Category Archives: Uncategorized

Role of Long Noncoding RNA Defined in Pathogenesis of MPNs

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August 22, 2024

Vicki Moore, PhD

A role for lnc-AC004893, a long noncoding RNA (lncRNA), in the pathogenesis of myeloproliferative neoplasms (MPNs) was revealed in a study reported in the journal Hematology.

“Treatment with JAK2 inhibitors combined with the inhibition of lnc-AC004893 might improve the clinical treatment efficiency in MPN patients,” the study investigators wrote in their report.

A lncRNA is a nonprotein coding transcript with a length of more than 200 nucleotides, which may potentially have a biological function and could be dysregulated in the setting of disease. The investigators set out to explore whether lncRNA may have a role in MPN pathogenesis.

To evaluate this, the investigators conducted lncRNA sequencing from bone marrow mononuclear cells in 3 patients with MPN and 3 control individuals. They identified approximately 500 different lncRNAs that appeared expressed at a level of greater than or less than 2.0-fold in patients with MPN, in comparison with the expression level in control individuals.

From among these lncRNAs, the investigators performed further analyses related to expression and other characteristics. These analyses identified lnc-AC004893 as being of potential interest.

The investigators further evaluated lnc-AC004893 in samples from 150 patients with MPN, compared with 20 control individuals, and identified an approximately 5-fold increase in lncRNA transcript in patients with MPN, compared with the control population.

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MPN Word of the Month: Cytokines

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MPN Word of the Month:

Cytokines

Recently, I heard someone describe cytokines as ingredients that make up a recipe. The recipe is a response to a specific event. Like, when we make chicken soup when someone we love has a cold. Each person with an MPN has their own special ingredients that come together in  response  to different events that happen inside and outside of the body. 

So what are cytokines, really? Cytokines are tiny proteins secreted by cells to communicate with one another.  What do they say? Basically, they say to activate (go from doing nothing to doing something), proliferate (make more cells), or differentiate (become more specialized, like becoming an eye cell or a liver cell).

Cytokines can send messages to increase inflammation (pro-inflammatory), or stop inflammation (anti-inflammatory). Inflammatory cytokines play a role in the development and progression of myeloproliferative neoplasms. 

Some research suggests that there are certain cytokines commonly associated with MPNs. For example, IL-1β (Interleukin-1beta), TNF-α (Tumor Necrosis Factor-alpha) , IL-6 (Interleukin-6), IL-8 (Interleukin-8), VEGF (Vascular Endothelial Growth Factor), PDGF (Platelet Derived Growth Factor), TGF-β (Transforming Growth Factor-beta), and IFNs (Interferons). These cytokines are expressed in different ways that may contribute to the various MPN subtypes. 

For example, a recipe may call for tomatoes, but there are different kinds of tomatoes based on their individual genetic makeup…Roma tomatoes, San Marzano tomatoes, Cherry tomatoes. This recipe (cytokine expression) can be seen in different subtypes. For example, people with polycythemia vera (PV) have been known to have elevated levels of IL-12, IL-4 and GM-CSF when compared to people with essential thrombocythemia (ET). Some cytokines, such as BLC, Eotaxin-2, M-CSF, and TIMP-1, may one day help diagnose and predict the progression of fibrosis in MPN subtypes. 

While it is not completely clear how your cytokine “recipe” can be affected by lifestyle, conventional wisdom tells us that healthy lifestyle changes can’t hurt. Reducing additional inflammation that may occur through lifestyle choices could help to support your body in ways that impact your experience of your symptoms at the least. A healthy diet, exercise, and stress reduction have all been associated with lowering inflammation in the body. 

Individualized Approaches and Challenges in Myelofibrosis

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Raajit Rampal, MD, PhD

Raajit K. Rampal, MD, PhD, hematologic oncologist at Memorial Sloan Kettering Cancer Center, discusses how the field of gene therapy and precision medicine is evolving in the context of myelofibrosis treatment. He also explains how treatment decisions are individualized for patients with myeloproliferative neoplasms, including myelofibrosis.

Rampal presented on this topic and more at the Fifth Annual Miami Cancer Institute Global Summit on Immunotherapies for Hematologic Malignancies, hosted by Dr. Guenther Koehne and Miami Cancer Institute.

In addition, Rampal discusses some of the unmet needs that exist in this space, including the need for disease-modifying therapy in this interview with Targeted OncologyTM.

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A Grand Time in Grand Rapids

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MPN Advocacy & Education International held an in-person patient/caregiver event in Grand Rapids, Michigan on April 25th. The room buzzed with excitement and camaraderie as patients and caregivers had the opportunity to engage with each other and MPN experts on a wide range of topics. 

Dr. Anas Al-Janadi gave an overview of the history of MPNs and defined where we are in our current understanding of the disease and what the future may hold. While exciting discoveries were made that supported the development of drug therapies for MPN patients; such as the JAK2 mutation in 2005 and later the MPL and CALR mutations, the MPN community is still working to better understand the reasons for disease progression and ways to reduce symptom burden.

Dr. Kristin Pettit, on the heels of her wedding (Congrats, Dr. Pettit), discussed the challenges MPN patients have flying, having elective or emergency surgeries, symptom management, and some critical women’s issues. Each topic had the following take-aways: check with your doctor and practice good self-care. Dr. Pettit emphasized hydration, healthy eating, exercise and reducing stress.

Dr. Aaron Gerds shared a play-by-play of diagnosing and treating MPNs. He began by situating ET, PV, and MF on the greater spectrum of Myeloid Neoplasms. Dr. Gerds, along with the other experts that presented, stressed the importance of a good clinical examination including a thorough history and a hands-on physical examination. Gerds went on to describe the testing required to make a proper MPN diagnosis, such as; blood counts, chemistries, infectious disease, bone marrow biopsy, and molecular testing. Afterwards, he walked us through the process of navigating individual risk and treatment options using the National Comprehensive Cancer Network (NCCN) Guidelines for Myelofibrosis. 

Justin Grinell, owner and head trainer of State of Fitness, reminded us that our health is not our fault, but it is our responsibility. He shared some ways to move toward a healthy lifestyle by incorporating an 11 min movement break in our day. To take just 11 minutes each day doing something active at your own Zone 2 (when your heart rate is 180 minus your age) can have an accumulative positive effect on not just your body but on your brain as well. Be sure to look for Justin this summer during our Healthy Summer Series webinars where you can join Justin for a quick lunch-time workout. 

Finally, Dr. Craig Kessler implored patients to ask questions. Ask your doctor questions about the treatment plan they create for you. Ask what component of MPN symptoms they are focusing on, and how the treatment they recommend will address that component (anemia, blood counts, spleen reduction, etc.). He stressed getting your COVID-19 vaccine and boosters. He also made clear that your questions matter and not to be afraid to ask.

We want to thank the specialists for sharing their valuable information and spending their time away from their respective institutions. We also want to thank our patients and their family members and friends for joining us and asking such thought-provoking questions. We hope that you will have a chance to join us at our next MPN Advocacy and Education International in-person event in Asheville, NC on Thursday August 22nd. To learn more, please visit www.mpnadvocacy.com/events-list.

Participants Discuss Treating a Patient With Myelofibrosis and Anemia

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Targeted Oncology Staff

PARTICIPANT LIST Abhirami Vivekanandarajah, MD | Hayan Moualla, MD | Subhash C. Proothi, MD | Meher Burki, MD | Simi Masand Rai, MD | Rajesh Thirumaran, MD | Nirmala Nathan, MD

CASE SUMMARY

A 76-year-old woman presented to her physician with symptoms of mild fatigue, night sweats, and abdominal pain/fullness for 4 months; she also reported an unexplained weight loss of 12 lb. Her spleen was palpable 8 cm below the left costal margin. She had no known comorbidities.

Laboratory values included a red blood cell count of 3.40 × 106/μL, hemoglobin of 9.8 g/dL, and a platelet count of 181 × 103/μL. Next-generation sequencing showed a JAK2 V617F mutation. Her karyotype was 46,XX. A bone marrow biopsy showed megakaryocyte proliferation and atypia with evidence of reticulin fibrosis. The patient received a diagnosis of primary myelofibrosis with a high-risk result from the Dynamic International Prognostic Scoring System, an intermediate risk result from the Mutation-Enhanced International Prognostic Score System (MIPSS70), and a high risk result from the MIPSS70+ version 2.0.

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Recombinant interferon alfa in BCR/ABL-negative chronic myeloproliferative neoplasms

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El Bitar S 1, Arcasoy MO 1

Abstract

The treatment landscape for BCR/ABL-negative myeloproliferative neoplasms (MPNs), driven by JAK2, CALR, and MPL mutations, has evolved significantly over the last decade. Recent regulatory approvals in polycythemia vera (PV) include the JAK inhibitor ruxolitinib, and more recently, a novel recombinant interferon alfa-2 (IFN-α) therapeutic agent. Many clinical trials have documented the safety and efficacy of IFN-α therapy in PV and essential thrombocythemia, the classical BCR/ABL-negative MPNs. Used off-label for more than 30 years as a cytoreductive agent, IFN-α therapy promotes significant clinical, hematologic, and molecular responses. In some IFN-α-treated patients, partial or complete reduction of the mutant JAK2 allele burden may lead to a durable measurable residual disease state, owing to the ability of long-term IFN-α therapy to selectively deplete mutant JAK2-harboring hematopoietic stem cells. Pegylated IFN-α forms were developed to improve the drug stability and tolerability of first-generation IFN-α therapeutics. More recently, a novel pegylated IFN-α, ropeginterferon alfa-2b, received approval for PV by the European Medicines Agency and the US Food and Drug Administration in 2019 and 2021, respectively. This article reviews the clinical research and recent advances that led to the first regulatory approval of IFN-α in a BCR/ABL-negative MPN and its future promise as a disease-modifying therapeutic agent.

MorphoSys Enters into Business Combination Agreement to be Acquired by Novartis for € 2.7 Billion Equity Value

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PLANEGG/MUNICH, Germany – February 5, 2024 – MorphoSys AG (FSE: MOR; NASDAQ: MOR) today announced the company entered into a Business Combination Agreement with Novartis data42 AG and Novartis AG (hereinafter collectively referred to as “Novartis”) based on Novartis’ intention to submit a voluntary public takeover offer for all outstanding MorphoSys no-par value bearer shares at an offer price of € 68.00 per share in cash. As part of the Business Combination Agreement with Novartis, Novartis seeks to obtain exclusive, worldwide rights to develop and commercialize pelabresib, an investigational BET inhibitor, and tulmimetostat, an investigational next-generation dual inhibitor of EZH2 and EZH1, across all indications. Separately, MorphoSys entered into a Purchase Agreement to sell and transfer all rights worldwide related to tafasitamab to Incyte Corporation (“Incyte”). Currently, MorphoSys partners with Incyte on the development and commercialization of tafasitamab. MorphoSys’ Management Board and Supervisory Board unanimously approved both agreements.

“Novartis shares our steadfast commitment to develop and deliver transformative medicines that address the dire needs of cancer patients. Pelabresib – the investigational therapy at the forefront of our promising oncology pipeline – has the potential to shift the treatment paradigm in myelofibrosis and further expand into other indications. Novartis will provide ample resources currently unavailable to MorphoSys as a standalone biotech company to help accelerate the development opportunities and maximize the commercialization potential of pelabresib at a greater speed and scale,” said Jean-Paul Kress, M.D., Chief Executive Officer of MorphoSys. “We are also pleased that Incyte will assume full responsibility of tafasitamab. Given the proposed acquisition by Novartis and our long-standing partnership with Incyte, we know Incyte is best positioned to drive tafasitamab’s future growth opportunities forward successfully and more efficiently on its own at this time. We believe these agreements are in the best interest of MorphoSys, our shareholders and cancer patients.”

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Preliminary data shows lowered cytokine levels in myelofibrosis with PIM1 kinase inhibitor

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December 19, 2023

SAN DIEGO — Treatment with a selective PIM1 kinase inhibitor showed positive clinical reactions in a sample of 23 patients with relapsed/refractory myelofibrosis, according to preliminary data presented at ASH Annual Meeting.

TP-3654, an oral investigational highly selective PIM1 kinase inhibitor, is the subject of the phase 1/phase 2 study evaluating monotherapy in relapsed/refractory myelofibrosis, according to results published by a team led by Lindsay A.M. Rein, MD, a hematologic oncologist at Duke Cancer Center.

Elevated circulating cytokines have previously been noted as having a strong association with myelofibrosis, and preclinical studies evaluating TP-3654 as both a monotherapy and in tandem with ruxolitinib (Jakafi, Incyte) displayed lowered cytokine response and other responses, such as spleen reduction and bone marrow fibrosis reduction.

As such, the phase 1/phase 2 study further examined TP-3654 monotherapy in a cohort of patients with intermediate or high-risk myelofibrosis, and who had been previously treated with or were ineligible for JAK inhibitor treatment.

The 23 patients — who had a median age of 73 years and all but one of whom had previously received JAK inhibitor treatment — were monitored for cytokine changes over 12 weeks of TP-3654 monotherapy. “Broad reductions” in cytokine levels were observed in as little as 24 hours, and over the course of 12 weeks, patients with higher cytokine reduction levels were found to have greater reduction in symptoms.

Twelve of 13 eligible patients saw a reduction in their total symptom score, with seven having their score reduced by 50% or more. Treatment-related adverse events, such as nausea and vomiting, were observed in over 20% of patients.

Rein noted that enrollment is still ongoing.

Reference:

Rein LAM, et al. Phase 1/2 study of TP-3654, a selective PIM1 kinase inhibitor: Preliminary data showed clinical activity and cytokine reductions in relapsed/refractory myelofibrosis patients. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2023; San Diego.

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MPN-Associated Anemia: What Nurses Should Look Out For

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Sharon Bledsoe, MSN, MBA, BSN, RN

When treating patients with blood cancers such as myeloproliferative neoplasms (MPNs), it is essential for oncology nurses to explain to patients what to expect and what symptoms they should call about. And when the patients talk, it is essential that their nurses are attentive, explained Sharon Bledsoe, MSN, MBA, BSN, RN.

“Make sure that you listen to your patient and that you absolutely follow up with all of their labs and watch and monitor their trends,” Bledsoe, a senior research nurse at The University of Texas MD Anderson Cancer Center, said in an interview with Oncology Nursing News®.

In the case of myelofibrosis (a type of MPN), patients may experience a slow downward trend in hemoglobin levels, as the bone marrow scarring inhibits the body’s ability to produce healthy red blood cells. In turn, patients end up developing anemia. Patients with myelofibrosis-associated anemia may experience a change in their typical MPN-related symptoms, increased fatigue, night sweats, or fever, according to Bledsoe.

However, decreases in blood levels for patients with myelofibrosis may not be as sharp or apparent for patients with myelofibrosis as they are for other malignancies, such as acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML), Bledsoe explained.

“It’s a slow trend. It’s not usually a sudden trend when you’re dealing with myelofibrosis, and it can progress slower than ALL or AML or any of those other blood cancers,” she said.

While the trend may be slow, it is important to catch anemia quickly, according to Bledsoe, so that treatments — namely blood transfusions or JAK inhibitors — can be started in a timely manner and ensure the best outcome for the patient.

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Socio-Racial Factors May Impact Primary Myelofibrosis Outcomes

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Russ Conroy

Mohammad Bakri Hammami, MD, highlights a need to address socio-racial disparities among Black and non-Black patients with primary myelofibrosis to ensure that everyone receives high-quality treatment.

Investigators retrospectively reviewed socio-racial characteristics as potential determinants of survival in patients with primary myelofibrosis and compared the dataset with single-center outcomes of patients treated at Montefiore Medical Center.

Investigators identified that certain socio-racial factors, including race, sex, and age, may potentially affect survival outcomes in patients with primary myelofibrosis, according to data from a retrospective review that were presented at the 2023 Society of Hematologic Oncology (SOHO) Annual Meeting.

Data collected from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2020 highlighted a median overall survival (OS) of 47 months in the overall population with primary myelofibrosis. Additionally, investigators reported an estimated OS rate of 69% at 2 years and 41% at 5 years.

According to presenting author Mohammad Bakri Hammami, MD, an internal medicine resident at Albert Einstein College of Medicine and Jacobi Medical Center, patient age significantly correlated with OS (HR, 1.042; 95% CI, 1.038-1.046; P <.001) in the SEER cohort. Additionally, investigators observed statistically significant worse OS outcomes in male patients compared with their female counterparts (HR, 1.399; 95% CI, 1.277-1.533; P <.001), as well as in Black patients compared with non-Black patients (HR, 1.202; 95% CI, 1.016-1.422; P <.032).

Hammami noted that patients pulled from the SEER database who were diagnosed with primary myelofibrosis after 2011 experienced significantly better survival with respect to cause-specific and all-cause mortality (P = .001). Being married was also a protective factor against all-cause mortality (P = .001).

In a cohort of patients with primary myelofibrosis treated at Montefiore Medical Center, the 2-year and 5-year OS rates, respectively, were 92% and 63%. The most common treatment modalities administered to Black and non-Black patients in the Montefiore cohort, respectively, included ruxolitinib (Jakafi; 50.0% and 43.9%), hydroxyurea (20.0% and 19.5%), and fedratinib (Inrebic; 10.0% and 0.0%). Additionally, 10.0% of Black patients and 14.6% of non-Black patients were treated as part of a clinical trial. Overall, Hammami stated that there were “no real differences” in the rates of treatment modalities between Black and non-Black patients treated at Montefiore.

In an analysis of genetic mutations in patients receiving treatment at Montefiore, Black and non-Black patients, respectively, typically had JAK2 (70% and 78%), CALR (20% and 16%), and ASXL1 (40% and 5%) mutations. According to Hammami, there was a generally similar distribution of genetic mutations in patients regardless of race, which was consistent with prior reports.

“There is a real role for social factors in terms of survival, especially when it comes to Black and non-Black patients,” Hammami said. “There is a need to focus on addressing these factors when we want to provide high-quality care to these patients.”

Investigators retrospectively reviewed socio-racial characteristics as potential determinants of survival in patients with primary myelofibrosis and compared the dataset with single-center outcomes of patients treated at Montefiore Medical Center. Patients with no histological confirmation of disease or active follow up were not included in the analysis. Additionally, investigators assessed medical records from patients treated at Montefiore Medical Center from 2007 to 2023.

Across the 17 SEER registries, investigators assessed data from 5403 patients. The overall population consisted of patients who were White (82.0%), Black (8.4%), and Asian or from the Pacific Islands (7.7%).

Among non-Black and Black patients included in the SEER cohort, respectively, the mean age was 69 years and 64 years (P <.001); most patients were male (60.7% vs 52.1%; P <.001). Additionally, the majority of non-Black patients were married (57.4%), whereas most Black patients were unmarried (63.4%; P <.001). Hammami also highlighted that 55.0% of non-Black patients had an annual income of over $70,000, while 59.6% of Black patients earned less than $70,000 per year.

The Montefiore cohort consisted of 51 patients, including 43 who were censored and 8 who died due to cancer. Additionally, 57% of patients were male, and 49% were married. The median patient age in this cohort was 66 years. The Montefiore population consisted of patients who were White (35%), Black (20%), Asian (10%), or another or unknown race (35%).

Reference

Hammami MB, Yang J, Thakur R, et al. Examining racial disparities in the incidence and survival of myelofibrosis: insights from SEER database and an institutional cohort (2000-2020). Presented at: 2023 Society of Hematologic Oncology (SOHO). Annual Meeting; September 6-9, 2023; Houston, TX. Abstract MPN-470.

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