Tag Archives: mpn

Age, Race, Insurance Status Can Predict CV Mortality for Those With MPNs

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November 2, 2024

Author(s): Mary Caffrey

Among those diagnosed with myeloproliferative neoplasms (MPNs), age, race, marital status, and insurance status can help predict cardiovascular mortality (CVM), based on an analysis of more than 24,000 US patient records.1

A new study finds that clinical factors and social determinants of health can predict cardiovascular mortality among patients with myeloproliferative neoplasms.

| Image Credit: yodiyim – stock.adobe.com

The study, appearing this week in Therapeutic Advances in Hematology,1 aimed to identify prognostic factors that can guide clinicians in treating patients with MPNs, which are a group of hematopoietic stem cell disorders that are generally diagnosed in individuals after age 40; according to the Leukemia & Lymphoma Society, most patients are diagnosed in their 60s or 70s.

The team from Sun Yat-sen University in China culled records for more than 48,000 patients diagnosed with MPNs between 2000 and 2018 from the Surveillance, Epidemiology, and End Results (SEER) database, but narrowed their analysis to those records for patients that lived at least a year and included other essential clinical information. That left a database of 24,277 patient records.

Among the demographic findings:

  • The database included 10,409 patients (42.9%) with polycythemia vera (PV), 3229 (13.3%) with myelofibrosis (MF) and 10,639 (43.8%) with essential thrombocythemia (ET).
  • Prevalence of the condition was higher among White males in PV and MF compared with females in ET.
  • At diagnosis, only 8.0% were younger than 40 years old; 29.0% were 40-59 years old, 47.0% were 60-79 years old; and 16% were older than 80 years of age.

The analysis took a snapshot of patients at 200 months of follow-up (16 years, 8 months) and found that the cumulative mortality was the following CVD (17.9%), other noncancer (22.1%), MPN (18.8%), and other cancers (6.1%). However, investigators found that more than 50% of patients initially diagnosed with MF died from their primary disease during this period, which may be due to conversion of their disease to acute myeloid leukemia.

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Ruxolitinib Plus Pegylated Interferon Alfa-2a Show Promise in Newly Diagnosed Polycythemia Vera

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November 1, 2024

Author(s): Alexandra Gerlach, Associate Editor

Ruxolitinib (Jakafi; Incyte Corp) in combination with pegylated interferon alfa-2a demonstrated efficacy and tolerability in patients with newly diagnosed polycythemia vera (PV). According to the 2-year end-of-study results from the phase 2 COMBI 2 clinical trial (EudraCT2018-004150-13), the treatment improved cell counts, bone marrow cellularity, and fibrosis in patients with PV.1

In the phase 2 COMBI 2 trial, researchers evaluated the safety and efficacy of ruxolitinib and low-dose peg-IFN-α2a in patients with newly diagnosed PV.

Image Credit: © MdBabul – stock.adobe.com

PV is a chronic, progressive myeloproliferative neoplasm characterized by the overproduction of red blood cells. The excess cells thicken the blood, slowing its flow and contributing to serious complications, such as blood clots. Almost all patients with PV have the JAK2V617F mutations, and the JAK2V617F variant allele frequency (VAF) is key for determining outcomes, including thrombosis and progression to myelofibrosis.2-4

Ruxolitinib is a Janus kinase inhibitor approved by the FDA in 2011 and is indicated for the treatment of patients with high-risk MF with reduced abnormal expression of PF4, which can lead to decreased fibrosis. It is additionally indicated as a second-line treatment of PV for patients who have an inadequate response to or cannot tolerate hydroxyurea. In the COMBI 2 trial, researchers assessed the efficacy of ruxolitinib in combination with pegylated interferon alfa-2a (peg-IFN-α2a) (Pegasys ProClick; Genentech), an injection commonly used to treat hepatitis B and C infections. According to data from prior studies, peg-IFN-α2a has been shown to induce durable hematologic and molecular remissions in patients with PV. However, approximately 20% to 40% of patients are intolerant or show limited response to peg-IFN-α2a.5-8

In the phase 2 COMBI 2 trial, researchers evaluated the safety and efficacy of ruxolitinib and low-dose peg-IFN-α2a in patients with newly diagnosed PV in an effort to counterbalance intolerance to peg-IFN-α2a. The primary end point was safety, with secondary end points including efficacy, based on hematologic parameters, quality-of-life measurements, and JAK2V617F variant allele frequency (VAF).8

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FORUS Therapeutics Inc. and PharmaEssentia Corporation Have Entered Into an Exclusive Licensing Agreement for The Registration and Distribution of BESREMi(R) (ropeginterferon alfa-2b) for The Treatment of polycythemia vera (PV), in Canada

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October 31, 2024 8:30 AM EDT | Source: FORUS Therapeutics Inc.

  • Under the terms of the agreement, FORUS is licensing BESREMi from PharmaEssentia for PV in Canada, with potential expansion to other investigational myeloproliferative neoplasms (MPN) indications.
  • FORUS will oversee the drug registration and commercialization of BESREMi in Canada, including securing approval of BESREMi in PV and meeting certain milestones.

Oakville, Ontario–(Newsfile Corp. – October 31, 2024) – FORUS Therapeutics Inc (“FORUS”) and PharmaEssentia Corporation (“PharmaEssentia”) have entered into an exclusive licensing agreement for the registration and distribution of BESREMi® (ropeginterferon alfa-2b) for the treatment of polycythemia vera (PV), in Canada.

“On behalf of the FORUS Therapeutics team, I am truly excited to announce this licensing agreement with PharmaEssentia and to commence the process of commercializing BESREMi in Canada. BESREMi represents the second novel therapeutic in the FORUS hematology-oncology pipeline and is another important step in fulfilling the organization’s mission and vision. We are committed to rapidly advancing BESREMi through the regulatory and reimbursement pathways to ensure that PV patients in Canada have broad access to this novel medication,” said Kevin Leshuk, President and CEO of FORUS. “We are making this announcement today to support the momentum created by the September 12th, Annual MPN Awareness Day and the International Congress on Myeloproliferative Neoplasms, recently held in Brooklyn, New York. We believe that continuing to elevate awareness with the goal of meeting the unmet needs of the MPN community is critical to making a difference in the lives of patients.”

“BESREMi is an important and significant development for clinicians who treat patients with PV. BESREMi as a potential future treatment option is particularly critical for Canada, where treatment options are notably limited for these patients,” says Dr. Shireen Sirhan, a founding member and the current President of the Canadian MPN group, and Vice-President for research in MPNs of the Groupe Québécois de recherche en LMC-NMP. “Canadian physicians have played a significant role in the clinical development program for BESREMi and we look forward to having this important treatment available in the clinic for our patients in need.”

“This is very exciting news for the PV community across Canada,” says Doug Chisholm and Patricia Saluk, the former and current Chair, Board of Directors of the Canadian MPN Network Patient Advocacy group. “Polycythemia vera is a rare blood cancer and the future commercialization of BESREMi in Canada offers highly anticipated new hope for patients, families, and their support networks. We hope the Canadian regulatory and payor systems will work as quickly as possible to ensure our patient community has access to this much needed new treatment regimen.”

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Inrebic May Reduce Spleen Volume in Myelofibrosis

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October 31, 2024

Author(s): Alex Biese

Fact checked by: Spencer Feldman

Among patients with myelofibrosis who have been previously treated with Jakafi (ruxolitinib), treatment with Inrebic (fedratinib) was beneficial, particularly regarding spleen volume reduction (SVR) when compared to treatment with otherwise best-available therapy (BAT), researchers have found.

Findings from the phase 3 FREEDOM2 trial were published in The Lancet Hematology.

“In the FREEDOM2 trial, patients with myelofibrosis previously treated with [Jakafi] showed superior SVR and symptom response when treated with [Inrebic] compared with BAT (predominantly [Jakafi]),” researchers concluded in the study. “The safety profile of [Inrebic] was consistent with previous trials, and mitigation measures effectively managed known adverse events. Overall, the results indicate that [Inrebic] is a promising option for second-line JAK inhibitor treatment of myelofibrosis.”

Inrebic, a type of tyrosine kinase inhibitor, works by blocking JAK2 and other proteins — which, as defined by the National Cancer Institute, may help keep abnormal blood cells or cancer cells from growing. It was approved by the Food and Drug Administration for the treatment of patients with myelofibrosis in 2019.

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Karyopharm to Host Investor Event with Leading Myelofibrosis KOLs and Provide a Favorable Study Design Update on October 31, 2024

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NEWTON, Mass., Oct. 30, 2024 /PRNewswire/ — Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, today announced it will host a conference call and audio webcast at 8:00 a.m. ET on Thursday, October 31, 2024 to provide a favorable study design update on the Company’s pivotal Phase 3 SENTRY study in JAKi naive myelofibrosis.

The call will feature leading myelofibrosis key opinion leaders Dr. Raajit Rampal, Director of the Center for Hematologic Malignancies and Director of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center and Dr. John Mascarenhas, principal investigator of the Phase 3 SENTRY trial, Professor of Medicine at the Icahn School of Medicine at Mount Sinai and Director of the Center of Excellence for Blood Cancers and Myeloid Disorders.

To access the conference call, please dial (800) 836-8184 (local) or (646) 357-8785 (international) at least 10 minutes prior to the start time and ask to be joined into the Karyopharm Therapeutics call. A live audio webcast of the call, along with accompanying slides, will be available under “Events & Presentations” in the Investor section of the Company’s website, http://investors.karyopharm.com/events-presentations. An archived webcast will be available on the Company’s website approximately two hours after the event.

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Ajax Therapeutics Announces First Patient Dosed in Phase 1 Clinical Trial Evaluating AJ1-11095, a First-in-Class Type II JAK2 inhibitor, for the Treatment of Myelofibrosis

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October 30, 2024

– AJ1-11095 is the first Type II JAK2 Inhibitor to enter the clinic –

– Preclinically, AJ1-11095 has demonstrated superior efficacy to Type I JAK2 inhibitors, such as ruxolitinib, with disease modifying effects on mutant allele burden and fibrosis –

NEW YORK & CAMBRIDGE, Mass.–(BUSINESS WIRE)–Ajax Therapeutics, Inc., a biopharmaceutical company developing next generation JAK inhibitors for patients with myeloproliferative neoplasms (MPNs), today announced the first patient has been dosed in its Phase 1 clinical trial evaluating AJ1‑11095, a first-in-class Type II JAK2 inhibitor, for the treatment of patients with myelofibrosis.

“We’re excited to announce dosing of the first patient enrolled in our first-in-human study with AJ1-11095” said David Steensma, MD, FACP, Chief Medical Officer at Ajax. “As a first-in-class therapy with a unique mechanism of action as a Type II inhibitor of JAK2, AJ1-11095 was developed to provide a much-needed new treatment for patients with myeloproliferative neoplasms by offering the potential for improved efficacy compared to existing therapies.”

AJ1-11095 is the first JAK2 inhibitor to enter the clinic that binds the Type II conformation of the JAK2 kinase as opposed to all the other approved JAK2 inhibitors, including ruxolitinib, that bind the Type I conformation. The advancement of AJ1-11095 into this Phase 1 clinical trial was based on preclinical studies in which AJ1-11095 showed superior efficacy when compared to Type I JAK2 inhibitors with significant disease modifying effects on mutant allele burden and fibrosis, two of the main hallmarks of myelofibrosis.

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Treatment Differences for Younger vs Older Patients With MPNs

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October 30, 2024

Author(s): Laura Joszt, MA, Mary Caffrey

The age distribution of people affected by myeloproliferative neoplasms (MPNs) is broad, explained Ruben Mesa, MD, FACP, executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center, president of Atrium Health Levine Cancer.

With younger patients, it’s important to understand the increased risk of their disease progressing given how long they’ll live with their illness, and the impact therapies may have on fertility.

This transcript was lightly edited for clarity.

Transcript

About 20% of patients with myeloproliferative neoplasms are in the adolescent to young adult population. Are there characteristics that differentiate this younger population from older ones or treatment considerations that differ among the age groups?

I would say that the median age is in the 60s. However, I would say that the distribution is broad. As opposed to it being a median in the 60s and there being a high concentration only in individuals that are older, it is a broader distribution. In particular the earlier phases of MPN, ET [essential thrombocythemia], and PV [polycythemia vera}, are not uncommon in those that are 30s, 40s and 50s years old. Teenagers and those in their 20s—that AYA [adolescent and young adult] population—certainly is less common, but it is more common than, I think, had been appreciated, that there’s a broader distribution affecting these individuals.

Clearly, with younger individuals, we’re mindful of several things. One, the length of time that they have the illness does increase our concern that they have a higher risk of the disease progressing to a more advanced myeloid neoplasm the longer they have the disease. Particularly individuals with 10 years or more of the disease have increasing risk from ET and PV progressing to myelofibrosis. Overall, we think myelofibrosis can be a life-threatening disease, where ET and PV usually can be managed without a decrease in survival. So, that progression is really a negative, and the younger you are, the more exposure you really have to that. Additionally, they have a higher risk of progressing to acute leukemia because of this increased length of time.

Additionally, there are issues as it relates to both the preservation of fertility and the selection of medical therapy. Historically, in ET and PV, there had been a lot of use of the medication hydroxyurea, that is counter indicated in pregnancy, and that has implications in terms of therapy selected, so that medications like interferons or long-acting interferons tend to be preferred in this group of patients, both for that reason, as well as there is the data suggesting that interferons may help to slow the progression of the disease. And again, in younger individuals, that makes it a more relevant therapy for these individuals.

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Mutated Calreticulin Could Lead to MF Onset

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Brian Murphy, PhD

Mutations in the CALR gene, including a 52 base pair (bp; CALR Del52) deletion and 5 bp insertion (CALR Ins5), affect several signaling pathways in cells leading to the pathogenesis of myelofibrosis (MF) and other myeloproliferative neoplasms (MPNs), according to a study published in the International Journal of Molecular Sciences.

Cells carrying CALR Del52 and CALR Ins5 mutations had increased activation of the Janus kinase/signal transducer and activator of the transcription (JAK/STAT) and the phosphatidylinositol 3-kinase/Protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathways which have been previously implicated in the pathogenesis of MPNs. These effects were still present in a cell culture model lacking MPL gene (thrombopoietin receptor) expression.

The CALR mutations resulted in reduced functionality of calreticulin proteins. Calreticulin generally functions as a major chaperone in the endoplasmic reticulum and is involved in several processes, including control of protein folding, calcium homeostasis, and responses to cellular stress.

The study found cells with CALR Del52 mutations had statistically significant higher levels of DNA damage compared to controls when exposed to hydrogen peroxide. Cells with CALR Ins5 had significantly higher levels of phosphorylated ATM and H2AX than controls. Both cell types were not able to repair DNA damage after 24 hours following oxidative stress.

Apoptosis levels were also significantly higher in cells with the CALR Ins5 mutation compared to controls. Those with CALR Del52 also had higher rates of apoptosis, but it did not reach significance. Further analysis found that the CALR mutations not only led to increased apoptosis after hydrogen peroxide exposure-induced oxidative stress but also tended to arrest the cells in the G2/M phase.

“Functional analysis revealed that the accumulation of G2/M-CALR-mutated cells indicates that oxidative stress-induced DNA damage is difficult to repair. The mentioned cell cycle delay has not been shown in other studies analyzing mutated calreticulin,” the authors said.

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Exploring Possibilities in Disease Modification in MPNs

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October 25, 2024

Author(s): Mary Caffrey

Treatment of myeloproliferative neoplasms (MPNs) has historically focused on delaying or avoiding transformation to acute myeloid leukemia (AML) as well as symptom relief and improving quality of life; strategies addressed thrombosis or enlarged spleen both with therapy and with nonpharmacological strategies such as smoking cessation or encouraging patients to lose weight.

Although these strategies were associated with improving life expectancy, they did not measure disease modification through molecular responses that signal survival benefits, in the way that trials do with AML and chronic myeloid leukemia (CML).

Claire N. Harrison, MD, FRCP, FRCPath | Image credit: Guy’s and St Thomas

Now, in an essay appearing in HemaSphere, a publication of the European Hematology Association (EHA), investigator Claire N. Harrison, MD, FRCP, FRCPath, of the Department of Haematology, Guy’s and St Thomas NHS Foundation Trust, asks whether the study and treatment of MPNs is ready for a new era with new end points, with data that show how survival benefits are biologically linked to changes in the spleen, reduction in fibrosis, or other responses.

The challenge, Harrison writes, is that the requirements will be different from today’s standards. “These data should hopefully influence a paradigm shift for the regulatory agencies and the field toward a focus instead of disease modification, but this will certainly require data extending beyond the recent standard of 24 weeks,” she writes.

In the perspective piece, “Are we ready for disease modification in myeloproliferative neoplasms?” Harrison notes that a dramatic shift that came with arrival of Janus kinase (JAK) inhibitor–based therapy for patients with myelofibrosis (MF) who could not receive a stem cell transplant. Therapy shows the capacity to reduce spleen size and symptoms. “Both of these facets of MF do probably reflect underlying pathophysiology and, furthermore, spleen size reduction has been shown to correlate with overall survival advantage.”

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INCA033989 May Address Need for Disease-Modifying Therapies in Myelofibrosis

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October 25, 2024

Author(s): Courtney Flaherty

Fact checked by: Megan Hollasch

Unlike the array of JAK inhibitors available for the treatment of patients with myelofibrosis, the novel monoclonal antibody INCA033989 may have disease-modifying potential among those expressing CALR type 1 mutations, potentially addressing an area of need in myeloproliferative neoplasm (MPN) management, according to Daniel J. DeAngelo MD, PhD.

“With the 4 [FDA-approved] JAK inhibitors, we see clear improvements in symptoms, reduction in spleen [volume], and decreased counts for patients with polycythemia or essential thrombocytopenia, but we’re not seeing eradication and normalization of the bone marrow,” DeAngelo said in an interview with OncLive®. “We don’t know if this agent is going to change that, but the hypothesis is that [INCA033989] may be getting at the heart of the disease, although only for patients with CALR type 1 mutations.”

In engineered cell lines and primary CD34-positive cells from patients with MPN, INCA033989 was shown to antagonize mutant CALR–driven signaling and cellular proliferation. Moreover, in a mouse model of MPN with mutant CALR, administration of an INCA033989 mouse surrogate antibody prevented the development of thrombocytosis and accumulation of platelet-producing megakaryocytes in the bone marrow. The agent’s disease-modifying potential is supported by its reduction of pathogenic self-renewal among MPN cells expressing CALR mutations in both primary and secondary transplantations.1

These preclinical data support the agent’s ongoing investigation in a phase 1 study (NCT06034002) for patients with MPN.2

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