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The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes

Two Janus‐associated kinase inhibitors (JAKi) (initially ruxolitinib and, more recently, fedratinib) have been approved as treatment options for patients who have intermediate‐risk and high‐risk myelofibrosis (MF), with pivotal trials demonstrating improvements in spleen volume, disease symptoms, an...

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Autores principales: Mascarenhas, John O., Verstovsek, Srdan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9324085/
https://www.ncbi.nlm.nih.gov/pubmed/35385124
http://dx.doi.org/10.1002/cncr.34222
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author Mascarenhas, John O.
Verstovsek, Srdan
author_facet Mascarenhas, John O.
Verstovsek, Srdan
author_sort Mascarenhas, John O.
collection PubMed
description Two Janus‐associated kinase inhibitors (JAKi) (initially ruxolitinib and, more recently, fedratinib) have been approved as treatment options for patients who have intermediate‐risk and high‐risk myelofibrosis (MF), with pivotal trials demonstrating improvements in spleen volume, disease symptoms, and quality of life. At the same time, however, clinical trial experiences with JAKi agents in MF have demonstrated a high frequency of discontinuations because of adverse events or progressive disease. In addition, overall survival benefits and clinical and molecular predictors of response have not been established in this population, for which the disease burden is high and treatment options are limited. Consistently poor outcomes have been documented after JAKi discontinuation, with survival durations after ruxolitinib ranging from 11 to 16 months across several studies. To address such a high unmet therapeutic need, various non‐JAKi agents are being actively explored (in combination with ruxolitinib in first‐line or salvage settings and/or as monotherapy in JAKi‐pretreated patients) in phase 3 clinical trials, including pelabresib (a bromodomain and extraterminal domain inhibitor), navitoclax (a B‐cell lymphoma 2/B‐cell lymphoma 2‐xL inhibitor), parsaclisib (a phosphoinositide 3‐kinase inhibitor), navtemadlin (formerly KRT‐232; a murine double‐minute chromosome 2 inhibitor), and imetelstat (a telomerase inhibitor). The breadth of data expected from these trials will provide insight into the ability of non‐JAKi treatments to modify the natural history of MF.
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spelling pubmed-93240852022-07-30 The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes Mascarenhas, John O. Verstovsek, Srdan Cancer Review Articles Two Janus‐associated kinase inhibitors (JAKi) (initially ruxolitinib and, more recently, fedratinib) have been approved as treatment options for patients who have intermediate‐risk and high‐risk myelofibrosis (MF), with pivotal trials demonstrating improvements in spleen volume, disease symptoms, and quality of life. At the same time, however, clinical trial experiences with JAKi agents in MF have demonstrated a high frequency of discontinuations because of adverse events or progressive disease. In addition, overall survival benefits and clinical and molecular predictors of response have not been established in this population, for which the disease burden is high and treatment options are limited. Consistently poor outcomes have been documented after JAKi discontinuation, with survival durations after ruxolitinib ranging from 11 to 16 months across several studies. To address such a high unmet therapeutic need, various non‐JAKi agents are being actively explored (in combination with ruxolitinib in first‐line or salvage settings and/or as monotherapy in JAKi‐pretreated patients) in phase 3 clinical trials, including pelabresib (a bromodomain and extraterminal domain inhibitor), navitoclax (a B‐cell lymphoma 2/B‐cell lymphoma 2‐xL inhibitor), parsaclisib (a phosphoinositide 3‐kinase inhibitor), navtemadlin (formerly KRT‐232; a murine double‐minute chromosome 2 inhibitor), and imetelstat (a telomerase inhibitor). The breadth of data expected from these trials will provide insight into the ability of non‐JAKi treatments to modify the natural history of MF. John Wiley and Sons Inc. 2022-04-06 2022-07-15 /pmc/articles/PMC9324085/ /pubmed/35385124 http://dx.doi.org/10.1002/cncr.34222 Text en © 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Review Articles
Mascarenhas, John O.
Verstovsek, Srdan
The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes
title The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes
title_full The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes
title_fullStr The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes
title_full_unstemmed The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes
title_short The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes
title_sort clinical dilemma of jak inhibitor failure in myelofibrosis: predictive characteristics and outcomes
topic Review Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9324085/
https://www.ncbi.nlm.nih.gov/pubmed/35385124
http://dx.doi.org/10.1002/cncr.34222
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