Category Archives: Myelofibrosis

Ryvu Therapeutics Presents Preclinical Data on RVU120 and Synthetic Lethality Programs at the 2024 AACR Annual Meeting

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10 Apr, 2024

  • Ryvu PRMT5 inhibitors show potential best-in-class profiles, including a strong antiproliferative effect on MTAP-deleted cell lines and a good safety window versus MTAP WT cells.
  • Ryvu’s WRN inhibitor program has demonstrated target engagement and selective potency with a synthetic lethal effect; in vivo efficacy studies exhibited pronounced tumor growth inhibition in an MSI-H colorectal cancer xenograft model.
  • Ryvu’s proprietary ONCO Prime discovery platform, which recently received a PLN 26 million (approx. USD 6.6 million) grant from the Polish Agency for Enterprise Development, has identified novel drug targets in KRAS-mutant patient-derived cells (PDCs) with therapeutic potential in colorectal cancer; the ONCO Prime platform has broad potential across multiple tumor types.
  • RVU120 shows efficacy both as a monotherapy and synergistically in combination with ruxolitinib in preclinical models of myeloproliferative neoplasms, including myelofibrosis and polycythemia vera.
  • MEN1703 (SEL24), presented by partner Menarini Group, shows cytotoxic activity in myelofibrosis cell lines as a monotherapy and synergistically in combination with ruxolitinib.

KRAKOW, Poland, April 10, 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, presents preclinical data from its synthetic lethality pipeline, RVU120, and MEN1703 (SEL24) at the 2024 AACR Annual Meeting, April 5-10 in San Diego, California.

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Disease Progression for Patients With Low-Risk Myelofibrosis Participating in the MOST Study

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Grace Taylor

03/26/2024

A group of researchers presented data on disease progression for patients with low-risk myelofibrosis (MF) participating in the prospective observational Myelofibrosis and Essential Thrombocythemia Observational Study (MOST) at the 2023 ASH Annual Meeting & Exposition.

In order to qualify for the MOST study, participants were required to have a physician-reported diagnosis of MF (primary myelofibrosis [PMF], post progression of polycythemia vera [post-PV], or post essential thrombocythemia [post-ET). They also could not have any risk factors per the Dynamic International Prognostic Scoring System (DIPSS) criteria. However, participants could be aged 65 years or older. The number of patients with MF enrolled in the study was 232. Of this population, 205 met the study criteria and were included in cohort A. Although the remaining 27 patients had  ≥1 DIPSS risk factor, they were included in the study in a separate cohort B.

For the study, disease progression was defined by the worsening of clinical or laboratory parameters, which included one or more of the following criteria: hemoglobin (Hb) <10 g/dL, platelets <100×109/L, presence of constitutional symptoms (weight loss, fever, or sweats), new or worsening splenomegaly, blasts >1%, white blood cell count >25×109/L, death due to disease progression, leukemic transformation (LT), or >1 red blood cell transfusion. The median follow-up was 52.9 months (42-68).

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Next-Generation JAK Inhibitors Signal the Future of Myelofibrosis Treatment Advances

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Ashling Wahner

Newer-generation JAK inhibitors are increasingly adept at controlling symptoms in patients with myelofibrosis and may recapture treatment response in patients who have progressed on prior ruxolitinib (Jakafi), according to Joseph G. Jurcic, MD.

“Using drugs that target all these particular abnormalities can result in symptom and spleen improvement, and in some, a reduction in cytokines and allelic burden,” Jurcic said in an interview with OncLive®.

In the interview, Jurcic discussed the benefits and limitations of several JAK inhibitors for patients with myelofibrosis, highlighting the treatment advances that have been made since the introduction of ruxolitinib to the treatment paradigm, considerations for the use of fedratinib (Inrebic), and the potential advantages of pacritinib (Vonjo) for patients with anemia.

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Momelotinib for myelofibrosis: our 14 years of experience with 100 clinical trial patients and recent FDA approval

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Ayalew Tefferi & Animesh Pardanani

Momelotinib is an ATP-competitive small molecule inhibitor of Janus kinase proteins (JAKi), including JAK1, JAK2, JAK3, and TYK2; its other clinically relevant targets include activin A receptor type 1 (ACVR1), also known as activin receptor like kinase 2 (ALK2) [1]. Momelotinib was recently approved (September 15, 2023) for use in anemic patients with high/intermediate risk myelofibrosis (MF), including primary (PMF) [2] and secondary variants, the latter emerging from antecedent polycythemia vera (post-PV) [3] or essential thrombocythemia (post-ET) [4]. All three MF variants belong to the broader category of myeloproliferative neoplasms (MPNs), which are characterized by the presence of JAK-STAT activating mutations (JAK2, CALR or MPL) and predominantly megakaryocytic myeloproliferation with variable degrees of bone marrow fibrosis [5]. Patients with MF face premature death with 10-year survival estimates ranging from >80% in very low-risk diseases to <5% in very high-risk diseases [6]. In addition, the clinical course of the disease in MF is complicated by progressive anemia, extramedullary hematopoiesis with marked splenomegaly and hepatomegaly, constitutional symptoms, and cachexia. Causes of death in MF include disease transformation into acute myeloid leukemia [7].

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A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis

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March 13, 2024

Tim Kong, Nicole Gaudin, Karyn Gordon, Maggie J. Cox, Amy W. Zhou, and Stephen T. Oh

Abstract

Janus kinase 2 (JAK2) inhibitors such as ruxolitinib have become standard-of-care therapy for patients with myeloproliferative neoplasms (MPNs); however, activation of alternate oncogenic pathways including nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) has limited durable response as single-agent therapy. With the rationale of targeting both pathways, we conducted a phase I dose escalation trial of pevonedistat in combination with ruxolitinib for the treatment of patients with myelofibrosis (NCT03386214). The primary objective was to assess the safety and tolerability of combination therapy with additional objectives of treatment efficacy and alterations of biomarkers. There were no dose-limiting toxicities observed with most adverse events being limited to grades 1/2. In secondary measures, anemia response was observed in two patients. Pro-inflammatory cytokines and iron parameters were longitudinally assessed, which revealed suppression of interleukin-6 and interferon-gamma in a dose-dependent manner across a subset of patients. These results suggest that combination therapy targeting both JAK2 and NFκB may hold clinical merit for MPN patients.

Triple-Negative Myelofibrosis: Disease Features, Response to Treatment and Outcomes

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Luis E. Aguirre, Akriti Jain, Somedeb Ball, Najla Al Ali, Virginia O. Volpe, Sara Tinsley-Vance, David Sallman, Kendra Sweet, Jeffrey Lancet, Eric Padrom, Seongseok Yun, Andrew Kuykendall, Rami Komrokji

Abstract

Background

Myelofibrosis is the most aggressive subtype among classical BCR::ABL1 negative myeloproliferative neoplasms. About 90% of cases are driven by constitutive activation of 1 of 3 genes impacting the JAK/STAT pathway: JAK2, CALR, and MPL. Triple-negative myelofibrosis (TN-MF) accounts for only 5-10% of cases and carries the worst outcomes. Little has been described about this subset of disease. Given the marked heterogeneity surrounding disease biology, clonal architecture, clinical presentation, and poor outcomes in TN-MF, identification of features of interest and assessment of treatment response are areas in need of further investigation.

Patients and methods

We collected and evaluated baseline clinical and molecular parameters from 626 patients with a diagnosis of myelofibrosis who presented to the H. Lee Moffitt Cancer Center in Tampa (Florida, US) between 2003-2021 and compared them based on presence or absence of the three classical phenotypic driver mutations.

Results

A small proportion of patients (6%) harbored TN-MF which correlated with inferior outcomes, marked by a 4-year reduction in overall survival time compared to the non-TN cohort (mOS 37.4 months vs. 85.7 months; p=.009) and higher rates of leukemic transformation. More pronounced thrombocytopenia and anemia, lower LDH, EPO levels, as well as lower percentage of marrow blasts at baseline were more commonly seen in TN-MF (p<0.05). Similarly, patients with TN-MF had higher risk disease per DIPSS+ and GIPSS. Mutations impacting RNA splicing, epigenetic modification and signaling, specifically SRSF2, SETBP1, IDH2, CBL and GNAS, were more commonly seen among those lacking a classical phenotypic driver. The prevalence of co-mutant ASXL1/SRSF2 clones was significantly higher in TN-MF as was trisomy 8. TN patients had fewer responses (46.2% vs 63.4%) and shorter duration of response to ruxolitinib.

Conclusion

TN-MF is invariably associated with significantly decreased survival and more aggressive clinical behavior with higher rates of leukemic transformation and shorter duration of response to ruxolitinib. Mutations impacting RNA splicing, epigenetic modification and signaling (SRSF2, SETBP1, IDH2, CBL and GNAS) are more common in TN-MF, which likely drive its aggressive course and may account for suboptimal responses to JAK inhibition.

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Combination Therapies and New Research Drive Progress in Myelofibrosis

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Jordyn Sava

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.

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Ryvu Therapeutics to Present Preclinical Data on RVU120 and Synthetic Lethality Programs at the 2024 AACR Annual Meeting

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Published: Mar 06, 2024

  • 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.

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Patients With Myelofibrosis Are at Higher Risk for Poor Cardiovascular Outcomes After Heart Failure Hospitalization

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Grace Taylor

03/05/2024

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.

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Non-Driver Gene Mutations Have Adverse Prognostic Impact in Primary Myelofibrosis

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Lauren Dembeck, PhD

A study published in the American Journal of Hematology has confirmed the adverse prognostic impacts of numerous non-driver gene mutations in primary myelofibrosis (PMF).

Researchers analyzed the impact of non-driver somatic mutations in patients with PMF treated at 60 institutions in Spain. Targeted next-generation sequencing (NGS) sequencing evaluating up to 56 non-myeloproliferative neoplasm driver genes was conducted. Of those, the team focused on 20 genes consistently analyzed across NGS panels. Only pathogenic or likely-pathogenic genetic variants with a variant allele frequency (VAF) higher than 1% were considered mutations.

A total of 312 patients with PMF according to World Health Organization criteria at the time of diagnosis and with availability of NGS data were included in the analysis. The median age of the cohort was 68 years. At a median follow-up duration of 4 years, 9% of patients had progressed to acute myeloid leukemia, and 47% had died.

Overall, 72% of patients had non-driver mutations, with 47% having 2 or more mutations (range, 0-7). The most frequent mutations detected were in ASXL1 (34%), TET2 (22%), SRSF2 (17%), U2AF1 Q157 (9%), CBL (8%), EZH2 (7%), TP53 (6%), DNMT3A (6%), and SETBP1 (5%).

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