indicate that increases in lactate dehydrogenase A (LDHA) have a central role in glycolysis, with high LDHA levels typically found in the sera of patients with MF, predicting shorter overall and leukemia-free survival. Within this context, excess lactate that is secreted by cancer cells can promote immune suppression and angiogenesis while also possibly playing a role in increasing the number of cancer-affiliated phenotypes (CAF), which promote fibrotic tumor formation, the investigators wrote.1,4

These authors sought to fill a gap in knowledge within the characterization of TME metabolic composition in patients with MF. Through their analysis, they demonstrated that the amount of circulating lactate increases in patients with MF, which eventually leads to the expansion of immunosuppressive subsets and the development of fibrosis. Furthermore, they observed that the expression of lactate export channel monocarboxylate transporter 4 (MCT4) in the TME becomes deeply remodeled during fibrotic transformation, “suggesting a link between lactate trafficking and pro-fibrotic establishment.”1

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

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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.

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Reevaluating Available Options for Anemia in Myelofibrosis

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February 6, 2025

By Targeted Oncology Staff
Fact checked by Jonah Feldman

DISCUSSION QUESTIONS

  • How do you monitor and manage anemia in patients with primary myelofibrosis prior to starting Janus kinase (JAK) inhibitor therapy?​
  • While receiving a JAK inhibitor therapy?

Andrew Kuykendall, MD: How do you monitor and manage anemia in patients with myelofibrosis even prior to starting a JAK inhibitor? If you’re initially evaluating someone, they come in with hemoglobin of 7 or 8 g/dL or something like that, how does that impact your thinking, and how do you work that up?

Lazaros Lekakis, MD: The first thing is to make sure that they don’t have something easily fixable [such as] iron, B12, or folate deficiency. Theoretically, if you don’t have any nutritional cause or any immune causes, you could use erythropoietin analogs, but they are very tricky because they don’t help with the spleen, at least in my experience, and they may increase the risk of clots. I try to avoid them if possible. If I have to start a JAK inhibitor, if they have symptoms, either I go away from ruxolitinib [Jakafi] or I start a low dose of ruxolitinib. Sometimes I use anabolic steroids and prednisone. We have the thalidomide/prednisone [regimen] that now is kind of forgotten about.

Kuykendall: Erythropoietin-stimulating agents [ESAs] are limited in what they do, and certainly not helping other aspects of the disease. You did mention one of my favorite regimens, thalidomide/prednisone, which is looked over a bit nowadays, but has quite a potential for efficacy in terms of improving hemoglobin. But it’s probably something that’s gone by the wayside in many practices.

Luis Sumoza, MD: As Dr Lekakis says, there are some other options that you can use. Danazol is sometimes something you can use perfectly in this patient population. From the JAK inhibitors, there is momelotinib [Ojjaara]. But a priority for me is to refer a patient for a stem cell transplant; when I was a fellow, we did the first allogeneic bone marrow transplant at the University of Illinois, Chicago, and it was a very nice experience.

Kuykendall: [Dr Lekakis] also mentioned steroids, [and we are] thinking about things like danazol, androgen derivatives. We saw from the MOMENTUM study [NCT04173494] looking at momelotinib that danazol is an active agent.1 It was a large, randomized trial, one of the first randomized trials with danazol. The focus there was on momelotinib, but there’s also a lot to learn about what danazol could do as well from that study.

Sumoza: You’re mainly talking about anemia here, and [if], the patient is not a candidate for a transplant or a clinical trial [there are] the data about navitoclax/ruxolitinib, which basically double the response and reduction of the spleen.2

Kuykendall: Yes, these emerging therapies to some degree may change how we approach this disease. But I think that with some of these older therapies, especially when you’re when you’re first talking about someone who’s coming in with anemia, you need to think about ESA, danazol, and thalidomide/prednisone.

I think that ESA is probably the most prominently used. How many of you are checking serum erythropoietin levels in these patients to assess their candidacy for ESAs, is that a common practice?

Mukesh Kumar, MD: Yes, I’m checking on all of my patients.

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Polycythemia vera and essential thrombocythemia in children, still a challenge for pediatricians

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February 4, 2025

Agathe Picard, Sophie Bayart, Marianna Deparis, Cécile Dumesnil De Maricourt, Sophie Haro, Anne Jourdain, Coralie Mallebranche, Fanny Rialland, Damien Luque Paz, Cedric Pastoret, Virginie Gandemer & Elie Cousin

Abstract

Polycythemia vera (PV) and essential thrombocythemia (ET) are rare myeloproliferative neoplasms (MPN) in children, adolescents and young adults. No recommendations are available concerning these patients’ management. Transposing to children the knowledge established in adult patients is not acceptable. For a better understanding of difficulties encountered by pediatricians and adult hematologists, we conducted a national practice analysis concerning follow-up of patients under 18 diagnosed with ET or PV, in France. Then, we present data from a multicentric, descriptive, retrospective study, including 17 patients with ET or PV, diagnosed under 18, coming from 7 hematopediatric departments in France. Interviewed physicians reported a lack of expertise and theoretical training in the hematological field to diagnose and follow children with MPNs. Data from 17 patients (15 ET, 2 PV) confirmed a high proportion of asymptomatic patients at the time of diagnosis (41%). Proportion of “triple-negative” patients (59%) was higher than in adult cohorts. 60% of patients underwent a bone marrow biopsy and 31% of cases were discussed during a multi-disciplinary staff meeting. 76.5% patients were treated, with a high frequency of antithrombotic and cytoreductive drugs. No complications were observed during the 45 months of median follow-up.
Conclusion: Physicians insisted on the need for training. Only the accumulation of descriptions of MPNs in children will lead to a better management of these diseases. Considering the small proportion of pediatric patients with complications after diagnosis, rapid therapeutic de-escalation seems essential to consider during the follow-up in a close collaboration with adult hematologists.

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Second-Line Fedratinib Produces Early Platelet Count Improvements in Myelofibrosis

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February 5, 2025

Author(s): Jax DiEugenio

Fact checked by: Chris Ryan

Patients with myelofibrosis who received second-line fedratinib (Inrebic) experienced early increases in platelet count compared with those given best available therapy (BAT), and a higher magnitude of benefit was observed in patients with a low platelet count at baseline, according to findings from the phase 3 FREEDOM2 trial (NCT03952039) presented at the 2024 ASH Annual Meeting.

Findings showed that in the overall safety population, fedratinib generated improvements in mean platelet count and mean change from baseline platelet count, most noticeably in early treatment cycles.

In patients with a low platelet count at baseline, defined as at least 50 to less than 100 x 109/L, patients treated with fedratinib (n = 34) experienced a mean increase in platelet count of 45% on day 15 of cycle 1 compared with 11% for those given BAT (n = 21). Among patients with a high platelet count at baseline of at least 100 x 109/L, these rates were 27% for fedratinib (n = 85) and –6% for BAT (n = 39).

During a presentation of the data, lead study author Haifa Kathrin Al-Ali, MD, explained that increased platelet count was not correlated with changes in spleen size, pointing to a potential benefit for fedratinib on thrombopoiesis.

“These data suggest a platelet-sparing effect of second-line fedratinib vs BAT, and support fedratinib as a promising second-line treatment option for patient with myelofibrosis with low or high baseline platelet count,” said Al-Ali, who is a professor of translational oncology and head of the Krukenberg Cancer Center at the University Hospital of Halle (Saale) in Germany.

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Calreticulin Mutations Can Worsen Survival Outcomes in Ruxolitinib-Treated Patients With Myelofibrosis

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January 31, 2025

Author(s): Luke Halpern, Assistant Editor

Patients with myelofibrosis (MF) who harbor calreticulin (CALR) mutations begin treatment with ruxolitinib presenting severe disease with a longer median time from diagnosis, with inferior spleen responses and lower rates of symptom responses observed at 6-months, according to study results published in Annals of Hematology.1

3D illustration Virus DNA molecule, structure. Concept destroyed code human genome. Damage DNA molecule. Helix consisting particle, dots. DNA destruction due to gene mutation or experiment
CALR mutations in patients with myelofibrosis being treated with ruxolitinib can lead to worsened outcomes. | Image Credit: © rost9 | stock.adobe.com

CALR mutations can be found in around 20% of patients with primary and post-essential thrombocythemia (ET) MF. Patients who harbor CALR mutations often present with distinct clinical features compared with Janus kinase (JAK)2-mutated patients. Typically, they feature lower levels of hemoglobin and white blood cells, present at younger age, and are associated with better survival rates.1,2

Ruxolitinib (Jakfafi; Incyte) is a targeted therapeutic option for patients with MF that has shown efficacy regardless of the driver mutation in patients. However, new therapies continue to be developed that specifically target CALR, necessitating further research on therapies that are currently standard in CALR-positive patients, according to the investigators.1,3

The study authors reported the outcomes of a sub-analysis of the RUX-MF clinical trial, documenting 135 patients with CALR mutation who received ruxolitinib in a real-world setting. The analysis was performed with major considerations, including that the younger age of CALR-mutated patients compared with JAK2-mutated patients may influence survival outcomes, and that younger patients are eligible for allogeneic stem cell transplantation, which the investigators noted could meaningfully impact the treatment algorithm.1

In total, 786 patients from the RUX-MF trial were JAK2-mutated, while 135 had a CALR mutation. Only 78 CALR-mutated patients were evaluable, in which their mutation was type 1-like in 66.7% of the population, while 30.8% had type 2-like mutation. At the beginning of ruxolitinib initiation, CALR-mutated patients were younger, had higher percentages of peripheral blasts, and lower median hemoglobin levels compared with JAK2-mutated patients.1

Responses to ruxolitinib and patient outcomes according to mutation type were reported at 6 months. There were no major differences in spleen responses (CALR: 21.4%; JAK2: 25.7%), and there were comparable rates of treatment-emergent anemia (CALR: 35.7%; JAK2: 30.4%) and both overall and treatment-emergent thrombocytopenia. However, symptoms response was significantly lower in CALR-mutated patients (56.1% vs 66.7%), and overall anemia rates (60.3% vs 50.3%) were higher in this population compared with JAK2-mutated participants.1

Across the 135 patients with CALR mutation, there were no factors associated with spleen or symptom response. Notably, factors correlated with worse survival included hemoglobin below 10 g/dL and a high burden of symptoms. In the subgroup of 72 CALR-mutated patients who began ruxolitinib over 2 years following diagnosis, anemia (HR: 1.92; 95% CI, 1.02-3.79) and the use of a reduced ruxolitinib initiation dose (HR: 2.29; 95% CI, 1.15-4.56) were associated with poor overall survival.1

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