Category Archives: Myelofibrosis

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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Broad next generation integrated sequencing of myelofibrosis identifies disease-specific and age-related genomic alterations

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Malathi Kandarpa; Dan Robinson; Yi-Mi Wu; Tingting Qin; Kristen Pettit; Qing Li; Gary Luker; Maureen Sartor; Arul Chinnaiyan; Moshe Talpaz
Purpose: Myeloproliferative neoplasms (MPNs) are characterized by the overproduction of differentiated myeloid cells. Mutations in JAK2, CALR and MPL are considered drivers of Bcr-Abl-ve MPNs, including essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic primary myelofibrosis (prePMF) and overt myelofibrosis (MF). However, how these driver mutations lead to phenotypically distinct and/or overlapping diseases is unclear. Experimental Design: To compare the genetic landscape of MF to ET/PV/PrePMF, we sequenced 1711 genes for mutations along with whole transcriptome RNA-seq of 137 MPN patients. Results: In addition to driver mutations, 234 and 74 genes were found to be mutated in overt MF (N=106) and ET/PV/PrePMF (N=31), respectively. Overt MF had more mutations compared to ET/PV/prePMF (5 vs 4 per subject, P=0.006). Genes frequently mutated in MF included high-risk genes (ASXL1, SRSF2, EZH2, IDH1/2 and U2AF1), and Ras pathway genes. Mutations in NRAS, KRAS, SRSF2, EZH2, IDH2 and NF1, were exclusive to MF. Advancing age, higher DIPSS and poor overall survival (OS) correlated with increased variants in MF. Ras mutations were associated with higher leukocytes and platelets, and poor OS. The comparison of gene expression showed upregulation of proliferation and inflammatory pathways in MF. Notably, ADGRL4, DNASE1L3, PLEKHGB4, HSPG2, MAMDC2 and DPYSL3 were differentially expressed in hematopoietic stem and differentiated cells. Conclusions: Our results illustrate that evolution of MF from ET/PV/PrePMF likely advances with age, accumulation of mutations, and activation of proliferative pathways. The genes and pathways identified by integrated genomics approach provide insight into disease transformation and progression, and potential targets for therapeutic intervention.

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Addition of Parsaclisib to Ruxolitinib Decreases Spleen Volume and Improves Symptom Scores Among Patients With Myelofibrosis

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Jordan Kadish

02/23/2024

The addition of parsaclisib to stable-dose ruxolitinib treatment decreased spleen volume, improved symptom scores, and yielded acceptable safety among patients with primary or secondary myelofibrosis (MF), according to findings from a phase 2 trial published in Blood Advances.

Abdulraheem Yacoub, MD, The University of Kansas Cancer Center, Kansas City, Kansas, and coauthors explained that although ruxolitinib has demonstrated beneficial results among patients with intermediate- or high-risk myelofibrosis, “suboptimal response may occur, potentially because of signaling via the phosphoinositide 3-kinase (PI3K)/protein kinase B pathway.”

In this phase 2 trial, the study authors aimed to measure the potential benefit of adding PI3Kδ inhibitor parsaclisib to ruxolitinib treatment among patients with primary or secondary myelofibrosis who did not have optimal responses to ruxolitinib alone. The primary end points were dosing, efficacy, and safety of this treatment combination.

All patients included in this study stayed on a stable dose of ruxolitinib. Among these patients, 32 were administered parsaclisib at 10 or 20 mg once daily for 8 weeks, then once weekly afterward (daily-to-weekly dosing). Additionally, 42 patients were administered parsaclisib at 5 or 20 mg once daily for 8 weeks, and then 5 mg once daily afterward (all-daily dosing).

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