Case series of dabrafenib-trametinib-induced pyrexia successfully treated with colchicine

Jesus Vera, Jonas Paludo, Lisa Kottschade, Jessica Brandt, Yiyi Yan, Matthew S Block, Robert R Mc Williams, Roxana S Dronca, Charles Lawrence Loprinzi, Axel F Grothey, Svetomir Nenad Markovic

Research output: Contribution to journalArticle

Abstract

The most common adverse event (AE) of dabrafenib and trametinib (DT) is pyrexia, which has been reported to occur in up to 71% of patients. Pyrexia resulted in therapy discontinuation in up to 26% of patients that otherwise were benefiting from the treatment. Little is known about the pathogenesis and optimal management of this common AE. We hypothesized that the etiology of pyrexia in patients treated with DT could be extrapolated from DT-related cutaneous adverse effects in which a paradoxical MAPK pathway activation has been identified. Based on preliminary data by our group suggesting an upregulation of the mitogen-activated protein kinases (MAPKs) in human lymphocytes exposed to dabrafenib and trametinib, specifically elevated expression of phosphorylated JNK (p-JNK), p38 MAPK (p-p38 MAPK), and ERK5 (p-ERK5), we hypothesized that the mechanism of MAPK pathway activation with DT therapy is similar to that reported in patients with familial Mediterranean fever (FMF), a rare, inherited condition characterized by episodes of fever and rash that responds exceedingly well to colchicine-based therapy in which the MAPK pathway is hyper-activated. Based on this association, our group explored the use of oral colchicine for the treatment of DT-associated pyrexia in five patients with metastatic melanoma.

Original languageEnglish (US)
JournalSupportive Care in Cancer
DOIs
StatePublished - Jan 1 2019

Fingerprint

Colchicine
Fever
Mitogen-Activated Protein Kinases
Familial Mediterranean Fever
Therapeutics
JNK Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
Exanthema
dabrafenib
trametinib
Melanoma
Up-Regulation
Lymphocytes
Skin

Keywords

  • Colchicine
  • Dabrafenib
  • MAPK pathway
  • Pyrexia
  • Trametinib

ASJC Scopus subject areas

  • Oncology

Cite this

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title = "Case series of dabrafenib-trametinib-induced pyrexia successfully treated with colchicine",
abstract = "The most common adverse event (AE) of dabrafenib and trametinib (DT) is pyrexia, which has been reported to occur in up to 71{\%} of patients. Pyrexia resulted in therapy discontinuation in up to 26{\%} of patients that otherwise were benefiting from the treatment. Little is known about the pathogenesis and optimal management of this common AE. We hypothesized that the etiology of pyrexia in patients treated with DT could be extrapolated from DT-related cutaneous adverse effects in which a paradoxical MAPK pathway activation has been identified. Based on preliminary data by our group suggesting an upregulation of the mitogen-activated protein kinases (MAPKs) in human lymphocytes exposed to dabrafenib and trametinib, specifically elevated expression of phosphorylated JNK (p-JNK), p38 MAPK (p-p38 MAPK), and ERK5 (p-ERK5), we hypothesized that the mechanism of MAPK pathway activation with DT therapy is similar to that reported in patients with familial Mediterranean fever (FMF), a rare, inherited condition characterized by episodes of fever and rash that responds exceedingly well to colchicine-based therapy in which the MAPK pathway is hyper-activated. Based on this association, our group explored the use of oral colchicine for the treatment of DT-associated pyrexia in five patients with metastatic melanoma.",
keywords = "Colchicine, Dabrafenib, MAPK pathway, Pyrexia, Trametinib",
author = "Jesus Vera and Jonas Paludo and Lisa Kottschade and Jessica Brandt and Yiyi Yan and Block, {Matthew S} and {Mc Williams}, {Robert R} and Dronca, {Roxana S} and Loprinzi, {Charles Lawrence} and Grothey, {Axel F} and Markovic, {Svetomir Nenad}",
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T1 - Case series of dabrafenib-trametinib-induced pyrexia successfully treated with colchicine

AU - Vera, Jesus

AU - Paludo, Jonas

AU - Kottschade, Lisa

AU - Brandt, Jessica

AU - Yan, Yiyi

AU - Block, Matthew S

AU - Mc Williams, Robert R

AU - Dronca, Roxana S

AU - Loprinzi, Charles Lawrence

AU - Grothey, Axel F

AU - Markovic, Svetomir Nenad

PY - 2019/1/1

Y1 - 2019/1/1

N2 - The most common adverse event (AE) of dabrafenib and trametinib (DT) is pyrexia, which has been reported to occur in up to 71% of patients. Pyrexia resulted in therapy discontinuation in up to 26% of patients that otherwise were benefiting from the treatment. Little is known about the pathogenesis and optimal management of this common AE. We hypothesized that the etiology of pyrexia in patients treated with DT could be extrapolated from DT-related cutaneous adverse effects in which a paradoxical MAPK pathway activation has been identified. Based on preliminary data by our group suggesting an upregulation of the mitogen-activated protein kinases (MAPKs) in human lymphocytes exposed to dabrafenib and trametinib, specifically elevated expression of phosphorylated JNK (p-JNK), p38 MAPK (p-p38 MAPK), and ERK5 (p-ERK5), we hypothesized that the mechanism of MAPK pathway activation with DT therapy is similar to that reported in patients with familial Mediterranean fever (FMF), a rare, inherited condition characterized by episodes of fever and rash that responds exceedingly well to colchicine-based therapy in which the MAPK pathway is hyper-activated. Based on this association, our group explored the use of oral colchicine for the treatment of DT-associated pyrexia in five patients with metastatic melanoma.

AB - The most common adverse event (AE) of dabrafenib and trametinib (DT) is pyrexia, which has been reported to occur in up to 71% of patients. Pyrexia resulted in therapy discontinuation in up to 26% of patients that otherwise were benefiting from the treatment. Little is known about the pathogenesis and optimal management of this common AE. We hypothesized that the etiology of pyrexia in patients treated with DT could be extrapolated from DT-related cutaneous adverse effects in which a paradoxical MAPK pathway activation has been identified. Based on preliminary data by our group suggesting an upregulation of the mitogen-activated protein kinases (MAPKs) in human lymphocytes exposed to dabrafenib and trametinib, specifically elevated expression of phosphorylated JNK (p-JNK), p38 MAPK (p-p38 MAPK), and ERK5 (p-ERK5), we hypothesized that the mechanism of MAPK pathway activation with DT therapy is similar to that reported in patients with familial Mediterranean fever (FMF), a rare, inherited condition characterized by episodes of fever and rash that responds exceedingly well to colchicine-based therapy in which the MAPK pathway is hyper-activated. Based on this association, our group explored the use of oral colchicine for the treatment of DT-associated pyrexia in five patients with metastatic melanoma.

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