Up to 20% of patients with myeloproliferative neoplasms (MPN) are adolescent and young adults (AYAs) and the population is growing; however, there is a paucity of data on the psychological needs of AYAs with MPN, according to a systematic scoping review published in Leukemia & Lymphoma.1
Previous research has shown AYAs with cancer can be overlooked2 and there is little information on how this population does during treatment and survivorship,3 but they can face unique psychosocial issues that impact their quality of life.4
“While the MPN AYA group generally reports a similar symptom burden to the adults with MPN, very little is known about the psychological impact and management of AYA with MPN,” the authors wrote. “Understanding psychosocial issues patients with MPN face are critical given the demands of cancer, and its treatment is often directly counter to the developmental needs of the age group.”
Jean-Jacques Kiladjian, Francisca Ferrer Marin, Haifa Kathrin Al-Ali, Alberto Alvarez-Larrán, Eloise Beggiato, Maria Bieniaszewska, Massimo Breccia, Veronika Buxhofer-Ausch, Olga Cerna, Ana-Manuela Crisan, Catalin Doru Danaila, Valerio De Stefano, Konstanze Döhner, Victoria Empson, Joanna Gora-Tybor, Martin Griesshammer, Sebastian Grosicki, Paola Guglielmelli, Valentin García-Gutierrez, Florian H. Heidel, Arpád Illés, Ciprian Tomuleasa, Chloe James, Steffen Koschmieder, Maria-Theresa Krauth, Kurt Krejcy, Mihaela-Cornelia Lazaroiu, Jiri Mayer, Zsolt György Nagy, Franck-Emmanuel Nicolini, Francesca Palandri, Vassiliki Pappa, Andreas Johannes Reiter, Tomasz Sacha, Stefanie Schlager, Stefan Schmidt, Evangelos Terpos, Martin Unger, Albert Wölfler, Blanca Xicoy Cirici & Christoph Klade
Abstract
Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). Current ET treatments aim to normalize hematological parameters and reduce the thrombotic risk, but they do not modify the natural history of the disease and hence, have no impact on disease progression. Ropeginterferon alfa-2b (trade name BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval, has demonstrated a robust and sustained efficacy in polycythemia vera (PV) patients. Given the similarities in disease pathophysiology and treatment goals, ropeginterferon alfa-2b holds promise as a treatment option for ET. The ROP-ET trial is a prospective, multicenter, single-arm phase III study that includes patients with ET who are intolerant or resistant to, and/or are ineligible for current therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman, leaving these patients with limited treatment options. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. Secondary endpoints include improvements in symptoms and quality of life, molecular response and the safety profile of ropeginterferon alfa-2b. Over a 3-year period the trial assesses longer term outcomes, particularly the effects on allele burden and clinical outcomes, such as disease-related symptoms, vascular events and disease progression. No prospective clinical trial data exist for ropeginterferon alfa-2b in the planned ET study population and this study will provide new findings that may contribute to advancing the treatment landscape for ET patients with limited alternatives.
Garima Pandey1, Lucia Mazzacurati1, Tegan M Rowsell1, Nathan P Horvat2, Narmin E Amin1, Guolin Zhang3, Afua A Akuffo2, Christelle M Colin-Leitzinger2, Eric B Haura3, Andrew T Kuykendall4, Ling Zhang5, Pearlie K Epling-Burnette2, Gary W Reuther14
Abstract
Myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocytosis, and primary myelofibrosis, are clonal hematopoietic neoplasms driven by mutationally activated signaling by the JAK2 tyrosine kinase. Although JAK2 inhibitors can improve MPN patients’ quality of life, they do not induce complete remission as disease-driving cells persistently survive therapy. ERK activation has been highlighted as contributing to JAK2 inhibitor persistent cell survival. As ERK is a component of signaling by activated RAS proteins and by JAK2 activation, we sought to inhibit RAS activation to enhance responses to JAK2 inhibition in preclinical MPN models. We found the SHP2 inhibitor RMC-4550 significantly enhanced growth inhibition of MPN cell lines in combination with the JAK2 inhibitor ruxolitinib, effectively preventing ruxolitinib persistent growth, and the growth and viability of established ruxolitinib persistent cells remained sensitive to SHP2 inhibition. Both SHP2 and JAK2 inhibition diminished cellular RAS-GTP levels, and their concomitant inhibition enhanced ERK inactivation and increased apoptosis. Inhibition of SHP2 inhibited the neoplastic growth of MPN patient hematopoietic progenitor cells and exhibited synergy with ruxolitinib. RMC-4550 antagonized MPN phenotypes and increased survival of an MPN mouse model driven by MPL-W515L. The combination of RMC-4550 and ruxolitinib, which was safe and tolerated in healthy mice, further inhibited disease compared to ruxolitinib monotherapy, including extending survival. Given SHP2 inhibitors are undergoing clinical evaluation in patients with solid tumors, our preclinical findings suggest that SHP2 is a candidate therapeutic target with potential for rapid translation to clinical assessment to improve current targeted therapies for MPN patients.
A review published in the American Journal of Hematology details current aspects of diagnosis, risk stratification, and management of essential thrombocythemia (ET). The review was written by Ayalew Tefferi, MD, of Mayo Clinic in Rochester, Minnesota; Alessandro Maria Vannucchi, MD, of the University of Florence in Florence, Italy; and Tiziano Barbui, MD, of Papa Giovanni XXIII Hospital in Bergamo, Italy.
Regarding ET diagnosis, Tefferi and colleagues highlighted criteria from the International Consensus Classification. This system involves multiple criteria for ET diagnosis, such as thrombocytosis (with a platelet count ≥450×109/L), exclusion of other myeloid neoplasms, and other features, such as possible mutation of JAK2, CALR, or MPL. However, the authors noted, up to 20% of patients having ET might be negative for mutations in all 3 of these genes.
According to data from the Surveillance, Epidemiology, and End Results Registry in the US, the 5-year survival rate among 8768 patients with ET was 88.7%. The median survival time for this population was 12.1 years.
Among risk factors related to survival with ET, the authors considered age to be most important. Additional risk factors identified for survival vary by the risk model being used. The triple A survival risk model, for example, includes absolute neutrophil count and absolute lymphocyte count, in addition to age, and stratifies patients into 4 risk groups with median survival times ranging from 8 years in the high-risk group to 47 years in the low-risk group. The authors emphasized age, presence of a thrombosis history, and presence of JAK2 mutation as risk factors for thrombosis with ET.
In describing their treatment approach to ET, the authors indicated they began with consideration of thrombosis risk stratification, with some treatment options within thrombosis risk groups based on cardiovascular risk.
Patients with phlebotomy-dependent polycythemia vera, a type of myeloproliferative neoplasm, treated with rusfertide experienced a response rate of 60% (n = 18/30) compared with 17% (n = 5/29) in those who received placebo (P = .002), according to updated findings from part 2 of the phase 2 REVIVE trial (NCT04057040) published in the New England Journal of Medicine.1
The international trial was designed with 3 parts: a 28-week, open-label, dose-finding portion in which rusfertide was added to a patient’s ongoing therapy of phlebotomy alone or cytoreductive therapy with optional phlebotomy; a double-blind, randomized withdrawal portion wherein patients were randomly assigned to receive rusfertide or placebo for 12 weeks (weeks 29 to 41); and an open-label extension period following patients on rusfertide therapy for up to 3 years.
Findings from part 1 showed that the estimated mean number of annual phlebotomies was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). Moreover, the mean maximum hematocrit level was 44.5±2.2% during part 1 vs 50.0±5.8% during the 28 weeks before the first dose of rusfertide. Patient quality of life was also improved on rusfertide, with a lower severity of disease-related symptoms.
“Rusfertide appears to represent a significant step forward in treating [patients with] polycythemia vera through its unique approach of limiting the amount of iron available for blood cell production,” Marina Kremyanskaya, MD, PhD, an associate professor of medicine (hematology and medical oncology) at Icahn School of Medicine at Mount Sinai in New York, New York, and lead author of the study, stated in a news release.2 “Pending further clinical studies, this injectable agent could become a valuable therapeutic tool for a disease which many patients and their physicians struggle to bring under control.”
2023 brought a wave of positive developments for patients with myeloproliferative neoplasms (MPNs), particularly myelofibrosis. According to Raajit K. Rampal, MD, PhD, one study of particular interest was the phase 3 MANIFEST-2 trial (NCT04603495) of ruxolitinib (Jakafi) with pelabresib (CPI-0610).1
This study, in addition to the TRANSFORM-1 trial (NCT04472598), showed significant improvement in spleen size and potential benefits in symptom reduction with combination therapies compared with single-agent treatments, suggesting that these combinations could become valuable options for treating patients with myelofibrosis upfront.1,2
Other studies, including early data of TP-3654 and selinexor (Xpovio), show potential for further advancements in myelofibrosis treatment.
“There is a lot to be excited about for the first time in a very long time. There are all of these other small molecule inhibitors in clinical trials [and] I think we will learn a lot from that,” said Rampal, hematologic oncologist at Memorial Sloan Kettering Cancer Center, in an interview with Targeted OncologyTM.
Updated preclinical data will be presented from Ryvu’s synthetic lethality pipeline, including PRMT5 inhibitors in MTAP-Deficient cancers, WRN inhibitors for the treatment of microsatellite unstable (MSI-H) tumors, and Ryvu’s cutting-edge synthetic lethality platform based on primary cancer cells.
Poster presentation to highlight the synergistic effects of RVU120 in combination with ruxolitinib in myeloproliferative neoplasms.
Ryvu’s partner Menarini to present data on MEN1703 (SEL24), demonstrating promising anti-tumor activity in preclinical models of myelofibrosis both as a single agent and combined with ruxolitinib.
KRAKOW, Poland, March 6, 2024 /PRNewswire/ — Ryvu Therapeutics (WSE: RVU), a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology, announced today that preclinical data from its synthetic lethality pipeline and RVU120 project, as well as on MEN1703 (SEL24), will be presented at the upcoming 2024 AACR Annual Meeting, scheduled for April 5-10 in San Diego, California.
Patients with myeloproliferative neoplasms (MPN) are at high risk of cardiovascular (CV) disease, including heart failure (HF). Those with myelofibrosis in particular have a higher chance of experiencing HF. In a study presented at the 2023 ASH Annual Meeting & Exposition, Orly Leiva, New York University Grossman School of Medicine, Boston, Massachusetts, and colleagues examined CV outcomes for patients with MPN (essential thrombocythemia [ET], polycythemia vera [PV], or MF) who were hospitalized for HF.
The authors completed a retrospective analysis using data from the National Readmission Database (NRD). They used ICD-10 codes to identify adult patients with a history of MPN who had a primary diagnosis of HF from 2017 and 2018 (N = 4632). Of these patients, 2639 had ET, 1109 had PV, and 884 had MF.
In response to rising drug costs, some states are creating Prescription Drug Affordability Boards, or PDABs, that have varying degrees of oversight. PDABs are tasked with determining reasonable drug prices based on things such as: if the price affects a patient’s access to a drug, if there are other drugs proven to do the same thing for a cheaper price, and what the drug manufacturer charges. Additionally, special consideration is to be taken for drugs that treat rare conditions, and input from patient communities is supposed to be included in the decision-making process.
Colorado was one of the first states to create a PDAB back in 2021 and they are currently reviewing 5 drugs, one of which is an orphan drug used by cystic fibrosis patients. Each state decides how they will select the drugs for review. Other states with PDABs are Maine, Maryland, Minnesota, New Hampshire, Oregon, and Washington. States that introduced PDAB legislation in 2023 are Connecticut, Michigan, New Jersey, New Mexico, Rhode Island, Vermont, and Virginia.
As a patient advocacy and education organization, we want to ensure that our MPN community is informed about PDABs and how they could impact your access to MPN drugs. We also want to make certain that the MPN patient voice is central to any board if an MPN drug comes up for review. Most importantly, we want to make sure that every MPN patient benefiting from an MPN drug has access to it.
We want to hear from you! Are you in a state with a Prescription Drug Affordability Board? If so, do you know how your board chooses which drugs will be reviewed or which drugs are currently up for review? Let us know by contacting Ann Brazeau at abrazeau@mpnadvocacy.com.
Stay tuned as we learn more about PDABs and make plans to ensure the MPN voices are heard!
I’m 38 today and was diagnosed with ET at age 21 while in college in 2007, following a routine blood test. I took the blood test so that I could donate bone marrow to earn money ($400 at the time) for an upcoming study abroad trip. Apart from the increased platelet count, I did not have other noticeable symptoms. The blood test results indicated an increased platelet count, and I was not permitted to donate bone marrow. I underwent a bone marrow biopsy many months later, which confirmed the diagnosis of ET. I am JAK2+.
Between that time period in college and today, I’ve been on and off hydroxyurea, on and off baby aspirin, got married, had two children, learned more about bleeding and other symptoms related to high platelet counts and have met new members of the MPN community. I wish I knew then how much hormone levels and clotting issues can impact women’s reproductive health. Interestingly, I learned after my son was born that I also carry the gene for hemophilia A, an incurable bleeding disorder. Call me if you’d like to talk about both clotting or bleeding!
These days, I do occasionally experience incredible fatigue and frequently find myself scratching itchy skin (particularly after the shower) and have noticed some vision changes but am not sure if that can be attributed to ET. Today, I’m so grateful for the knowledge I’ve gained and the support available to me in the MPN community, especially MPN Advocacy and Education International.
