Chiara Demichelis1,2, Andrea Balestra3,4, Caterina Lapucci5,3, Angela Zuppa5,3, Stefano G Grisanti5,3, Valeria Prada5, Giampaola Pesce3,6, Ilaria Grasso5, Paola Queirolo3, Angelo Schenone5,3, Luana Benedetti3, Marina Grandis5,3. 1. Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy. demichelis.chiara@gmail.com. 2. IRCCS Ospedale Policlinico San Martino, Genoa, Italy. demichelis.chiara@gmail.com. 3. IRCCS Ospedale Policlinico San Martino, Genoa, Italy. 4. Department of Internal Medicine, University of Genoa, Genoa, Italy. 5. Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy. 6. Autoimmunity Laboratory DiMI, University of Genoa, Genoa, Italy.
Abstract
INTRODUCTION: In the last years, many new drugs have been developed targeting different oncology pathways, overall improving both quality of life and survival in several malignancies. However, the increase of those therapies is associated with novel toxicities, mainly immune-related adverse events (irAEs), never observed before. Different irAEs are now well characterized, and, among them, neuromuscular complications, following immune checkpoint inhibitor (ICPi) therapy, are increasingly studied and described. However, there are also neurological complications related to the use of other targeted therapies, less known and probably underestimated. Herein we describe two oncological patients who developed neuromuscular diseases after administration of targeted therapies, different from ICPi. CASE REPORTS: The first patient was treated with the combination of Vemurafenib and Cobimetinib, BRAF and MEK inhibitors, respectively, for a cutaneous melanoma. One year after the beginning of the combined treatment, she developed a sub-acute motor neuropathy with predominant cranial nerve involvement. She was successfully treated with methylprednisolone. The second patient received therapy with Imatinib, tyrosine kinase inhibitor and precursor of the targeted therapy, for a gastrointestinal stromal tumour. Few days after the first administration, he developed generalized myasthenia gravis with respiratory failure. Clinical remission was obtained with plasma-exchange, intravenous immunoglobulins and steroids. DISCUSSION AND CONCLUSION: We strengthen the relevance of neuromuscular complications which may occur long after treatment start or in patients receiving not only the latest ICPi but also "older" and apparently better-known targeted therapies. Also in the latter cases, an immune-mediated "off-target" pathogenic mechanism can be hypothesized, and consequences can be life threatening, if not promptly diagnosed and appropriately managed.
INTRODUCTION: In the last years, many new drugs have been developed targeting different oncology pathways, overall improving both quality of life and survival in several malignancies. However, the increase of those therapies is associated with novel toxicities, mainly immune-related adverse events (irAEs), never observed before. Different irAEs are now well characterized, and, among them, neuromuscular complications, following immune checkpoint inhibitor (ICPi) therapy, are increasingly studied and described. However, there are also neurological complications related to the use of other targeted therapies, less known and probably underestimated. Herein we describe two oncological patients who developed neuromuscular diseases after administration of targeted therapies, different from ICPi. CASE REPORTS: The first patient was treated with the combination of Vemurafenib and Cobimetinib, BRAF and MEK inhibitors, respectively, for a cutaneous melanoma. One year after the beginning of the combined treatment, she developed a sub-acute motor neuropathy with predominant cranial nerve involvement. She was successfully treated with methylprednisolone. The second patient received therapy with Imatinib, tyrosine kinase inhibitor and precursor of the targeted therapy, for a gastrointestinal stromal tumour. Few days after the first administration, he developed generalized myasthenia gravis with respiratory failure. Clinical remission was obtained with plasma-exchange, intravenous immunoglobulins and steroids. DISCUSSION AND CONCLUSION: We strengthen the relevance of neuromuscular complications which may occur long after treatment start or in patients receiving not only the latest ICPi but also "older" and apparently better-known targeted therapies. Also in the latter cases, an immune-mediated "off-target" pathogenic mechanism can be hypothesized, and consequences can be life threatening, if not promptly diagnosed and appropriately managed.
Authors: Oliver Klein; Antoni Ribas; Bartosz Chmielowski; Grant Walker; Arthur Clements; Georgina V Long; Richard F Kefford Journal: J Clin Oncol Date: 2013-03-18 Impact factor: 44.544
Authors: Grant A McArthur; Paul B Chapman; Caroline Robert; James Larkin; John B Haanen; Reinhard Dummer; Antoni Ribas; David Hogg; Omid Hamid; Paolo A Ascierto; Claus Garbe; Alessandro Testori; Michele Maio; Paul Lorigan; Celeste Lebbé; Thomas Jouary; Dirk Schadendorf; Stephen J O'Day; John M Kirkwood; Alexander M Eggermont; Brigitte Dréno; Jeffrey A Sosman; Keith T Flaherty; Ming Yin; Ivor Caro; Suzanne Cheng; Kerstin Trunzer; Axel Hauschild Journal: Lancet Oncol Date: 2014-02-07 Impact factor: 41.316
Authors: James S Wilmott; Georgina V Long; Julie R Howle; Lauren E Haydu; Raghwa N Sharma; John F Thompson; Richard F Kefford; Peter Hersey; Richard A Scolyer Journal: Clin Cancer Res Date: 2011-12-12 Impact factor: 12.531