Immune Checkpoint Inhibitor Therapy- Toxicity Management

Immune Related Hepatitis

• Summary of guideline
• Background
• Diagnosis
• Investigations
• Treatment/Management
• Evidence search Strategy

Summary of Guideline

Majority of cases are asymptomatic and are detected on routine monitoring or pre-administration. Some patients report general constitutional symptoms like fatigue, nausea etc. It is rare for a patient to arrive in fulminant liver failure. Patients presenting with deranged liver function on ICPI therapies should have a targeted history for risk factors of acute hepatitis (for example, foreign travel, risk factors for exposure to hepatitis A virus, unwell contact, recent piercings/tattoos, sexual history, alcohol intake) 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 underlying chronic liver disease, acute liver failure and other causes of deranged LFTs. Targeted abdominal examination should be carried out to identify hepatomegaly or decompensated liver disease.
Diagnosis is based on the demonstration of deranged liver function tests. This can then be graded as per the European society of medical oncology guidance (ESMO).
A chronic etiology liver screen is done if patients are found to have deranged LFTs prior to administration of ICPI therapy. Acute hepatitis screen is done for new onset deranged Liver Function Tests whilst receiving ICPI therapy. These can be found on ICE in Liver Medicine Tab.
Treatment is focused at suppressing the immune activation responsible for the deranged liver function and in the first instance this should be done with corticosteroids (administered orally or intravenously as per the severity based on grading the liver dysfunction 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

All patients should have baseline liver function checked prior to commencing an immune checkpoint inhibitor therapy. Patients can have deranged liver function whilst receiving treatment with one or more immune checkpoint inhibitors. These are identified on routine pre-treatment blood monitoring or in the context of symptoms reported by patients. They should have a full set of blood tests to screen for various immune-related toxicities. This list should include full blood count, urea and electrolytes, bone profile, magnesium, thyroid function, cortisol (ideally early morning), liver function tests and a clotting screen. Hepatitis occurs in around 5-10% of patients treated with single agent immune checkpoint inhibitor therapies and up to 25% in those with combinations of checkpoint inhibitor therapies (1).

In patients presenting to a primary care team, where there is concern regarding a toxicity of treatment patients can be encouraged to contact their oncology team. All patients are given then details of a 24/7 contact number for the oncology acute assessment team based at St James’ hospital. However, if patients are presenting with non-specific symptoms, which are not clearly temporally related to treatment then ensuring the patient is investigated with the above recommended investigations in primary care would be a useful way of excluding a treatment related toxicity.

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Diagnosis

The diagnosis of immune-related hepatitis is based on blood results and the exclusion of other causes that could explain the liver function test abnormalities. Liver function tests should be checked prior commencing Immunotherapy. If baseline LFTs are abnormal, a full non-invasive liver screen should be performed.

Full Non-invasive liver screen can be requested via ICE at LTH. (Adult Services J-O--Liver Med--Liver -Aetiology Chronic tab)

LFTs should be checked at every visit as asymptomatic elevations can occur.

Patients can have one or more immune-related toxicities (e.g. eye disease, endocrine disorders, colitis) simultaneously and these should be carefully evaluated at the same time.

Examination should be performed to look for evidence of underlying chronic liver disease and sequelae of acute liver dysfunction.

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Investigations

Liver function tests should be checked prior commencing Immunotherapy.

If baseline LFTs are abnormal, a full non-invasive liver screen should be performed.

Full Non-invasive liver screen can be requested via ICE at LTH. (Adult Services J-O--Liver Med--Liver -Aetiology Chronic tab)

LFTs should be checked at every visit as asymptomatic elevations can occur.

If abnormal LFTs are identified after administration of Immunotherapy, the following should be checked as a part of work up.

FBC, LFTs, U&Es, Clotting Screen

Hepatitis A screen, Hepatitis B surface antigen, Hepatitis B core antibody, Hepatitis C Screen and Hepatitis E screen.

CMV IgM, EBV IgM (PCR if IgM +ve)

Immunoglobulins

Auto Antibodies

Ultrasound of Liver and Doppler of portal vasculature.

If LFTs deteriorate whilst receiving treatment for Immune related Hepatitis, the following additional investigations should be requested if not had in the last 4 weeks.

Hepatitis B surface antigen and HBV PCR (if core ab +ve on screening) CMV PCR and EBV PCR

If there is history to suggest viral hepatitis, please check for Hepatitis A & E.

Imaging (USS of liver and Doppler to start with).

Role of Liver Biopsy

From our limited experience and speaking to colleagues across other units, liver biopsy is not routinely performed in Immune-related hepatitis.

Liver biopsy can be considered if there is poor response to escalation therapy or in cases of atypical presentation or if diagnosis is in doubt.

This guidance might change in the future and we might biopsy all patients for better understanding of check point therapy toxicity which might aid in subsequent management.

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Treatment/Management

Treatment is based on the grading of liver dysfunction as shown below:

Grade I
Weekly monitoring whilst continuing Immunotherapy.

Grade 2

Grade 3-4

*MMF: Mycophenolate mofetil (see below)

Steroid wean:

Below is a recommended steroid weaning plan for patients. We recommended using Prednisolone commencing at 60mg once daily and then following the below guidance. All patients commencing regular steroids should be concomitantly commenced on gastro-protection with a proton pump inhibitor, bone protection and consideration given to PJP prophylaxis.

If the ALT starts to rise whilst on the steroid wean, the dose of prednisolone should be increased by 10mg for at least 2 weeks before attempting further reduction. If this recurrently happens on steroid wean then consideration should be given to commencing further immunosuppressive agents (e.g. mycophenolate mofetil/Tacrolimus) following exclusion of other causes (see above).

For further information on steroid treatment with immunotherapy toxicity please see specific guidance document on this.

Steroid sparing agents and Non responders to Mycophenolate Mofetil.

1. Mycophenolate Mofetil

Mycophenolate Mofetil is suggested by both ESMO and ASCO guidelines. The recommended dose is 1 gram twice daily. Some patients might not be able to tolerate this dose and will need dose reduction.

Please be aware of diarrhoea, CMV reactivation, leukopenia including neutropenia whilst on mycophenolate mofetil. See SPC for full list of drug toxicities.

Tacrolimus (To be prescribed brand specific as different formulations are available)

Tacrolimus (we recommend Advagraf as a once a day preparation) in patients not responding to Steroid and mycofenolate mofeltil combination or those intolerant of Mycophenolate Mofetil.

The starting dose is 2mg PO OD and this can be increased depending on trough tacrolimus levels. Aim for a trough tacrolimus level of 5. Higher levels can be aimed if not responding to lower levels.

Please monitor potassium and renal function whilst taking Tacrolimus. It can cause headaches and tremors. Please be vigilant in patients with history of seizures. See SPC for full list of drug toxicities.

Macrolides are contraindicated with Tacrolimus and patients should be given Information leaflet whilst prescribing second line therapies.

ATG (Anti Thymocyte Globulin)

Although this is suggested and successfully used in other centres for patients not responding to triple therapy or very severe presentation (coagulopathy), we have not used this locally. We suggest discussion with Hepatologists in the first instance.

Plasma Exchange

There are case reports of successful treatment with Plasma Exchange in patients who became encephalopathic secondary to severe liver injury. This can be facilitated at Leeds if needed. Please discuss with Hepatologists.

Approach to the patient presenting with immune-mediated hepatitis

The majority of patients presenting with ICPI-mediated toxicities will have low grade (grade 1-2). Whilst these patients need urngent investigation to reduce the risk of deteriorating liver function and the accompanying morbidity, patients do not immediate review. Patients requiring a non-invasive liver screen (including liver ultrasound) should be referred through to JONA for assessment on the next working day so that a planned appointment for liver USS with Doppler can be arranged. This requires the patient to be fasted for 6 hours pre procedure to allow a thorough assessment, including the gallbladder.

In patients who are clinically well with deranged liver function only, but of a severity high enough to require IV methylprednisolone therapy, IV treatment can be delivered through the supportive care unit (J87) if the patient is not requiring admission for any other reason. Please see the SOP for IV methylprednisolone via supportive care for further information on the requirements for this.

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Evidence Search Strategy

Based on Professional society guidelines, tertiary liver centre observational studies and expert consensus.