Tag Archives: mpn

Azacitidine Plus Ruxolitinib Demonstrates ‘Promising’ Efficacy in Myelofibrosis

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Amber Denham

05/31/2024

Azacitidine in combination with ruxolitinib demonstrates promising efficacy for patients with myelofibrosis (MF), according to long-term follow-up results from a phase 2 clinical trial presented at the 2024 American Society of Clinical Oncology (ASCO) Annual meeting.

The trial included adult patients aged ≥18 years with MF intermediate 1 to 2 or high-risk disease, measured by the Dynamic International Prognostic Scoring System (DIPSS). From March 2013 to October 2021, a total of 61 patients were treated in the trial. Patients had a median age of 66 years (46 to 87). The median hemoglobin was 10.1 g/dl (6.8 to 16.2) and bone marrow blasts 2% (0 to 14%). Overall, 14 (23%) patients had BM blasts ≥5%. Furthermore, JAK2 was mutated in 35 (57%) patients and 38 (62%) patients had intermediate-2 or high-risk DIPSS disease.

Study results showed an International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) response occurred in 44 (72%) patients. A clinical improvement was noted in 37 (61%) patients, including IWG-MRT spleen reduction >50% in 28 (61%) of 46 patients with baseline length ≥5 cm below left costal margin, and 31 (61%) of 51 patients with baseline total symptom score (TSS) >12 having a >50% improvement in TSS 50. In addition, a partial response was seen in 4 patients and cytogenetic complete remission in 3 patients.

With a median follow-up of 93 months, median overall survival (OS) was 46 months (95% confidence interval [CI], 25 to 66), median event-free survival was 33 months (95% CI, 24 to 43), and median duration of any objective response was 43 months (95% CI, 24 to 62). It was noted that disease transformation to AML occurred in 14 (23%) patients with a median time to transformation of 19 months. In addition, 20 (33%) patients received a stem cell transplant (SCT), and 11 (55%) patients had intermediate-2/high-risk DIPPS disease. It was observed that patients in the Intermediate-2/high-risk DIPPS group who received a SCT showed a trend towards improved median OS vs those who did not receive a transplant (38 vs 27 months, P = .2).

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Advances in Interferon Therapy for Myeloproliferative Neoplasms

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Kumar Das, Dibash PhD

Oncology Times 46(6):p 1,14, June 2024. | DOI: 10.1097/01.COT.0001024068.38723.15

In the ever-evolving landscape of myeloproliferative neoplasms (MPNs), clinicians continue to explore and refine treatment strategies to improve patient outcomes. A recent review published in Therapeutic Advances in Hematology sheds light on the pivotal role of interferons, particularly pegylated formulations, in managing MPNs effectively (2024; doi: 10.1177/20406207241229588).

The advent of pegylated interferons, including peginterferon alfa-2a and ropeginterferon alfa-2b-njft, marks a significant turning point in MPN therapeutics. These agents, renowned for their potent immunomodulatory capabilities and profound impact on disease progression, have reshaped treatment paradigms outlined in the National Comprehensive Cancer Network (NCCN) Guidelines for polycythemia vera (PV), essential thrombocythemia, and primary myelofibrosis. This article delves deep into the multifaceted influence of pegylated interferons, shedding light on their efficacy, safety profiles, and future implications in MPN management.

Clinical trials, including landmark Phase II and III studies such as MPD-RC 111 and MPD-RC 112, have provided crucial insights into the efficacy of pegylated interferons. These trials meticulously assessed response rates, molecular remissions, and hematological improvements in MPN patients resistant to or intolerant of hydroxyurea. Noteworthy reductions in JAK2 V617F variant allele frequency (VAF) have underscored the molecular response achievements of pegylated interferons, highlighting their disease-modifying potential.

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Predictors of symptom scores in myeloproliferative neoplasms: A real-world retrospective cohort study

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Muhammad Ali Khan, Syed Arsalan Ahmed Naqvi, Irbaz Bin Riaz, and Jeanne M. Palmer

Abstract

Background: Although high symptom burden indicates poor survival and informs treatment decisions, little is known about the impact of demographic, clinical, and laboratory features on total symptom score (TSS) in patients with myeloproliferative neoplasms (MPN).
Methods: Patients with MPN (polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF)) were identified from the retrospective chart review. TSS, individual symptom scores (fatigue, early satiety, abdominal discomfort, inactivity, concentration problems, fever, night sweats, itching, bone pain, weight loss), demographic characteristics (race, ethnicity, age, gender), clinical features (time since diagnosis, depression status, obesity status, spleen size), laboratory results and season at the time of visit were recorded from the clinical encounter when index assessment of TSS was performed for each patient. Normality was assessed using visual inspection of data distribution, whereas multicollinearity was assessed using various inflation factors. A univariable regression followed by a multivariable regression analysis was conducted using a backward selection approach. A p-value <0.05 indicated a statistically significant association of a given feature with TSS.
Results: The chart review identified 252 patients (PV: 78; ET: 81; MF: 93). Mean age was 59 (SD: 17.7), 67 (SD: 13.0), and 68 (SD: 10.9) years for ET, PV, and MF respectively. Most patients were white (PV, MF: 92%; ET: 83%) and females (ET: 75%; PV: 60%; MF: 53%). The TSS of patients was highest with PV (mean: 18.5; SD: 16.9) followed by MF (mean: 18.1; SD: 15.4) and ET (mean: 14.3; SD: 15.9). Fatigue was the most reported symptom whereas the least reported symptoms were fever and weight loss. Univariable regression analyses showed depression (B: 17.7; p=0.02), female gender (B: 10.6; p=0.01), platelet count (B: 0.03; p=0.03), and hemoglobin (Hb) (B: -2.6; p=0.01) in PV patients, depression (B: 19.8, p=2×10-5) in ET patients and depression (B: 11.0, p=0.03), white blood cell (WBC) count (B: 0.2; p=0.01), neutrophil count (B: 0.3, p=0.01), and non-neutrophil WBC count (B: 0.6; p=0.02) in MF patients to have significant association with TSS. Multivariable regression analyses (Table) showed Hb (B: -2.5; p=0.01) and platelet count (B: 0.02; p=0.03) in PV patients, depression (B: 19.7; p=2×10-5) in ET patients and depression (B: 12.3, p=0.01) and WBC count (B: 0.3; p=0.002) in MF patients to have a significant association with TSS.
Conclusions: Depression in ET and MF and low Hb in PV were identified as significant drivers of symptom burden. Identifying and managing patients with these comorbidities could improve their quality of life with a potential survival benefit.

JAK Inhibitor–Based Combinations Could Represent the Next Frontier in Myelofibrosis

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Ryan Scott

In an interview with OncLive® following the Vanderbilt Stem Cell Transplant and Cellular Therapy Symposium, Ashwin Kishtagari, MD, discussed advancements in the treatment of patients with intermediate-risk to high-risk myelofibrosis and highlighted recent data from the 2023 ASH Annual Meeting for combination therapies using JAK inhibitors.

Studies presented at the meeting included the phase 3 TRANSFORM-1 clinical trial (NCT04472598) evaluating navitoclax plus ruxolitinib (Jakafi), as well as the phase 3 MANIFEST-2 trial (NCT04603495) investigating pelabresib (CPI-0610) in combination with ruxolitinib.1,2

Kishtagari, who serves as an assistant professor of medicine in the Department of Hematology and Oncology at Vanderbilt University Medical Center, as well as a clinical research fellow in Bick Lab at Vanderbilt University School of Medicine in Nashville, Tennessee, provided further updates on JAK inhibitors for the treatment of patients with myelofibrosis in another interview with OncLive.

OncLive: How do you see the treatment paradigm for myelofibrosis evolving in the future?

Kishtagari: We have 4 JAK inhibitors which are FDA approved for the treatment of [patients with] myelofibrosis, with the first being ruxolitinib. Fedratinib [Inrebic] was the second agent approved in 2019. Pacritinib [Vonjo] was approved by the FDA in 2022, and momelotinib [Ojjaara]was approved in 2023.

We are moving toward combination therapies because our goal is to have a more significant improvement in splenomegaly response and symptom improvement. The whole field of myelofibrosis is moving toward combination therapy, especially for patients with higher- or intermediate-risk myelofibrosis.

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Sobi to present new myelofibrosis data at the ASCO 2024 Annual Meeting

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WALTHAM, Mass., May 24, 2024 (GLOBE NEWSWIRE) — Sobi North America, the North American affiliate of Swedish Orphan Biovitrum AB (Sobi®), today announced the presentation of three abstracts that highlights data from its myelofibrosis treatment option at the American Society of Clinical Oncology (ASCO) Annual Meeting taking place in Chicago from May 31 – June 4, 2024.

Sobi’s commitment to delivering innovative treatments for people living with hematological diseases is seen in global studies spanning multiple rare disorders, including myelofibrosis.

A retrospective analysis will be presented that demonstrates the efficacy of pacritinib in spleen volume reduction, symptom benefit and red blood cell transfusion response, compared with best available therapy, in patients with myelofibrosis who have both thrombocytopenia and anemia.

An additional retrospective analysis will be presented that shows the substantial symptom benefit pacritinib provides compared with best available therapy or low-dose ruxolitinib, specifically in patients who required red blood cell transfusion at the time of pacritinib initiation. The number of patients experiencing treatment emergent Grade 3 anaemia was similar between pacritinib and BAT groups.

New real-world data will be presented that demonstrates treatment with pacritinib provides stability or improvement in thrombocytopenia and/or anemia in patients with myelofibrosis, regardless of baseline counts, and has favorable overall survival similar to other JAK inhibitor historical controls.

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Metformin Use Linked to Lower Odds of Myeloproliferative Neoplasms

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By: Elana Gotkine

Medically Reviewed By: Mark Arredondo, M.D.

THURSDAY, May 23, 2024 (HealthDay News) — Metformin use, including long-term use, is associated with significantly lower odds of myeloproliferative neoplasm (MPN) diagnosis, according to a study published online May 17 in Blood Advances.

Daniel Tuyet Kristensen, M.D., from Aalborg University Hospital in Denmark, and colleagues conducted a population-based case-control study using Danish registers to examine the association between metformin use and the risk for MPN. Cases with MPN diagnosed between 2010 and 2018 were identified, and metformin use prior to MPN diagnosis was ascertained. Metformin use was compared among cases with MPN and an age- and sex-matched control group from the Danish general population (3,816 cases and 19,080 controls).

The researchers found that 7.0 and 8.2 percent of cases and controls were categorized as ever-users of metformin, respectively (odds ratio [OR] for MPN, 0.84; adjusted OR for MPN, 0.70). Long-term metformin use (at least five years) was more infrequent and occurred in 1.1 and 2.0 percent of cases and controls, respectively (OR, 0.57; adjusted OR, 0.45). When cumulative duration of treatment was analyzed, there was a dose-response relationship observed; in stratified analyses of sex, age, and MPN subtypes, this was consistent.

Scientists team up with York Hospital to study DNA mutations behind blood cancers

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Posted on 23 May 2024

Scientists from the University of York are working with doctors and patients at York Hospital to understand the DNA mutations linked to a group of chronic blood cancers, and investigate why, in some cases, they can suddenly become more aggressive.

The researchers, from the newly formed Centre for Blood Research at the University of York, are recruiting participants from York Hospital with myeloproliferative neoplasms (MPNs), a group of blood cancers characterised by the overproduction of red blood cells and/or platelets.

There are around 4,000 cases of MPNs in the UK each year and they most commonly affect people over 60. Often, they remain stable and progress slowly, which means people can live with them for a long time without being very unwell.

However, in a few rare cases, they can transform into more aggressive cancers which need urgent treatment, such as acute myeloid leukaemia (AML), where faulty myeloid cells – which include red blood cells and platelets – build up in the body and stop the blood and immune system from functioning normally.

Valuable insights

Dr Katherine Bridge, from the Department of Biology and Centre for Blood Research at the University of York, said: “We want to better understand the DNA mutations that cause these cancers, and to see whether there are additional factors that cause them to suddenly transform and become more aggressive.

“MPNs behave like the early stages of other blood cancers, offering valuable insights into their progression. Often, these crucial initial stages occur too quickly in other cancers for us to be able to track them effectively. By focusing on MPNs, we have a unique opportunity to scrutinise these early events, potentially uncovering strategies to halt the advancement of more aggressive malignancies.”

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JAK Inhibitor–Based Combinations Could Represent the Next Frontier in Myelofibrosis

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Ryan Scott

In an interview with OncLive® following the Vanderbilt Stem Cell Transplant and Cellular Therapy Symposium, Ashwin Kishtagari, MD, discussed advancements in the treatment of patients with intermediate-risk to high-risk myelofibrosis and highlighted recent data from the 2023 ASH Annual Meeting for combination therapies using JAK inhibitors.

Studies presented at the meeting included the phase 3 TRANSFORM-1 clinical trial (NCT04472598)evaluating navitoclax plus ruxolitinib (Jakafi), as well as the phase 3 MANIFEST-2 trial (NCT04603495) investigating pelabresib (CPI-0610) in combination with ruxolitinib.1,2

Kishtagari, who serves as an assistant professor of medicine in the Department of Hematology and Oncology at Vanderbilt University Medical Center, as well as a clinical research fellow in Bick Lab at Vanderbilt University School of Medicine in Nashville, Tennessee, provided further updates on JAK inhibitors for the treatment of patients with myelofibrosis in another interview with OncLive.

OncLive: How do you see the treatment paradigm for myelofibrosis evolving in the future?

Kishtagari: We have 4 JAK inhibitors which are FDA approved for the treatment of [patients with] myelofibrosis, with the first being ruxolitinib. Fedratinib [Inrebic] was the second agent approved in 2019. Pacritinib [Vonjo] was approved by the FDA in 2022, and momelotinib [Ojjaara]was approved in 2023.

We are moving toward combination therapies because our goal is to have a more significant improvement in splenomegaly response and symptom improvement. The whole field of myelofibrosis is moving toward combination therapy, especially for patients with higher- or intermediate-risk myelofibrosis.

Read more

Metformin May Help Reduce the Risk of Developing Myeloproliferative Neoplasms

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By The ASCO Post Staff

Posted: 5/21/2024 9:31:00 AM
Last Updated: 5/21/2024 12:27:21 PM

 

Treatment with metformin may be associated with a lower risk of developing myeloproliferative neoplasms over time, according to a recent study published by Kristensen et al in Blood Advances.

Background

Myeloproliferative neoplasms are a group of diseases that develop over long periods of time and affect how bone marrow produces blood cells, resulting in an overproduction of red blood cells, white blood cells, or platelets that can lead to bleeding problems, a greater risk of stroke or heart attack, and organ damage.

Metformin—a therapy used to treat high blood sugar in patients with type 2 diabetes—works by increasing the effect of insulin, reducing how much glucose is released from the liver, and increasing the body’s glucose absorption.

Previous analyses have demonstrated that the therapy may reduce the risk of gastrointestinal cancer, breast cancer, urologic cancer, as well as other solid tumors and hematologic malignancies.

“Our team was interested in understanding what other effects we see with commonly prescribed treatments like metformin,” explained senior study author Anne Stidsholt Roug, MD, PhD, Clinical Associate Professor at Aalborg University Hospital and Chief Physician at Aarhus University Hospital in Denmark. “The anti-inflammatory effect of metformin interested us, as [myeloproliferative neoplasms] are very inflammatory diseases,” she added.

Study Methods and Results

In the recent study, investigators examined metformin use among 3,816 patients diagnosed with myeloproliferative neoplasms and 19,080 matched controls from the Danish general population between 2010 and 2018.

The investigators found that 7.0% (n = 268) of the patients with myeloproliferative neoplasms and 8.2% (n = 1,573) controls received metformin. Just 1.1% of the patients with myeloproliferative neoplasms had received the therapy for over 5 years vs 2.0% of controls. After adjusting for potential confounders, the investigators noted that the protective effect of metformin was observed in all subtypes of myeloproliferative neoplasms.

Conclusions

“We were surprised by the magnitude of the association we saw in the data,” emphasized lead study author Daniel Tuyet Kristensen, MD, a PhD student at Aalborg University Hospital. “We saw the strongest effect in [patients] who had taken metformin for more than 5 years as compared [with] those who had taken the treatment for less than 1 year,” he added.

The investigators revealed that the study was limited by its registry-based retrospective design and an inability to account for lifestyle factors influencing cancer risk such as smoking, obesity, and dietary habits. They hope to conduct additional studies to better understand the mechanisms behind the therapy’s protective effects against the development of myeloproliferative neoplasms. The investigators further plan to identify any similar trends with myelodysplastic syndromes and acute myeloid leukemia in population-level data in future studies.

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Ajax Therapeutics Announces FDA Clearance of IND Application for AJ1-11095, a First-in-Class Type II JAK2 inhibitor, for the Treatment of Myelofibrosis

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

– Phase 1 dose escalation study expected to begin in 2H 2024 –

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 that it has received clearance for its Investigational New Drug (IND) application from the U.S. Food and Drug Administration (FDA) to initiate a Phase 1clinical study of AJ1‑11095, a first-in-class Type II JAK2 inhibitor, for the treatment of patients with myelofibrosis.

“This is an important milestone for our company and our first program to enter the clinic and the first clinical study to ever evaluate a Type II JAK2 inhibitor in patients.”

“We are thrilled to obtain clearance to advance AJ1-11095 into the clinic and excited to bring this innovative new medicine to patients with myelofibrosis,” said Martin Vogelbaum, co-founder and CEO of Ajax Therapeutics. “This is an important milestone for our company and our first program to enter the clinic and the first clinical study to ever evaluate a Type II JAK2 inhibitor in patients.”

“We look forward to the clinical development of AJ1-11095 in myelofibrosis and to initiating our Phase 1 dose escalation study, AJX-101, later this year,” said David Steensma, MD, FACP, Chief Medical Officer at Ajax. “As a first-in-class therapy with a unique mechanism as a Type II inhibitor of JAK2, AJ1-11095 was developed to provide a much-needed new treatment for patients with myelofibrosis by offering the potential for improved efficacy with disease modifying effects compared to existing therapies.”

About AJ1-11095

AJ1-11095 was designed by Ajax, through our collaboration with Schrödinger, to be a next generation JAK2 inhibitor by using structure-based drug design and computational methods at scale to selectively bind the Type II conformation of the JAK2 kinase and to provide greater efficacy with disease modification compared to all currently approved JAK2 inhibitors which bind the Type I conformation of JAK2. Additionally, AJ1-11095 has been shown in preclinical studies to reverse marrow fibrosis, reduce mutant allele burden and maintain efficacy against MPN cells that become resistant to chronic Type I JAK2 inhibition.

About Myelofibrosis

Myelofibrosis (MF) is a rare blood cancer that affects approximately 20,000 patients in the United States. The disease is characterized by spleen enlargement, scarring (fibrosis) in the bone marrow, progressive anemia, and debilitating symptoms, such as fatigue, night sweats, itching, and abdominal discomfort, which can impair a patient’s’ quality of life. The most widely used treatment for MF patients are Type I JAK2 inhibitors which can reduce spleen size and provide symptomatic improvement but have little effect on the underlying cause of disease. Over time, most MF patients stop Type I JAK2 inhibitor therapy. The most common causes for treatment discontinuation include a lack of benefit or loss of response, adverse events, and disease progression, leaving significant unmet treatment needs for these patients.

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