Cargando…
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...
Autores principales: | , |
---|---|
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 |
_version_ | 1784756720669556736 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9324085 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT mascarenhasjohno theclinicaldilemmaofjakinhibitorfailureinmyelofibrosispredictivecharacteristicsandoutcomes AT verstovseksrdan theclinicaldilemmaofjakinhibitorfailureinmyelofibrosispredictivecharacteristicsandoutcomes AT mascarenhasjohno clinicaldilemmaofjakinhibitorfailureinmyelofibrosispredictivecharacteristicsandoutcomes AT verstovseksrdan clinicaldilemmaofjakinhibitorfailureinmyelofibrosispredictivecharacteristicsandoutcomes |