Tag Archives: myeloproliferative neoplasms

Immunofluorescence microscopy on the blood smear identifies patients with myeloproliferative neoplasms

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July 17, 2024

Carlo Zaninetti, Leonard Vater, Lars Kaderali, Carl C. Crodel, Tina M. Schnöder, Jessica Fuhrmann, Leonard Swensson, Jan Wesche, Carmen Freyer, Andreas Greinacher & Florian H. Heidel

Myeloproliferative neoplasms (MPN) are a group of clonal stem cell disorders with heterogeneous clinical presentation [1]. Due to the risk of severe thromboembolic complications and disease progression, the early recognition of an MPN prior to the appearance of clinical complications is clearly warranted to facilitate early pharmacologic intervention [2,3,4]. Detection of the somatic mutations by genotyping has become an essential part of the diagnostic work-up of suspected subjects, as well as of the risk stratification after the diagnosis of MPN has been confirmed [5]. However, in many parts of the world molecular testing is barely affordable.

We have established an immunofluorescence microscopy (IF)-based method for platelet phenotyping on the peripheral blood smear [6]. This method has been proven to be highly efficient in the diagnosis of diverse hereditary platelet disorders by recognizing disease-specific changes of cell structures, including alterations of leukocytes and red blood cells (RBC) [7, 8]. Major advantages of this approach are the need of small amounts of blood (<100 μL) and the possibility to send the blood films by regular mail even long distances.

It is well-known that morphology of peripheral blood cells is also often altered in MPN [9, 10]. However, due to different methods and the heterogeneity of the patients’ populations, results are difficult to compare.

In the present study, we aimed at assessing platelet phenotype using our IF method in a cohort of patients diagnosed with MPN. The study has been registered in the German Clinical Trials Register (DRKS-ID: DRKS00032588). Three German reference centers for diagnosis and treatment of MPN took part in the study: Internal Medicine C, University Medicine Greifswald; Internal Medicine 2, University Hospital Jena; and Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Germany. The study protocol was approved by the institutional review boards of all centers. Patients or their legal guardians signed written informed consent to the investigation, which was conducted according to the Declaration of Helsinki. Healthy controls were enrolled among blood donors at the Institute for Transfusion Medicine, University Medicine Greifswald, Germany.

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Ph- MPN in Adolescent and Young Adult Patients

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June 26, 2024

Elizabeth L. Courville, MD

England JT, Szuber N, Sirhan S, et al. Clinical features and long-term outcomes of a pan-Canadian cohort of adolescents and young adults with myeloproliferative neoplasms: a Canadian MPN group study. Leukemia. 2024;38(3):570-578.

The classical BCR:: ABL1-negative myeloproliferative neoplasms (Ph- MPNs) polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are typically diseases of older adults, with a median age at diagnosis within the sixth decade of life. In two large case series from cancer centers in the United States, adolescent and young adult (AYA) patients were reported to account for 11 to 12% of the Ph- MPNs evaluated.1,2  The data on AYA patients with Ph- MPNs is less robust than that available for their older counterparts, and this patient population may not be represented in cohorts used to develop prognostic scoring systems.

Recently, James T. England, MD, MSc, and colleagues investigated the clinical features and long-term outcomes of a cohort of 609 patients (17 pediatric patients aged <18 years and 592 patients aged 18-45 years) with Ph- MPNs from across eight participating centers in Canada. Initial diagnoses are shown in Figure 1. Clinical features from the current study cohort are compared with those of a 2018 Mayo Clinic AYA cohort1  (Table). The patients were diagnosed between 2000 and 2022, with MPN driver mutation analysis performed in 89% and next-generation sequencing (NGS) of clinically relevant myeloid genes performed in 48%. More than one-third of patients (211) had NGS testing first performed during initial disease phase, with a median time from diagnosis of 3.9 years (range, 0-29 years). Sixty-four patients had NGS first performed during the post-ET/post-PV secondary myelofibrosis (SMF) phase, while 19 had NGS first performed during the accelerated phase (AP)/blast phase (BP) of disease. Non-MPN driver mutations were detected in a higher proportion of patients evaluated during disease progression (secondary myelofibrosis or elevated blasts) than during initial disease phase, including more frequent high molecular risk (HMR) mutations (Figure 2). Mutations defined as HMR included pathogenic and likely pathogenic variants in ASXL1, EZH2, IDH1/2, SRSF2, TP53, and U2AF1Q157. Among those patients with NGS testing performed during the initial disease phase, additional mutations were most frequently detected in those with overt PMF (26%).

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Dr Gerds on the Clinical Implications of Pelabresib Plus Ruxolitinib in Myelofibrosis

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June 14, 2024

Author: Aaron Gerds, MD

Aaron Gerds, MD, assistant professor, medicine, Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, discusses the clinical implications of safety outcomes with of pelabresib (CPI-0610) plus ruxolitinib (Jakafi) in patients with JAK inhibitor–naive myelofibrosis.

At the 2024 ASCO Annual Meeting, investigators presented updated safety and efficacy data from the phase 3 MANIFEST-2 trial (NCT04603495), which investigated pelabresib in combination with ruxolitinib in JAK inhibitor–naive patients with myelofibrosis. The study revealed significant reductions in splenomegaly with combination therapy compared with ruxolitinib alone at week 24, along with rapid, deep, and sustained spleen reduction. The combination therapy also generated a trend toward greater improvement in total symptom score and higher rates of deeper hemoglobin responses vs ruxolitinib monotherapy, with fewer patients requiring transfusions and fewer anemia-related adverse effects observed.

In this updated readout, patients receiving the combination experienced a significantly higher spleen volume response rate at week 24 compared with those receiving ruxolitinib alone. The combination therapy also resulted in more sustained spleen volume responses and greater reductions in total symptom score, although the difference in the latter did not reach statistical significance. Hemoglobin levels remained higher over time in the combination arm, and fewer patients in this arm required red blood cell transfusions. Improvements in bone marrow fibrosis and reductions in key inflammatory cytokines were also observed with the combination therapy.

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Myeloproliferative neoplasms in the adolescent and young adult population: A comprehensive review of the literature

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Hannah Goulart, Lucia Masarova, Ruben Mesa, Claire Harrison, Jean-Jacques Kiladjian, Naveen Pemmaraju 

Abstract

Myeloproliferative neoplasms (MPN) are characterized by a clonal proliferation of myeloid lineage cells within the bone marrow. The classical BCR-ABL negative MPNs are comprised of polycythaemia vera, essential thrombocythaemia and primary myelofibrosis. Historically, the majority of MPNs are diagnosed in adults older than 60 years of age; however, in recent years, there has been recognition of MPNs in the adolescent and young adult (AYA) population. AYAs with MPN, typically defined as between the ages of 15 and 39 years old, may comprise up to 20% of patients diagnosed with MPN. They demonstrate unique patterns of driver mutations and thrombotic events and remain at risk for progression to more aggressive disease states. Given the likely long length of time they will live with their disease, there is a significant unmet need in identifying well-tolerated and effective treatment options for these patients, particularly with the advent of disease modification. In this review, we provide a comprehensive overview of the clinical features, disease course and management of AYA patients with MPN and, in doing so, highlight key characteristics that distinguish them from their older counterparts.

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Platelet proteome reveals potential mediators of immunothrombosis and proteostasis in myeloproliferative neoplasms

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Sarah Kelliher, Sara Gamba, Luisa Weiss, Zhu Shen, Marina Marchetti, Francesca Schieppati, Caitriona Scaife, Stephen Madden, Kathleen Bennett, Anne Fortune, Su Maung, Michael Fay, Fionnuala Ní Áinle, Patricia Maguire, Anna Falanga, Barry Kevane, and Anandi Krishnan

Myeloproliferative neoplasms (MPN) are chronic bone marrow malignancies characterised by clonal proliferation of hematopoietic precursors and elevated cell counts in peripheral blood. Patients with MPN are at risk of progression to myelofibrosis or acute leukemia and experience a substantial burden of
microvascular symptoms. However, thrombosis ( both arterial and venous), represents the leading
cause of morbidity and mortality for patients with PV and ET.

Translational studies have indicated that the platelet proteome influences pathways relating to immune
response, inflammation, and malignancy. Thrombocytosis and platelet hyperactivity are hallmarks of
MPN, however platelet count in isolation is not predictive of clinical outcome, and conventional
antiplatelet therapy does not fully mitigate thrombotic risk. A comprehensive picture of the MPN platelet
molecular profile is lacking and to date, no studies have evaluated the unbiased platelet proteome in a
sizeable clinical cohort of affected patients. In this present study, we performed untargeted quantitative
profiling of the platelet proteome in a large (n= 140) cohort of patients with PV and ET.

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Advances in Interferon Therapy for Myeloproliferative Neoplasms

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Kumar Das, Dibash PhD

Oncology Times 46(6):p 1,14, June 2024. | DOI: 10.1097/01.COT.0001024068.38723.15

In the ever-evolving landscape of myeloproliferative neoplasms (MPNs), clinicians continue to explore and refine treatment strategies to improve patient outcomes. A recent review published in Therapeutic Advances in Hematology sheds light on the pivotal role of interferons, particularly pegylated formulations, in managing MPNs effectively (2024; doi: 10.1177/20406207241229588).

The advent of pegylated interferons, including peginterferon alfa-2a and ropeginterferon alfa-2b-njft, marks a significant turning point in MPN therapeutics. These agents, renowned for their potent immunomodulatory capabilities and profound impact on disease progression, have reshaped treatment paradigms outlined in the National Comprehensive Cancer Network (NCCN) Guidelines for polycythemia vera (PV), essential thrombocythemia, and primary myelofibrosis. This article delves deep into the multifaceted influence of pegylated interferons, shedding light on their efficacy, safety profiles, and future implications in MPN management.

Clinical trials, including landmark Phase II and III studies such as MPD-RC 111 and MPD-RC 112, have provided crucial insights into the efficacy of pegylated interferons. These trials meticulously assessed response rates, molecular remissions, and hematological improvements in MPN patients resistant to or intolerant of hydroxyurea. Noteworthy reductions in JAK2 V617F variant allele frequency (VAF) have underscored the molecular response achievements of pegylated interferons, highlighting their disease-modifying potential.

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Predictors of symptom scores in myeloproliferative neoplasms: A real-world retrospective cohort study

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Muhammad Ali Khan, Syed Arsalan Ahmed Naqvi, Irbaz Bin Riaz, and Jeanne M. Palmer

Abstract

Background: Although high symptom burden indicates poor survival and informs treatment decisions, little is known about the impact of demographic, clinical, and laboratory features on total symptom score (TSS) in patients with myeloproliferative neoplasms (MPN).
Methods: Patients with MPN (polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF)) were identified from the retrospective chart review. TSS, individual symptom scores (fatigue, early satiety, abdominal discomfort, inactivity, concentration problems, fever, night sweats, itching, bone pain, weight loss), demographic characteristics (race, ethnicity, age, gender), clinical features (time since diagnosis, depression status, obesity status, spleen size), laboratory results and season at the time of visit were recorded from the clinical encounter when index assessment of TSS was performed for each patient. Normality was assessed using visual inspection of data distribution, whereas multicollinearity was assessed using various inflation factors. A univariable regression followed by a multivariable regression analysis was conducted using a backward selection approach. A p-value <0.05 indicated a statistically significant association of a given feature with TSS.
Results: The chart review identified 252 patients (PV: 78; ET: 81; MF: 93). Mean age was 59 (SD: 17.7), 67 (SD: 13.0), and 68 (SD: 10.9) years for ET, PV, and MF respectively. Most patients were white (PV, MF: 92%; ET: 83%) and females (ET: 75%; PV: 60%; MF: 53%). The TSS of patients was highest with PV (mean: 18.5; SD: 16.9) followed by MF (mean: 18.1; SD: 15.4) and ET (mean: 14.3; SD: 15.9). Fatigue was the most reported symptom whereas the least reported symptoms were fever and weight loss. Univariable regression analyses showed depression (B: 17.7; p=0.02), female gender (B: 10.6; p=0.01), platelet count (B: 0.03; p=0.03), and hemoglobin (Hb) (B: -2.6; p=0.01) in PV patients, depression (B: 19.8, p=2×10-5) in ET patients and depression (B: 11.0, p=0.03), white blood cell (WBC) count (B: 0.2; p=0.01), neutrophil count (B: 0.3, p=0.01), and non-neutrophil WBC count (B: 0.6; p=0.02) in MF patients to have significant association with TSS. Multivariable regression analyses (Table) showed Hb (B: -2.5; p=0.01) and platelet count (B: 0.02; p=0.03) in PV patients, depression (B: 19.7; p=2×10-5) in ET patients and depression (B: 12.3, p=0.01) and WBC count (B: 0.3; p=0.002) in MF patients to have a significant association with TSS.
Conclusions: Depression in ET and MF and low Hb in PV were identified as significant drivers of symptom burden. Identifying and managing patients with these comorbidities could improve their quality of life with a potential survival benefit.

Myeloid Neoplasms: Better Understanding of their Molecular Pathogenesis with Improvised Genomic Testing: A Ray of Hope for Better Clinical Outcomes

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With the increase in incidence and prevalence of myeloid neoplasms in India, it has become a necessity to understand its molecular mechanisms, acquisition of genomic alterations, and understand its primary and secondary resistance pathways which ultimately impact the decision of therapeutics. The objective of this review is to investigate the molecular aspects of this disease type and identify the biomarkers that help with diagnosis, risk assessment, prognosis, and selecting the best line of treatment for a speci icmyeloid neoplasm. Advancements and innovations in molecular technologies from simplest Real-Time PCR to high throughput next-generation sequencing have played a vital role in screening the most common mutations and fusions to the novel and rare. Molecular technologies have helped to enumerate the genomic landscape of myeloid malignancies. The understanding of both- the mechanisms and the technology is a strong combination as it has helped revolutionize precision oncology and helped in giving better therapeutic choices with better clinical outcomes. The importance of cellular morphology, clinical symptoms, and molecular pathology in assessing the risk of myeloid malignancies is emphasized and summarized in the review. The review concludes that understanding molecular pathogenesis can be improved by using clinical-pathological-molecular strategies for diagnosis and therapy decision-making.

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Abstract WP249: Risk for Ischemic and Hemorrhagic Stroke is Increased in Veterans Exposed to Agent Orange and Those With Myeloproliferative Neoplasms

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Natasha Mathur, Andrew Tiu, Zoe McKinnell, Puneet Gill, Martha Antonio, Shanshan Liu, Guoqing Diao, Ramesh Subrahmanyam, Craig M Kessler and Maneesh R Jain

Abstract

Agent Orange (AO) is a dioxin containing defoliant and carcinogen used in the Korean and Vietnam War. There is limited evidence of the association between AO exposure among Veterans and stroke. Stroke is not yet part of the list of presumptive conditions according to the Promise to Address Comprehensive Toxics (PACT) Act which provides Veterans and their survivors disability compensation for conditions arising from exposure to AO. Myeloproliferative Neoplasms (MPN) are uncommon etiologies of stroke but whether AO exposure increases incidence of stroke in MPN has not been described.

Utilizing the Veterans Affairs Informatics and Computing Infrastructure (VINCI) database, a case-control study was performed from 1/1/2006 – 1/26/2023 on the Veterans from Illinois, the state most representative of the US population. ICD-9 and -10 codes identified Veterans with stroke and MPN. AO exposure was verified on the Veterans’ service duration and location. Qualitative data were compared by chi-square tests.

Among 586,555 Veterans from Illinois, there were 15,455 ischemic stroke (IS), 1,593 hemorrhagic stroke (HS), 2,752 MPN, and 59,393 with AO exposure. Among MPNs, there were 237 IS (41 with AO) and 26 HS (3 with AO). IS and HS were associated with AO exposure, OR 1.34 95% CI 1.28-1.41, p<0.0001, and OR 1.20 95% CI 1.03-1.39, p=0.02, respectively. MPN is associated with IS and HS, OR 3.52, 95% CI 3.08-4.03, and OR 3.54, 95% CI 2.4-5.23, both p<0.0001, respectively. There is no significant association with AO exposure among Veterans with MPN with stroke. Among non-MPN Veterans with AO exposure, there was an earlier median age of IS and HS, 67 vs. 70 and 67 vs. 71, both p<0.0001. There was no difference in median age of stroke among MPN Veterans with or without AO exposure. There were no differences with rates of hypertension, hyperlipidemia, diabetes, smoking, heart failure, and pulmonary hypertension among MPN Veterans with stroke with and without AO exposure.

In conclusion, there is an association of AO exposure with IS and HS with an earlier onset among those exposed. There is a strong association between MPN and stroke independent of AO exposure. The biologic plausibility of endothelial dysfunction and accelerated atherosclerosis from AO exposure warrants further investigation.

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Ambitious £4 million project to develop clinical platform for blood cancer prevention

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4th Feb 2024 – Edward Pinches

Professor George Vassiliou from the Wellcome-MRC Cambridge Stem Cell Institute (CSCI), University of Cambridge will spearhead the project, which focuses on myeloid blood cancers, a group of blood cancers that accounts for more than 11,000 deaths each year in the UK.

The blood cancers, which affect both the bone marrow and blood, include acute myeloid leukaemia (AML), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and rarer cancers like chronic myelomonocytic leukaemia (CMML).

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