Inflammation and the Development of Leukemia Are Connected

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Penny Min

Published September 15, 2023

In blood stem cells with p53 mutations — the so-called “guardian of the genome” — research has uncovered hitherto unrecognized impacts of persistent inflammation on the emergence of cancer.

The protein p53, generated by the gene TP53, is regarded as “the guardian of the genome,” according to research published in Nature Genetics. Apoptosis, a process by which cells “self-destruct” to stop themselves from procreating additional damaged cells, is triggered when p53 is activated. However, mutations can make p53 ineffective, which allows injured cells to continue dividing unchecked.

As many as 50% to 60% of human malignancies have a TP53 mutation, which can result in cancer development. Hematopoietic stem cells (HSCs) with TP53 mutations have been associated with acute myeloid leukemia (AML), an aggressive kind of blood cancer.

By creating all different types of blood cells, they are in charge of preserving a healthy blood system. The processes behind how these mutant HSCs multiply to produce cancer were largely unknown. In the current study, researchers from the University of Oxford examined how chronic inflammation affects TP53-mutant HSCs in cancer development.

The study team used TARGET-seq, a single-cell method, to examine the impact of the mutation. This enabled them to use cells provided by individuals with myeloproliferative neoplasms, a condition that predisposes them to leukemia, to explore how TP53 mutations in HSCs impact cancer progression.

What did the results entail?

Researchers discovered that cells from individuals with TP53 mutations exhibited higher levels of inflammation-related gene activation. They established, using laboratory mice, that these mutant cells multiplied when the animals were exposed to inflammatory stimuli.

Additionally, compared to healthy HSCs, the mutant HSCs generated fewer white blood cells and were more resistant to cell death, which is normally brought on by inflammation. This indicates that compared to non-mutant HSCs, the mutated HSCs were better able to grow when exposed to inflammation and were more “fit” to survive.

The inability of TP53-mutated cells to effectively repair mistakes in their genetic coding when subjected to inflammation may exacerbate this impact and aid in cancer growth.

“Overall, these findings offer valuable insights into how genetic defects and inflammation interact in the development of blood cancer.”

– Co-first author Alba Rodriguez-Meira

Additionally, she continues that this research may lead to novel approaches for TP53-mutant leukemia therapy and other cancer types, improving results for cancer patients.

The connection between inflammation and genetic evolution in cancer has broad implications, says senior author Adam Mead. The challenge is to figure out how scientists might intervene in this process to treat or prevent the inflammation linked to cancer progression more effectively.

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Momelotinib Receives FDA Approval for Myelofibrosis With Anemia

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Ariana Pelosci

The News

The FDA has approved momelotinib (Ojjaara) for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary and secondary myelofibrosis, who are experiencing anemia, according to a press release from GSK.1

The approval was based on results from the phase 3 MOMENTUM trial (NCT04173494), which was previously presented at the 2022 American Society of Clinical Oncology Annual Meeting, with other supporting data coming from a subpopulation of the phase 3 SIMPLIFY-1 trial (NCT01969838). 2,3

Momelotinib, a once daily oral JAK1/2 inhibitor, is the only approved treatment for this indication.

Expert Perspective

“I think [momelotinib] will make an immediate impact. There clearly are individuals now who are on JAK inhibitors like ruxolitinib [Jakafi] or fedratinib [Inbrec] who have significant anemia who will immediately be potential candidates,” Ruben A. Mesa, MD, said in an interview with CancerNetwork® prior to the approval. “We’ll see how the [National Comprehensive Cancer Network] guidelines form but there’s a case to be made for consideration [for momelotinib] as the initial JAK inhibitor selected for people who have significant anemia.”

Mesa is the president of the Enterprise Cancer Service Line and senior vice president at Atrium Health; executive director of the National Cancer Institute-designated Atrium Health Wake Forest Baptist Comprehensive Cancer Center; and vice dean for Cancer Programs at Wake Forest University School of Medicine

The MOMENTUM Trial

The MOMENTUM trial included 195 patients who were randomly assigned 2:1 to receive either momelotinib (n = 130) at 200 mg per day plus placebo or danazol (n = 65) at 600 mg per day plus placebo. At week 24 patients in the danazol arm were allowed to crossover to the momelotinib arm. The primary end point was total symptom score at week 24, and the secondary end points included transfusion independence and splenic response rate.

In the momelotinib arm, 27.7% of patients discontinued treatment for several reasons including adverse effects (AEs; n = 16), patient decision (n = 6), or death (n = 4). In the danazol arm, 41.5% of patients discontinued treatments because of AEs (n = 11), patient decision (n = 5), or death (n = 3). Additionally, 4 patients crossed over to the momelotinib arm early.

The median age in the momelotinib arm was 71.0 years vs 72.0 years in the danazol arm, 60.8% vs 67.7% were male, and 82.3% vs 76.9% were White, respectively. In terms of myelofibrosis subtype, 60.0% of those in the momelotinib arm had a primary subtype vs 70.8% in the danazol arm, 20.8% vs 16.9% had post-polycythemia vera, and 19.2% vs 12.3% had post-essential thrombocytopenia.

At week 24, the total symptom score response rate was 24.6% (95% CI, 17.49%-32.94%)in the momelotinib arm vs 9.2% (95% CI, 3.46%-19.02%) in the danazol arm (P = .0095). Moreover, 40.0% (95% CI, 31.51%-48.95%) of patients in the momelotinib arm had a 25% reduction in splenic volume vs 6.2% (95% CI, 1.70%-15.01%; P <.0001) in the danazol arm. Additionally, 35% reduction in spleen volume was observed in 23.1% (95% CI, 16.14%-31.28%) in the momelotinib arm and 3.1% (95% CI, 0.37%-10.68%; P = .0006) in the danazol arm.

At baseline, the transfusion independence rate at baseline was 13% in the momelotinib arm vs 15% in the danazol arm. Comparatively, the rate week 24 was 31% in the momelotinib arm vs 20% in the danazol arm (P = .0064).

SIMPLIFY-1 Trial

In this randomized, multicenter study, momelotinib was investigated vs ruxolitinib (Rituxan) in patients who had not received prior treatment with a JAK inhibitor. A total of 432 patients were analyzed with patients received 200 mg orally daily of momelotinib or 20 mg of ruxolitinib once per day.

A 50% of more reduction in the total symptom score was observed in 28.4% of patients receiving momelotinib vs 42.2% receiving ruxolitinib (P = .98). Momelotinib improved the transfusion rate, transfusion independence, and transfusion dependence (P ≤ .19).

Safety

In terms of safety findings from the MOMENTUM trial, the most common grade 3 or higher nonhematologic AEs included acute kidney injury (3.1% vs 9.2%), nausea (2.3% vs 3.1%), and dyspnea (2.3% vs 1.5%) in the momelotinib and danazol arms, respectively. Hematologic AEs of grade 3 or higher included anemia (60.8% vs 75.4%), thrombocytopenia (27.7% vs 26.2%), and neutropenia (12.3% vs 9.2%) in the momelotinib and danazol arms, respectively.

Grade 3 or higher AEs occurred in 53.8% vs 64.6%, and serious AEs occurred in 34.6% vs 40.0% of patients in the momelotinib and danazol arms, respectively. Investigators reported a hazard ratio (HR) of 0.734 (95% CI, 0.382-1.409; P = .3510) for overall survival overall and 0.506 up to week 24 (95% CI, 0.238-1.076; P = .0719).

Safety data from the SIMLIFY-1 trial indicated that AEs occurred in 7% of patients who received momelotinib vs 3% who received ruxolitinib. In 10% of patients, treatment-related neuropathy occurred with momelotinib treatment vs 5% with ruxolitinib.

References

  1. Ojjaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia, News release. GSK. September 15, 2023. September 15, 2023.
  2. Mesa RA, Gerds AT, Vannucchi A, et al. MPN-478 MOMENTUM: phase 3 randomized study of momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor. J Clin Oncol. 2022;40(suppl 16):7002. doi:10.1200/JCO.2022.40.16_suppl.7002
  3. Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: A phase III randomized trial of momelotinib versus ruxolitinib in janus kinase inhibitor–naïve patients with myelofibrosis. J Clin Oncol. 2017;34(suppl 34):3844-3850. doi:10.1200/JCO.2017.73.4418

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PharmaEssentia and MPN Advocacy & Education International Launch New Educational Initiative to Empower People Living With Polycythemia Vera (PV)

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Published: Sep 14, 2023

PV&ME™ campaign features personal stories from people living with PV and their journeys navigating the rare blood cancer

BURLINGTON, Mass. & EAST LANSING, Mich.–(BUSINESS WIRE)– PharmaEssentia USA Corporation, a subsidiary of PharmaEssentia Corporation (TPEx:6446), a global biopharmaceutical innovator based in Taiwan leveraging deep expertise and proven scientific principles to deliver new biologics in hematology and oncology, and MPN Advocacy & Education International, a leading advocacy group dedicated to providing the knowledge, support and resources patients will need as they adjust to living with a myeloproliferative neoplasm (MPN), today announced a new educational initiative for the MPN community called PV&ME. The goal of the campaign is to bring to light the unique and challenging experiences of living with polycythemia vera (PV) in the hopes of raising awareness, empowering patients to advocate for themselves and ensuring newly diagnosed patients feel supported in their journeys. PV&ME features the stories of four inspiring individuals – Buzz, Deb, Patti and Steven – living with this chronic cancer and their perspectives on navigating diagnosis, addressing burdensome symptoms and seeking comprehensive care.

PV is the most common MPN and a long-term, potentially life-threatening cancer that has had limited treatment options for many years. Patients with PV are at a more significant increased risk of developing thromboembolic events than the general population with cardiovascular disease, due to increased blood cell counts. They also have a long-term risk of progression to myelofibrosis or transformation to acute myeloid leukemia.1-5

“People living with PV often face feelings of isolation as they navigate a long and confusing road to diagnosis and adjust to extreme fatigue or other often debilitating symptoms,” said Ann Brazeau, Chief Executive Officer, MPN Advocacy & Education International. “The stories shared in this new PV&ME campaign show just how important the right support and resources can be for this community. We hope this new initiative will help people with PV feel connected and empowered to advocate for themselves on their PV journeys.”

“At PharmaEssentia, we are committed to being an essential partner for the MPN community and know that a critical component of that is listening to and amplifying stories from individuals living with PV themselves,” said Raymond Urbanski, M.D., Ph.D., Senior Vice President and U.S. Head of Clinical Development and Medical Affairs at PharmaEssentia. “This MPN Awareness Day, we are proud to partner with MPN Advocacy & Education International to share these inspiring stories with the MPN community and help encourage patients to take a proactive approach in their care.”

The PV&ME educational video series launched on MPN Awareness Day (September 14) and can be found by visiting us.pharmaessentia.com/patients/patient-stories/. Throughout Blood Cancer Awareness Month, PharmaEssentia and MPN Advocacy & Education International will continue to share important educational content for the MPN community.

Follow PharmaEssentia USA on Twitter and LinkedIn for news and updates.

About Polycythemia Vera (PV)

Polycythemia vera (PV) is a cancer originating from a disease-initiating stem cell in the bone marrow resulting in a chronic increase of red blood cells, white blood cells, and platelets. PV may result in cardiovascular complications such as thrombosis and embolism, and often transforms to secondary myelofibrosis or leukemia. While the molecular mechanism underlying PV is still subject of intense research, current results point to a set of acquired mutations, the most important being a mutant form of JAK2.6

About PharmaEssentia

PharmaEssentia (TPEx: 6446), headquartered in Taipei, Taiwan, is a global and rapidly growing biopharmaceutical innovator. Leveraging deep expertise and proven scientific principles, PharmaEssentia aims to deliver effective new biologics for challenging diseases in the areas of hematology and oncology, with one approved product and a diversifying pipeline. Founded in 2003 by a team of Taiwanese-American executives and renowned scientists from U.S. biotechnology and pharmaceutical companies, today PharmaEssentia is expanding its global presence with operations in the U.S., Japan, China, and Korea, along with a world-class biologics production facility in Taichung, Taiwan.

For more information about PharmaEssentia USA, visit the website, LinkedIn or Twitter.

About MPN Advocacy & Education International

MPN Advocacy and Education International provides educational programs, materials, and resources for patients, caregivers, physicians, and entire healthcare teams to improve their understanding of myelofibrosis, polycythemia vera, and essential thrombocythemia. They are dedicated to making a difference in the lives of those affected by MPNs and strive to grow awareness and advocate on behalf of the MPN community.

For more information about MPN Advocacy and Education International, visit the website, Facebook or Twitter.

© 2023 PharmaEssentia Corporation. All rights reserved.

PharmaEssentia, the PharmaEssentia logo, and PV&ME are trademarks or registered trademarks of PharmaEssentia Corporation.

1 Griesshammer M, Kiladjian J-J, Besses C. Thromboembolic events in polycythemia vera. Ann Hematol. 2019;98:1071–82. DOI: 10.1007/s00277-019-03625-x
2 Antithrombotic Trialists (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373:1849-1860. https://doi.org/10.1016/S0140-6736(09)60503-1
3 Yusef S, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. NEJM. 2016;374(21):2021-2031. DOI: 10.1056/NEJMoa1600176
4 Risk and Prevention Study Collaborative Group;​ Roncaglioni M, et al. N-3 fatty acids in patients with multiple cardiovascular risk factors. NEJM. 2013;368:1800-1808. DOI: 10.1056/NEJMoa1205409
5 Barbui T, et al. In contemporary patients with polycythemia vera, rates of thrombosis and risk factors delineate a new clinical epidemiology. Blood. 2014;124:3021-3023. https://doi.org/10.1182/blood-2014-07-591610
6 Cerquozzi S, Tefferi A. Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors. Blood Cancer J. 2015;5, e366; DOI:10.1038/bcj.2015.95

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Ezobresib by Bristol-Myers Squibb for Myelofibrosis: Likelihood of Approval

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September 14, 2023

Ezobresib is under clinical development by Bristol-Myers Squibb and currently in Phase II for Myelofibrosis. According to GlobalData, Phase II drugs for Myelofibrosis have a 40% phase transition success rate (PTSR) indication benchmark for progressing into Phase III. GlobalData’s report assesses how Ezobresib’s drug-specific PTSR and Likelihood of Approval (LoA) scores compare to the indication benchmarks. 

GlobalData tracks drug-specific phase transition and likelihood of approval scores, in addition to indication benchmarks based off 18 years of historical drug development data. Attributes of the drug, company and its clinical trials play a fundamental role in drug-specific PTSR and likelihood of approval.

Ezobresib overview

Ezobresib (BMS-986158) is under development for the treatment of solid tumors including triple-negative breast cancer, small-cell lung cancer, epithelial ovarian cancer, peritoneal cancer, renal cell carcinoma, fallopian tube cancer, Burkitt’s lymphoma/leukemia, Uveal melanoma, Uterine carcinosarcoma, NUT-midline carcinoma, Non-small cell lung cancer, metastatic hormone refractory (castration resistant, androgen-Independent) prostate cancer, blood cancer (hematologic malignancies), primary myelofibrosis (PMF), post-essential thrombocythemia (ET) or post-polycythemia vera (PV) myelofibrosis. It is administered orally as a capsule. The drug candidate acts by targeting bromodomain and extra-terminal (BET) proteins. It was under development for Ewing sarcoma.

Bristol-Myers Squibb overview

Bristol-Myers Squibb (BMS) is a specialty biopharmaceutical company that is engaged in discovery, development, licensing and manufacturing, marketing, distribution and sale of medicines and related medical products to patients with serious diseases. Its primary focus is on cancer, cardiovascular, immunology and fibrotic therapeutic projects. The company offers its products across the world to wholesalers, retail pharmacies, medical professionals, hospitals and government entities. BMS provides its products in the US, Europe, and Japan. The company conducts research to focus on the discovery and development of novel medicines that address serious diseases in areas of significant unmet medical need. BMS is headquartered in New York City, New York, the US.

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An Update on Current and Emergent Therapies for Essential Thrombocytosis

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Daniel H. Foley, MD
Kristen Pettit, MD

Our understanding of pathophysiology driving Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) has evolved considerably over the past decade. As a result, the therapeutic landscape is shifting toward a goal of meaningful disease modification. For patients with essential thrombocytosis (ET), the immediate goals remain thrombosis risk reduction and symptom control, but newer therapies on the horizon are likely to change our treatment paradigms considerably for this disease.

How do you approach a new patient with ET?
When it comes to the treatment of patients with ET, the main goal of current approved therapy is to mitigate the risk of thrombotic events, as the treatments have minimal impact on disease progression. The choice of treatment is determined by an individual’s specific risk factors for these events. The International Prognostic Score for Thrombosis in ET revised score is used to stratify patients into 4 risk groups: very low risk, low risk, intermediate risk, and high risk. For the majority of low-risk patients, low-dose aspirin is recommended, as it aids in preventing clotting, but patients classified as intermediate or high risk are generally advised to undergo cytoreductive therapy.

What are the standard options for cytoreductive therapy?

The selection of the most suitable cytoreductive agent depends on factors such as the patient’s comorbidities, tolerability of the treatment, future family planning, and individual preferences. Hydroxyurea (HU) and pegylated interferon alfa (peg-IFN) are the primary options for frontline cytoreductive treatment. In the phase 3 study MPD-RC 112 [NCT01259856], which included patients with both ET and polycythemia vera (PV), HU and peg-IFN demonstrated comparable rates of complete response and thrombotic events after 12 months.1 However, over time peg-IFN has shown improved molecular responses in both ET and PV.1-4 Although the clinical implications of these molecular responses aren’t yet entirely clear, these findings are quite exciting to see in this disease that has been so difficult to target. A longer-acting interferon (ropeginterferon alfa-2b-njft; Besremi) is currently in evaluation for patients with ET and has been approved in the United States for patients with PV. In cases where initial treatment approaches do not yield satisfactory results, anagrelide is another option, though its use is often limited by toxicities (eg, headaches, dizziness, palpitations, and fluid retention).

What is on the horizon for treatment of ET?

As we delve deeper into understanding the biologic drivers of ET, promising new therapeutic directions are emerging, including JAK inhibitors, epigenetic agents, and mutation-specific biologic/immunologic therapies.Ruxolitinib (Jakafi), a JAK1/2 inhibitor already widely used for other MPNs, continues to be evaluated in ET. In a randomized study, MAJIC [NCT05057494], ruxolitinib was compared with best available therapy (BAT) for patients with ET who had resistance or intolerance to HU. Both treatments showed similar rates of hematologic response, thrombosis, and hemorrhage. However, ruxolitinib outperformed BAT in improving disease-related symptoms.5 Another ongoing trial called Ruxo-BEAT [NCT02577926] is further exploring the use of ruxolitinib in ET.

When it comes to epigenetic regulators, BET inhibitors and LSD1 inhibitors are emerging as potential therapeutic targets. Both BET inhibitors and LSD1 inhibitors have shown the ability to reduce cytokine production via different mechanisms and impair self-renewal of malignant hematopoietic stem cells, so they may have more significant disease-modifying activity compared with other agents.6,7 The BET inhibitor pelabresib (CPI-0610) is currently being evaluated for ET as well as myelofibrosis. The LSD1 inhibitor bomedemstat is also being studied for both ET and MF, and preliminary reports from the ET study show encouraging ability to control platelets and improve symptoms for many patients.8

Biologic and immunologic approaches are emerging as promising strategies as well. Recently, at the American Society of Hematology annual meeting in 2022, preclinical data were presented on a monoclonal antibody that targets mutant CALR, a key diver for approximately 25% of patients with ET.9 This antibody showed impressive potency in selectively targeting mutant CALR-driven oncogenic mechanisms. There are also other antibody-based therapies showing significant efficacy in preclinical studies, and these strategies are now moving toward the development phases.10 Furthermore, the discovery of T-cell responses against mutant CALR has sparked the development of vaccine-based treatment strategies.11,12 

What are your final thoughts regarding the future of ET?

The development of more targeted agents with the potential to meaningfully disrupt the mechanisms driving MPNs provides a lot of optimism for the future in these diseases. As these therapies move toward “prime time,” we will need to reassess our treatment goals for our patients. Hopefully we will be able to raise the bar for response from simply hematologic control and thrombosis prevention toward the more lofty aims of lengthening survival, improving quality of life, and lowering risk of disease progression.

REFERENCES:

1. Mascarenhas J, Kosiorek HE, Prchal JT, et al. A randomized phase 3 trial of interferon-alpha vs hydroxyurea in polycythemia vera and essential thrombocythemia. Blood. 2022;139(19):2931-2941. doi:10.1182/blood.2021012743

2. Masarova L, Patel KP, Newberry KJ, et al. Pegylated interferon alfa-2a in patients with essential thrombocythaemia or polycythaemia vera: a post-hoc, median 83 month follow-up of an open-label, phase 2 trial. Lancet Haematol. 2017;4(4):e165-e175. doi:10.1016/S2352-3026(17)30030-3

3.Quintás-Cardama A, Abdel-Wahab O, Manshouri T, et al. Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon α-2a. Blood. 2013;122(6):893-901. doi:10.1182/blood-2012-07-442012

4.Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112(8):3065-3072. doi:10.1182/blood-2008-03-143537

5.Harrison CN, Mead AJ, Panchal A, et al. Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide. Blood. 2017;130(17):1889-1897. doi:10.1182/blood-2017-05-785790

6.Kleppe M, Koche R, Zou L, et al. Dual targeting of oncogenic activation and inflammatory signaling increases therapeutic efficacy in myeloproliferative neoplasms. Cancer Cell. 2018;33(1):29-43.e27. doi:10.1016/j.ccell.2017.11.009

7.Jutzi JS, Kleppe M, Dias J, et al. LSD1 inhibition prolongs survival in mouse models of MPN by selectively targeting the disease clone. Hemasphere. 2018;2(3):e54. doi:10.1097/HS9.0000000000000054

8.Gill H, Palandri F, Ross DM, et al. A phase 2 study of the LSD1 inhibitor bomedemstat (IMG-7289) for the treatment of essential thrombocythemia (ET). Blood. 2022;140(suppl 1):1784-1787. doi:10.1182/blood-2021-148210

9.Reis E, Buonpane R, Celik H, et al. Discovery of INCA033989, a monoclonal antibody that selectively antagonizes mutant calreticulin oncogenic function in myeloproliferative neoplasms (MPNs). Blood. 2022;140(suppl 1):14-15. doi:10.1182/blood-2022-159435

10.Tvorogov D, Thompson-Peach CAL, Foßelteder J, et al. Targeting human CALR-mutated MPN progenitors with a neoepitope-directed monoclonal antibody. EMBO Rep. 2022;23(4):e52904. doi:10.15252/embr.202152904

11.Holmström MO, Martinenaite E, Ahmad SM, et al. The calreticulin (CALR) exon 9 mutations are promising targets for cancer immune therapy. Leukemia. 2018;32(2):429-437. doi:10.1038/leu.2017.214

12.Holmström MO, Riley CH, Svane IM, Hasselbalch HC, Andersen MH. The CALR exon 9 mutations are shared neoantigens in patients with CALR mutant chronic myeloproliferative neoplasms. Leukemia. 2016;30(12):2413-2416. doi:10.1038/leu.2016.233

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PharmaEssentia and MPN Advocacy & Education International Launch New Educational Initiative to Empower People Living With Polycythemia Vera (PV)

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PV&ME™ campaign features personal stories from people living with PV and their journeys navigating the rare blood cancer

BURLINGTON, Mass. & EAST LANSING, Mich.–(BUSINESS WIRE)–PharmaEssentia USA Corporation, a subsidiary of PharmaEssentia Corporation (TPEx:6446), a global biopharmaceutical innovator based in Taiwan leveraging deep expertise and proven scientific principles to deliver new biologics in hematology and oncology, and MPN Advocacy & Education International, a leading advocacy group dedicated to providing the knowledge, support and resources patients will need as they adjust to living with a myeloproliferative neoplasm (MPN), today announced a new educational initiative for the MPN community called PV&ME. The goal of the campaign is to bring to light the unique and challenging experiences of living with polycythemia vera (PV) in the hopes of raising awareness, empowering patients to advocate for themselves and ensuring newly diagnosed patients feel supported in their journeys. PV&ME features the stories of four inspiring individuals – Buzz, Deb, Patti and Steven – living with this chronic cancer and their perspectives on navigating diagnosis, addressing burdensome symptoms and seeking comprehensive care.

PV is the most common MPN and a long-term, potentially life-threatening cancer that has had limited treatment options for many years. Patients with PV are at a more significant increased risk of developing thromboembolic events than the general population with cardiovascular disease, due to increased blood cell counts. They also have a long-term risk of progression to myelofibrosis or transformation to acute myeloid leukemia.1-5

“People living with PV often face feelings of isolation as they navigate a long and confusing road to diagnosis and adjust to extreme fatigue or other often debilitating symptoms,” said Ann Brazeau, Chief Executive Officer, MPN Advocacy & Education International. “The stories shared in this new PV&ME campaign show just how important the right support and resources can be for this community. We hope this new initiative will help people with PV feel connected and empowered to advocate for themselves on their PV journeys.”

“At PharmaEssentia, we are committed to being an essential partner for the MPN community and know that a critical component of that is listening to and amplifying stories from individuals living with PV themselves,” said Raymond Urbanski, M.D., Ph.D., Senior Vice President and U.S. Head of Clinical Development and Medical Affairs at PharmaEssentia. “This MPN Awareness Day, we are proud to partner with MPN Advocacy & Education International to share these inspiring stories with the MPN community and help encourage patients to take a proactive approach in their care.”

The PV&ME educational video series launched on MPN Awareness Day (September 14) and can be found by visiting us.pharmaessentia.com/patients/patient-stories/. Throughout Blood Cancer Awareness Month, PharmaEssentia and MPN Advocacy & Education International will continue to share important educational content for the MPN community.

Follow PharmaEssentia USA on Twitter and LinkedIn for news and updates.

About Polycythemia Vera (PV)

Polycythemia vera (PV) is a cancer originating from a disease-initiating stem cell in the bone marrow resulting in a chronic increase of red blood cells, white blood cells, and platelets. PV may result in cardiovascular complications such as thrombosis and embolism, and often transforms to secondary myelofibrosis or leukemia. While the molecular mechanism underlying PV is still subject of intense research, current results point to a set of acquired mutations, the most important being a mutant form of JAK2.6

About PharmaEssentia

PharmaEssentia (TPEx: 6446), headquartered in Taipei, Taiwan, is a global and rapidly growing biopharmaceutical innovator. Leveraging deep expertise and proven scientific principles, PharmaEssentia aims to deliver effective new biologics for challenging diseases in the areas of hematology and oncology, with one approved product and a diversifying pipeline. Founded in 2003 by a team of Taiwanese-American executives and renowned scientists from U.S. biotechnology and pharmaceutical companies, today PharmaEssentia is expanding its global presence with operations in the U.S., Japan, China, and Korea, along with a world-class biologics production facility in Taichung, Taiwan.

For more information about PharmaEssentia USA, visit the website, LinkedIn or Twitter.

About MPN Advocacy & Education International

MPN Advocacy and Education International provides educational programs, materials, and resources for patients, caregivers, physicians, and entire healthcare teams to improve their understanding of myelofibrosis, polycythemia vera, and essential thrombocythemia. They are dedicated to making a difference in the lives of those affected by MPNs and strive to grow awareness and advocate on behalf of the MPN community.

For more information about MPN Advocacy and Education International, visit the website, Facebook or Twitter.

© 2023 PharmaEssentia Corporation. All rights reserved.

PharmaEssentia, the PharmaEssentia logo, and PV&ME are trademarks or registered trademarks of PharmaEssentia Corporation.

1 Griesshammer M, Kiladjian J-J, Besses C. Thromboembolic events in polycythemia vera. Ann Hematol. 2019;98:1071–82. DOI: 10.1007/s00277-019-03625-x
2 Antithrombotic Trialists (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373:1849-1860. https://doi.org/10.1016/S0140-6736(09)60503-1
3 Yusef S, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. NEJM. 2016;374(21):2021-2031. DOI: 10.1056/NEJMoa1600176
4 Risk and Prevention Study Collaborative Group;​ Roncaglioni M, et al. N-3 fatty acids in patients with multiple cardiovascular risk factors. NEJM. 2013;368:1800-1808. DOI: 10.1056/NEJMoa1205409
5 Barbui T, et al. In contemporary patients with polycythemia vera, rates of thrombosis and risk factors delineate a new clinical epidemiology. Blood. 2014;124:3021-3023. https://doi.org/10.1182/blood-2014-07-591610
6 Cerquozzi S, Tefferi A. Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors. Blood Cancer J. 2015;5, e366; DOI:10.1038/bcj.2015.95

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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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Improved Molecular Understanding of AP/BP MPN Better Informs Management Approaches

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Tony Berberabe, MPH

Developing an optimal treatment strategy for patients with accelerated- or blast-phase myeloproliferative neoplasms (MPN AP or MPN BP) requires consideration of a patient’s ability to tolerate intensive induction as initial therapy, their eligibility for allogeneic stem cell transplant (ASCT), and whether prior cytoreduction is necessary, according to a presentation by Olatoyosi Odenike, MD, at the 2023 SOHO Annual Meeting.

Few treatment options are available for patients with MPN that is in AP (10% or more blasts) or BP (20% or more blasts), with only ASCT offering the potential for cure, although only a minority of patients are eligible for this intervention. From a targeted therapy perspective, single agent hypomethylating agents (HMAs) or HMAs in combination with ruxolitinib (Jakafi®; Incyte) or venetoclax (Venclexta®; Genentech and AbbVie)can also be considered.

The paucity of approaches coupled with a median overall survival of 3 months for patients who present with BP and 12 to 18 months for patients in the AP adds “urgency to determine who is at highest risk for transformation because that is when intervention can have the most impact,” said Odenike, a professor of medicine and director, Leukemia Program at the University of Chicago Medicine in Illinois.

The treatment choices for initial therapy are affected by the patient’s fitness and ability to undergo intensive induction. However, the choice for pursuing intensive or less intensive induction is somewhat unclear, as prospective randomized trials are lacking. “But retrospective trials that evaluate intense vs less intense approaches portray outcomes evenly, with no clear survival advantage of 1 approach over the other,” Odenike said, bringing up a study by McNamara, et al.2

For this analysis, intensive therapy was defined as chemotherapy; less intensive therapy could include low dose cytarabine, HMAs, or a clinical trial intervention. In the analysis, when intensive therapy was stratified by receipt of ASCT, many of the supposed benefits were found more closely tied to the transplant itself.2 The investigators also noted that patients who underwent intensive therapy but didn’t proceed to transplant had worse outcomes than those who received less intensive therapy.2

“Retrospective studies are subject to all kinds of bias,” Odenike said. “But this study is suggestive that we should have a path forward to transplant if we decide to go the intensive route.”

Molecularly Complex

The high mutational burden and molecular complexity of AP and BP MPN contributes to its poor outcomes, with almost half of patients exhibiting mutations in 4 or more genes. As more is learned about the genes implicated in the disease, the role of targeted therapies becomes more important.

“It’s interesting to think about targeted therapies, since we are starting to better understand the molecular underpinnings of MPNs in general, including when they progress to the accelerated or blast phase,” Odenike said.

Distinct molecular differences exist between AP and BP MPN, which has been referred to as secondary acute myeloid leukemia (AML), and de novo AML, Odenike said. In many cases, AP/BP MPN appears to be enriched for IDH1 and IDH2, making it a potential path for targeted therapies. In particular, IDH1/2 mutations occur in about 25% of patients with BP and leads to epigenetic dysregulation.

IDH1/2 inhibitors have been shown to be active in IDH mutant AML, making these an established treatment for this disease.3,4 For patients with AP/BP MPN, clinical responses to IDH1/2 inhibitors have been positive, with 1 trial reporting a median duration of treatment of 258 days5 and others reporting significant clinical responses to IDH1/2 inhibition.6

As one of the only curative interventions, the focus on getting patients to ASCT and achieving the best responses is paramount. Better responses are seen with ASCT when patients are first cytoreduced and in remission, but outcomes are overall inferior compared with AML that arises de novo, according to Odenike. The same chemotherapy regimens to treat AML are available, but outcomes are not optimal. “Even when the patient is able to have an ASCT, the outcomes are only modestly improved. So, to me, this is a call to action,” Odenike said.

Investigational efforts to explore approaches in the myeloid space are currently focused on epigenomic modulators, novel posttranslational modulators, immune checkpoint inhibitors, and novel targeted agents, including BCL2/BCLXL, IDH1/2, kinase, and MDM2 inhibitors.

Odenike closed with a schema detailing how she treats patients with Philadelphia-negative MPN. In the accelerated and blast phase, she advocates for next-generation sequencing, to identify the molecular profile. “I recommend clinical trial enrollment if available,” she said. “If the patient has a TP53 mutation, those patients generally don’t do well with intensive therapy. With other mutations, I have relative equipoise between intensive and a less intensive approach. But I would only treat using an intensive approach if I had a plan to quickly move the patient to transplant and if the patient is fit.”

References

  1. Odenike O. Managing accelerated- and blast-phase MPN. Presented at: 11th Annual Meeting of the Society of Hematologic Oncology (SOHO 2023). September 7, 2023. Houston, Texas.
  2. McNamara CJ, Panzarella T, Kennedy JA, et al. The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes. Blood Adv. 2018;2(20):2658–2671. doi:10.1182/bloodadvances.2018021469
  3. Green A, Beer P. Somatic Mutations of IDH1 and IDH2 in the Leukemic Transformation of Myeloproliferative Neoplasms. N Engl J Med. 2010;362(4):369-370. doi: 10.1056/NEJMc0910063
  4. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731. doi:10.1182/blood-2017-04-779405
  5. Patel AA, Cahill K, Charnot-Katsikas A, et al. Clinical outcomes of IDH2-mutated advanced-phase Ph-negative myeloproliferative neoplasms treated with enasidenib. Br J Haematol. 2020;190(1):e48-e51. doi:10.1111/bjh.16709
  6. Chifotides HT, Masarova L, Alfayez M, et al. Outcome of patients with IDH1/2-mutated post–myeloproliferative neoplasm AML in the era of IDH inhibitors. Blood Adv. 2020;4(21):5336–5342. doi:10.1182/bloodadvances.2020001528

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Research Nurse Breaks Down Myelofibrosis-Related Anemia

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Brielle Benyon

Anemia is a common and potentially dangerous condition that can occur in patients with myelofibrosis, a type of myeloproliferative neoplasm. While anemia is a blanket term that describes low hemoglobin levels, myelofibrosis-related anemia behaves quite differently than anemia in patients with a blood cancer diagnosis, explained Sharon Bledsoe.

Bledsoe, a senior research nurse at The University of Texas MD Anderson Cancer Center in Houston, recently explained myelofibrosis-related anemia, including its cause and treatment.

CURE®: What causes anemia in patients with myelofibrosis?

Myelofibrosis is basically a disease in which the bone marrow gets replaced by connective tissue in a process called fibrosis. The bone marrow’s main objective is to produce blood cells, and in producing the blood cells — the red blood cells, the white blood cells and the platelets. When the fibrosis interferes with the production of the cells, scar tissue starts to form in the bone marrow, and the bone marrow is the soft spongy tissue in the center of the bones.

As the scar tissue starts to grow, the bone marrow loses its ability to make enough healthy blood cells. So, it produces too many abnormal blood cells. The lifespan of a true red blood cell or of a normal human red blood cell is 120 days, which is about roughly four months. When you have a patient dealing with myelofibrosis, with the scarring and all of that, they’re producing the red blood cells, but they’re not maturing; when they’re not mature, they die off faster. So, they’re producing a whole lot a whole lot, but they’re dying fast. Then you have the anemia that starts because they’re not living for enough time, so they’re not getting four months of life; within days, weeks, they’re dying off.

How is myelofibrosis-associated anemia treated?

When patients’ (hemoglobin levels) start to get low, we start to monitor their trends. We monitor their hemoglobin; we start to monitor in to see if they’re if they are going to need a transfusion. And if they need transfusions, how often are they needing the transfusions? So we’re going to monitor all of that, whether they need the transfusions and how often they need the transfusions.

That’s one way that it’s treated.

And then doctors may put them on drugs that will help the anemia, drugs like danazol and Jakafi (ruxolitinib). When those red blood cells are being produced so quickly, there’s not enough room within the bone marrow, so (they) go into the spleen, or into the liver, which is now causing them to have enlarged spleens and enlarged liver. And sometimes, because it can’t be treated, the spleen has to be removed.

(Jakafi) can take the spleen size down. However, with (Jakafi), you fall into the area where they can get skin cancers, secondary skin cancers, squamous cell carcinoma, basal cell carcinoma and things like that; you have to really, really watch for that. In treating the anemia, you have to watch for so many other things that may crop up.

What is the difference between myelofibrosis-related anemia and general anemia that is experienced in patients without an MPN?

There is a major difference, because anemia that a person would have that doesn’t have cancer presents differently than the anemia (related to MPNs). For a person who has a blood cancer, their anemia is going to come with other things (such as) possibly filling up faster (when eating), night sweats (and) extreme fatigue. And some of them have (feelings of) wanting to faint because the hemoglobin is so low.

In a person that has just routine anemia, they won’t have those types of symptoms, they’ll just probably feel a little tired or a little sluggish.

What advice do you have for patients with myelofibrosis who may be experiencing anemia?

We tell the patients to let us know if you have increased fatigue, let us know if any of your symptoms change, you have increased fatigue, you have increased night sweats, you start having fevers or things like that, let us know if any of those things are taking place. That way, I can give that information to the to the oncologist and then they know what to do for the patient.

Make sure that you are proactive as a patient, if there’s something that’s wrong, and you know that it hasn’t been an issue before, make sure that you follow up and follow through, don’t just accept (symptoms). If you have to go to 5 doctors, go to as many as it takes to get the diagnosis, because with time, time loss is not time that can be regained. So, you need to be proactive and monitor your care and know what your norms are and what’s not normal for you.

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Research Developments Advancing Involving CALR-Mutated MPNs

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September 6, 2023

Vicki Moore, PhD

A review article published in the Journal of Cellular and Molecular Medicine details recent progress in the development of antibodies targeting mutated calreticulin, aimed at providing a novel therapy option for myeloproliferative neoplasms (MPN). The review was authored by Frederike Kramer, PhD, and Ann Mullally, MD, of Harvard Medical School in Boston, Massachusetts.

Calreticulin is encoded by the CALR gene and alterations in this gene are common drivers of the development of MPN. In most cases, these occur as 1 of 2 mutations in exon 9 of this gene, as Kramer and Mullally explained in their review. Approximately half of the patients with a CALR mutation have a 52-bp deletion, whereas approximately 30% of patients with a CALR mutation have an insertion of 5 bp in the sequence of this gene.

These types of mutations in CALR lead to a frameshift that causes formation of an altered C-terminus in calreticulin, resulting in the absence of an endoplasmic reticulum retention signal. The altered calreticulin is thus directed toward the cell’s surface, where it shows aberrant binding to the thrombopoietin receptor protein (MPL), with the interaction ultimately contributing to activation of the JAK-STAT signaling pathway and cell transformation.

Currently, patients with MPN are often treated with cytoreductive therapies. Allogeneic stem cell transplantation can be curative for patients with CALR-mutated MPN, but this approach carries risks of morbidity and mortality.

However, the interaction of altered calreticulin and MPL provides a possible substrate for a potential targeted treatment approach. Monoclonal antibodies (mAbs) directed at altered calreticulin have been the subject of research, and a range of studies have generated results indicating this may be a possible approach to treatment of CALR-mutated MPN.

Additional immunological approaches to treating MPN that have been under investigation involve peptide vaccination directed at altered calreticulin and T cell-directed targeting agents. Antibody-drug conjugates could also present a possible avenue of treatment, with these agents potentially binding to both mutated calreticulin and MPL within a complex, rather than binding to mutated calreticulin that has simply been secreted.

“Recent advances in identifying the mechanisms by which mutant calreticulin causes MPN paved the path for immunological targeting of CALR-mutant MPN cells, and specific mutant calreticulin targeting mAbs have been developed and found to be efficacious in preclinical mouse models,” the authors wrote in their report, also noting safety and efficacy with these agents have not yet been evaluated in this patient population.

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of disclosures.

Reference

Kramer F, Mullally A. Antibody targeting of mutant calreticulin in myeloproliferative neoplasms. J Cell Mol Med. Published online August 7, 2023. doi:10.1111/jcmm.17896

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