March 13, 2024
Tim Kong, Nicole Gaudin, Karyn Gordon, Maggie J. Cox, Amy W. Zhou, and Stephen T. Oh
March 13, 2024
Tim Kong, Nicole Gaudin, Karyn Gordon, Maggie J. Cox, Amy W. Zhou, and Stephen T. Oh
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
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.
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.
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.
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.
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.
Published: Mar 06, 2024
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.
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%).
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).
During a Targeted Oncology™ Case-Based Roundtable™ event, Raajit K. Rampal, MD, gave an overview of the classification, risk assessment, and current therapy options for patients with myelofibrosis.
RAAJIT K. RAMPAL, MD, PHD: Nothing has changed in terms of the 2022 [World Health Organization] classification, unlike what has happened with myelodysplastic syndrome.1 JAK-STAT signaling is a hallmark of MPN pathogenesis, and all of the mutations that we’re aware of at the moment—JAK2, CALR [calreticulin], and MPL—function in the JAK-STAT pathway. MPL is the thrombopoietin receptor which complexes with JAK [Janus kinase].
CALR is interesting, because CALR was discovered in 2013 but we think at the moment CALR complexes with MPL and results in the aberrant activation of MPL, but CALR does traffic to the cell surface.2,3 That makes it a target for immunotherapy. That is the target of a couple of clinical trials; one is open [LIMBER (NCT06034002)] and the other is about to open, which is really interesting [and] could change everything in MPNs.
All that being said, there are still at least 8% to 15% of myelofibrosis cases that are “triple negative.”2,3 If you look at those cases by gene expression profiling, they have the JAK-STAT signature. The issue with those cases is that we haven’t identified the particular lesion that occurs there, but it is a JAK-STAT–activated lesion, regardless of what the actual driver is. Those are the important things to think about with regards to how the disease is driven.
February 6, 2024
Jonathan Goodman, MPhil
A study published in the Annals of Hematology has highlighted the characteristics of patients with post-essential thrombocythemia or post-polycythemia vera myelofibrosis (PET-MF and PPV-MF, respectively) treated during the ruxolitinib era.
Although the characteristics of patients with primary MF are well-established, less research has evaluated real-world data from patients with PET-MF or PPV-MF. Given that primary and secondary forms of the disease may have different prognoses, a greater understanding of the clinical and patient characteristics in the latter group is important. For this prospective study, researchers in Japan aimed to determine the real-world characteristics and prognoses among patients with PET-MF or PPV-MF.
Overall, data from 314 patients were evaluated, among whom 197 had PET-MF while 117 had PPV-MF. At the time of diagnosis, in the PET-MF and PPV-MF groups, the median ages were 70 and 70 years, respectively, 49.7% and 53.8% of patients were male, and the periods from ET or PV diagnosis to MF progression were 9.64 and 10.38 years. The majority of patients in both groups received ruxolitinib treatment (74.6% in the PET-MF group and 83.8% in the PPV-MF group).