Just as we learned with ipi, as more folks take anti-PD1 products, we are learning how serious some of the immune related side effects can be. First there was this: Fasciitis and encephalopathy after Keytruda. And more recently, this: Immune reactions with anti-pd1 can be serious!
Now these reports have been published:
Cytotoxic cutaneous adverse drug reactions during anti-PD-1 therapy. Goldinger, Stieger, Meier, et al. Clin Cancer Res. 2016 Mar 8.
Cytotoxic cutaneous adverse drug reactions during anti-PD-1 therapy. Goldinger, Stieger, Meier, et al. Clin Cancer Res. 2016 Mar 8.
Immunotherapy experienced
impressive progresses in cancer treatment. Antibodies against PD-1 improved
survival in different types of cancer including melanoma. They are generally
well tolerated. However, skin toxicities including pruritus, rashes and
vitiligo are reported. Although frequent, they are have not been further
characterized yet. In this analysis we aimed to systematically assess and
characterize the adverse cutaneous reactions observed in melanoma patients
treated with anti-PD-1 antibodies.
Melanoma patients were
treated with anti-PD-1 antibodies within clinical trials and early access
program. Adverse cutaneous eruptions emerged in our melanoma patient cohort
were systematically investigated and classified using histology and gene
expression profiling in comparison to maculopapular drug rash, cutaneous graft
versus host disease and the severe drug eruption toxic epidermal necrolysis.
Between Feb 2013 and Sept
2015, 68 stage IV melanoma patients were treated at the University Hospital
Zurich; 15 patients (22%) developed cutaneous reactions and 10 (15%) vitiligo.
The cutaneous reactions ranged from small erythematous papules with mild
pruritus to disseminated erythematous maculopapular rashes without signs of
epidermal involvement to severe maculopapular rashes including epidermal
detachment and mucosal involvement. Although skin involvement varied from mild
rash to bullous drug eruptions, gene expression profiling pathogenically
classified all investigated cases as toxic epidermal necrolysis-like reactions.
As predicted by the PD-1
knock out mouse, anti-PD-1 antibodies frequently cause adverse cutaneous reactions.
Gene expression profiling reminds in all cases to a toxic epidermal
necrolysis-like pattern suggesting that PD-1/PD-L1 interaction is required to
preserve epidermal integrity during inflammatory skin reactions.
Systemic inflammation in a melanoma patient treated
with immune checkpoint inhibitors-an autopsy study. Koelzer, Rothschild, Zihler,
et al. Immunother Cancer. 2016 Mar 15.
Immune checkpoint inhibitors
targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed
cell death protein 1 (PD-1) have been recently approved for treatment of
patients with metastatic melanoma and non-small cell lung cancer (NSCLC).
Despite important clinical benefits, these therapies are associated with a
diverse spectrum of immune-related adverse events (irAEs) that are typically
transient, but occasionally severe or even fatal.
This autopsy case illustrates
that clinically overt irAEs may represent only a fraction of the total spectrum
of immune-related organ pathology in patients treated with immune checkpoint
inhibitors. We report a comprehensive analysis of systemic irAE pathology based
on the autopsy of a 35-year-old female patient with metastatic melanoma treated
first with ipilimumab and then nivolumab. The clinical course was characterized
by a mixed tumor response with regression of skin and lung metastases and fatal
progression of metastatic disease in the small bowel, peritoneum and brain.
During therapy with ipilimumab, radiographic features of immune-related
pneumonitis were noted. The autopsy examination established a sarcoid-like
granulomatous reaction of the lung, pulmonary fibrosis and diffuse alveolar
damage. Importantly, a clinically unapparent but histologically striking
systemic inflammation involving the heart, central nervous system, liver and
bone marrow was identified. Severe immune-related end-organ damage due to
lymphocytic myocarditis was found.
Autopsy studies are an
important measure of quality control and may identify clinically unapparent
irAEs in patients treated with immunotherapy. Pathologists and clinicians need
to be aware of the broad spectrum of irAEs for timely management of
treatment-related morbidity.
Anti-PD1-induced collagenous colitis in a melanoma
patient. Baroudjian, Lourenco, Pagès, et al. Melanoma Res. 2016 Mar 17.
Targeted immunotherapy has
markedly improved the survival of melanoma patients. We report the case of a
melanoma patient who developed a collagenous colitis under an anti-PD1 regimen.
A 68-year-old woman was treated for a stage IV melanoma. An anti-PD1,
pembrolizumab, was introduced after the failure of a first-line therapy with an
anti-CTLA4. At cycle 14, pembrolizumab was interrupted because of grade 3 diarrhea.
Histologic analysis of colon mucosa showed a thickened apical subepithelial
collagen layer with irregular collagen deposition of more than 25 µm thickness.
Budesonide 9 mg/day and cholestyramin 8 g/day were then introduced, leading to
a decrease in the number of stools to grade 2. Because of the prognosis of the
disease, the efficacy of pembrolizumab in this patient and the lack of other
efficient treatments, pembrolizumab was restarted, with no worsening of the
diarrhea after a follow-up of 8 weeks. In the era of immunotherapy, a new type
of drug-induced colitis has emerged because of monoclonal antibodies targeting
immune checkpoints such as CTLA-4 and PD1. Gastrointestinal tract
immune-mediated adverse effects are now well described with ipilimumab. To the
best of our knowledge, this is the first report of a collagenous colitis in a
patient treated with pembrolizumab, thus suggesting a new mechanism of
toxicity. Classically, collagenous colitis first-line treatment is based on
discontinuation of the suspected treatment. However, there may be a strong
benefit to maintaining an anti-PD1 regimen in our patients. In this case,
symptomatic management associated with budesonide and cholestyramin enabled
continuation of pembrolizumab.
New-onset toxicity with programmed death-1 inhibitor
rechallenge. Ludlow, Andrews, Pasikhova, Hill. Melanoma Res. 2016 Mar 15.
Immunotherapy has become a
mainstay in the treatment of metastatic melanoma. Cytotoxic
T-lymphocyte-associated antigen-4 (CTLA-4) inhibitors and programmed death-1
(PD-1) inhibitors, which have been added more recently, represent two of the
main classes of immunomodulating agents. PD-1 inhibitors are well tolerated
and are known to have a decreased rate of occurrence of adverse effects
compared with CTLA-4 inhibitors. However, the risk remains for serious
immune-mediated adverse reactions. Given their long half and extended
efficacy, treatment with a CTLA-4 inhibitor before use of a PD-1 inhibitor
may increase the risk of adverse effects. In addition, caution should be
exercised when rechallenging grade 3 or 4 adverse effects with the same agent
or a different agent of the same class. The re-emergence of a previous
toxicity may occur or, as found in this case, a new severe effect may arise.
This article will present a case of
fatal immune-related hepatoxicity in a patient treated with a CTLA-4
inhibitor, followed by treatment with a PD-1 inhibitor.
|
Nivolumab-induced thyroid dysfunction. Tanaka, Fujisaw, Maruyama, et
al. Jpn J Clin Oncol. 2016 Mar 23.
Nivolumab (ONO-4538) is an
anti-programmed death-1 specific monoclonal antibody, which has become a
standard treatment for metastatic malignant melanoma. Nivolumab induces
autoimmune adverse events, defined as immune-related adverse events. Herein, we
report a case of nivolumab-induced thyroid dysfunction in the clinical setting.
Fourteen patients were treated with nivolumab at our institute, of which three
developed thyroid dysfunction, an incidence higher than previously reported in
the initial clinical trials. Interestingly, one patient achieved complete
remission; suggesting that in some patients, the occurrence of immune-related
adverse events, including thyroid dysfunction, might reflect the drug's
antitumour efficacy. No patient died or discontinued nivolumab treatment owing
to thyroid dysfunction. Although thyroid dysfunction first appeared to be
asymptomatic, two of the three patients developed symptoms related to
hypothyroidism soon after, requiring hormone replacement therapy. Another
patient developed hyperthyroidism that was initially asymptomatic; the patient
subsequently developed myalgia with fever >39.5°C after two additional
courses of nivolumab. Treatment with nivolumab was therefore discontinued, and
treatment with prednisolone was initiated. Symptoms resolved within a few days,
and thyroid function normalized. Thyroid dysfunction is sometimes difficult to
diagnose because its symptoms similar to those of many other diseases. In
addition, thyroid-related immune-related adverse events may present with unique
symptoms such as myalgia with high fever, abruptly worsening patients' quality
of life. Consequently, thyroid dysfunction should be considered as a possible
immune-related adverse event. Thus, it is important to test for thyroid
dysfunction at baseline and before the administration of each nivolumab dose if
possible.
Limbic encephalitis following immunotherapy against
metastatic malignant melanoma. Salam, Lavin, Turan. BMJ Case Rep. 2016 Mar 23.
Novel immunotherapies are
increasingly being used to treat malignant melanoma. The use of such agents has
been associated with triggering autoimmunity. However, there has been a paucity
in reports of limbic encephalitis associated with these immunotherapies.
Pembrolizumab, a monoclonal antibody against programmed cell death antigen
(PD-1), is currently being trialled in the UK to treat malignant melanoma. We
report a unique case of antibody-negative limbic encephalitis presenting 1 year
after starting pembrolizumab, in the context of malignant melanoma. The patient
presented with progressive cognitive decline. MRI of the brain revealed signal
change within the limbic structures. Cerebrospinal fluid studies confirmed
evidence of inflammation with raised white cell count and protein. We were able
to prevent further progression of symptoms by stopping pembrolizumab and
treating the patient instead with steroids. We advocate considering autoimmune
neuroinflammation as a differential for neurological disorders presenting in
patients receiving PD-1 antagonist treatment and immunotherapy in general.
I don't want to frighten anyone with all the crazy events documented here. Overall, anti-PD1 products have minimal side effects compared to many other cancer treatments. However, I published these so that should any "strange" things start happening to you after, or during, anti-PD1 therapy, you can speak with your doctor and get them checked out as quickly as possible. After all, as Dr. Weber mused YEARS ago, 'This stuff is weird!" - c
I don't want to frighten anyone with all the crazy events documented here. Overall, anti-PD1 products have minimal side effects compared to many other cancer treatments. However, I published these so that should any "strange" things start happening to you after, or during, anti-PD1 therapy, you can speak with your doctor and get them checked out as quickly as possible. After all, as Dr. Weber mused YEARS ago, 'This stuff is weird!" - c
