Category Archives: Uncategorized

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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Ruxolitinib Shows Benefit for Certain Patients with Polycythemia Vera

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Conor Killmurray

Results from the phase 2 MAJIC-PV study showed that patients with polycythemia vera who are intolerant to hydroxycarbamide chemotherapy had superior efficacy results on ruxolitinib.

Patients with polycythemia vera (PV) that are intolerant or resistant to hydroxycarbamide chemotherapy had superior responses with ruxolitinib compared to patients on the best available therapy (BAT), according to results from the MAJIC-PV (ISRCTN61925716) study.1

Results from the phase 2 open-label, randomized controlled trial of ruxolitinib in these patients who were resistant or intolerant of hydroxycarbamide reached their primary end point of a complete response to treatment within 12 months. CR was defined as hematocrit levels less than 45% without venesection for 3 months; platelets equal to or less than 400 × 109/L; a white blood cell (WBC) count of less than or equal to 10 × 109/L, and normal spleen size. Of the 180 patients eligible for the analysis, 93 patients were randomized to the ruxolitinib arm and 87 were given BAT, of those 93 patients in the ruxolitinib arm 43% (n = 40) had a CR vs 26% (n = 23) in the BAT arm (OR, 2.12; 90% CI, 1.25-3.60, P = .02).

A best response of partial response (PR) was seen in 50 patients (54%) of the patients on ruxolitinib compared with 58 (67%) of patients in the BAT arm during the first year. Between these 2 groups 45 patients in the ruxolitinib arm had a hematocrit level less than 0.45 and were venesection-free for 3 months during their first PR, in comparison, this was seen in 50 patients in the BAT arm. The overall response rate (ORR) was similar between the ruxolitinib and BAT arms, at 97% vs 93%, respectively, but the duration of CR in patients on the JAK2 inhibitor was more durable (HR, 0.38; 95% CI, 0.24-0.61, P < .001).

In the BAT-treatment arm, 52% of patients had at least 1 venesection compared with 29% in the ruxolitinib arm, but hemoglobin and hematocrit levels were lower in the ruxolitinib arm and thromboembolic event-free, but not hemorrhage-free, survival (EFS) was significantly improved with ruxolitinib (HR, 0.56; 95% CI, 0.32-1.00; P = .05). EFS overall was better with ruxolitinib than BAT (HR, 0.58; 95% CI, 0.35-0.94, P = .03) and was associated with a better outcome for patients that had a CR at 12 months (HR, 0.41; 95% CI, 0.21-0.78, P = .01). The 3-year progression-free survival (PFS) continued to demonstrate the effectiveness of ruxolitinib with a PFS of 75% (95% CI, 63%-83%) for BAT and 84% (95% CI, 74%-90%) for ruxolitinib and overall survival showing similar results.

“The MAJIC-PV study delivers several important insights into management of PV patients who are resistant or intolerant to hydroxycarbamide. Novel findings included that ruxolitinib prolonged thrombosis free survival, and event free survival, and that controlling blood count and spleen size was also associated with better EFS,” Claire Harrison, MD, FRCP, consultant hematologist and deputy director, and professor at Guy’s and St. Thomas’ Hospital, NHS Foundation Trust, told Targeted Oncology™.

What they observed in the study was that ruxolitinib was associated with patients who had a 50% reduction in their VAF (P < .001) and that those who responded to the JAK2V617F molecular inhibitor at a year were also more likely to have a CR (P = .09). This association was also seen for an improved PFS (P =.001), EFS (P = .006), and OS (P = .04) for those patients on ruxolitinib. Moreover, early JAK2V617F molecular responders had an event occur in 24% of responders compared with 43% of non-responders (P = .005).

At a median age of 66 years old with a median follow up of 4.8 years at the time of data cut off, 54 patients were resistant to hydroxycarbamide chemotherapy, 80 patients were intolerant, and 46 were both resistant and intolerant to hydroxycarbamide chemotherapy. Patients with diabetes and hypertension were more prevalent in the ruxolitinib arm, but adverse events (AEs) on this study were consistent with AEs observed on ruxolitinib before.

The most common grade 3 blood related AEs for patients on ruxolitinib included 12 patients with anemia and 20 patients overall with any grade blood related AEs. Thirty-three patients between both arms had any grade infections and infestations with 55 patients on ruxolitinib having any grade respiratory infections and 31 with cutaneous infections. Moreover, the most common any grade malignant neoplasms were a squamous cell carcinoma transformation in 11 patients.

“The MAJIC PV study is the first study ever to show that reduction of the JAK2 V617F variant allele frequency by 50%, which was more frequent with ruxolitinib, was linked to prolonged overall and progression-free survival as well as event free survival. In ruxolitinib molecular responders single cell studies demonstrated that treatment resulted in clearance of diseased stem cells,” said Harrison

Reference:
Harrison CN, Nangalia J, Boucher R, et al. Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial. J Clin Oncol. 2023 May 1:JCO2201935. doi: 10.1200/JCO.22.01935

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AOP Health: Completed Study Strengthens Clinical Development Program for ropeginterferon alpha 2b (Besremi®) in polycythaemia vera

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Dr. Rudolf Widmann, Founder and Board Member of the AOP Health Group/ Copyright: Studio Koekart: Natasche Unkart & Isabella Köhle

June 1, 2023

VIENNA–(BUSINESS WIRE)–With the publication of the final results from the LOW-PV study in the New England Journal of Medicine Evidence conducted by Fondazione per la Ricerca dell’Ospedale di Bergamo (FROM) under the leadership of Professor Tiziano Barbui, AOP Health announces an important advancement reinforcing its clinical development program for ropeginterferon alpha-2b (BESREMi®) in polycythaemia vera (PV), a rare blood cancer. The academic LOW-PV study supported and funded by AOP Health and public organizations in Italy complements a series of trials performed by AOP Health over more than 10 years to achieve marketing authorization in Europe and the Middle East. With these clinical studies, including PEGINVERA, PROUD-PV, and CONTINUATION-PV, AOP Health opened a new area of treatment options for patients suffering from PV. A further study (PEN-PV) was performed to develop a pen for self-injection allowing ease of self-administration, exact dosing and minimal waste of the medical product. AOP Health’s comprehensive development program in PV is considered by many key opinion leaders as the most significant development in the field of PV treatment in the past 30 years.

This series of studies has enabled marketing authorizations to be obtained in numerous countries in addition to the AOP Health territories EU, Switzerland, Liechtenstein and Israel and allows patients to have access to BESREMi® in countries including Taiwan, Korea, the US, and Japan. Further studies are ongoing to substantiate the long-term safety and efficacy of BESREMi®. A post-approval safety study (BESREMI-PASS) with a recruitment period of about three years has just completed patient recruitment.

“The global marketing authorizations of BESREMi®, all based on AOP Health´s clinical development program conducted in Europe, are proof of the integrated drug development and commercialization expertise of AOP Health. Our success and know-how allow us to further pursue our goal of making treatment options for rare diseases available to patients worldwide” says Dr. Rudolf Widman, Founder and Board Member of the AOP Health Group.

About BESREMi®

BESREMi® is the first and currently only interferon approved for polycythaemia vera, a myeloproliferative neoplasm (MPN), indicated in the European Union as monotherapy in adults for treatment of polycythaemia vera without symptomatic enlarged spleen. Its overall safety and efficacy were demonstrated in multiple clinical studies.

BESREMi® (ropeginterferon alfa-2b) is a long-acting, mono-pegylated proline interferon (ATC L03AB15). It is administered with a pen (250 and 500 ug) for self-injection once every 2 weeks initially, or up to every 4 weeks after stabilization of blood values. BESREMi® is designed to be self-administered subcutaneously with a pre-filled pen.

For the EMA Summary of Product Characteristics please visit: BESREMi®

Link: https://www.ema.europa.eu/en/documents/product-information/besremi-epar-product-information_en.pdf

The drug substance Ropeginterferon alfa-2b was discovered by PharmaEssentia, a long-term partner of AOP Health. In 2009, AOP Health in-licensed the exclusive rights for clinical development and commercialization of ropeginterferon alfa-2b in polycythaemia vera and other MPNs such as chronic myelogenous leukemia (CML) for European, Commonwealth of Independent States (CIS), and Middle Eastern markets.

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Conversations With Clinicians Make Way for MPN Symptom Control

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Darlene Dobkowski, MA

Some symptoms of myeloproliferative neoplasms are “pretty broad,” highlighting the importance of open communication with cancer teams to manage the symptoms and improve quality of life.

Patients with myeloproliferative neoplasms (MPNs) may experience a broad range of symptoms — fatigue, aches and pains, and insomnia, among others — emphasizing the importance of open communication with care teams to address them accordingly, an expert said.

Lindsey Lyle, a physician’s assistant who previously worked at Rocky Mountain Cancer Center, a U.S. Oncology Community Practice Group, spoke with CURE® about the symptoms of MPNs, how they can be challenging to assess and how patients can aid in the management of these symptoms.

What are some of the symptoms of MPN?

Since MPN symptoms can mimic other health conditions, it is sometimes difficult to determine what is causing the issue, an expert said.

The symptom burden in patients with a myeloproliferative neoplasm can be pretty broad. And unfortunately, these symptoms are not very specific for one thing in particular, and this is what makes the assessment of these symptoms in patients fairly challenging.

There are a number of symptoms that are fairly commonly recognized to be associated with MPNs. And these consist of fatigue, bone aches and pains, night sweats, unintentional weight loss, itching — especially after a hot shower or being out in warm weather — and then pain under the left ribs, early satiety (the feeling of being full very easily), and sometimes concentration problems even, insomnia, difficulty sleeping.

Can treatment alleviate the symptoms for the disease?

Current treatments for myelofibrosis were approved based on improvement in symptoms. And so, we do know that a number of these treatments — JAK inhibitors specifically, which are the FDA-approved therapies for myelofibrosis — really can help with improving symptom burden. This was one of the main endpoints for the study that led to the approval of all of these JAK inhibitors, as well as spleen volume reduction. So we would expect that symptoms would improve, to some degree, on therapy.

Similarly, with polycythemia vera, we do hope that as we gain better control of the disease, that we are not only improving symptoms by lowering the counts to help improve symptoms by that way, but also really slowing down overactive cytokine production. And by doing that, help alleviate some symptoms.

Now, there are some potential side effects with whatever treatment the patient is on. And so then, certainly, the patient may experience some symptom that is possibly related to the treatment. But this is really where teasing out symptoms prior to and then after starting therapy can be really helpful.

And are symptoms easily managed?

The symptoms that that occur as a result of the disease, sometimes these can be really challenging to treat, honestly. Even if the patient is on appropriate therapy, they may still have symptoms of the disease. And then we have to get creative and utilize our resources, utilize what’s reported in the literature about how best to manage these symptoms that are not necessarily being controlled perhaps by the primary therapy.

Side effects from the therapies that are used to treat polycythemia vera and myelofibrosis are generally really well managed. And most of the patients, even on any of these trials, had a very low discontinuation rate due to the symptoms that were thought to be related to the therapy that was being studied.

What advice would you give patients about their symptoms?

The first thing that is important for patients to understand is what symptoms could possibly be related to their MPN. I generally ask my patients to just keep track, not to become obsessed with these things and write them down on a daily basis, but if they notice that there’s some symptoms, that is impairing their quality of life, preventing them from doing something, I do ask them to write it down.

Oftentimes, when patients come to their visit, they forget different things that have happened throughout the time since they last saw you, maybe they are just a little overwhelmed by the visit itself. And so they just unintentionally forget to bring these things up. So, writing them down and having a way for patients to track their symptoms is really important.

And some of the best conversations I have with patients come from those patients who do write these things down. They say, ‘Gosh, on this day, I really realized this was happening. And how can we improve this?’

I think that from a patient’s perspective, No. 1, having the knowledge about what symptoms may be associated with their MPN is critically important, making sure that they’re jotting down symptoms that they are experiencing. And then also just jotting down any other things that happen in their medical history. So we may be seeing these patients monthly, we may be seeing them every three months, depending on their stability. But most of these patients are in their 60s or 70s. And so they may have other things going on as well. So just keeping a good track of anything else that has popped up will be really helpful in the assessment.

How can patients with MPNs work with their care team to address any symptoms they may be experiencing?

Don’t be afraid to talk to your nurse (or) your health care provider about anything that’s going on, because that is our job to figure out if this is related to the MPN or if we should maybe pursue other investigations for these symptoms.

You don’t have to do it alone. That’s why we’re here for you. So don’t be afraid to bring anything up, and then we can go from there and hopefully find ways to improve whatever you’re experiencing.

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Link Found Between Agent Orange Exposure and Myeloproliferative Neoplasms in Veterans

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By Rob Dillard

US veterans who were exposed to Agent Orange (AO) have an increased risk of myeloproliferative neoplasms (MPNs), bleeding, arterial thrombosis (AT), and venous thrombosis (VT), according to an analysis that will be presented at the 2023 American Society of Clinical Oncology Annual Meeting.

AO is a chemical herbicide that was weaponized and heavily used during the Vietnam War. The chemical is associated with the development of sarcomas and B-cell lymphomas, but, until now, less has been known about its link to MPNs, bleeding, AT, and VT.

To conduct their analysis, lead author Andrew Chua Tiu and colleagues used the VA Informatics and Computing Infrastructure database to identify 95,768 patients with MPN and any AT, VT, and bleeding events.

According to the results, there was a notable correlation between AO exposure and the development of MPNs (odds ratio, 1.61; 95% CI, 1.57-1.65; P<.0001). Specifically, the researchers observed that compared with patients with MPNs who were not exposed to AO, patients with MPNs who were exposed to AO had higher rates of AT (36.0% vs 28.2.%), higher rates of AT (28.7% vs 24.0%), and more bleeding events (41.2% vs 39.0%).

“This is the largest database evaluating MPNs, thrombosis, and bleeding in veterans exposed to AO. There is an association of increased risk of development of MPNs, increased AT, and increased bleeding with AO exposure,” the researchers concluded. They added that further studies “including JAK2 mutation, [clonal hematopoiesis of indeterminate potential], and cardiovascular risk factors will be needed to evaluate contribution to thrombosis and bleeding risk.”

Source: Tiu AC, McKinnell Z, Liu S, et al. Association of Agent Orange and myeloproliferative neoplasms, thrombosis, and bleeding among veterans. Abstract #7011. Published for the 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, Illinois.

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Study Assesses Outcomes of Patients With AF and Myeloproliferative Neoplasms

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By Rob Dillard

Patients admitted for atrial fibrillation (AF) who have myeloproliferative neoplasms (MPNs) have an increased risk of any-cause and bleeding-related readmissions, according to a study that will be presented at the 2023 American Society of Clinical Oncology Annual Meeting.

Individuals with MPNs, essential thrombocythemia, polycythemia vera, and primary myelofibrosis face an increased risk of cardiovascular disease, including atrial thrombosis (AT). “[AF] is also associated with increased risk of AT and often coexists with MPN. However, thrombotic and bleeding outcomes in patients with MPN compared with those without have not been thoroughly investigated,” the investigators noted.

In this analysis, first author Orly Leiva and colleagues assessed 468,094 patients with AF and 1617 patients with a history of MPN in 2017 and 2018. Patients of interest were 18 years of age and older and were identified using the National Readmission Database. The study’s key end points were 30-day and 90-day any-cause, AT-related (including stroke, myocardial infarction, arterial thromboembolism), and bleeding-related readmissions.

According to the findings, patients with MPN had an increased risk of 30-day all-cause (hazard ratio [HR], 1.72; 95% CI, 1.70-1.74), AT-related (HR, 1.45; 95% CI, 1.38-1.53), and bleeding-related (HR, 2.21; 95% CI, 2.01-2.44) readmissions. Moreover, researchers found that patients with MPN had an increased risk of 90-day any-cause (HR, 1.38; 95% CI, 1.37-1.40) and bleeding-related (HR, 1.76; 95% CI, 1.65-1.88) but not AT-related (HR, 1.03; 95% CI, 0.99-1.08) readmissions.

“Among patients admitted for AF, MPN is associated with increased risk of 30-[day] and 90-[day] any-cause and bleeding readmissions and 30-[day] AT readmissions despite similar CHA2DS2-VASC and HAS-BLED risk scores,” the researchers concluded. They added that further studies “are needed to identify risk factors for bleeding and AT in patients with MPN and AF and improve on current risk scores, which do not include MPN status.”

Source: Leiva O, How Chi-Joan, Brunner A, Grevet J, Hobbs G. Outcomes of patients with a myeloproliferative neoplasm and atrial fibrillation. Abstract #7070. Published for the 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, Illinois.

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Abbas Looks at the Use of Ruxolitinib and Fedratinib in Myelofibrosis

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May 30, 2023

Targeted Oncology Staff

In the second part of a live discussion on treating patients with myelofibrosis, Jonathan Abbas, MD, led a talk on the impact of ruxolitinib for these patients and where physicians stand with the use of fedratinib.

CASE SUMMARY

A 68-year-old woman presented to her physician with symptoms of mild fatigue, moderate night sweats and abdominal pain/fullness lasting 4 months; she also reported increased bruising and unexplained weight loss​. Her spleen was palpable 8 cm below the left costal margin. Genetic testing showed she was negative for a JAK2 V617F or CALR mutation. Her karyotype was 46XX​ and a bone marrow biopsy showed megakaryocyte proliferation and atypia with evidence of reticulin fibrosis.

A blood smear revealed leukoerythroblastosis and she was diagnosed with primary myelofibrosis​ with a risk score of Dynamic International Prognostic Scoring System intermediate-2 and was also considered intermediate risk on the MIPSS70 score. However, the patient is not interested in transplant and a decision was made to initiate ruxolitinib (Jakafi).

DISCUSSION QUESTION

What data demonstrates the efficacy of ruxolitinib for a patient like this?

JONATHAN ABBAS, MD: [In the final analysis of the phase 1b EXPAND dose finding study (NCT01317875)], in patients who started with a lower dose of ruxolitinib, there was some thrombocytopenia [at 40%], but platelets were pretty much OK with only 25% of patients with decreasing platelets and then anemia was acceptable [at 25% as well].1 So you can still have efficacy with some acceptable cytopenias is the take home if you put the effort into the ruxolitinib dosing.

In looking at spleen response [of these patients] at lower doses because of the thrombocytopenia, we are still seeing patients have tremendous clinical improvement, and spleen response. In their total symptom scores [TSS], looking at response, you can definitely see improvement [there as well].

In patients with profound anemia [in the COMFORT-I study (NCT00952289)], I don’t know if there’s a tremendous amount of conclusions there other than the ruxolitinib patients, regardless of having anemia, did very well whereas anemic patients who were on best available therapy or on placebo, not surprisingly, are the ones who [had lower efficacy].2

GREGG SHEPARD, MD: The main problem I have with a lot of my patients is anemia becoming more emergent during treatment and becoming more transfusion dependent over time. I dose reduce and they’re on 10 mg once a day, or 5 mg twice a day, and we saw the data previously where efficacy is not great when the dose is that low. So, I don’t know that’s just a struggle [I have].

If the efficacy is not there at less than 10 mg twice a day, then do you just stop the drug completely, or give people supportive care, or look for a trial, or try to increase the dose back up to 10 or 15 mg twice a day and just give them more transfusions?

ABBAS: If you put someone on a Janus kinase [JAK] inhibitor and they’re doing great and symptoms are then improving, but now you’re driving anemia into a transfusion-dependent state so you dose reduce. Now you’re starting to see possibly a loss of clinical response that you had to dose reduce so much, even if the anemia might be getting better. What’s our next step there? Are we offering patients growth factor support when we’re treating them? Is that a scenario people have run into?

IBRAHIM NAKHOUL, MD: We’ve frequently had to use erythropoiesis stimulating agents (ESAs), but it’s not been all that successful.

JACK ERTER, MD: I’ll echo that. I have tried ESA support, and things of that nature, with no benefit.

ABBAS: I’m with you. I’ve tried it and I can’t say it’s ever been terribly successful. While we’re on this topic, 1 thing that’s out there which might not be a too off label to try if you want, is luspatercept [Reblozyl]. Luspatercept in some early studies did have some nice effects on anemia in myeloproliferative neoplasms and is in some later-phase trials.3 So that’s a drug that might be able to provide some better hematologic support for these patients, but…that’s a potential file-away for later options.

DISCUSSION QUESTION

How has data from the JAKARTA trial (NCT01437787) impacted your practice?

ABBAS: The JAKARTA trial randomly assigned fedratinib [Inrebic] or placebo to patients with either primary or secondary myelofibrosis.4 Spleen volume reduction was excellent with a tremendous…number of people who clinically benefited [with 37% vs 1% in the placebo arm], so you can see how well the fedratinib arm did.

Now, we do see some gastrointestinal [GI] toxicities [at all adverse event (AE) grades] with fedratinib [like diarrhea (66%)]. We don’t like cross-trial comparisons, but we live off it anyways, and I think there is a little more GI signaling in fedratinib [than ruxolitinib]. Then we saw degrees of anemia [74%] and thrombocytopenia [47%] comparable with what we’ve seen with ruxolitinib.

The rare AEs with fedratinib included 1 case of Wernicke encephalopathy on treatment, 1 case with an unknown origin, and 2 cases after data lock. This did lead to a black box warning for this, so you do want to make sure the thiamine deficiency isn’t something you want to worry about in a fedratinib patient. Have any of you used fedratinib?

MICHAEL BYRNE, DO: I’ve used it. My experience with it was not positive. I thought it was toxic and not effective, so I’ve not been in a rush to use it.

ABBAS: In my clinical experience…it was the exact same experience as you.

SHEPARD: I have a patient currently on it who’s in the waiting period to get an allogeneic transplant because they failed ruxolitinib and they were off all therapy for a while, just on supportive care. We put her on fedratinib in hope that it would get better…but I have not seen any improvement so far. The patient’s still anemic and transfusion dependent, tolerating it fine, just no better.

ABBAS: What was the ruxolitinib failure? Was it a non-response, was it due to non-tolerability, or both?

SHEPARD: It was interesting. It was a patient who was put on it because they had post- polycythemia vera myelofibrosis and primarily symptomatic with anemia, but never had symptomatic splenomegaly at all. They were put on ruxolitinib, and it did not help their anemia get any better, so [they were] taken off it. It was the same thing with fedratinib. So, now we’re waiting for a possible allogeneic transplant for them.

ABBAS: That’s great. How do we monitor the patient from our case…do people do serial imaging?

ERTER: In this specific disease, yes, I think the splenomegaly is so obvious that I don’t think there’s a huge advantage to getting ultrasounds or CT scans compared with a lot of other diseases we treat.

References

1. Vannucchi AM, Te Boekhorst PAW, Harrison CN, et al. EXPAND, a dose-finding study of ruxolitinib in patients with myelofibrosis and low platelet counts: 48-week follow-up analysis. Haematologica. 2019;104(5):947-954. doi:10.3324/haematol.2018.204602

2. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012 Mar 1;366(9):799-807. doi:10.1056/NEJMoa1110557

3. Kubasch AS, Fenaux P, Platzbecker U. Development of luspatercept to treat ineffective erythropoiesis. Blood Adv. 2021;5(5):1565-1575. doi:10.1182/bloodadvances.2020002177

4. Pardanani A, Tefferi A, Masszi T, et al. Updated results of the placebo-controlled, phase III JAKARTA trial of fedratinib in patients with intermediate-2 or high-risk myelofibrosis. Br J Haematol. 2021;195(2):244-248. doi:10.1111/bjh.17727

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Luspatercept Nearly Doubles Likelihood of Transfusion Independence in Lower-Risk MDS

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May 25, 2o23

Caroline Seymour

Luspatercept-aamt (Reblozyl) led to a higher rate of sustained transfusion independence compared with erythropoiesis stimulating agents (ESAs) in patients with ESA-naïve, lower-risk myelodysplastic syndrome (MDS), according to data from the phase 3 COMMANDS trial (NCT03682536) presented in a press briefing prior to the 2023 ASCO Annual Meeting.1,2

In the intention-to-treat population, 58.5% of patients who received luspatercept achieved transfusion independence for at least 12 weeks with hemoglobin increase of at least 1.5 g/dL compared with 31.2% of patients who received epoetin alfa, meeting the primary end point of the study (P < .0001).

“Luspatercept is the first and only therapy to demonstrate superiority in a head-to-head study against ESAs in transfusion-dependent lower-risk MDS, [and this should be] considered a paradigm shift in the treatment of lower-risk MDS–associated anemia,” Guillermo Garcia-Manero, MD, lead study author and professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, said in a presentation of the data.

Anemia is one of the main symptom burdens for patients with MDS, and chronic anemia and transfusion dependence in lower-risk MDS presents challenges in the clinic, often leading to increased risk of death compared with patients who are transfusion independent. Additionally, standard treatment with ESAs is associated with modest activity, leaving an unmet need for treatment in this population.

Luspatercept is a monoclonal antibody that affects the TGF-beta pathway, leading to increased erythrocytosis. The agent is currently indicated for the treatment of patients with ring sideroblast–positive, lower-risk MDS with progression on or ineligibility for an ESA.

COMMANDS was an open-label, global, randomized trial that enrolled patients at least 18 years of age with Revised International Prognostic Scoring System very low–, low-, or intermediate-risk MDS with or without ring sideroblasts by World Health Organization 2016 criteria with less than 5% blasts in bone marrow. In addition, patients had to have required between 2 and 6 packed red blood cell units per 8 weeks for at least 8 weeks prior to randomization, endogenous serum erythropoietin less than 500 U/L, and lack of prior exposure to ESA therapy.

Patients were stratified by baseline serum erythropoietin level (≤200 U/L vs >200-500 U/L), baseline red blood cell transfusion burden (<4 U/8 weeks vs ≥4 U/8 weeks), and ring sideroblast status (positive vs negative).

The primary end point of the study was the rate of red blood cell transfusion independence for 12 weeks or more with concurrent mean hemoglobin increase of at least 1.5 g/dL.

Eligible patients were randomly assigned 1:1 to receive 1.0 mg/kg of subcutaneous luspatercept every 3 weeks titrated up to 1.75 mg/kg (n = 178) or 450 IU/kg of subcutaneous epoetin alfa every week titrated up to 1050 IU/kg (n = 178). Patients were evaluated for response at day 169 and every 24 weeks thereafter. Treatment was discontinued in the absence of clinical benefit or disease progression per International Working Group criteria. After treatment was completed, patients were followed for other malignancies, high-risk MDS or acute myeloid leukemia (AML) progression, subsequent therapy, and survival for 5 years from the first dose of study treatment of 3 years from the last dose, whichever occurred last.

The median duration of treatment was 41.6 weeks (range, 0-165) with luspatercept vs 27.0 weeks (range, 0-171) with epoetin alfa.

Additional results demonstrated higher rates of transfusion independence with luspatercept regardless of stratification criteria. Moreover, patients experienced improved rates of transfusion independence with luspatercept regardless of SF3B1 mutation status.

Notably, treatment with luspatercept led to prolonged transfusion independence regardless of ring sideroblast status. “Luspatercept provided clinical benefit regardless of patient subgroups,” Garcia-Manero added.

In all patients, the median duration of transfusion independence for at least 12 weeks was 126.6 weeks (95% CI, 108.3–not evaluable [NE]) with luspatercept vs 77.0 weeks (95% CI, 39.0-NE) with epoetin alfa (HR, 0.456; 95% CI, 0.260-0.798). In ring sideroblast–positive patients, the median durations were 120.9 weeks (95% CI, 76.4-NE) and 47.0 weeks (95% CI, 36.6-NE) with luspatercept and epoetin alfa, respectively (HR, 0.626; 95% CI, 0.361-1.085). In ring sideroblast–negative patients, the median durations were NE (95% CI, 46.0-NE) and 95.1 weeks (95% CI, 35.3-NE), respectively (HR, 0.492; 95% CI, 0.148-1.638).

Regarding safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in 92.1% (n = 164) of patients in the luspatercept arm vs 85.2% (n = 150) of patients in the epoetin alfa arm.

“The toxicity profile was consistent with previous clinical experience,” Garcia-Manero stated.

Any-grade hematologic toxicities in the luspatercept and epoetin alfa arms, respectively, included anemia (9.6% vs 9.7%), thrombocytopenia (6.2% vs 1.7%), neutropenia (5.1% vs 7.4%), and leukocytopenia (1.1% vs 1.7%). Any-grade TEAEs of interest include fatigue (14.6% vs 6.8%), diarrhea (14.6% vs 11.4%), peripheral edema (12.9% vs 6.8%), asthenia (12.4% vs 14.2%), nausea (11.8% vs 7.4%), dyspnea (11.8% vs 7.4%), and thromboembolic event (4.5% vs 2.8%).

Moreover, patients in the luspatercept arm experienced fewer progressions to high-risk MDS and AML compared with patients in the epoetin alfa arm, at 2.8% (n = 5) and 2.2% (n = 4) vs 4.0% (n = 7) and 2.8% (n = 5), respectively. Thirty-two fatalities occurred in both arms.

“In patients with anemia with lower-risk MDS who depend on red blood cell transfusions, luspatercept almost doubles the number of people who achieve independence from transfusions for a period lasting 12 weeks or more, when compared with epoetin alfa, a current standard of care treatment. Luspatercept may be an effective first treatment option for anemia associated with lower-risk MDS,” Olatoyosi Odenike, MD, FASCO, a professor of medicine and director of the Leukemia Program at University of Chicago Medicine, stated in a news release.

References

  1. Garcia-Manero G, Platzbecker U, Santini V, et al. Efficacy and safety results from the COMMANDS trial: A phase 3 study evaluating luspatercept vs epoetin alfa in erythropoiesis-stimulating agent (ESA)‑naive transfusion-dependent (TD) patients (pts) with lower‑risk myelodysplastic syndromes (LR-MDS). J Clin Oncol. 2023;41(suppl 16):7003. doi:10.1200/JCO.2023.41.16_suppl.7003
  2. Luspatercept improves anemia and reduces reliance on blood transfusions for people with lower-risk myelodysplastic syndromes. News release. ASCO. May 25, 2023. Accessed May 25, 2023. https://old-prod.asco.org/about-asco/press-center/news-releases/luspatercept-improves-anemia-and-reduces-reliance-blood

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