Immune Checkpoint Inhibitor Therapy- Toxicity Management

Immune related colitis

• Summary
• Background
• Diagnosis
• Investigation
• Treatment/Management
• Appendix 1 - Patient Information Leaflet Infliximab for immunotherapy related colitis
• Appendix 2 - Sample administration sheet for Ambulatory care
• Appendix 3 - Organising an infliximab infusion for immunotherapy-related colitis patients
• Appendix 4 - Appendix 4: SOP for Urgent Flexible Sigmoidoscopy for Possible Immunotherapy Induced Colitis

Summary of Guideline

Patients with immune related colitis with usually present with new onset of diarrhoea following commensal of the immune checkpoint inhibitor, this can either be through a gradual change in bowel habit or a sudden change. It is rare for a patient to present with an acute complication of immune related colitis e.g. bowel perforation. Patients presenting with new diarrhoea on ICPI therapies should have a full GI history taken to ensure any other risk factors for a new change in bowel habit are screened for (e.g. thyroid dysfunction, infective, diverticular disease) and also screen for symptoms of other immune related toxicities as it is possible to present with multiple toxicities at the same time.
Examination should assess for signs of dehydration and evidence of acute severe colitis (e.g. peritonism, abdominal distension).
Diagnosis is based on the exclusion of any other cause of diarrhoea in a patient receiving treatment with an ICPI, treatment should not be delayed whilst awaiting the results of any investigations.
Investigations are performed to look for any other cause for the change in bowel habit (e.g. infection) and are detailed further below. It is important that those with grade 3 and 4 colitis undergo an urgent flexible sigmoidoscopy to review the macroscopic and microscopic appearance of the bowel and all patients having sigmoidoscopy should have biopsies, even if the macroscopic appearance is normal.
Treatment is focused at suppressing the immune activation responsible for the inflammatory process and in the first instance this should be done with corticosteroids (administered orally or intravenously as per the severity based on grading the diarrhoea (see below) this will also dictate the regularity of monitoring. If steroids are not effective then patients may require further management with other immunosuppressive agents. Please see below for more details.

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Background

Immunotherapy is now an established therapeutic option across a growing number of malignancies. Some of the most commonly used agents include ipilimumab (anti-CTLA4), nivolumab (anti- PD1) and pembrolizumb (Anti-PD-L1).

These treatments however can lead to autoimmune-like adverse events related to their ability to induce the immune system. While the toxicities may be severe, early management can be associated with limited impact on organ function and quality of life.

Epidemiology
Gastrointestinal (GI) toxicity is one of the most commonly recognised adverse events. Diarrhoea is seen in 19% of patients receiving anti-PD-1/PD-L1, 33% receiving anti-CTLA-4 medications and 44% of patients receiving combination therapy.1,2 Colitis defined clinically, radiologically or endoscopically in patients receiving anti‐CTLA‐4 therapy has ranged from 8% to 22%.1

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Diagnosis

Clinical Evaluation
The pattern for developing colitis is unpredictable and can occur anytime during therapy. Figure 1 shows timing of developing GI symptoms on ipilimumab. Patients usually present with diarrhoea, abdominal pain, nausea, vomiting, haematochezia, weight loss and fever. In severe cases patient may become clinically dehydrated. Patients need to be graded from 1-4 according to clinical symptoms to aid investigation and management.

Figure 1. Timeline of ipilimumab related adverse event. Reprinted from (3) VC 2012 American Society of Clinical Oncology.

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 Investigation

 

1. Infective causes of diarrhoea need to be ruled out by performing stool samples for microscopy and culture, ova, parasites, cryptosporidia and Clostridium difficile toxin.
2. The sensitivity and specificity of faecal calprotectin are not yet known with conflicting evidence from observational studies.
3. Baseline blood tests including FBC, U+E, LFT, TFTs and CRP should be obtained.
4. The other possible differential is tumor related metastatic causes which would need to be ruled out in certain malignancies such as melanoma.
5. Radiology: An abdominal plain film should be performed if patients complain of abdominal pain. In case of severe symptoms abdominal CT is required to rule out serious complications such as perforation.
6. Endoscopic investigations: Flexible sigmoidoscopy with biopsies is the diagnostic standard for patients with grade 3-4 symptoms or those with persistent grade 2 symptoms. Opportunistic infections such as CMV infection need to be ruled out by immunohistochemical staining of biopsy samples. The inflammatory changes tend to be more diffuse rather than patchy. It should be noted that there are also emerging cases of microscopic colitis (particularly with pembolizumab or nivolumab), so histopathology results are still important if the colonic mucosa looks normal.4 Ileocolonoscopy should be considered in patients with treatment-refractory or persistent diarrhoea, particularly if the flexible sigmoidoscopy and biopsies are normal. Endoscopy and duodenal biopsies may also be important if colonoscopy and biopsies are normal.5(Please see the appendix below regarding the procedure for referral to endoscopy).
7. In patients whom infliximab is being considered, screening for this should take place including, hepatitis B and C screens, HIV, Varicella zoster, quantiferon testing.

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Treatment/Management

Treatment of immunotherapy induced diarrhoea/colitis is based on the grading of symptoms (Figure 2). Patients with grade 1 symptoms should be managed with supportive measures such as loperamide, encouragement of oral fluids and electrolyte replacement (e.g. dioralyte) solution. Those with persistent and/or worsening grade 1 symptoms or those with grade 2 toxicity should commence prednisolone. The starting dose of prednisolone is 60 mg OD and this is tapered by 10 mg every 5 days. Patients should also receive bone protection and PPI cover during steroid treatment alongside PJP prophylaxis using co-trimoxazole (please see separate steroid guideline for further details).

Patients with persistent, worsening or relapsing grade 2 symptoms or those with severe grade 3/4 toxicity should be admitted for IV methylprednisolone at a dose of 2 mg/kg/day. On admission patients need to be screened for infliximab suitability by performing Hepatitis B+C screen, VZV IgG and a recent CXR to rule out latent TB. Patients need to be monitored closely for 72 hours. Patients who respond to IV steroids should switch to oral tapering form after 3-5 days. Patients who do not respond to IV steroids or those who have a relapse requiring an increase in the dose of steroids should be switched to infliximab, providing there are no contra-indications. Infliximab is given at a dose of 5 mg/kg. A further dose 2 weeks later may be required in some patients. Rarely a third dose 6 weeks later may be needed. Overall one third to two thirds of patients fail to respond to steroids.

In patients whom there is a clinical concern regarding escalation of treatment then specialist gastroenterology advice can be sought via the on-call consultant via ward J91 or J92 or the on call consultant on the weekend. For patients who are not responding to infliximab there is the potential to escalate treatment further but this would require individual patient discussion and funding discussion.