Category Archives: Uncategorized

Scientists create a tool to identify individuals at risk of developing different myeloid leukemias

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August 24, 2023

by Wellcome-MRC Cambridge Stem Cell Institute

Scientists have created a new test for identifying people at risk of developing acute myeloid leukemia and related cancers, years before they do. The new platform, “MN-predict,” will allow doctors and scientists to identify those at risk and to design new treatments to prevent them from developing these potentially lethal cancers.

Researchers at the Wellcome-MRC Cambridge Stem Cell Institute (CSCI), the University of Cambridge’s Department of Haematology, and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA) analyzed data from more than 400,000 individuals participating in the United Kingdom Biobank.

Using this data, the scientists have created “MN-predict,” a platform for predicting the risk of developing blood cancers such as acute myeloid leukemia, myelodysplastic syndromes and myeloproliferative neoplasms over a 10–15-year period.

This test, now available in NHS clinics, requires patients to provide a blood sample from which DNA is extracted for limited sequencing, alongside basic blood cell counts. With this information, MN-predict identifies those at high risk of any of these cancers and can be used in specialist clinics for leukemia prevention.

Professor George Vassiliou, senior author of the study said, “We all know that prevention is better than cure, but it is not easy to prevent diseases like leukemia without knowing who is at risk. MN-predict makes it possible to identify at-risk individuals, and we hope it can become an essential part of future leukemia prevention programs.”

The myeloid neoplasms are a group of related cancers encompassing acute myeloid leukemia, myelodysplastic syndromes and myeloproliferative neoplasms. Treatments for these cancers have improved in the last few years, but most cases remain incurable.

In the last few years, scientists discovered that these cancers develop over decades through the accumulation of DNA mutations in blood stem cells, the cells responsible for normal blood formation. These mutations encourage these stem cells to grow faster than normal and, as more mutations accumulate, they can progress towards leukemia.

Thankfully, while mutations that promote cell growth are common, leukemia develops only in a small minority of cases. Identifying these cases early on helps efforts to prevent the cancers from developing.

Dr. Muxin Gu, first author of the paper, said, “We hope that MN-predict will help clinicians to identify people at risk of myeloid cancers and use novel treatment to prevent the cancers from developing.”

Dr. Pedro M. Quiros, joint senior author of the study, said, “Despite some recent advances in their treatment, these cancers remain lethal to many sufferers. We hope that our efforts will help advance prevention in favor of treating the full-blown disease.”

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Ajax Therapeutics Appoints Dr. David Steensma as Chief Medical Officer

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– A leading expert in hematologic malignancies with more than 25 years of oncology clinical and research experience, Dr. Steensma joins Ajax as its lead JAK2 inhibitor advances to the clinic –

NEW YORK–(BUSINESS WIRE)–Ajax Therapeutics, Inc., a biopharmaceutical company applying computational chemistry and structure-based technologies to develop next generation JAK inhibitors for patients with myeloproliferative neoplasms (MPNs), today announced the appointment of David P. Steensma, MD, FACP, as Chief Medical Officer. A renowned expert in hematologic malignancies, Dr. Steensma was formerly the Global Head of Hematology at Novartis Institutes for Biomedical Research, where he led early clinical development in malignant and non-malignant hematology conditions.

“His deep knowledge of hematologic malignancies and extensive experience leading clinical studies will be invaluable as we prepare to enter our first in human studies in myelofibrosis in 1H 2024.”

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“We are very fortunate to have such a veteran hematology drug developer as David join the Ajax team as we near the clinic with our next generation Type II JAK2 inhibitor program for MPNs,” said Martin Vogelbaum, CEO of Ajax Therapeutics. “His deep knowledge of hematologic malignancies and extensive experience leading clinical studies will be invaluable as we prepare to enter our first in human studies in myelofibrosis in 1H 2024.”

“I have collaborated with David for many years and consider him one of the top thought leaders in hematology oncology,” said Dr. Ross Levine, Chair of Ajax’s SAB and Deputy Physician-in-Chief, Translational Research, Laurence Joseph Dineen Chair in Leukemia Research and Member of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center. “We are very pleased to have David on board as his unique combination of translational and clinical skills will help us effectively design and execute clinical studies to demonstrate the unique and differentiating clinical properties of our lead Type II JAK2 inhibitor program.”

“I am excited to join Ajax at this pivotal stage of the company’s development,” said Dr. Steensma. “Patients with MPNs continue to have major unmet clinical needs as current therapies, including approved JAK inhibitors, such as ruxolitinib, often fail to provide adequate symptomatic relief and have no effect on the course of their disease. Ajax’s Type II JAK inhibitor is a more selective and potent JAK inhibitor with the potential to significantly improve efficacy, overcome disease persistence and, more importantly, provide disease modification.”

Dr. Steensma has a more than 25-year distinguished career as a clinician, investigator and researcher in hematology-oncology. Prior to his R&D leadership role at Novartis Institutes for Biomedical Research, he was a faculty member at Harvard Medical School and Institute Physician in the Adult Leukemia Program in the Division of Hematological Malignancies at the Dana-Farber Cancer Institute, where he cared for patients with hematological malignancies and bone marrow failure and served as the Edward P. Evans Chair in Myelodysplastic Syndromes (MDS). Earlier in his career, Dr. Steensma was a fellow and then faculty member in the Division of Hematology, Department of Medicine, at the Mayo Clinic. Since 2000, he has been on numerous committees and held several editorial roles for the American Society of Hematology and served as consultant editor for the Journal of Clinical Oncology. He was also a voting member of the Oncology Drug Advisory Committee (ODAC) for the U.S. Food and Drug Administration (FDA), and member of the Board of Directors of the MDS Foundation. Dr. Steensma has published over 200 original research papers as well as numerous reviews, editorials and book chapters. He received his medical degree from the University of Chicago’s Pritzker School of Medicine.

About Ajax Therapeutics

Ajax Therapeutics, Inc. is pursuing uniquely selective approaches to develop novel next generation JAK2 therapies for myeloproliferative neoplasms (MPNs), including myelofibrosis. By combining the deep cancer and structural biology insights of our founding scientists with the industry’s most advanced computational drug discovery and protein structure platforms from our founding partner, Schrödinger, Inc., we aim to discover and develop more precisely designed therapies to address the significant unmet needs for patients with MPNs.

Please find more information at www.ajaxtherapeutics.com.

NOTE: Dr. Ross Levine serves on the board of directors of, has provided advisory services for, and has equity interests in Ajax Therapeutics. Dr. Levine also has intellectual property rights and interests that MSK has licensed to Ajax. MSK has intellectual property rights and other financial interests related to Ajax.

Lindsey Lyle on Differentiating MPN Symptoms From Other Health Issues

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June 30, 2023

Lindsay Lyle, PA-C, MS

It can often be difficult for oncology nurses and other clinicians to determine if a patient’s symptoms are related to their myeloproliferative neoplasm (MPN) or another underlying cause, making a detailed medical history extremely important, explained Lindsey Lyle, PA-C, MS, a nurse practitioner who specializes in hematologic malignancies.

“This is a big challenge for nurses, advanced practice providers and physicians alike,” Lyle said in an interview with Oncology Nursing News®.

Common MPN symptoms — including fatigue, bone aches and pains, night sweats, unintentional weight loss, rib pain and feeling full after eating small amounts of food — are relatively broad and can be associated with numerous health conditions, Lyle said, noting that it is important to rule out other possible causes.

To ensure that these symptoms are not related to another cause, nurses must ask patients about their past medical history, other health conditions, changes in medications, and timing of symptoms. Lyle noted that the patient’s primary care physician can also be a good source of information regarding the timing of a patient’s symptoms.

“When a patient does have a diagnosis of an MPN, we certainly can assume that maybe it is the MPN until other contributors have been ruled out,” Lyle said. “So timing of these symptoms is really important; a nurse can ask about when symptoms first started, what they were doing when these symptoms happened and what makes them better, or what makes them worse.”

Additionally, Lyle mentioned that nurses should ask patients about how treatments change their symptoms, as some drugs that are currently used to treat MPNs — such as the JAK inhibitors ruxolitinib (Jakafi), fedratinib (Inrebic), and pacritinib (Vonjo) — can decrease symptoms, such as splenomegaly. In fact, last year, the Food and Drug Administration (FDA) approved pacritinib for patients with intermediate- or high-risk primary or secondary myelofibrosis because the phase III PERSIST-2 trial showed that the drug decreased spleen volume by at least 35% in 29% of patients.1

Reference

  1. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4(5):652-659. doi:10.1001/jamaoncol.2017.5818

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Rusfertide Offers Durable Hematocrit Control in Phlebotomy-Dependent Polycythemia Vera

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June 11, 2023

Caroline Seymour

Rusfertide (PTG-300) demonstrated freedom from phlebotomy, sustained hematocrit control, and 12-week treatment completion in 69.2% (n = 18/26) vs 18.5% (n = 5/27) of patients with phlebotomy-dependent polycythemia vera who received placebo (P = .0003), meeting the primary end point of the phase 2 REVIVE trial (NCT04057040). Findings were presented at the 2023 EHA Congress.

“The REVIVE study demonstrated significantly higher efficacy with rusfertide compared with placebo in subjects with polycythemia vera,” said Marina Kremyanskaya, MD, PhD, lead study author and assistant professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai in New York, New York, in a presentation of the data. “Current standard-of-care therapy in polycythemia vera does not consistently maintain hematocrit below 45%, thereby potentially increasing the risk of thromboembolic events. Rusfertide has the potential to consistently maintain hematocrit [levels] below 45%.”

Polycythemia vera is a myeloproliferative neoplasm (MPN) that produces red blood cells in excess and is often marked by elevated hematocrit. Hematocrit, when uncontrolled, can lead to higher fatality from cardiovascular causes or thrombotic events. Although guidelines from the National Comprehensive Cancer Network and European LeukemiaNet state that hematocrit should be maintained below 45%, current standard-of-care therapy fails to do so in most patients.

Hepcidin is a peptide hormone that controls iron availability for red blood cell formation. Rusfertide is a novel hepcidin mimetic that mirrors the effects of hepcidin on erythropoiesis, representing a potential add-on therapy to standard therapy with improved activity. This hypothesis was tested in the phase 2 REVIVE trial.

To be eligible for enrollment in the study, patients had to have phlebotomy-dependent polycythemia vera per 2016 World Health Organization criteria, having received at least 3 phlebotomies in 28 weeks with or without concurrent cytoreductive therapy. Additionally, all patients had to be phlebotomized to hematocrit levels below 45% prior to the first dose of rusfertide to standardize the starting hematocrit.

The study consisted of 3 parts: dose finding, blinded randomized withdrawal, and open-label extension. Rusfertide was administered subcutaneously in doses ranging from 10 mg to 120 mg weekly. In part 1, rusfertide was titrated for the first 16 weeks to determine the clinically effective dose. Efficacy was evaluated in weeks 17 to 28. In part 2, patients were randomly assigned 1:1 to receive active or placebo doses of rusfertide in weeks 29 to 41. Study treatment continued in part 3 for up to 3 years.

Safety and efficacy served as key end points of the trial. Efficacy was characterized by the proportion of responders in part 2, defined by the proportion of patients who maintained hematocrit below 45% and the percentage reduction in phlebotomies. Patient outcomes were evaluated with the MPN Symptoms Assessment Form Total Symptom Score.

A total of 70 patients were included in the dose-finding portion of the research. Fifty-nine patients were treated in part 2, 53 of which were included in the primary efficacy analysis set. Fifty-two patients are ongoing treatment in part 3

Regarding baseline characteristics of those included in part 2, most patients were male, above the age of 50 years at diagnosis, had polycythemia vera for approximately 5 years, and received hydroxyurea as the primary means of cytoreductive therapy. Across the arms, 52.7% of patients were high risk and 47.4% were low risk. Body mass index was 30.1 ± 5.76 kg/m2 and 28.7 ± 4.55 kg/m2 in the placebo and rusfertide arms, respectively.

Additional findings demonstrated similar benefit in time to treatment failure with rusfertide in responders (P < .0001), patients ineligible for phlebotomy plus hydroxyurea (P < .0001), and those with hematocrit under 45% (P < .0001).

Kremyanskaya also explained that rusfertide led to meaningful reductions in the need for phlebotomy, both with phlebotomy only (n = 37) and phlebotomy plus cytoreductive therapy (n = 33).

Although the focus of the presentation centered around outcomes in part 2, investigators also evaluated symptom improvement in part 1. Notably, moderate or severe symptoms of problems with concentration (P =.0018), itching (P = .0054), fatigue (P =.0074), and inactivity (P =.0005) were all improved following treatment with rusfertide. Kremyanskaya noted that meaningful comparison of symptom improvement was not possible in part 2 because most patients who were randomized to placebo discontinued prior to the 12-week symptom assessment.

In terms of safety, Kremyanskaya stated that rusfertide was “generally well tolerated.” Treatment-emergent adverse effects (TEAEs) included injection site erythema (64.3%), injection site pain (41.4%), injection site pruritus (40.4%), fatigue (31.4%), injection site mass (25.7%), pruritus (25.7%), arthralgia (24.3%), injection site swelling (24.3%), dizziness (22.9%), headache (22.9%), nausea (22.9%), anemia (20.0%), COVID-19 (20.0%), injection site irritation (18.6%), and injection site bruising (15.7%). Most events were grade 1/2 (83%), and 17% of patients experienced grade 3 events. No grade 5 events occurred.

“Most common TEAEs were injection site reactions, which decreased in incidence with continued treatment,” Kremyanskaya noted. “Additionally, events were localized, grade 1 or 2 in severity, and generally did not lead to treatment discontinuation,”

Two treatment-related events of mild thrombocytosis and recurrent grade 1 injection site erythema led to treatment discontinuation.

Patients who completed the REVIVE study will be eligible to enroll in PTG-300-21, a separate, 2-year follow-on extension trial. The agent is also under evaluation in the phase 3 VERIFY trial (NCT05210790), where it is being compared with placebo in patients with polycythemia vera maintaining hematocrit control and in improving symptoms of disease.

Disclosures: Dr Kremyanskaya reported receiving honoraria and being on the advisory board for Protagonist Therapeutics, Inc.

Reference

Kremyanskaya M, Kuykendall A, Pemmaraju N, et al. Targeted therapy of uncontrolled erythrocytosis in polycythemia vera with the hepcidin mimetic, rusfertide: – blinded randomized withdrawal results of the REVIVE study. Presented at: 2023 EHA Congress; June 8-11, 2023; Frankfurt, Germany. Abstract LBA2710.

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Agent Orange Linked to Increased Risk of Blood Cancers in Veterans

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June 5, 2023

Key points:

  • New research links Agent Orange to an increased risk of blood cancers in veterans.
  • Specifically, exposure could result in myeloproliferative neoplasms (MPNs), which are acquired stem cell disorders that can lead to overproduction of mature blood cells.
  • Agent Orange has previously been associated with sarcomas and B-cell lymphomas, but not MPNs or leukemias.

Research conducted using a database of veterans exposed to Agent Orange found an association for an increased risk of developing myeloproliferative neoplasms (MPNs), which are acquired stem cell disorders that can lead to overproduction of mature blood cells complicated by an increased risk of blood clots in arteries and veins. When MPNs progress, they can become deadly leukemias.

The Agent Orange chemical has previously been associated with sarcomas and B-cell lymphomas, but not MPNs or leukemias.

For this study, researchers utilized the Veterans Affairs Informatics and Computing Infrastructure (VINCI) database and examined records of 93,269 MPN patients among 12,352,664 veterans over 17 years. The team used veterans from the state of Illinois as a control population since Illinois is highly representative of the United States, according to the U.S. Census Bureau.

According to the findings, the odds of Agent Orange exposure among MPNs are 1.63 times greater than the odds of exposure among controls. When comparing people with MPNs vs. age-, gender-, and race-matched controls, there was more clotting in the arteries (37% vs. 18.5%), more clotting in the veins (14.8% vs. 5.2%) and more bleeding events (39.1% vs. 13.5%), respectively.

Additionally, people with MPNs had more hypertension (75.5% vs. 43.2%), diabetes (31.2% vs. 19%), and more heart failure (26.1% vs. 11%) than age-, gender, and race-matched controls, respectively.

The odds of Agent Orange exposure among matched controls with arterial clots are 1.38 times greater than the odds of exposure among controls without arterial clots. The odds of Agent Orange exposure among MPNs with arterial clots are 1.49 times greater than the odds of exposure among MPNs without arterial clots.

Because the findings only point to possible associations and not causes, lead author Andrew Tiu said the researchers will need to dive more deeply into the biology of the disease. Specifically, they want to look at JAK2 mutations, which are one of the three driver mutations of MPNs that can cause uncontrolled proliferation of stem cells. JAK2 has also been associated with an increased risk of clotting.

“There are several associations between Agent Orange and health disorders that are not well understood and we hope our work helps uncover a few of these,” said Tiu.

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Pelabresib Monotherapy Is Beneficial in Patients With High-Risk Essential Thrombocythemia

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By Rob Dillard

June 3, 2o23

Pelabresib used as a monotherapy appears clinically beneficial in patients who have high-risk essential thrombocythemia (HR ET) and are intolerant to hydroxyurea (HU), according to a study presented at the 2023 American Society of Clinical Oncology Annual Meeting.

In this analysis of arm 4 of the MANIFEST study, lead investigator Francesco Passamonti and colleagues evaluated 20 patients with HR ET who received pelabresib monotherapy 225 mg QD. Their key end point of interest was complete hematologic response (CHR), which was defined as normalization of platelet count (≤400 x 109/L) and WBC count (≤10 x 109/L), confirmed after 1 cycle (3 weeks), and normal spleen size. Secondary end points included partial hematologic response (PHR; platelet count, 400-600 x 109/L and WBC, ≤10 x 109/L), symptom improvement (≥50% thrombosis with thrombocytopenia [TSS] reduction), and safety.

The investigators found that the majority of patients had a hematologic response (90% [18/20] unconfirmed CHR or PHR); confirmed CHR was observed in 40% of patients, and TTS reduction was observed in 86% of patients, with Hgb levels remaining stable through week 24. The investigators went on to note that the most common nonhematologic adverse events (AEs) were nausea (60%; 10% grade 3), diarrhea (35%; 5% grade 3), and dysgeusia (35%; no grade 3). No events of thrombocytopenia and no AEs of grade 4 or higher were reported.

“Preliminary results from arm 4 of the MANIFEST study suggest potential clinical benefit with [pelabresib] monotherapy in [patients] with HR ET refractory or intolerant to HU as supported by hematologic responses and symptom improvement. Safety results are consistent with the known safety profile of [pelabresib] and as expected in the underlying study population,” the researchers concluded.

Source: Passamonti F, Patriarca A, Knapper S, et al. Pelabresib (CPI-0610) monotherapy in high-risk essential thrombocythemia refractory or intolerant to hydroxyurea: preliminary results from MANIFEST study. Abstract #7019. Published for the 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, Illinois.

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Glutaminase May Be a Therapeutic Target in Ph- and JAK2-V617F-Driven MPNs

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By Rob Dillard

June 3, 2o23

The up-regulation of the enzyme glutaminase (GLS), which plays a critical role in cancer cell metabolism, is a common feature in Philadelphia-negative (Ph-) and JAK2-V617F-driven myeloproliferative neoplasms (MPNs), according to a study presented at the 2023 American Society of Clinical Oncology Annual Meeting.

Almost all MPNs are driven by somatic mutations in either JAK2, CALR, or MPL. While these mutations lead to activation of JAK/STAT signaling, lead researcher Michele Ciboddo and colleagues noted that “JAK inhibitors are not curative and fail to alter disease progression and display unwanted side effects. Allogeneic stem cell transplantation remains the only curative therapy for MPNs but is associated with substantial morbidity and mortality.”

Recent data have shown that glutaminolysis plays a chief role in cancer cell metabolism. In this 2-step reaction process, GLS acts as a catalyst, helping to turn glutamine into glutamate. Subsequently, glutamate fuels energy production in the tricarboxylic acid cycle. “As many cancers have proven to be dependent on this pathway, targeting GLS has become an attractive therapeutic avenue,” the researchers wrote.

In this analysis, Dr. Ciboddo and colleagues assessed mRNA levels of GLS in peripheral blood mononuclear cells from 30 patients with MPN and 5 healthy donors. They tested GLS by stably overexpressing either JAK2-, CALR-, or MPL-mutated proteins. CALR overexpression was treated with the JAK inhibitor ruxolitinib. Subsequently, the sensitivity of MPN cells to GLS inhibition was assessed with a GLS inhibitor, CB-839, which is currently in advanced-phase clinical trials for other cancers, including myelodysplastic syndrome.

According to the findings, GLS mRNA expression increased in all patients with MPNs regardless of the driver mutation. The researchers observed that GLS expression in JAK2-V617F patients was higher in those patients with myelofibrosis than in those with essential thrombocythemia. Moreover, GLS protein expression and activity were increased in TF-1 cells expressing JAK2, MPL, and CALR mutations. “We also found that GLS mRNA and protein expression was up-regulated in a JAK/STAT-dependent manner,” the researchers wrote. “Interestingly, despite increased expression of GLS across all MPN driver mutations, only JAK2-V617F cells demonstrated significant sensitivity to GLS inhibition with CB-839 in vitro and with preliminary data in vivo. We found that combination treatment with [the] JAK inhibitor ruxolitinib further inhibited cell viability.” They concluded that “treatment with CB-839 may thus represent a novel therapeutic avenue for JAK2-V617F [positive] MPNs.”

Source: Ciboddo M, Yan G, Coen C, et al. GLS in Philadelphia-negative and JAK2 V617F-driven myeloproliferative neoplasms (MPNs). Abstract #e15092. Published for the 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, Illinois.

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Spleen Volume Reduction Linked to Overall Survival in Myelofibrosis

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By Rob Dillard

June 2, 2023

Patients with myelofibrosis (MF) with a certain platelet (PLT) count who achieve spleen volume reduction (SVR) on pacritinib have notably better overall survival (OS), according to a study presented at the 2023 American Society of Clinical Oncology Annual Meeting. That association was not observed in patients taking best available therapy (BAT).

One of the characteristics of MF is splenomegaly, or spleen enlargement. JAK2 inhibitors have been known to reduce spleen volume, which is considered a surrogate for disease response. Investigators, led by Helen Ajufo, MD, noted that ≥10% SVR on ruxolitinib is associated with improved OS among patients with PLT counts ≥100×109/L, and ruxolitinib cannot be administered at full dose in patients with a lower PLT count. Pacritinib is a JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 that has shown SVR benefit versus BAT. This study analyzed SVR and OS in patients from the PERSIST-2 trial.

Researchers assessed PERSIST-2 patients on pacritinib who were alive and treated at the start of the 12-week SVR window (study week 10) on pacritinib 200 mg BID or BAT. Spleen volume was assessed radiographically, OS was analyzed using various SVR thresholds (≥35%, ≥20%, ≥10%, and >0%), and OS was compared using the log-rank test.

Results showed that among patients on pacritinib (n=89), any SVR at 12 weeks was notably linked with improved survival (hazard ratio [HR], 0.08; 95% CI, 0.01-0.51, P=.0007). Across all SVR response thresholds, SVR ≥10% showed the greatest separation in OS curves between responders and nonresponders on pacritinib, with no deaths among 65 responders versus 5 deaths among 24 nonresponders (HR, 0.0; 95% CI, 0.0-0.14; P<.0001). By contrast, the investigators noted, SVR did not predict OS benefit on BAT (n=84), including ruxolitinib (n=39).

“In MF patients with PLTs ≤100×109/L, achieving SVR on full-dose [pacritinib] was associated with significant OS benefit. By contrast, this association was not found with BAT, even though most responders were on [ruxolitinib], albeit at low doses,” the researchers concluded. “As [pacritinib] can be given at full dose regardless of PLT count, it is possible that [pacritinib] may offer a unique survival advantage for MF patients with moderate or severe thrombocytopenia who achieve spleen reduction.”

Source: Ajufo H, Bewersdorf JP, Harrison C, et al. Spleen volume reduction (SVR) predicts overall survival (OS) in myelofibrosis (MF) patients on pacritinib (PAC) but not best available therapy (BAT): PERSIST-2 landmark OS analysis. Abstract #7018. Published for the 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, Illinois.

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Veterans exposed to Agent Orange may be at increased risk of developing progressive blood cancers

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By Georgetown University Medical Center

Research conducted at Georgetown University’s Lombardi Comprehensive Cancer Center and the Washington DC VA Medical Center on a database of veterans exposed to Agent Orange found an association for an increased risk of developing myeloproliferative neoplasms (MPNs), which are acquired stem cell disorders that can lead to overproduction of mature blood cells complicated by an increased risk of blood clots in arteries and veins. When MPNs progress, they can become deadly leukemias.

Agent Orange is an herbicide that was utilized by the United States military in Korea and Vietnam to clear foliage during combat. It has been associated with sarcomas and B-cell lymphomas, but not MPNs or leukemias to date.

“MPNs are associated with serious cardiovascular events and people with this disease have decreased overall survival chances,” says Andrew Tiu, MD, a second-year hematology/oncology fellow with Medstar Georgetown University Hospital who conducts research at Georgetown Lombardi Comprehensive Cancer Center and is the lead author of this finding.

“But until now, we haven’t been able to fully ascertain whether Agent Orange exposure truly leads to the development of myeloproliferative neoplasms, which is why we’ve undertaken what is the biggest population-based study to date to try to answer this question.”

To explore associations between Agent Orange and MPNs in addition to blood clots, bleeding, and a number of cardiovascular factors, the researchers utilized the Veterans Affairs Informatics and Computing Infrastructure (VINCI) database and examined records of 93,269 MPN patients among 12,352,664 veterans over 17 years. The researchers used veterans from the state of Illinois as a control population since Illinois is highly representative of the United States according to the US Census Bureau.

Significant findings from the study include:

  • The odds of Agent Orange exposure among MPNs are 1.63 times greater than the odds of exposure among controls.
  • When comparing people with MPNs vs. age-, gender-, and race-matched controls, there was more clotting in the arteries (37% vs. 18.5%), more clotting in the veins (14.8% vs. 5.2%) and more bleeding events (39.1% vs. 13.5%), respectively.
  • People with MPNs had more hypertension (75.5% vs. 43.2%), diabetes (31.2% vs. 19%), and more heart failure (26.1% vs. 11%) than age-, gender, and race-matched controls, respectively.
  • The odds of Agent Orange exposure among matched controls with arterial clots are 1.38 times greater than the odds of exposure among controls without arterial clots.
  • The odds of Agent Orange exposure among MPNs with arterial clots are 1.49 times greater than the odds of exposure among MPNs without arterial clots.

Because their findings only point to possible associations and not causes, Tiu notes that the researchers will need to dive more deeply into the biology of the disease. Specifically, they want to look at JAK2 mutations, which are one of the three driver mutations of MPNs (the other two being MPL and CALR mutations) that can cause uncontrolled proliferation of stem cells. JAK2 has also been associated with an increased risk of clotting.

“There are several associations between Agent Orange and health disorders that are not well understood and we hope our work helps uncover a few of these,” says Tiu. “We are proud of the fact that our work was selected for a 2023 Conquer Cancer Merit Award and we’ll be using those funds to further our research efforts.”

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Ruxolitinib Plus Magrolimab May Be an Effective Combination for Myelofibrosis

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By Rob Dillard

June 2, 2023

A proof-of-concept study indicates the combined use of ruxolitinib and magrolimab is effective in the treatment of myelofibrosis (MF). The results were presented at the 2023 American Society of Clinical Oncology Annual Meeting.

“In solid tumors, calreticulin (CALR) overexpression produces a prophagocytic signal and is counteracted by concomitant expression of antiphagocytic CD47, reflecting an apoptosis versus survival mechanism. We have previously found that CD47, not CALR, is overexpressed on the membrane of patients with [myeloproliferative neoplasms]. Anti-CD47 magrolimab is currently being evaluated in clinical trials in [acute myelogenous leukemia and myelodysplastic syndromes] but has yet to be tested, either in monotherapy or in combination, in MF,” the researchers noted.

In this study, lead researcher Ciro Roberto Rinaldi and colleagues collated mononuclear cells from the bone marrow of 6 patients with MF and 2 controls. Cell expression of CALR and CD47 was measured by flow cytometry before and after incubation with ruxolitinib alone and in combination with magrolimab.

According to the results, CD47 membrane expression was 57% in untreated MF cells versus 12% in the control samples, while CALR membrane expression was observed at almost 52% in untreated MF cells compared with 12.5% in the control samples. Following incubation with ruxolitinib, MF CD34+ cell survival decreased to 98.2%, and after incubation with magrolimab alone, MF CD34+ cells showed no changes in survival. Notably, the analysis showed a significant membrane overexpression of CALR was observed in MF CD34+ cells when incubated with ruxolitinib and magrolimab (74.1%) versus ruxolitinib alone (52.6%), magrolimab alone (53.4%), and in untreated (51.8%).

“In vitro, treatment with ruxolitinib or ruxolitinib plus magrolimab slightly reduces the overall cell survival rate in CD34+ MF samples compared with no significant changes in single-agent magrolimab. However, the combination of ruxolitinib and magrolimab significantly increases CALR membrane expression compared with [ruxolitinib] or magrolimab alone, signaling a much stronger prophagocytic message in MF cells compared with controls,” the researchers concluded. They added that these findings “support the rationale of combining ruxolitinib with magrolimab in the next clinical trial stage in myelofibrosis.”

Source: Rinaldi C, Boasman K, Simmonds M. Effects of ruxolitinib and magrolimab on calreticulin in myelofibrosis CD34+ cells in vitro: proof of concept for combination therapy. Abstract #7064. Published for the 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, Illinois.

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