Ten years after ruxolitinib approval for myelofibrosis: a review of clinical efficacy

Pemmaraju, Naveen; Bose, Prithviraj; Rampal, Raajit K.; Gerds, Aaron T.; Fleischman, Angela; Verstovšek, Srđan

doi:10.1080/10428194.2023.2196593

Cited by 12 publications

(6 citation statements)

References 106 publications

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“…In 2011, the first JAK1/2 inhibitor, ruxolitinib, was approved for the treatment of primary and secondary myelofibrosis [ 28 ]. Subsequently, its approval was extended to include polycythemia vera and acute graft versus host disease.…”

Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Cardiovascular Toxicity of Antineoplastic Treatments in Hematological Diseases: Focus on Molecular Mechanisms to Improve Therapeutic Management

Barachini,

Buda,

Petrini

2024

JCM

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In recent years, advancements in the treatment of hematologic neoplasms have led to more effective and less toxic therapeutic schemes, resulting in prolonged patient life expectancy. However, the success of these treatments has also brought about an increased prevalence of cardiovascular adverse events, becoming a significant concern for the growing population of cancer survivors. Antineoplastic therapies, targeting both tumor and organ vessels, contribute to vascular toxicity, influenced by genetic factors and pre-existing vascular diseases. Chemotherapeutic agents and targeted treatments can induce cardiovascular toxicity by affecting endothelial cells and cardiomyocytes through various mechanisms, including hypoxia, vasculature abnormalities, and direct effects on cardiomyocytes. Cardiovascular adverse events encompass a wide range, from cardiac dysfunction to an elevated risk of arrhythmias. While early cardiac events are well-described in clinical trials, delayed toxicities are gaining relevance due to prolonged patient survival. The review focuses on the cardiac and vascular toxicity of antineoplastic drugs in hematological disorders, providing insights into the molecular physiopathology of cancer therapy-associated cardiotoxicity. Understanding how these drugs interact with the heart and blood vessels is essential for predicting, detecting, and managing chemotherapy-related heart issues.

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Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Cardiovascular Toxicity of Antineoplastic Treatments in Hematological Diseases: Focus on Molecular Mechanisms to Improve Therapeutic Management

Barachini,

Buda,

Petrini

2024

JCM

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“…In 2011, ruxolitinib (RUX) was approved in the United States for the treatment of medium-risk and high-risk MF, and was shown to be effective in improving patients' symptoms, overall survival (OS), and quality of life [20,23]. Analysis of 5-year data from the clinical studies COM-FORT-I and COMFORT-II showed that RUX was associated with long-term control of splenic outgrowth [3,24], and pooled analysis showed that reduction of splenic volume at week 24 of RUX treatment was associated with patients' prolonged OS [25].…”

Section: Timing Of Allogeneic Hematopoietic Stem Cell Transplantation...mentioning

confidence: 99%

The application of JAK inhibitors in the peri-transplantation period of hematopoietic stem cell transplantation for myelofibrosis

Wang,

Jin,

Zeng

et al. 2024

Ann Hematol

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Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with a poor prognosis, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with curative potential. Ruxolitinib, a JAK1/2 inhibitor, has shown promising results in improving patients’ symptoms, overall survival, and quality of life, and can be used as a bridging therapy to HSCT that increases the proportion of transplantable patients. However, the effect of this and similar drugs on HSCT outcomes is unknown, and the reports on their efficacy and safety in the peri-transplantation period vary widely in the published literature. This paper reviews clinical data related to the use of JAK inhibitors in the peri-implantation phase of hematopoietic stem cell transplantation for primary myelofibrosis and discusses their efficacy and safety.

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“…Ruxolitinib is currently the standard of care for high-risk MF, including both PMF and SMF. Ruxolitinib has been proven not only to alleviate the symptoms, and effectively reduce spleen size, but also to lower the level of blood cytokines, and possibly increase the overall survival although the conclusion remains controversial [120,121]. Three additional small-molecule kinase inhibitors have been approved by the United States Food and Drug Administration (US FDA) for the treatment of MF [122,123] (Table 3).…”

Section: Treatment Implicationsmentioning

confidence: 99%

“…Overall, ruxolitinib as a single agent in frontline therapy has not demonstrated a consistent biological effect in reducing the mutation burden [126]; the improvement in survival is significant in MF patients with a high mutation burden [124], but overall still controversial [125,127]. Discontinuation due to failed response, disease progression, or intolerance is up to 60% of patients within 3 years [121,128,129]. During MF disease progression, most patients develop cytopenia, usually anemia or thrombocytopenia.…”

Section: Treatment Implicationsmentioning

confidence: 99%

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

Verma,

Papadantonakis,

Peker Barclift

et al. 2024

Cancers

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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.

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Ten years after ruxolitinib approval for myelofibrosis: a review of clinical efficacy

Cited by 12 publications

References 106 publications

Cardiovascular Toxicity of Antineoplastic Treatments in Hematological Diseases: Focus on Molecular Mechanisms to Improve Therapeutic Management

Cardiovascular Toxicity of Antineoplastic Treatments in Hematological Diseases: Focus on Molecular Mechanisms to Improve Therapeutic Management

The application of JAK inhibitors in the peri-transplantation period of hematopoietic stem cell transplantation for myelofibrosis

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

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