Category Archives: Research

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.

Sobi to present new myelofibrosis data at the ASCO 2024 Annual Meeting

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WALTHAM, Mass., May 24, 2024 (GLOBE NEWSWIRE) — Sobi North America, the North American affiliate of Swedish Orphan Biovitrum AB (Sobi®), today announced the presentation of three abstracts that highlights data from its myelofibrosis treatment option at the American Society of Clinical Oncology (ASCO) Annual Meeting taking place in Chicago from May 31 – June 4, 2024.

Sobi’s commitment to delivering innovative treatments for people living with hematological diseases is seen in global studies spanning multiple rare disorders, including myelofibrosis.

A retrospective analysis will be presented that demonstrates the efficacy of pacritinib in spleen volume reduction, symptom benefit and red blood cell transfusion response, compared with best available therapy, in patients with myelofibrosis who have both thrombocytopenia and anemia.

An additional retrospective analysis will be presented that shows the substantial symptom benefit pacritinib provides compared with best available therapy or low-dose ruxolitinib, specifically in patients who required red blood cell transfusion at the time of pacritinib initiation. The number of patients experiencing treatment emergent Grade 3 anaemia was similar between pacritinib and BAT groups.

New real-world data will be presented that demonstrates treatment with pacritinib provides stability or improvement in thrombocytopenia and/or anemia in patients with myelofibrosis, regardless of baseline counts, and has favorable overall survival similar to other JAK inhibitor historical controls.

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Metformin Use Linked to Lower Odds of Myeloproliferative Neoplasms

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By: Elana Gotkine

Medically Reviewed By: Mark Arredondo, M.D.

THURSDAY, May 23, 2024 (HealthDay News) — Metformin use, including long-term use, is associated with significantly lower odds of myeloproliferative neoplasm (MPN) diagnosis, according to a study published online May 17 in Blood Advances.

Daniel Tuyet Kristensen, M.D., from Aalborg University Hospital in Denmark, and colleagues conducted a population-based case-control study using Danish registers to examine the association between metformin use and the risk for MPN. Cases with MPN diagnosed between 2010 and 2018 were identified, and metformin use prior to MPN diagnosis was ascertained. Metformin use was compared among cases with MPN and an age- and sex-matched control group from the Danish general population (3,816 cases and 19,080 controls).

The researchers found that 7.0 and 8.2 percent of cases and controls were categorized as ever-users of metformin, respectively (odds ratio [OR] for MPN, 0.84; adjusted OR for MPN, 0.70). Long-term metformin use (at least five years) was more infrequent and occurred in 1.1 and 2.0 percent of cases and controls, respectively (OR, 0.57; adjusted OR, 0.45). When cumulative duration of treatment was analyzed, there was a dose-response relationship observed; in stratified analyses of sex, age, and MPN subtypes, this was consistent.

Scientists team up with York Hospital to study DNA mutations behind blood cancers

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Posted on 23 May 2024

Scientists from the University of York are working with doctors and patients at York Hospital to understand the DNA mutations linked to a group of chronic blood cancers, and investigate why, in some cases, they can suddenly become more aggressive.

The researchers, from the newly formed Centre for Blood Research at the University of York, are recruiting participants from York Hospital with myeloproliferative neoplasms (MPNs), a group of blood cancers characterised by the overproduction of red blood cells and/or platelets.

There are around 4,000 cases of MPNs in the UK each year and they most commonly affect people over 60. Often, they remain stable and progress slowly, which means people can live with them for a long time without being very unwell.

However, in a few rare cases, they can transform into more aggressive cancers which need urgent treatment, such as acute myeloid leukaemia (AML), where faulty myeloid cells – which include red blood cells and platelets – build up in the body and stop the blood and immune system from functioning normally.

Valuable insights

Dr Katherine Bridge, from the Department of Biology and Centre for Blood Research at the University of York, said: “We want to better understand the DNA mutations that cause these cancers, and to see whether there are additional factors that cause them to suddenly transform and become more aggressive.

“MPNs behave like the early stages of other blood cancers, offering valuable insights into their progression. Often, these crucial initial stages occur too quickly in other cancers for us to be able to track them effectively. By focusing on MPNs, we have a unique opportunity to scrutinise these early events, potentially uncovering strategies to halt the advancement of more aggressive malignancies.”

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Metformin May Help Reduce the Risk of Developing Myeloproliferative Neoplasms

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By The ASCO Post Staff

Posted: 5/21/2024 9:31:00 AM
Last Updated: 5/21/2024 12:27:21 PM

 

Treatment with metformin may be associated with a lower risk of developing myeloproliferative neoplasms over time, according to a recent study published by Kristensen et al in Blood Advances.

Background

Myeloproliferative neoplasms are a group of diseases that develop over long periods of time and affect how bone marrow produces blood cells, resulting in an overproduction of red blood cells, white blood cells, or platelets that can lead to bleeding problems, a greater risk of stroke or heart attack, and organ damage.

Metformin—a therapy used to treat high blood sugar in patients with type 2 diabetes—works by increasing the effect of insulin, reducing how much glucose is released from the liver, and increasing the body’s glucose absorption.

Previous analyses have demonstrated that the therapy may reduce the risk of gastrointestinal cancer, breast cancer, urologic cancer, as well as other solid tumors and hematologic malignancies.

“Our team was interested in understanding what other effects we see with commonly prescribed treatments like metformin,” explained senior study author Anne Stidsholt Roug, MD, PhD, Clinical Associate Professor at Aalborg University Hospital and Chief Physician at Aarhus University Hospital in Denmark. “The anti-inflammatory effect of metformin interested us, as [myeloproliferative neoplasms] are very inflammatory diseases,” she added.

Study Methods and Results

In the recent study, investigators examined metformin use among 3,816 patients diagnosed with myeloproliferative neoplasms and 19,080 matched controls from the Danish general population between 2010 and 2018.

The investigators found that 7.0% (n = 268) of the patients with myeloproliferative neoplasms and 8.2% (n = 1,573) controls received metformin. Just 1.1% of the patients with myeloproliferative neoplasms had received the therapy for over 5 years vs 2.0% of controls. After adjusting for potential confounders, the investigators noted that the protective effect of metformin was observed in all subtypes of myeloproliferative neoplasms.

Conclusions

“We were surprised by the magnitude of the association we saw in the data,” emphasized lead study author Daniel Tuyet Kristensen, MD, a PhD student at Aalborg University Hospital. “We saw the strongest effect in [patients] who had taken metformin for more than 5 years as compared [with] those who had taken the treatment for less than 1 year,” he added.

The investigators revealed that the study was limited by its registry-based retrospective design and an inability to account for lifestyle factors influencing cancer risk such as smoking, obesity, and dietary habits. They hope to conduct additional studies to better understand the mechanisms behind the therapy’s protective effects against the development of myeloproliferative neoplasms. The investigators further plan to identify any similar trends with myelodysplastic syndromes and acute myeloid leukemia in population-level data in future studies.

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Pooled Analysis Shows Cytoreduction to Be Safe, Tolerable in Younger Patients With PV

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Ashling Wahner

Cytoreductive therapy with interferon alfa (rIFNα) or hydroxyurea is safe and well tolerated in patients with polycythemia vera (PV) under the age of 60 years and induces annualized discontinuation rates comparable to those reported with these agents in older patients with PV, for whom cytoreductive therapy is routinely used, according to findings from a meta-analysis that were published in Blood Advances.1

Across the 14 studies included in this analysis, rIFNα discontinuation rates ranged from 4.6% to 37% over median durations of 0.4 to 6.3 years. Hydroxyurea discontinuation rates ranged from 2.6% to 17% over median durations of 0.5 to 14 years.

Although the use of cytoreductive agents, such as rIFNα and hydroxyurea, is associated with reduced thrombosis risk in PV, these agents are not routinely recommended by the European LeukemiaNet (ELN) or the National Comprehensive Cancer Network (NCCN) for patients with PV under the age of 60 years. The ELN recommends cytoreductive therapy for patients with PV who are younger than 60 years of age and have not had prior thrombotic events provided that they have strictly defined phlebotomy intolerance, symptomatic progressive splenomegaly, persistent or progressive leukocytosis, extreme thrombocytosis, persistently high cardiovascular risk, inadequate hematocrit control requiring phlebotomies, and/or persistently high symptom burden.2 The NCCN does not recommend cytoreductive therapy as initial treatment for patients with low-risk disease.3

“Unfortunately, effective and potentially life-prolonging cytoreductive therapy is often deferred in younger patients who are considered ‘low-risk’ because of their age and lack of thrombosis history,” senior study author Ghaith Abu-Zeinah, MD, an instructor in medicine at Weill Cornell Medical College and an assistant attending physician at the NewYork Presbyterian Hospital in New York, New York, and coauthors, wrote in the paper.1 “The rationale for withholding cytoreductive therapy is data-sparse and driven by theoretical concerns for toxicity and unknown benefits from early treatment. Yet, there is some evidence that early treatment is both well tolerated and potentially useful.”

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Serum Albumin Levels May Predict Survival Among Patients With Myelofibrosis Treated With Ruxolitinib

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Jonathan Goodman, MPhil

Serum albumin may function as a dynamic surrogate marker for clinical outcomes among patients with myelofibrosis treated with ruxolitinib, according to research published in JCO Precision Oncology. The utility of this surrogate measure may, however, vary by a given patient’s treatment status.

Previous work has established ruxolitinib, a JAK inhibitor, as a standard of care among patients with myelofibrosis. Yet although this treatment may help to reduce spleen size and symptom burden, it is unclear whether it improves overall survival (OS) rates.

New models, such as the RR6 model, have aimed to provide a prognostic surrogate measure for OS, though whether these models effectively distinguish high-risk disease from cases where there is no response to treatment is unclear. For this study, researchers aimed to evaluate whether serum albumin — which is linked with an anti-inflammatory response to treatment — is an effective surrogate marker for OS among patients with myelofibrosis.

Overall, data from 396 patients were included. In the cohort, among evaluable patients, 91 had received ruxolitinib while 305 were naïve to treatment, 58% of patients were male sex, and 72% of patients had primary myelofibrosis.

Analysis suggested that serum albumin levels frequently dropped among all patients, though this was less pronounced among patients treated with ruxolitinib. Relatedly, patients with a high serum albumin level at baseline had improved median OS periods (53.5 months) compared to patients with low levels (29.8 months; odds ratio, 1.95; P <.001).

The link between serum albumin levels and OS was independent of variables included in the dynamic international prognostic scoring system, though only among patients who were naïve to ruxolitinib.

Future efforts to incorporate serum albumin with other inflammatory markers into an inflammatory index and assess its relevance in the context of other JAK inhibitors and combinations are ongoing.

Furthermore, among patients treated with ruxolitinib, changes in serum albumin levels predicted OS. Among patients with stable levels or an increase, median OS was 82.7 months, compared with 64.1 months among patients with a decrease (P =.04).

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Genetics and Genetic Testing to Inform Myelofibrosis Clinical Management

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by Charles Bankhead, Senior Editor, MedPage Today May 1, 2024

The history of primary myelofibrosis dates back to 1951 and the description of four distinct clinicopathologic entitiesopens in a new tab or window that came to be known as myeloproliferative neoplasms (MPNs): chronic myeloid leukemia (CML), polycythemia vera, essential thrombocythemia, and myelofibrosis.

Discovery of the Philadelphia (Ph) chromosome in 1960opens in a new tab or window paved the way to identification of BCR/ABL as the principal genetic driver of CML. Another 45 years passed before the discovery of a first genetic driver of non-Ph MPNs, a mutation in the Janus kinase 2 (JAK2) gene,opens in a new tab or window which occurs in 50-60% of myelofibrosis cases.

“The identification of that particular pathway was foundational, and it has changed the face of how we treat patients,” said James Rossetti, DO, of the University of Pittsburgh. “The JAK2 mutation is not present in everyone with myelofibrosis, and there are other mutations as well.”

Researchers identified a third key driver in 2013opens in a new tab or window: calreticulin gene (CALR). The mutation is associated with about 25% of myelofibrosis cases.

Most studies have shown that JAK2, MPL, and CALR are mutually exclusiveopens in a new tab or window and do not occur together. However, a few studies have shown co-occurrence of the three key mutations. Even though JAK2, MPL, and CALR usually do not occur together, numerous other mutations have been identified in association with the three primary mutations. As many as 80% of patients with myelofibrosisopens in a new tab or window have one or more other mutations.

Historically, myelofibrosis treatment was palliative in nature, aimed at relieving specific symptoms. The discovery of the JAK2 driver mutation has transformed treatment. Since 2011 four JAK2 inhibitors have received FDA approval: ruxolitinib (Jakafi)opens in a new tab or window, fedratinibopens in a new tab or window (Inrebic), pacritinibopens in a new tab or window (Vonjo), and momelotinibopens in a new tab or window (Ojjaara). All four drugs demonstrated ability to reduce splenomegaly, a major clinical manifestation of myelofibrosis, as well as symptoms.

Some of the co-occurring mutations are targetable, creating interest in combination therapies that simultaneously target different signaling pathways, said Aaron Gerds, MD, of the Cleveland Clinic. One such combination was evaluated in a clinical trial that paired a JAK2 inhibitor with an IDH2 inhibitor.

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Direct and indirect costs for patients with myeloproliferative neoplasms

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Jingbo Yu, James Nelson, Taylor Marlin, Evan Braunstein, & Michelle Jerry

Abstract

Myeloproliferative neoplasms (MPNs) are associated with substantial healthcare resource use and productivity loss. This retrospective cohort analysis used disability leave and medical claims data to measure direct and indirect healthcare costs associated with MPNs. The analysis included 173 patients with myelofibrosis (MF), 4477 with polycythemia vera (PV), 6061 with essential thrombocythemia (ET), and matched controls (n = 519, n = 13,431, and n = 18,183, respectively). Total healthcare costs were significantly higher for cases versus controls in each cohort (mean cost difference: MF, $67,456; PV, $10,970; ET, $22,279). Cases were more likely than controls to take disability leave and incurred higher disability-related costs. Among subgroups with thrombotic events, direct and indirect costs were higher for cases versus controls. Thrombotic events substantially increased direct costs and disability leave for patients with PV or ET compared with the full PV or ET cohorts. These findings demonstrate increased economic burden for patients with MPNs.

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Lack of Mutations Associated With Favorable Prognosis in MPN-U

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Laura Joszt, MA

Among patients with myeloproliferative neoplasm, unclassifiable (MPN-U), bone marrow blast and the Dynamic International Prognostic Scoring System (DIPSS) plus score can predict overall survival (OS), according to a study published in American Journal of Clinical Pathology.1 In addition, the study found that the lack of certain mutations seemed to be associated with a better prognosis.

MPN-U is a type of MPN that doesn’t fit one of the other types of MPNs, such as chronic myelogenous leukemia (CML), myelofibrosis (MF), essential thrombocythemia (ET), or polycythemia vera (PV).2 Janus kinase (JAK) mutations are often present in PV, ET, and primary MF; MPL or CALR mutations are often present in ET and primary MF; and chromosome errors are present in patients with CML.2

This study identified additional potential poor prognostic markers for patients with MPN-U, which is important as MPN-U is a heterogeneous category with features that typically preclude classification. MPN-U cases show “a range of clinicopathologic presentations and differences in prognosis depending on the stage of disease,” the authors explained. “Creating further challenges, MPN-U cases remain relatively understudied.”

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