Tag Archives: myelofibrosis

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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Disease-, Age-, Genomic-Specific Factors Increase Risk of ET, PV, PrePMF Developing Into Overt MF

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Laura Joszt, MA

The risk of essential thrombocytopenia (ET), polycythemia vera (PV), and prefibrotic primary myelofibrosis (PrePMF) developing into overt myelofibrosis (MF) increases with age, the accumulation of mutations, and the activation of proliferative pathways, which identifies new targets for therapeutic intervention.

The findings, based on an analysis of the mutational landscape of more than 1700 genes and the gene expression of various cells from patients with myeloproliferative neoplasms (MPNs), was published in Clinical Cancer Research.1

ET, PV, PMF, and MF are all part of a group of diseases MPNs, in which a mutation in the bone marrow causes too many red blood cells, white blood cells, or platelets.2 In addition to being the most common MPNs, ET, PV, and PMF share the presence of mutations in either Janus kinase 2 (JAK2), calreticulin (CALR), and/or MPL.3 ET and PV are less aggressive forms of MPN, but they still can progress to MF. According to the Leukemia & Lymphoma Society, Pre-PMF will likely progress to PMF, “suggesting that more regular observations for pre-fibrotic PMF patients is warranted.”3

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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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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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JAK-STAT Pathway–Targeting Approaches in Myelofibrosis Are Evolving

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Targeted Oncology Staff

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.

Targeted Oncology: What is the latest understanding of the classification and pathogenesis of myeloproliferative neoplasms (MPNs)?

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.

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Molecular Genetic Profile of Myelofibrosis: Implications in the Diagnosis, Prognosis, and Treatment Advancements

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by Tanvi Verma 1, Nikolaos Papadantonakis2, Deniz Peker Barclift1 and Linsheng Zhang

Simple Summary

Myelofibrosis refers to fibrosis in the bone marrow associated with certain bone marrow cancers. It is a characteristic of primary myelofibrosis and may develop later in other bone marrow cancers with overproduction of blood cells, such as polycythemia vera and essential thrombocythemia. It has been confirmed that mutations in three key genes, Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia oncogene (MPL), can increase the activity of blood-producing cells, make them grow more actively, and are associated with the development of myelofibrosis. Approximately 80% of myelofibrosis cases carry additional mutations that often involve proteins that control how genes are turned on and off. The presence of mutations provides evidence of a cancerous process. The order in which these mutations occur can influence how the disease manifests. Studies have shown that fibrosis is secondary to the cancerous process and is closely linked to abnormal cell growth driven by mutations. Sophisticated scoring systems have been developed to guide treatment decisions. Specific mutations and genetic changes significantly affect the scores and survival of individual patients. Currently, common treatment involves JAK inhibitors, which can help improve clinical symptoms; however, only a small number of patients show significant alleviation in the biology of the malignant process. New treatments being explored in clinical trials include drugs that target the regulation of genes and substances that modulate the immune system or inflammatory processes. Combining these with JAK inhibitors shows promising results, especially in patients with complex genetic profiles. In the future, by studying more genes, it is expected that researchers will uncover the reasons behind cases where mutations are not found in the three key genes and understand how genetic changes are connected to variable disease presentations, ultimately guiding personalized treatment plans for better outcomes with a chance for cures.

Abstract

Myelofibrosis (MF) is an essential element of primary myelofibrosis, whereas secondary MF may develop in the advanced stages of other myeloid neoplasms, especially polycythemia vera and essential thrombocythemia. Over the last two decades, advances in molecular diagnostic techniques, particularly the integration of next-generation sequencing in clinical laboratories, have revolutionized the diagnosis, classification, and clinical decision making of myelofibrosis. Driver mutations involving JAK2, CALR, and MPL induce hyperactivity in the JAK-STAT signaling pathway, which plays a central role in cell survival and proliferation. Approximately 80% of myelofibrosis cases harbor additional mutations, frequently in the genes responsible for epigenetic regulation and RNA splicing. Detecting these mutations is crucial for diagnosing myeloproliferative neoplasms (MPNs), especially in cases where no mutations are present in the three driver genes (triple-negative MPNs). While fibrosis in the bone marrow results from the disturbance of inflammatory cytokines, it is fundamentally associated with mutation-driven hematopoiesis. The mutation profile and order of acquiring diverse mutations influence the MPN phenotype. Mutation profiling reveals clonal diversity in MF, offering insights into the clonal evolution of neoplastic progression. Prognostic prediction plays a pivotal role in guiding the treatment of myelofibrosis. Mutation profiles and cytogenetic abnormalities have been integrated into advanced prognostic scoring systems and personalized risk stratification for MF. Presently, JAK inhibitors are part of the standard of care for MF, with newer generations developed for enhanced efficacy and reduced adverse effects. However, only a minority of patients have achieved a significant molecular-level response. Clinical trials exploring innovative approaches, such as combining hypomethylation agents that target epigenetic regulators, drugs proven effective in myelodysplastic syndrome, or immune and inflammatory modulators with JAK inhibitors, have demonstrated promising results. These combinations may be more effective in patients with high-risk mutations and complex mutation profiles. Expanding mutation profiling studies with more sensitive and specific molecular methods, as well as sequencing a broader spectrum of genes in clinical patients, may reveal molecular mechanisms in cases currently lacking detectable driver mutations, provide a better understanding of the association between genetic alterations and clinical phenotypes, and offer valuable information to advance personalized treatment protocols to improve long-term survival and eradicate mutant clones with the hope of curing MF.