Management of Severe Colitis in the Setting of Experimental Immunotherapy Combination
Alejandro Garcia-Alvarez1, Alberto Hernando1, Fabiola Amair-Pinedo1 and Eva Muñoz Couselo1,2
1Department of Medical Oncology, Vall d’Hebron University Hospital, Spain
2 Vall d’Hebron Institute of Oncology (VIHO), Spain
Submission: January 02, 2018; Published: April 18, 2018
*Corresponding author: Alejandro Garcia-Alvarez, Department of Medical Oncology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain, Tel: +34 93 489 30 00; Email: [email protected]
How to cite this article: Alejandro Garcia-Alvarez, Alberto H, Fabiola Amair-Pinedo, Eva M C. Management of Severe Colitis in the Setting of
Experimental Immunotherapy Combination. 2018; 3(1): 555602. DOI: 10.19080/JTMP.2018.03.555602
Introduction:Immune checkpoint inhibitors have changed the landscape for the treatment of metastatic melanoma and other solid malignancies. With their increasing use, physicians are facing a new spectrum of immune-related adverse effects. Diarrhea and enterocolitis are among the most common adverse effects.
Case report:We report the case of a patient with advanced metastatic malignant melanoma, previously treated with anti- Cytotoxic T-Lymphocyte Antigen 4 (anti-CTLA4) and anti- Programmed Death-1 (anti-PD-1) antibodies, who developed grade 3 immune-related colitis under experimental treatment with anti-PD-1 and anti-Lymphocyte Activation Gene 3 (anti-LAG3) antibodies. She received treatment with high-dose intravenous glucocorticosteroids with favorable evolution.
Discussion:Treatment of anti-PD-1 and anti-CTLA4 mediated grade 2-3 colitis consists in intravenous glucocorticosteroids. However, no treatment has been previously described for colitis related to anti-LAG3 treatment. The case of our patient highlights the fact that corticosteroids are nowadays the mainstream treatment for any immunotherapy related colitis and is an evidence of efficacy in the context of anti-LAG3 treatment.
Treatment of metastatic melanoma has profoundly changed in the last years. The durable and even complete responses achieved with immunotherapy have changed the therapeutical objectives from quality of life maintenance and symptoms management to increase in overall survival .
Thus, based on the results of several phase III trials which included more than 4400 patients [1-4], two therapeutic strategies have been approved for first-line treatment in unresectable or metastatic melanoma, namely: antibodies against the immune-checkpoint modulators Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Programmed Death-1 (PD-1) receptors, either alone or combined [1-3], and molecules that inhibit products of the oncogenes BRAF and MEK in those tumors which carry mutations in the BRAF gene . The checkpoint inhibitors Ipilimumab (anti-CTLA4 antibody), Nivolumab and Pembrolizumab (anti-PD-1) enhance the host antitumor immunity via T-cell activation and proliferation . Although 20% of patients under Ipilimumab  and 34% of patients under Nivolumab  maintain response at 10 and 5 years respectively, early disease progression has been noted with immunotherapy agents. This fact compels the search of new targets that might achieve increased and maintained responses.
The Lymphocyte Activation Gene 3 (LAG3) is a membrane protein upregulated in activated T cells that binds the Major Histocompatibility Complex (MHC) Class II molecules with high affinity . Similarly to PD-1 and CTLA-4, LAG3 negatively regulates T cells and is over expressed in tumor infiltrating lymphocytes (TILs) which suggest that this membrane protein might be a feasible target for tumoral immune modulation [7,8].
Several trials demonstrate that immunotherapy is well tolerated and adverse effects associated with these treatments are mostly grade 1 or 2 (G1-G2) according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 . Nevertheless, the evidence of a wider spectrum of adverse effects (AE) is growing as their use increase. Undesired adverse effects are thought to be related to the systemic activation of the immune system .
As new immunotherapy drugs and combinations develop physicians are constantly required to learn related adverse events, toxicities and their management with a multidisciplinar approach. This will allow creating and improving work-up algorithms. In this scenario, education of patients on early recognition of adverse events related with immunotherapy is essential. Here, we report the case of a patient with advanced metastatic malignant melanoma treated with anti-CTL4, anti-PD-1 and anti-LAG3 antibodies who
developed G3 immune-related colitis.
A 67-year-old woman with no previous medical history was
diagnosed in July 2014 of malignant nodular melanoma on her right
leg. The main lesion was a 1.5cm diameter papule surrounded by
two smaller satellite lesions (less than 1cm of diameter). Punch
biopsy histology showed signs compatible with malignant nodular
melanoma, Breslow’s depth 2,8mm, no vascular invasion neither
tumoral necrosis. Baseline LDH levels were 465UI/L. The tumour
was BRAF wild type. Selective sentinel lymph node biopsy discarded
local lymphatic invasion and PET-TC showed no distant metastases.
The tumor stage corresponded to T2 N0 M1a (Stage IV).
First-line metastatic treatment based on Dacarbazine (DTIC,
1000mg/m2 every 3 weeks) was administered in November
2014. After 2 cycles of treatment, local cutaneous progression was
observed. In December 2014, Ipilimumab (3mg/kg every 3 weeks)
was initiated as second-line treatment. The patient received four
cycles showing Stable Disease (SD) as best response. A delay of the
dose between cycle 3 and 4 was required due to Grade 2 enteritis.
In May 2015, after six months of therapy, a CT scan showed nodal
The patient was recruited into a phase III clinical trial for patients
with unresectable stage III or stage IV melanoma progressing to
an anti-CTLA4 monoclonal antibody, receiving Nivolumab since
July 2015. Partial Response (PR) was assessed after 3 cycles. Local
progression was observed by CT scan after 11 months and 21 cycles
of Nivolumab. G1 asthenia was the only adverse effect reported
within the time of treatment.
After progression, in July 2016, the patient was included in
the phase I/IIa clinical trial (Clinicaltrials.gov NCT 01968109) and
randomized to receive the combination of Nivolumab (3mg/kg
every week) and anti-LAG3 (1mg/kg every week).
At week 8, treatment was stopped because of G3 diarrhea (5
to 7 non-bloody stools per day). The patient was admitted the on
July 2016 in the Emergency Room. When admitted the patient was
febrile, without tachycardia or hypotension. Her abdomen was
benign, with no tenderness or distension and normal bowel sounds.
White blood cell count was normal. Abdominal X-Ray showed
colonic haustra without signs of bowel inflammation. Infectious
colitis was ruled out by negative bacteriological, virological and
parasitological analyses of stools including Clostridium difficile
toxin. Blood cultures were also negative.
Under suspicion on diagnosis of immune-mediated colitis in
a patient under experimental immunotherapy in which infectious
etiology has been ruled out, methylprednisolone 1mg/Kg/day was
started, according to established management guidelines .
After 3 days of treatment, diarrhea worsened to 7-8 bloody
stools per day. Taking into account the initial presumption diagnosis
and the complementary tests performed so far, an endoscopic
exploration was requested. Colonoscopy showed erythema, loss of
vascular pattern and small ulcers (up to 7mm of diameter) all along
the colonic mucosa from the rectum to the hepatic flexure. Biopsies
showed ulcerated mucosa with polymorphonuclear infiltrate of the
lamina propia as well as cryptitis and crypt abscesses (Figure 1 & 2).
These findings have been previously described in immunotherapyinduced
colitis . Methylprednisolone dose was then increased to
The patient symptoms improved in the following 72 hours.
The number of stools decreased progressively over 10 days and
the patient initiated oral intake. After 21 days of intravenous
methylprednisolone, oral prednisone (at equivalent dosage) was
started. The patient continued with 1-2 stools per day with oral
corticoids tapered off along 50 days after discharge.
Immune checkpoint inhibitors have changed the landscape for
the treatment of metastatic melanoma and other solid malignancies
[1-3]. With the increasing use of immune-based therapies for
oncology patients, physicians are likely to see a growing burden of
immune-mediated gastrointestinal toxicities . Similarly to Anti
PD1/PDL1, anti-LAG 3 modifies self-regulation of immune system,
increasing the host anti-tumor response. Hence, this might increase
the incidence of immune adverse effects .
Diarrhea and enterocolitis are among the most common
immune-related AE. Gastrointestinal symptoms usually appear
within 6-8 weeks after initiating the immune checkpoint regulators
therapy . Incidences of G3-4 enterocolitis vary between 1-3% in
anti-PD-1 therapy, being less frequent in patients treated with anti-
CTLA4 [3,5]. However, It has been reported up to 8% of G3-4 colitis
in patients treated with combined checkpoint inhibitors , and the
incidence of these events after concomitantly receiving anti-PD-1
and anti-LAG3 antibodies was one of the endpoints of the trial in
which was the patient enrolled when the gastrointestinal event was
Up to date there is no evidence that previous treatment
with anti-CTLA4 increases the toxicity of subsequent anti-PD-1
treatments. However, little is known about the safety profile of
patients treated with anti-PD-1 and anti-LAG 3 combination.
Immune mediated-colitis as usually reveals erythema, mucosal
friability and ulceration, predominantly in distant colon . Even
though colonic ulceration has been described as an independent
predictor of steroid-refractory course in enterocolitis related to
anti-CTLA4 , our patient did show a favorable evolution as she
improved in less than 48 hours after corticosteroids dose increment.
Pathologic features described in anti-CTLA4 related colitis
include both neutrophilic and lymphocytic infiltrates which are
frequently observed in chronic inflammatory bowel disease .
No biopsy proven colitis with anti-PD-1/PD-L1 has been reported
to date and in our case, other potential entities as infectious colitis
were ruled out and the patient lacked of a history of autoimmune
disorders. Hence, the changes observed in the colon mucosa may be
attributed to the experimental treatment.
Treatment of anti-PD-1 and anti-CTLA4 mediated G2-3 colitis
consists in intravenous (IV) glucocorticosteroids (1-2mg/kg
every 24 hours). If symptoms do not improve within 5 days of IV
corticoids administration, 5mg/Kg doses of the anti-TNF antibody
Infliximab should be started [5,10]. As there is no published data on
management of anti-LAG3 related colitis, we applied to our patient
the treatment algorithms for anti-PD-1 and anti-CTLA4 related
In our case, as the toxicity was secondary to experimental drugs
under clinical trial an experienced gastroenterologist evaluation was
required to optimize medical management according to immune related AEs and chronic inflammatory bowel disease protocols.
This case emphasizes the fact that corticosteroids are nowadays the
mainstream treatment for any immunotherapy related colitis and is
an evidence of efficacy in the context of anti-LAG3 treatment.
Corticosteroids doses were slowly tapered for almost two
months at the outpatient evaluation and no infliximab was required
as prompt recovery occurred. As in the case of immune related
hepatitis, enterocolitis may persist. Hence, prolonged or repeated
corticosteroid tapers (minimum of 3 weeks suggested) and/or
additional immunosuppression could be required [5,10].
Clinical trials are required to improve the outcomes of
gastrointestinal toxicities in patients treated with immunotherapy.
New approaches are needed to dilucidate the pathophysiology of
gastrointestinal immune adverse effects.
As new immunotherapies are being implemented, new
multidisciplinary protocols should carry into effect, registering new
data in protocols which involves training and expertise from other
The case of our patient highlights the importance of prompt
identification of immune-related adverse effects by both physicians
and patients, and their management. Differential diagnosis from
other plausible causes is mandatory during this process in order
to avoid detrimental effects from treatment. Finally, prompt
instauration of immunosuppressant treatment is the last step to
correctly diagnose and manage immunotherapy related symptoms.
To our concern this is the first reported case of enterocolitis in a
patient treated with a combination of anti-PD-1 anti-LAG3 therapy