2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

CHECKPOINT PROTEIN INHIBITOR TOXICITY MANAGEMENT
colon. 12 Neutrophilic infiltrates are seen in 46% of patients,
lymphocytic infiltrates in 15%, and a mixed neutrophiliclymphocytic
infiltrate in 38%. 12,14
Low-grade diarrhea (grade 1, an increase of 2 over baseline
in 24 hours) should be treated symptomatically using
loperamide, oral hydration, and electrolyte substitution. The
American Dietary Association colitis diet is useful. With
persistent or higher-grade diarrhea, bacterial or parasitic
infection, viral gastroenteritis, or the first manifestation of
an IBD must be ruled out by examination for stool leukocytes,
stool cultures, and a Clostridium difficile titer. Grade
2 diarrhea can be treated with the addition of oral diphenoxylate
hydrochloride and atropine sulfate four times daily
and budesonide 9 mg daily. Endoscopy is recommended to
confirm or rule out colitis with persistent grade 2 diarrhea or
grades 1 to 2 diarrhea with bleeding. Endoscopy can generally
be done safely in patients with the GI side effects from
ipilimumab, although there is the risk of perforation with
biopsies. The presence and nature of colitis may change
one’s therapeutic management, since diffuse ulceration and
bleeding in the setting of grade 2 diarrhea may mandate a
course of oral steroids and skipping a dose and can also
represent an increased risk for the development of a bowel
perforation.
For grade 3 or 4 diarrhea (7 or more increase over baseline
in 24 hours), treatment with ipilimumab should be permanently
discontinued and intravenous steroids and replenishment
of fluid and electrolytes intravenously should be
instituted. Intravenous methylprednisolone 125 mg should
be given. Oral dexamethasone 4 mg every four hours or
prednisone 1 to 2 mg/kg/daily can be given thereafter,
followed by a taper and discontinuation over the next 6
weeks. Generally, there is a significant improvement of GI
symptoms within 1 to 2 weeks. Steroid therapy must be
tapered over at least 4 weeks to ensure complete resolution
of symptoms. In patients with diffuse and severe ulceration
and/or bleeding, a tapering of up to 6 to 8 weeks is appropriate
since rapid tapering can result in recurrence or
worsening of symptoms. The use of opiates and other analgesics
may mask pain associated with colitis induced by
ipilimumab. A low threshold for concern about GI complications,
including perforation and obstruction, should be maintained.
A low threshold for imaging with plain films or
computed tomography (CT), as well as a surgical consult—
especially in any patients admitted to the hospital for GI
irAE management—is appropriate.
KEY POINTS
● Immune-related adverse events (irAEs) represent a
unique spectrum of toxicities with checkpoint protein
inhibition.
● Colitis, hepatitis, endocrinopathies, and dermatologic
toxicities are seen with ipilimumab and the key to
proper management of these irAEs is good patientcaretaker
communication.
● irAEs are generally managed successfully with steroids
and other immune suppressants.
● irAEs are also observed with the anti-PD-1 antibody
BMS-936558.
If intravenous steroids followed by high-dose oral steroids
does not decrease symptoms within 48 to 72 hours, treatment
with infliximab at 5 mg/kg every 2 weeks is an
alternative. 5,15 Once relief of symptoms is achieved, which
can be very rapid and dramatic, it should be discontinued
and a prolonged steroid taper over 45 to 60 days should be
instituted. There may be a waxing and waning of the GI
toxicities of ipilimumab during the course of steroids. As
steroids are tapered, symptoms may worsen, mandating a
retapering of steroids starting at a higher dose of 80 or 100
mg, a more prolonged taper, and additional use of infliximab.
Ipilimumab should be permanently discontinued for
grade 3 or 4 diarrhea or colitis.
Dermatologic Toxicity
A diffuse, erythematous maculopapular rash that can be
intensely pruritic was observed in 47% to 68% of patients,
starting an average of 3 to 4 weeks after ipilimumab. 1-3,7-9
In 4% of patients, it was severe. Ipilimumab-induced rashes
can be quite focal or even patchy. Microscopic examination
shows a perivascular lymphocytic infiltrate that extends
deep into the dermis in most cases. 4 Immunohistochemical
staining showed that CD4-positive and Melan-A-specific
CD8-positive T cells were in close proximity to apoptotic
melanocytes, suggesting that an immune response was
directed against melanocytes. 4 This is consistent with a
reported 11% rate of vitiligo with ipilimumab. 7 Most skin
eruptions and pruritus associated with ipilimumab are generally
managed symptomatically and usually do not require
skipping a dose or discontinuation. Topical glucocorticosteroids
(e.g., betamethasone 0.1% cream) or urea-containing
creams in combination with oral antipruritics (e.g., diphenhydramine
HCl or hydroxyzine HCl) are recommended. 3 For
grade 3 dermatologic irAEs, one should hold a dose and treat
witha3to4-week tapering course of oral steroids, starting
at 1 mg/kg prednisone or dexamethasone 4 mg four times
orally daily. Ipilimumab can be held for moderate to severe
skin toxicity but should be permanently discontinued for
severe, life-threatening skin toxicity and steroids initiated
at 1 to 2 mg/kg prednisone orally or its equivalent tapering
over not less than 30 days. Rare cases of toxic epidermal
necrolysis, as well as Stevens-Johnson syndrome, both in less
than 1% of patients, have been reported with ipilimumab,
and several patients with those conditions have died.
Endocrinopathies
Hypophysitis is an uncommon complication of treatment
with ipilimumab with an incidence of approximately
1.5%. 16,17 Behavioral change, fatigue, severe headaches,
blurring or diplopia, myalgias, loss of appetite, or nausea
and vomiting have been seen, but symptoms can be vague.
Visual changes and/or headaches in patients with metastatic
melanoma should also prompt concern for possible
central nervous system or ocular metastases and should be
evaluated by magnetic resonance imaging (MRI) of the brain
with gadolinium. Hypophysitis can present as a diffuse,
heterogenous enlargement of the pituitary on a brain MRI
but can be completely normal. 18 When hypophysitis with
pituitary dysfunction is suspected, blood tests including
thyroid-stimulating hormone (TSH), free T4, adrenocorticotropic
stimulating hormone, cortisol, leutinizing hormone,
and follicle-stimulating hormone should be obtained in
women, and the first four plus testosterone in men. Typically
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