Which Factors Predict Thrombotic Events in Essential Thrombocythemia?

Posted on by

August 13, 2024

The risk for essential thrombocythemia-related events in patients with the disease can be predicted using currently available clinical data, researchers wrote in a letter to the editor appearing in Blood Cancer Journal.

“Although considered the most indolent myeloproliferative neoplasm (MPN), essential thrombocythemia (ET) is linked to burdensome vasomotor symptoms and potentially fatal complications that include thrombosis, hemorrhage, and disease progression to myelofibrosis and aggressive myeloid neoplasms,” Ghaith Abu-Zeinah, MD, a hematologist and oncologist at the Richard T. Silver Myeloproliferative Neoplasms Center at Weill Cornell Medicine, New York, and colleagues wrote. “Prognostic measures to identify those at greatest risk for thrombosis, progression, and death in ET [events] are important for timely risk-adapted intervention with available treatments, and for development of interventional trials to improve event-free survival [EFS]. But predicting risks of events in ET has been difficult because ET is an uncommon and clinically heterogeneous chronic disease.”

Predicting excess mortality and disease progression related to ET presents challenges because such events often occur decades after a patient is diagnosed, the researchers continued.

“Thus, retrospective analysis of large cohorts with sufficiently long follow-up is required to identify prognostic measures to stratify risk in patients with ET,” they wrote.

Read more

Triple-Negative Myelofibrosis Associated With Decreased Survival, Aggressive Clinical Behavior and Shorter Duration of Response to Ruxolitinib

Posted on by

August 14, 2024

Amber Denham

According to recently published research in Clinical Lymphoma, Myeloma & Leukemia, triple-negative myelofibrosis (TN-MF) was found to be continually associated with decreased survival, enhanced aggressive clinical behavior with higher rates of leukemic transformation, and a shorter duration of response to ruxolitinib.

“Myelofibrosis is the most aggressive subtype among classical BCR::ABL1 negative myeloproliferative neoplasms…Triple-negative myelofibrosis accounts for only 5% [to] 10% of cases and carries the worst outcomes,” explained lead study author Luis Aguirre, MD, Dana-Farber Cancer Institute, Harvard Medical School, Cambridge, Massachusetts, and colleagues. They added, “Little has been described about this subset of disease…identification of features of interest and assessment of treatment response are areas in need of further investigation.”

Researchers evaluated baseline clinical and molecular parameters from 626 patients with myelofibrosis who presented to the H. Lee Moffitt Cancer Center in Tampa, Florida, between 2003 and 2021. These data were compared based on the presence or absence of the 3 classical phenotypic driver mutations.

Read more

Development of a natural language processing pipeline for assessment of cardiovascular risk in myeloproliferative neoplasms

Posted on by

August 8, 2024

Andrea Duminuco, Joshua Au Yeung, Raj Vaghela, Sukhraj Virdee, Claire Woodley, Susan Asirvatham, Natalia Curto-Garcia, Priya Sriskandarajah, Jennifer O’Sullivan, Hugues de Lavallade, et al.

A central feature of myeloproliferative neoplasms (MPN) is an increased risk of cardiovascular thrombotic complications, and this is the primary determinant for the introduction of cytoreductive therapy.1 The landmark ECLAP study in polycythemia vera (PV) patients, showed cardiovascular mortality accounted for 45% of all deaths, with a thrombosis incidence rate of 1.7/100 person/year and a cumulative incidence of 4.5% over a median follow-up of 2.8 years.2

Natural language processing (NLP) is a branch of machine learning involving computational interpretation and analysis of human language. CogStack (https://github.com/CogStack), is an open-source software ecosystem, that retrieves structured and unstructured components of electronic health records (EHR). The Medical Concept Annotation Toolkit (MedCAT), the NLP component of CogStack, structures clinical free text by disambiguating and capturing synonyms, acronyms, and contextual details, such as negation, subject, and grammatical tense, and mapping text to medical Systematized Nomenclature of Medicine–Clinical Terms (SNOMED-CT) concepts. This technique is known as “named entity recognition and linkage” (NER+L). MedCAT has previously been used and validated in many studies to structure EHR data across a range of medical specialties for auditing, observational studies, de-identifying patient records, operational insights, disease modeling, and prediction.3–8

We employed our NLP pipeline, Cogstack, and MedCAT, to determine the prevalence and impact of cardiovascular risk factors upon thrombotic events during follow-up. We used Cogstack to retrieve outpatient hematology clinic letters and hematology discharge letters. MedCAT was then used for NER+L of relevant clinical free-text to respective SNOMED-CT codes that were determined by two hematology specialists. The base MedCAT model was trained unsupervised on >18 million EHR documents, and this was further fine-tuned using a 80:20 train:test split with 600 clinician-annotated MPN-specific documents. Total SNOMED-CT code counts were aggregated and grouped by individual patient, a unique threshold count was then applied to “infer” presence of the respective SNOMED code. In this process, hematology specialists read through clinical documents and manually highlight correct words or phrases detected by MedCAT that correspond to the SNOMED concept of interest.

Read more

Efficacy of a JAK2/mTOR Inhibitor Combination in Controlling Acute Graft-vs-Host Disease

Posted on by

By The ASCO Post Staff
Posted: 8/8/2024

Adding a Janus kinase 2 (JAK2) inhibitor to standard immunosuppressive drugs may not improve prevention of acute graft-vs-host disease in patients with hematologic malignancies undergoing treatment with allogeneic hematopoietic cell transplantation, according to a recent study published by Pidala et al in Blood.

Background

Hematopoietic cell transplantation may offer a potential cure in patients with hematologic malignancies; however, between 10% and 20% of patients who receive stem cells from a donor through allogeneic hematopoietic cell transplantation develop acute graft-vs-host disease within the first 100 days following transplant. This condition occurs when a donor’s immune cells identify the patient’s cells as foreign and attack them. Apart from disease recurrence, graft-vs-host disease can be life threatening and greatly impact a patient’s quality of life posttransplant.

While JAK inhibition is often effective in treating graft-vs-host disease—the JAK1/2 inhibitor ruxolitinib is indicated for the treatment of refractory graft-vs-host disease—the researchers conducting the recent trial addressed whether JAK inhibitors could have a role in graft-vs-host disease prophylaxis. JAK2 inhibitors are capable of turning off the JAK2 gene—which promotes inflammation and contributes to the development of graft-vs-host disease.

“JAK inhibitors are active in treating [graft-vs-host disease] that does not respond to steroids,” explained senior study author Brian Betts, MD, Vice Chair of Strategic Initiatives for Transplant & Cellular Therapy at the Roswell Park Comprehensive Cancer Center. “But the question over the past 10 years has been whether JAK inhibition could prevent [graft-vs-host disease],” he added.

Read more

Myeloproliferative neoplasms: young patients, current data and future considerations

Posted on by

August 7, 2024

Marta Sobas, Jean-Christophe Ianotto, Jean-Jacques Kiladjian & Claire Harrison

Abstract

The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders predominantly occurring in elderly, whereas in children and young adults are quite infrequent. Therefore, less is known about clinical presentation, genetic abnormalities, prognosis and best management strategies for this groups of patients. Currently, more cases of younger MPN patients are diagnosed. Nevertheless, diagnosis of MPNs, especially in childhood, may be difficult due to lower incidence of JAK2V617F and CALR mutations and differences in peripheral blood counts between adults and children. Challenges for younger MPN patients are longer life expectances, specific psychosocial need, fertility and pregnancy need and a long term therapy side effect (including second cancers). The most severe MPNs complication is transformation to secondary myelofibrosis (MF) or acute myeloid leukemia (AML). Optimal management of young MPNs remains a challenge as the classical risk scores fail in young MPNs. Moreover, the main objective of young MPNs therapy should be the disease outcome modification. Therefore, international collaborative work between pediatricians and “adult hematologists” is required to measure outcomes and generate protocol of management of young MPNs.

Read more

 

Cardiovascular Risk in Philadelphia-Negative Myeloproliferative Neoplasms: Mechanisms and Implications—A Narrative Review

Posted on by

by Samuel Bogdan Todor, Cristian Ichim, Adrian Boicean, and Romeo Gabriel Mihaila

Abstract

Myeloproliferative neoplasms (MPNs), encompassing disorders like polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are characterized by clonal hematopoiesis without the Philadelphia chromosome. The JAK2 V617F mutation is prevalent in PV, ET, and PMF, while mutations in MPL and CALR also play significant roles. These conditions predispose patients to thrombotic events, with PMF exhibiting the lowest survival among MPNs. Chronic inflammation, driven by cytokine release from aberrant leukocytes and platelets, amplifies cardiovascular risk through various mechanisms, including atherosclerosis and vascular remodeling. Additionally, MPN-related complications like pulmonary hypertension and cardiac fibrosis contribute to cardiovascular morbidity and mortality. This review consolidates recent research on MPNs’ cardiovascular implications, emphasizing thrombotic risk, chronic inflammation, and vascular stiffness. Understanding these associations is crucial for developing targeted therapies and improving outcomes in MPN patients.

Underreporting of Patient-Reported Outcomes Seen in Blood Cancer Trials

Posted on by
Caleb Rans, PharmD

The incorporation of patient-reported outcomes (PROs) in clinical trials provides a means for researchers to measure health-related quality of life (HRQOL) and patient-specific outcomes. When evaluating subjective symptoms, for example, patients are usually the most reliable source of feedback. Consequently, PROs are seen as the gold standard for assessing subjective symptoms.1

According to the authors, PROs are not often collected or reported in solid tumor trials, but less is known about RCTs focusing on blood cancers.2

Read more

Donor Type Impacts Survival in MF Cell Transplantation

Posted on by
Leonardo Jaimes

Patients with myelofibrosis (MF) who receive hematopoietic cell transplantation (HCT) from a matched sibling donor appear to have better overall survival (OS) than those who receive transplants from other donor types, according to a recently published study in Blood Advances.

“Understanding the impact of donor type is crucial not only to improve the clinical outcomes with HCT but also to establish the donor pool with viable options and eventually improve access to HCT,” the authors wrote.

HCT is currently the only disease-modifying therapy available for MF, the study team noted. The outcome after transplantation is diverse and dependent on several disease- and patient-associated factors, they added. According to recent research, donor type could also influence the prognosis of patients with MF after HCT. One study showed that patients with matched sibling donors had a better OS than the rest.

However, previous research has not taken the impact of posttransplantation cyclophosphamide for graft versus host disease prophylaxis into consideration, the researchers noted. Furthermore, no patients in previous studies had received vHLA-haploidentical donor grafts, they continued.

Therefore, the authors aimed to assess the impact of donor type in OS, considering the factors above and using the Center for International Blood and Bone Marrow Transplant Research registry data for HCTs done between 2013 and 2019. The study included over 1000 patients who received HCTs for MF.

Results showed that similarly to previous findings, matched sibling transplants were associated with better overall survival and lower graft failure than the rest. However, OS was only superior to the rest in the first 90 days after transplant. There was no significant difference in OS among patients who received mismatched unrelated, matched unrelated, and haploidentical donor transplants.

Despite the findings, the authors remarked that HCTs should not be delayed in the search for fully matched donors and highlighted the need for solutions regarding graft failure.

Read more

Prospective Study to Evaluate Fedratinib Plus Nivolumab in Myelofibrosis

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

A single-arm, phase 2 study of fedratinib, a selective JAK2 inhibitor, plus nivolumab is planned for patients with myelofibrosis (MF) who had a suboptimal or no response to a JAK inhibitor was initiated, according to a report published in the Annals of Hematology.

“This study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives,” the researchers wrote in their report. Currently, 23 of 30 planned patients are enrolled in the study and recruitment is expected to be completed by December 2024.

The open-label FRACTION trial will treat patients with MF from 9 academic centers in Germany, who will receive 400 mg of fedratinib daily in 28-day cycles, followed by 240 mg of nivolumab every 2 weeks beginning in cycle 2. Treatment will be given until progressive disease, relapse, death, or study discontinuation.

This study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives.

The primary efficacy endpoints will be response rate within 12 treatment cycles and RCT independency. Secondary endpoints will include safety, incidence of leukemic transformation, clinical benefit, duration of response, progression-free survival, overall survival, and disease burden. Molecular analyses will also serve as exploratory endpoints for the study.

Patients with MF primary or secondary MF are eligible if they had a suboptimal or no response to a JAK inhibitor, which is defined by persistent symptoms, splenomegaly, cytopenia, or hyperproliferation. Patients who have received a prior immune checkpoint inhibitor or history of uncontrolled autoimmune disease are not eligible for the study.

Disclosures: This research was supported in part by Celgene/Bristol Myers Squibb. Please see the original reference for a full list of disclosures.

Read more

MPN Word of the Month: Hematocrit

Posted on by

Hematocrit is a key measurement in hematology that represents the proportion of blood volume occupied by red blood cells (RBCs). Expressed as a percentage, it provides crucial insights into an individual’s red blood cell mass and overall blood health. Typically, hematocrit levels are assessed through a routine blood test, often as part of a complete blood count (CBC).

In the context of myeloproliferative neoplasms (MPNs)—hematocrit plays a significant role in diagnosis and management. Polycythemia vera, essential thrombocythemia, and myelofibrosis each affect blood cell production but in different ways.

  1. Polycythemia Vera (PV): One of the indicators of PV is an elevated hematocrit level. In PV, the bone marrow produces an excess of red blood cells, leading to a high hematocrit. This can increase how thick the blood is (viscosity), potentially causing complications such as blood clots, strokes, or heart attacks. Regular monitoring of one’s hematocrit is essential for managing PV and assessing the effectiveness of treatments aimed at reducing the risk of these complications.
  2. Essential Thrombocythemia (ET): While ET primarily involves elevated platelet counts, a high hematocrit may also be observed due to secondary effects or overlapping features with other MPNs. Management focuses on controlling platelet levels to prevent thrombotic events, but monitoring hematocrit remains important for comprehensive disease management.
  3. Primary Myelofibrosis (PMF): In PMF, hematocrit levels may be low due to the replacement of bone marrow with fibrous tissue, leading to anemia. The disease’s progression can cause varying hematocrit levels, which are crucial for tracking disease progression and response to treatment.

In summary, hematocrit is more than just a routine blood test value; it is a vital indicator in the diagnosis, treatment, and management of myeloproliferative neoplasms.