Dr Al-Ali on the Safety and Efficacy of BMS-986158 Plus Ruxolitinib or Fedratinib in Myelofibrosis

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Haifa Kathrin Al-Ali, MD
Conference|European Hematology Association Congress

Haifa Kathrin Al-Ali, MD, discusses the safety and efficacy findings from the dose-escalation portion of the phase 1/2 CA011-023 trial of BMS-986158 in combination with ruxolitinib or fedratinib in patients with intermediate- or high-risk myelofibrosis.

Haifa Kathrin Al-Ali, MD, professor of Translational Oncology and head of the Krukenberg Cancer Center at the University Hospital of Halle (Saale) in Germany, discusses the safety and efficacy findings from the dose-escalation portion of the phase 1/2 CA011-023 trial (NCT04817007) of BMS-986158 in combination with ruxolitinib (Rituxan) or fedratinib (Inrebic) in patients with intermediate- or high-risk myelofibrosis.

BMS-986158 is a potent, oral BET inhibitor. In the dose-escalation phase, the agent was evaluated in combination with ruxolitinib in ruxolitinib-naïve patients for part 1A, and in combination with fedratinib in patients who were refractory/relapsed or intolerant to prior ruxolitinib for part 1B. The dose-expansion portion of the study, which will open for enrollment soon, will evaluate BMS-986158 at the recommended phase 2 dose or the previously tolerated dose in combination with ruxolitinib in parts 2A1 and 2A2, and with or without fedratinib in parts 2B1 and 2B2.

Data from the dose-escalation portion of the trial presented at the 2023 EHA Congress showed that both BMS-986158–based combinations had tolerable safety profiles, Al-Ali says. The most common adverse effects (AEs) included thrombocytopenia and gastrointestinal (GI) toxicities, including diarrhea and nausea. GI AEs were generally mild and did not lead to treatment discontinuation in any patients, according to Al-Ali.

Regarding efficacy, first-line BMS-986158 plus ruxolitinib led to a spleen volume reduction of at least 35% (SVR35) in 73% (95% CI, 39%-94%) of patients at week 12 (n =11), 100% (95% CI, 66%-100%) at week 24 (n = 9), and 80% (95% CI, 28%-100%) at week 48 (n = 5). The mean spleen volume change was –46.7%, –59.9%, and –56.3% at weeks 12, 24, and 48, respectively.

In those given BMS-986158 plus fedratinib in the second-line setting, the SVR35 was 38% (95% CI, 9%-76%) at week 12 (n = 8), 43% (95% CI, 10%-82%) at week 24 (n = 7), and 50% (95% CI, 1%-99%) at week 48 (n = 2). The mean change in spleen volume at weeks 12, 24, and 48 was –29.1%, -30.8%, and -33.0%, respectively.

Evidence for disease modification may have been observed in the form of JAK2 allele burden reduction, which was noted starting in cycle 6 for patients with JAK2 mutations, Al-Ali explains. Additionally, bone marrow fibrosis regression was observed in patients with follow-up bone marrow biopsies, she concludes.

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JAK2 gene: Function, conditions, and research

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By Oladimeji Ewumi

June 9, 2023

The JAK2 gene is a protein-coding gene of the Janus kinase family. It plays a role in cellular signaling. Evidence notes connections between this gene and some medical conditions.

The JAK2 geneTrusted Source is present on chromosome 9. It produces a protein that sends signals in cells to help control how many blood cells the bone marrow produces.

Variations in this gene may cause the body to produce too many blood cells. Evidence suggests a link between alterations in the JAK2 gene and some types of blood conditions.

This article will provide an overview of the JAK2 gene, including its functions and related medical conditions.

According to a 2014 article, the JAK2 gene instructs cells to make the JAK2 protein. This protein helps control cell growth and division. Specifically, JAK2 proteins help control the activation and production of hematopoietic stem cells.

Hematopoietic stem cellsTrusted Source are immature cells present in bone marrow. They can differentiate into all blood cell types, including red blood cells, white blood cells, and blood platelets.

A 2017 reviewTrusted Source suggests that the JAK2 gene regulates the JAK-STAT signaling pathway — a chain of enzymatic interactions that controls cell division, immunity, cell death, and tumor formation.

Dysregulation of the JAK-STAT pathway can result in immune disorders. The National Library of MedicineTrusted Source notes that the JAK2 gene and the JAK-STAT signaling pathway are therapeutic targets for treating excessive inflammatory responses and viral infections.

JAK2 function

The following are the most common functions of the JAK2 gene:

  • regulating the production of blood cells
  • promoting cellular processes, including cell growth, development, differentiation, and modifications
  • mediating essential signaling events in immunity
  • acting as a diagnostic biomarker for most myeloproliferative neoplasms (MPNs), which are rare disorders of the bone marrow
JAK2 and blood conditions 

Evidence notes an association between the expression of the JAK2 gene and some blood conditions. For example, MPNs are a group of hematopoietic stem cell conditions that arise due to an overproduction of mature blood cells.

JAK2 V617F is the most common alteration of the JAK2 gene present in blood conditions. According to a 2019 study, this alteration has a prevalence rate of 0.2% in the general population.

Primary myelofibrosis

In primary myelofibrosis (PMF), JAK2 gene variations replace typical bone marrow cells with scar tissue. This alteration affects 50%Trusted Source of people with PMF.

These JAK2 variations lead to the overproduction of atypical megakaryocytes that stimulate other cells to release collagen in the bone marrow. This causes scar tissue to form in a process called fibrosis. Due to this fibrosis, the bone marrow cannot produce enough typical blood cells, leading to symptoms of PMF.

Polycythemia vera

Polycythemia vera (PV) occurs when JAK2 overstimulates the production of red blood cells, causing an excess in the circulatory system. About 96%Trusted Source of people with PV have the V617F variation of the JAK2 gene.

Having extra cells in the bloodstream increases the risk of atypical blood clots. In addition, the thicker blood flows more slowly through the vessels, reducing the amount of oxygen in body tissues.

Essential thrombocythemia

In around 50% of people with essential thrombocythemia (ET), the JAK2 V617F alteration results in the body replacing the amino acid valine with phenylalanine. Switching these amino acids results in the continual activation and production of the JAK2 protein, leading to an overproduction of megakaryocytes.

Since platelets form from megakaryocytes, an increased number of platelets may result in more blood clots.

JAK2 and inflammatory bowel disease

Inflammatory bowel disease (IBD)Trusted Source is a term for two conditions: Crohn’s disease and ulcerative colitis. Both occur due to inflammation of the gastrointestinal tract.

According to a 2016 studyTrusted Source, increased expression of the JAK2 gene may impact inflammatory responses, causing severe gut inflammation in people with IBD.

JAK2 and other conditions

Research suggests that JAK2 may play a role in other blood disorders, including leukemia and Budd-Chiari syndrome (BCS).

A 2018 studyTrusted Source indicates that JAK2 variation is rare in de novo acute myeloid leukemia, an aggressive cancer of the bone marrow.

Additional research from 2015 that analyzed JAK2 alteration in those with BCS suggests that 20% had latent MPNs. BCS occurs when a blood clot blocks the hepatic veins. This blockage can cause blood to flow back to the liver.

JAK2 research

Many clinical trials are focusing on trying to manipulate the JAK2 gene and enzyme to find a better treatment for many related conditions the protein causes.

These suggest that therapeutic approaches targeting the JAK2 signaling pathways may prove Trusted Source effective in inhibiting pathogenic variations, providing new insights for developing pharmacological interventions.

For example, ruxolitinibTrusted Source is part of a Janus kinase inhibitor class of medication doctors prescribe to treat several conditions, including PMF and PV. Some other examples of Janus kinase inhibitors include Trusted Source:

  • abrocitinib
  • baricitinib
  • filgotinib
  • delgocitinib
Summary

The JAK2 gene is a protein-coding gene of the Janus kinase family. It initiates several cellular signaling processes, including cell division, immunity, and tumor formation.

Evidence notes that problems with this gene can result in the body producing too many blood cells. Medical experts have found links between the JAK2 gene and some blood conditions, including myelofibrosis, polycythemia vera, and thrombocythemia.

Last medically reviewed on June 9, 2023

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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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PharmaEssentia Selects Pint-Pharma as Commercial Partner for BESREMi® (ropeginterferon alfa-2b-njft) in Latin America

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June 2, 2023

TAIPEI–(BUSINESS WIRE)–PharmaEssentia Corporation (TPEx:6446), a leading fully integrated biopharmaceutical company in Taiwan, today announced that it has entered into an exclusive license agreement with Pint-Pharma GmbH for the registration and promotion of BESREMi® (ropeginterferon alfa-2b-njft) for the treatment of polycythemia vera (PV), a rare blood cancer, in Brazil, Argentina, Colombia, Chile, Peru, Ecuador, and Mexico.

“Expanding our geographic reach is critical to our mission to address clear gaps in therapeutic options for people with myeloproliferative neoplasms (MPNs). With its track record of successfully commercializing therapeutics for rare diseases and oncology, and its strong regional network, we’re confident that Pint-Pharma is the right partner to bring BESREMi to PV patients in Latin America,” said Ko-Chung Lin, Ph.D., Founder and Chief Executive Officer, PharmaEssentia. “This regional expansion is a logical extension of our growing leadership in the Americas, led by Meredith Manning. With strong momentum in the U.S., we know Meredith and her team will effectively champion the PharmaEssentia mission into Latin and South America.”

Under the terms of the agreement, PharmaEssentia may be eligible for certain milestone payments and royalties based on sales. Pint-Pharma will be responsible for obtaining and maintaining all marketing authorizations and for commercializing BESREMi in the region. PharmaEssentia will continue to be responsible for the supply of BESREMi. Pint-Pharma is an Austria-based pharmaceutical company with extensive experience in registering and commercializing rare disease, oncology and specialty treatments throughout Latin America. With this new partnership, Pint-Pharma further cements its position amongst the leaders in the field of haemato-oncology in Latin America.

“Our partnership with PharmaEssentia gives us the opportunity to provide another new treatment option to people living with MPNs in the region who are in need of effective therapies,” said David Munoz, Chief Executive Officer, Pint-Pharma. “We look forward to the potential to add BESREMi to our established haemato-oncology portfolio.”

About Polycythemia Vera
Polycythemia Vera (PV) is a cancer originating from a disease-initiating stem cell in the bone marrow resulting in a chronic increase of red blood cells, white blood cells, and platelets. PV may result in cardiovascular complications such as thrombosis and embolism, and often transforms to secondary myelofibrosis or leukemia. While the molecular mechanism underlying PV is still subject of intense research, current results point to a set of acquired mutations, the most important being a mutant form of JAK2.1

About BESREMi (ropeginterferon alfa-2b-njft)
BESREMi is an innovative monopegylated, long-acting interferon. With its unique pegylation technology, BESREMi has a long duration of activity in the body and is aimed to be administered once every two weeks (or every four weeks with hematological stability for at least one year), allowing flexible dosing that helps meet the individual needs of patients.

BESREMi has orphan drug designation for treatment of polycythemia vera (PV) in the United States. The product was approved by the European Medicines Agency (EMA) in 2019, in the United States in 2021, and has also received approval in Taiwan, South Korea and most recently, Japan. The product was invented by PharmaEssentia and is manufactured in the company’s Taichung plant, which was cGMP certified by TFDA in 2017 and by EMA in January 2018. The company retains full global intellectual property rights for the product in all indications.

BESREMi was approved in the US with a boxed warning for risk of serious disorders including aggravation of neuropsychiatric, autoimmune, ischemic and infectious disorders.

Please see accompanying full Prescribing Information, including Boxed Warning.

About PharmaEssentia

PharmaEssentia (TPEx: 6446), headquartered in Taipei, Taiwan, is a leading fully integrated biopharmaceutical company in Taiwan. Leveraging deep expertise and proven scientific principles, PharmaEssentia aims to deliver effective new biologics for challenging diseases in the areas of hematology and oncology, with one approved product and a diversifying pipeline. Founded in 2000 by a team of Taiwanese-American executives and renowned scientists from U.S. biotechnology and pharmaceutical companies, today PharmaEssentia is expanding its global presence with operations in the U.S., Japan, China, and Korea, along with a world-class biologics production facility in Taichung, Taiwan.

Forward Looking Statement

This press release may contain forward-looking statements, including statements regarding the commercialization plans and expectations for commercializing BESREMi in Latin America, the registration and regulatory approval of BESREMi in the region, and the potential benefits of BESREMi. For those statements, we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995 and similar legislation and regulations under Taiwanese law. These forward-looking statements are based on management expectations and assumptions as of the date of this press release, and actual results may differ materially from those in these forward-looking statements as a result of various factors. These factors include PharmaEssentia’s dependence on the commercial success of BESREMi, the ability to receive regulatory approvals for BESREMi in the region, whether BESREMi is successfully adopted by physicians and patients in the region, and the extent to which reimbursement is available for BESREMi in the region. Any forward-looking statements set forth in this press release speak only as of the date of this press release. We do not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof.

1 Cerquozzi S, Tefferi A. Blast Transformation and Fibrotic Progression in Polycythemia Vera and Essential Thrombocythemia: A Literature Review of Incidence and Risk Factors. Blood Cancer J. 2015;5, e366; doi:10.1038/bcj.2015.95

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