And it continues.... Here is a link to Part 8 as well as prior posts: The Saga of Side effects to Immunotherapy
Now these:
Immunotherapy-induced sarcoidosis in patients with melanoma treated with PD-1 checkpoint inhibitors: Case series and immunophenotypic analysis. Lomax, McGuire, McNeil, et al. Int J Rheum Dis. 2017 May 8.
Sarcoidosis is a multisystem granulomatous disease. This condition has a documented association with the diagnosis of melanoma and can be induced in melanoma patients receiving anti-neoplastic therapy. We evaluated a case series of melanoma patients who developed immunotherapy-induced sarcoidosis. Three patients with melanoma (n = 1 resected Stage III, n = 2 metastatic) treated with anti-programmed cell death (PD)-1 antibody therapy at two institutions developed biopsy-proven sarcoidosis. We used mass cytometry to determine expression of the relevant chemokine receptors (CR) by peripheral blood mononuclear cells for two of the three patients who developed sarcoidosis and 13 melanoma patients who did not. Blood samples were collected before receiving PD-1 checkpoint inhibitor therapy. Immunophenotypic analysis demonstrated abnormally high numbers of circulating Th17.1...cells prior to commencing PD-1 checkpoint inhibitor therapy in five of 15 melanoma patients, including both the patients who developed sarcoidosis during the course of therapy. Our findings support prior literature implicating Th17.1 cells in the pathogenesis of sarcoidosis. However, we demonstrate these findings in patients with melanoma prior to administration of checkpoint therapy and before the onset of clinically symptomatic sarcoidosis. The identification of elevated Th17.1 cells in melanoma patients who have not developed sarcoidosis may reflect the established association between melanoma and sarcoidosis. With some patients receiving these agents over a prolonged period, the clinical course of immunotherapy-induced sarcoidosis is uncertain.
Inflammatory
Myopathy and Axonal Neuropathy in a Patient With Melanoma Following
Pembrolizumab Treatment. Diamantopoulos,
Tsatsou, Benopoulou, et al. J Immunother. 2017 May 11.
Immune-mediated
adverse effects of immune checkpoint inhibitors are rather common,
but neuromyopathic immune-related adverse events are very rare. In
this report, we present a unique case of a patient with a complex
neuromyopathic syndrome with axonal neuropathy and inflammatory
myopathy after a single dose of pembrolizumab. An 82-year-old patient
with a previously untreated stage IIIc melanoma developed ptosis in
the left eye, generalized weakness, and neck and shoulder pain 15
days after pembrolizumab administration. He had left-sided ptosis and
miosis, with a normal pupillary light reflex, horizontal diplopia,
and voice hoarseness, along with weakness of the neck muscles and a
hypokinetic right vocal cord at laryngoscopy. The laboratory
evaluation was remarkable for the marked increase in the serum
lactate dehydrogenase and creatine phosphokinase levels. Further
evaluation revealed findings compatible with axonal neuropathy and
inflammatory myopathy. The patient was treated with corticosteroids,
immunoglobulin, and plasmapheresis, with a minor response; the
patient eventually died. This case represents a newly described
syndrome probably associated with pembrolizumab administration.
Neurologic
Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or
Nivolumab Alone in Advanced Melanoma, Including a Case Series of
Encephalitis.Larkin,
Chmieloski, Lao, Hodi, Weber, et al. Oncologist. 2017 May 11.
Despite
unprecedented efficacy across multiple tumor types, immune checkpoint
inhibitor therapy is associated with a unique and wide spectrum of
immune-related adverse events (irAEs), including neurologic events
ranging from mild headache to potentially life-threatening
encephalitis. Here, we summarize neurologic irAEs associated with
nivolumab and ipilimumab melanoma treatment, present cases of
treatment-related encephalitis, and provide practical guidance on
diagnosis and management. We
searched a Global Pharmacovigilance and Epidemiology database for
neurologic irAEs reported over an 8-year period in patients with
advanced melanoma receiving nivolumab with or without ipilimumab from
12 studies sponsored by Bristol-Myers Squibb. Serious neurologic
irAEs were reviewed, and relationship to nivolumab or ipilimumab was
assigned. In
our search of 3,763 patients, 35 patients (0.93%) presented with 43
serious neurologic irAEs, including neuropathy (n = 22),
noninfective meningitis (n = 5), encephalitis (n = 6),
neuromuscular disorders (n = 3), and nonspecific adverse
events (n = 7). Study drug was discontinued (n = 20),
interrupted (n = 8), or unchanged (n = 7). Most
neurologic irAEs resolved (26/35 patients; 75%). Overall, median time
to onset was 45 days (range 1-170) and to resolution was 32 days
(2-809+). Median time to onset of encephalitis was 55.5 days (range
18-297); four cases resolved and one was fatal. Both
oncologists and neurologists need to be aware of signs and symptoms
of serious but uncommon neurologic irAEs associated with checkpoint
inhibitors. Prompt diagnosis and management using an established
algorithm are critical to minimize serious complications from these
neurologic irAEs. The Oncologist 2017;22:1-10Implications
for Practice: With increasing use of checkpoint inhibitors in
cancer, practicing oncologists need to be aware of the potential risk
of neurologic immune-related adverse events and be able to provide
prompt treatment of this uncommon, but potentially serious, class of
adverse events. We summarize neurologic adverse events related to
nivolumab alone or in combination with ipilimumab in patients with
advanced melanoma from 12 studies and examine in depth 6 cases of
encephalitis. We also provide input and guidance on the existing
neurologic adverse events management algorithm for nivolumab and
ipilimumab.
Autoimmune
diabetes induced by PD-1 inhibitor-retrospective analysis and
pathogenesis: a case report and literature review. Gauci, Laly,
Vidal-Trecan, et al. Cancer
Immunol Immunother. 2017 Jun 20.
Anti-PD-1
antibody treatment is approved in advanced melanoma and provides
median overall survival over 24 months. The main
treatment-related side effects are immune-related adverse events,
which include rash, pruritus, vitiligo, thyroiditis, diarrhoea,
hepatitis and pneumonitis. We report a case of autoimmune diabetes
related to nivolumab treatment. A 73-year-old man was treated in
second line with nivolumab at 3 mg/kg every two weeks for
metastatic melanoma. At 6 weeks of treatment, he displayed
diabetic ketoacidosis. Nivolumab was withheld 3.5 weeks and
insulin therapy was initiated, enabling a normalization of glycaemia
and the disappearance of symptoms. Laboratory investigations
demonstrated the presence of islet cell autoantibodies, while
C-peptide was undetectable. Retrospective explorations on serum
banked at week 0 and 3 months before the start of nivolumab,
already showed the presence of autoantibodies, but normal insulin,
C-peptide secretion and glycaemia. Partial response was obtained at
month 3, and nivolumab was then resumed at the same dose. The
clinical context and biological investigations before, at and after
nivolumab initiation suggest the autoimmune origin of this diabetes,
most likely induced by anti-PD-1 antibody in a predisposed patient.
The role of PD-1/PD-L1 binding is well known in the pathogenesis of
type 1 diabetes. Therefore, this rare side effect can be expected in
a context of anti-PD-1 treatment. Glycaemia should be monitored
during PD-1/PD-L1 blockade. The presence of autoantibodies before
treatment could identify individuals at risk of developing diabetes,
but systematic titration may not be relevant considering the rarity
of this side effect.
Myasthenia gravis: An emerging
toxicity of immune checkpoint inhibitors. Makarious, Horwood,
Coward. Eur J Cancer. 2017 Jun 27.
The advent of immunotherapy has
heralded a number of significant advances in the treatment of
particular malignancies associated with poor prognosis (melanoma,
non-small-cell lung, renal and head/neck cancers). The success
witnessed with therapeutic agents targeting cytotoxic
T-lymphocyte-associated protein 4, programmed cell death protein 1
and programmed cell death ligand 1 immune checkpoints has inevitably
led to an explosion in their clinical application and the subsequent
recognition of specific toxicity profiles distinct from those long
recognised with chemotherapy. Consequently, as the utility of such
therapies broaden, understanding the nature, timing and management of
these immune-related adverse events (irAEs) becomes increasingly
significant. Although neurological irAEs are considered relatively
rare in comparison with hepatitis, colitis, pneumonitis and
endocrinopathies, one emerging side-effect is myasthenia gravis (MG).
Among the 23 reported cases of immune checkpoint inhibitor-associated
MG, 72.7% were de novo presentations, 18.2% were exacerbations of
pre-existing MG and 9.1% were exacerbations of subclinical MG. The
average onset of symptoms was within 6 weeks (range 2-12 weeks) of
treatment initiation. In addition, there was no consistent
association with elevated acetylcholine antibody titres and the
development of immune checkpoint inhibitor-related MG. Significantly,
there was a 30.4% MG-specific-related mortality, which further
emphasises the importance of early recognition and robust treatment
of this toxicity. In addition to a review of the existing literature,
we present a new case of pembrolizumab-induced MG and provide
insights into the underlying mechanisms of action of this phenomenon.
Pretty crazy stuff can develop as a side effect from immunotherapy. Over 7 years ago, Weber told me, "This stuff is weird!" No kidding. So, as best you can...report any worrying signs or symptoms to your doc as soon as you can. It may not result in completely eradicating the problem, but it could go a long way in curtailing additional damage or save your life! Furthermore, there is good data that rapid treatment with prednisone, sometimes with a break in treatment and sometimes not, can:
1. Bring the problem under control.
2. Often allows a return to therapy.
3. Does NOT adversely impact response to the melanoma treatment!!!!
Here are previously posted reports on how to deal with side effects to immunotherapy:
A discussion by Weber and Agarwala from 2015: Side effects and how to manage them in targeted and immunotherapy for melanoma
From 2016: How to deal with GI, endocrine, hepatic and pulmonary side effects subsequent to anti-PD-1
From 201: Neurologic side effects to immunotherapy with treatment algorithm
Hang in there peeps!!! - c
Pretty crazy stuff can develop as a side effect from immunotherapy. Over 7 years ago, Weber told me, "This stuff is weird!" No kidding. So, as best you can...report any worrying signs or symptoms to your doc as soon as you can. It may not result in completely eradicating the problem, but it could go a long way in curtailing additional damage or save your life! Furthermore, there is good data that rapid treatment with prednisone, sometimes with a break in treatment and sometimes not, can:
1. Bring the problem under control.
2. Often allows a return to therapy.
3. Does NOT adversely impact response to the melanoma treatment!!!!
Here are previously posted reports on how to deal with side effects to immunotherapy:
A discussion by Weber and Agarwala from 2015: Side effects and how to manage them in targeted and immunotherapy for melanoma
From 2016: How to deal with GI, endocrine, hepatic and pulmonary side effects subsequent to anti-PD-1
From 201: Neurologic side effects to immunotherapy with treatment algorithm
Hang in there peeps!!! - c
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