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

Posted on June 6, 2023June 6, 2023 by mpn_admin

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.

Conversations With Clinicians Make Way for MPN Symptom Control

Posted on June 6, 2023June 6, 2023 by mpn_admin

Published on: May 31, 2023

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.

Link Found Between Agent Orange Exposure and Myeloproliferative Neoplasms in Veterans

Posted on May 31, 2023May 31, 2023 by mpn_admin

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.

Study Assesses Outcomes of Patients With AF and Myeloproliferative Neoplasms

Posted on May 31, 2023May 31, 2023 by mpn_admin

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.

Abbas Looks at the Use of Ruxolitinib and Fedratinib in Myelofibrosis

Posted on May 31, 2023May 31, 2023 by mpn_admin

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}

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

Posted on May 30, 2023May 30, 2023 by mpn_admin

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

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
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

Adoption of Mediterranean diet shows promise in easing symptoms for myeloproliferative neoplasm patients

Posted on May 30, 2023May 30, 2023 by mpn_admin

By Dr. Priyom Bose PhD

May 25, 2023

Myeloproliferative neoplasm (MPN) represents a group of inflammatory diseases, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). MPNs are linked to hematologic malignancies and are characterized by clonal outgrowth of hematopoietic cells with an acquired mutation in JAK2.

Multiple studies have shown that the Mediterranean diet positively impacts diseases associated with chronic subclinical inflammation. In addition to the Mediterranean diet, the gut microbiome also plays a crucial role in improving hematologic disorders.

A new study published to the medRxiv* preprint server assesses the feasibility of an education-focused Mediterranean diet intervention among MPN patients.

Background

Clinical manifestations of MPN include abnormal blood counts, thrombosis, and transformation to acute leukemia. One of the key characteristic features of MPN is increased plasma cytokines.

Chronic inflammation leads to abnormal blood count. Although JAK inhibitors alleviate MPN symptoms, these drugs are associated with certain risks, such as immunosuppression, skin cancer, and weight gain.

The recent National Comprehensive Cancer Network (NCCN) guidelines for MPN proposed several interventions to reduce symptom burden, irrespective of the prognosis scoring category.

Since many MPN patients do not meet the criteria for a cytoreductive agent, their symptoms are maintained without specific interventions. As a result, the quality of life of these patients is adversely affected due to the inability to limit disease progression.

Lifestyle modification, mainly through diet, can reduce inflammation. For example, a healthy diet high in anti-inflammatory agents can improve symptom burden among MPN patients. Adherence to this type of diet can decrease inflammation and significantly delay or prevent disease progression.

The Mediterranean diet is a primarily plant-based diet, which is associated with the consumption of nuts, extra virgin olive oil (EVOO), vegetables, fish, fruits, legumes, and whole grain products. Controlling inflammation through nutrition is a low-risk therapeutic approach to mitigate the burden of symptoms for MPN patients.

About the study

The primary aim of the current study was to determine the willingness of MPN patients to engage in dietary education to manage symptom burden. Participants were randomly assigned to either a standard U.S. Dietary Guidelines for Americans (USDA) group or Mediterranean diet group. Both groups received separate but equal education through written dietary resources and registered dietician counseling.

Patients were followed for adherence, feasibility, and symptom burden assessments. To explore changes in the gut microbiome and inflammatory biomarkers, biological samples were collected at four distinct time points throughout the 15-week study period.

Study findings

MPN patients found the Mediterranean diet program equally easy to follow as a program based on the U.S. Guidelines for Americans. Over 80% of participants in the Mediterranean diet group could maintain good adherence throughout the intervention period as compared to less than 50% in the USDA group. This serves as evidence that, with proper dietician counseling and written curriculum, MPN patients can feasibly adopt a Mediterranean diet.

MPN patients can adopt a Mediterranean eating pattern with dietician counseling and education. (A) Percentage of participant with MEDAS scores ≥8 at each time point with orange shaded area depicting the active intervention period (B) Participant responses to feasibility question during active intervention period (C) HEI-2015 was calculated from each 24 hour diet recall, and scores for each participant were averaged for the pre-intervention (weeks 1-2), active intervention (weeks 3-12), and post-intervention (weeks 13-15) period. Data shown represents median with interquartile range.

In MPN, an important goal is to target symptoms, as symptoms can significantly affect the patient’s’ quality of life. In the USDA group, 31% of the cohort exhibited more than a 50% reduction in the MPN-Total Symptom Score (TSS) at 15 weeks, whereas 53% of the Mediterranean diet group exhibited more than a 50% reduction in the MPN-TSS.

As compared to the USDA diet, the Mediterranean diet had a better effect on alleviating MPN symptoms. The length of the diet intervention and intensity are important factors in alleviating MPN symptoms.

Changes in symptom burden during study. (A) waterfall plots of percentage change in MPN-SAF (MPN-TSS) at each week compared to baseline (baseline defined as average MPN-TSS of weeks 1 and 2) (B) Raw change in specific symptoms at each week compared to baseline (mean±SD).

Future outlook

Both diets investigated in the current study led to a reduction in MPN symptom burden. Thus, these findings demonstrate that a 10-week intervention is sufficient to detect a change in symptoms.

In the future, a longer intervention period is required to assess whether improvements in symptoms continue. A longer intervention period would also help detect people with delayed symptom improvement.

The current analysis highlights that MPN symptoms may stem from different root causes; therefore, some symptoms change quickly compared to others. Due to the small sample size, a decrease in the inflammatory cytokines could not be detected. Therefore, future studies with a larger cohort are needed to elucidate how diets impact inflammatory cytokine levels.

Journal reference:

Preliminary scientific report. Luque, M. F. L., Avelar-Barragan, J., Nguyen, H., et al. (2023) The NUTRIENT Trial (NUTRitional Intervention among myeloproliferative Neoplasms): Feasibility Phase. medRxiv. doi:10.1101/2023.05.09.23289740

Data from Across Incyte’s Oncology Portfolio Accepted for Presentation at the 2023 ASCO Annual Meeting and EHA2023 Hybrid Congress

Posted on May 30, 2023May 30, 2023 by mpn_admin

May 25, 2023 05:01 PM Eastern Daylight Time

WILMINGTON, Del.–(BUSINESS WIRE)–Incyte (Nasdaq:INCY) today announced that multiple abstracts featuring data from across its oncology portfolio will be presented at the upcoming 2023 American Society of Clinical Oncology (ASCO) Annual Meeting held June 2-6 in Chicago, and at the European Hematology Association 2023 (EHA2023) Hybrid Congress held in Frankfurt, Germany, from June 8-11 and virtually from June 14-15.

“Our presence at ASCO and EHA illustrates Incyte’s ongoing commitment to science that can lead to additional, needed solutions for patients with cancer”

“Our presence at ASCO and EHA illustrates Incyte’s ongoing commitment to science that can lead to additional, needed solutions for patients with cancer,” said Steven Stein, M.D., Chief Medical Officer, Incyte. “These data underscore the potential of our oncology pipeline, and highlight the variety of approaches we are exploring to advance research in areas where we believe we can have the greatest impact for patients.”

Key abstracts accepted by ASCO and EHA include:

ASCO Abstracts

Abstracts are available to registered attendees on the ASCO Congress platform. Posters and slides will be available to registered attendees at the scheduled session start time.

Poster Discussion

LIMBER

Phase 1/2 Study of the Activin Receptor-Like Kinase (ALK)-2 Inhibitor Zilurgisertib (INCB000928, LIMBER-104) as Monotherapy or with Ruxolitinib (RUX) in Patients (pts) with Anemia due to Myelofibrosis (MF) (Abstract #7017. Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant. Monday, June 5, 12:30 p.m. – 2:00 p.m. ET)

Poster Presentations

CK0804

Phase 1b, Open-Label Study of Add-On Therapy with CK0804 in Participants with Myelofibrosis, with Suboptimal Response to Ruxolitinib (Abstract #TPS7087. Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant. Monday, June 5, 9:00 a.m. – 12:00 p.m. ET)¹

Immuno-oncology (IO)

A Phase 1/2 Study of Retifanlimab (INCMGA00012, Anti–PD-1), INCAGN02385 (Anti–LAG-3), and INCAGN02390 (Anti–TIM-3) Combination Therapy in Patients (Pts) with Advanced Solid Tumors (Abstract #2599. Session: Developmental Therapeutics—Immunotherapy. Saturday, June 3, 9:00 a.m. – 12:00 p.m. ET)

Itacitinib

Rates of Cytokine Release Syndrome (CRS) and Immune Effector Cell–Associated Neurotoxicity Syndrome (ICANS) from Center for International Blood and Marrow Transplant Research (CIBMTR) Data on U.S. Subjects (SUBJ) with Lymphoma Following Chimeric Antigen Receptor T Cell (CAR-T) Therapy (Abstract #7528. Session: Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia. Monday, June 5, 9:00 a.m. – 12:00 p.m. ET)

LIMBER

Bromodomain and Extra-Terminal (BET) Inhibitor INCB057643 (LIMBER-103) in Patients (pts) with Relapsed or Refractory Myelofibrosis (R/R MF) and Other Advanced Myeloid Neoplasms: A Phase 1 Study (Abstract #7069. Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant. Monday, June 5, 9:00 a.m. – 12:00 p.m. ET)

EHA Abstracts

Abstracts are available on the EHA2023 Congress platform and accessible for on-demand viewing until August 15, 2023.

Oral Presentations

Ponatinib

PhALLCON: A Phase 3 Study Comparing Ponatinib vs Imatinib in Newly Diagnosed Ph+ALL (Abstract #S110. Session: Immune Therapeutic Treatment in ALL. Friday, June 9, Date, 8:45 a.m. – 9:00 a.m. ET)²

Ruxolitinib

Ruxolitinib in Pediatric Patients with Treatment-Naive or Steroid Refractory Chronic Graft-Versus-Host Disease: Primary Findings from the Phase 2 REACH 5 Study (Abstract #S245. Session: SCT Clinical. Saturday, June 10, 5:30 a.m. – 6:45 a.m. ET)³

Poster Presentations

LIMBER

Bromodomain and Extra-Terminal (BET) Inhibitor INCB057643 in Patients (pts) with Relapsed or Refractory Myelofibrosis (R/R-MF) and Other Advanced Myeloid Neoplasms: A Phase 1 Study (Abstract #P1055. Session: Myeloproliferative Neoplasms – Clinical. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)

Phase 1/2 Study of the Activin Receptor-like Kinase 2 (ALK2) Inhibitor Zilurgisertib (INCB000928, LIMBER-104) as Monotherapy or with Ruxolitinib in Patients with Anemia due to Myelofibrosis (Abstract #P1022. Session: Myeloproliferative Neoplasms – Clinical. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)

Parsaclisib

A Phase 2, Multicenter, Single-Arm Study of Parsaclisib, a PI3Kδ Inhibitor, in Relapsed or Refractory Follicular Lymphoma in China: Updated Results from the Study (Abstract #P1099. Session: Indolent and Mantle-Cell Non-Hodgkin Lymphoma – Clinical. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)⁴

Ponatinib

Multicenter, Prospective and Retrospective Observational Cohort Study of Ponatinib in Patients with CML in Italy: Long-Term Follow-Up Results of the OITI Trial (Abstract #P663. Session: Chronic Myeloid Leukemia – Clinical. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)

Early Cytogenetic or Molecular Landmark Response to Ponatinib Treatment Predicts Outcomes in Heavily Pretreated Patients with Chronic-Phase Chronic Myeloid Leukemia in PACE: 5-Year Data (Abstract #P670. Session: Chronic Myeloid Leukemia – Clinical. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)³

Post Hoc Analysis of Patient Responses by T315I Mutation Status from the 3-Year Update of the OPTIC Trial: A Dose-Optimization Study of Three Starting Doses of Ponatinib (Abstract #P662. Session: Chronic Myeloid Leukemia – Clinical. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)³

Ruxolitinib

Characteristics and Clinical Outcomes in Patients (Pts) With Polycythemia Vera (PV) Receiving Ruxolitinib (RUX) after Hydroxyurea (HU): A Longitudinal Analysis from REVEAL (Abstract #P1032. Session: Myeloproliferative Neoplasms – Clinical. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)

Disease Progression and Leukemic Transformation in Patients with Lower-Risk Myelofibrosis (MF): An Analysis from MOST (Abstract #P1045. Session: Myeloproliferative Neoplasms – Clinical. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)

Treatment Comparison of Hydroxyurea vs Ruxolitinib in Essential Thrombocythemia (ET): A Matched Cohort Analysis (Abstract #P1046. Session: Myeloproliferative Neoplasms – Clinical. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)

Tafasitamab

Comprehensive Molecular Subtyping of Diffuse Large B-Cell Lymphoma Cell Lines and Association with Tafasitamab Activity (Abstract #P1227. Session: Lymphoma Biology & Translational Research. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)

Five-Year Efficacy and Safety of Tafasitamab in Patients with Relapsed or Refractory DLBCL: Final Results from the Phase 2 L-MIND Study (Abstract #P1138. Session: Aggressive Non-Hodgkin Lymphoma – Clinical. Friday, June 9, 12:00 p.m. – 1:00 p.m. ET)⁵

For full session details and data presentation listings, please see the ASCO (https://conferences.asco.org) and EHA2023 (https://ehaweb.org/congress) online programs.

About Jakafi^® (ruxolitinib)
Jakafi^® (ruxolitinib) is a JAK1/JAK2 inhibitor approved by the U.S. FDA for treatment of polycythemia vera (PV) in adults who have had an inadequate response to or are intolerant of hydroxyurea; intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF in adults; steroid-refractory acute GVHD in adult and pediatric patients 12 years and older; and chronic GVHD after failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older.

Jakafi is marketed by Incyte in the United States and by Novartis as Jakavi^® (ruxolitinib) outside the United States. Jakafi is a registered trademark of Incyte Corporation. Jakavi is a registered trademark of Novartis AG in countries outside the United States.

About Iclusig^® (ponatinib) tablets
Ponatinib (Iclusig^®) targets not only native BCR-ABL but also its isoforms that carry mutations that confer resistance to treatment, including the T315I mutation, which has been associated with resistance to other approved TKIs.

In the EU, Iclusig is approved for the treatment of adult patients with chronic phase, accelerated phase or blast phase chronic myeloid leukemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation, or the treatment of adult patients with Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) who are resistant to dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation.

Click here to view the Iclusig EU Summary of Medicinal Product Characteristics.

Incyte has an exclusive license from Takeda Pharmaceuticals International AG to commercialize ponatinib in the European Union and 29 other countries, including Switzerland, UK, Norway, Turkey, Israel and Russia. Iclusig is marketed in the U.S. by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

About Tafasitamab (Monjuvi^® / Minjuvi^®)
Tafasitamab is a humanized Fc-modified CD19 targeting immunotherapy. In 2010, MorphoSys licensed exclusive worldwide rights to develop and commercialize tafasitamab from Xencor, Inc. Tafasitamab incorporates an XmAb^® engineered Fc domain, which mediates B-cell lysis through apoptosis and immune effector mechanism including Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP).

In the United States, Monjuvi^® (tafasitamab-cxix) is approved by the U.S. Food and Drug Administration in combination with lenalidomide for the treatment of adult patients with relapsed or refractory DLBCL not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant (ASCT). This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

In Europe, Minjuvi^® (tafasitamab) received conditional marketing authorization in combination with lenalidomide, followed by Minjuvi^® monotherapy, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for autologous stem cell transplant (ASCT).

Tafasitamab is being clinically investigated as a therapeutic option in B-cell malignancies in several ongoing combination trials.

Monjuvi^® and Minjuvi^® are registered trademarks of MorphoSys AG. Tafasitamab is co-marketed by Incyte and MorphoSys under the brand name MONJUVI^® in the U.S., and marketed by Incyte under the brand name Minjuvi^® in Europe and Canada.

XmAb^® is a registered trademark of Xencor, Inc.

About Zynyz™ (retifanlimab-dlwr)
Zynyz (retifanlimab-dlwr), is an intravenous PD-1 inhibitor indicated in the U.S. for the treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Zynyz is marketed by Incyte in the U.S. In 2017, Incyte entered into an exclusive collaboration and license agreement with MacroGenics, Inc. for global rights to retifanlimab.

Zynyz is a trademark of Incyte.

About LIMBER
Incyte is a leader in the discovery and development of therapies for patients with myeloproliferative neoplasms (MPNs) and graft-versus-host disease (GVHD). The LIMBER clinical trial program is designed to evaluate multiple monotherapy and combination strategies to improve and expand treatments for patients with MPNs and GVHD. These include ruxolitinib-based combinations with BET and ALK2, new therapeutic options including axatilimab and novel targets such as mutant CALR.

New Risk Score Assists in Predicting Myeloid Neoplasms in Individuals With Clonal Hematopoiesis

Posted on May 30, 2023May 30, 2023 by mpn_admin

May 25, 2023

Vicki Moore, PhD

Researchers developed a clonal hematopoiesis risk score (CHRS) for patients with clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS), and they evaluated its capacity to predict myeloid neoplasm (MN) risk in a recent study. Results were presented in the journal NEJM Evidence.

The study investigators obtained data from 438,890 individuals without MN who participated in the UK Biobank. Data on genetic mutations, laboratory values, and MN outcomes from 193,743 individuals were included in a subset used for derivation of the prognostic model, with the remaining 245,147 individuals included in a validation cohort. The primary study outcome was incident MN occurring after month 6 of study enrollment.

A total of 11,337 individuals in the derivation cohort were identified as meeting criteria for having either CHIP (10,479 individuals) or CCUS (858 individuals). The median follow-up duration was 11.7 years. In this cohort, there were 269 incident MN events reported, reflecting a rate of 2.37% in this population.

Several factors appeared associated with MN risk. These included high-risk mutations, single DNMT3A mutations, having 2 or more mutations, an age of 65 or more years, the presence of CCUS rather than CHIP, a mean corpuscular volume 100 fL or more, a red cell distribution width of 15% or more, and a variant allele fraction of 0.2 or more for any clonal hematopoiesis variant. Most of these features were linked to greater MN risk.

DNMT3A mutations were associated with a greater MN risk in individuals with CHIP/CCUS than in people without CHIP/CCUS. However, among individuals with CHIP/CCUS, DNMT3A mutations were associated with a lower risk of MN in comparison with other genotypes.

Using CHRS values developed with the prognostic model, the researchers categorized individuals with CHIP/CCUS into 3 risk groups. A low-risk group included 10,018 (88.4%) individuals, while an intermediate-risk group included 1196 (10.5%), and a high-risk group included 123 (1.1%).

In these groups, the 10-year cumulative incidence of MN was 0.669 ⁺ 0.0827% for the low-risk group, 7.83 ⁺ 0.807% for the intermediate-risk group, and 52.2 ⁺ 4.96% for the high-risk group. Ten-year survival rates were 93.7 ⁺ 0.243%, 84.0 ⁺ 1.06%, and 51.2 ⁺ 4.51%, respectively. In comparison, individuals without CHIP/CCUS in this study had a 10-year survival rate of 95.8 ⁺ 0.0471%.

“The CHRS robustly defines three distinct CHIP/CCUS risk groups and shows the low absolute risk of progression to overt MN in the vast majority of CHIP and CCUS,” the study investigators wrote in their report. They also concluded the CHRS may have a role in identifying individuals with CHIP/CCUS who may require greater surveillance and intervention.

The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Feasibility Phase

Posted on May 30, 2023May 30, 2023 by mpn_admin

Laura F. Mendez Luque,^1,² Julio Avelar-Barragan,³ Hellen Nguyen,¹ Jenny Nguyen,¹ Eli M. Soyfer,¹ Jiarui Liu,¹ Jane H. Chen,¹ Nitya Mehrotra,¹ Heidi E. Kosiorek,⁴ Amylou Dueck,⁴ Alexander Himstead,¹ Elena Heide,¹ Melinda Lem,¹ Kenza El Alaoui,¹ Eduard Mas Marin,¹ Robyn M. Scherber,⁵ Ruben A. Mesa,⁶ Katrine L. Whiteson,³ Andrew Odegaard,¹ and Angela G. Fleischman¹

Abstract

Purpose:

Chronic inflammation is integral to Myeloproliferative Neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among MPN patients.

Experimental Design:

We randomly assigned participants to either a Mediterranean diet or standard US Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four time points during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome.

Results:

The Mediterranean diet was as easy to follow for MPN patients as the standard USDA diet. Over 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of ≥8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of ≥8 at any time point. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention.

Conclusions:

With dietician counseling and written education MPN patients can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially even be incorporated into the management of other chronic clonal hematologic conditions.