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BITOX

Belgian Multidisciplinary Immunotoxicity Board (BITOX)

Combination therapy: ICI + TKI

ICI: Immune Checkpoint Inhibition
TKI: Tyrosine Kinase Inhibition
AE: adverse event

Note: This is not a diagnosis/management tool for patients. Patients should always consult their treating specialist.

General principles

Types of AEs:

  • most frequent overlapping AEs: fatigue, diarrhea, hepatotoxicity, endocrine toxicity and skin reactions
  • see image below: overview of typical AEs with TKI and ICI, adapted from McGregor et al 2021 Cancer Treatment Reviews

Timing of AE:

  • TKI: usually early (< weeks) after treatment initiation and quick to regress following dose hold
  • ICI: unpredictable, can be months after treatment discontinuation

Management principles:

  • according to CTCAE v5.0 grade and probable culprit
grade 1 mild: a- to paucisymptomatic no intervention required
grade 2 moderate: minimal symptoms local/non-invasive treatment
grade 3 severe: important symptoms, hospitalisation required medical treatment
grade 4 life threatening urgent intervention



* treatment options:

 
 
 
 

In case of preexisting autoimmunity contact the organ specialist who treats the autoimmune disorder

In collaboration with

Rhumato-onco taskforce KBVR/SRBR (Yves Piette, Ellen Delanghe)

Gauthier Remiche, ULB Erasme

Olivier Lambotte, AP-HP, Hôpital Bicêtre, Service de Médecine Interne et Immunologie Clinique, Paris, France

Dimitri Psimaras, Praticien Hospitalier, Département de Neurologie Mazarin, GHPS, Paris, France

 

Hepatitis

Assessment and investigations

  • Review medications: e.g. statins, antibiotics, alcohol history and alternative medicines (herbs)
  • Perform liver screen: – Hepatitis A/B/C serology – Hepatitis E PCR – Anti-ANA/SMA/LKM/SLA/LP/LCI – Iron studies
  • Consider imaging for metastases/portal trombosis

Skin toxicity

General information regarding skin toxicity

Skin toxicity is among one of the most common AEs observed with ICPi and usually develops within the first few weeks after treatment initiation. However, serious skin toxicity is rare and usually does not require dose reductions, or treatment discontinuation. The most frequent skin AEs are rash, pruritus and vitiligo. More rarely, other skin AEs have been reported with ICPI: alopecia areata, stomatitis, xerosis cutis and photosensitivity. Exacerbation of psoriasis has also been anecdotally reported, as well as psoriasiform or lichenoid skin reactions in patients without any history of such skin disease.

Arthritis

Symptom Grade

  • Moderate or severe pain
  • Limiting instrumental activities of daily living and may disable self care
  • Signs of inflammation such as joint swelling
  • Awaking of pain at night
  • Early morning stiffness (>30min)
  • Multiple joints may be affected

Skin toxicity – Grade 1

 
Assessment and investigations
  • Perform anamnesis, clinical assessment, and basic lab tests

Management escalation pathway

  • Apply local therapy (topical ultra-high and high potency corticosteroids)
  • Prescribe second-generation antihistamines
  • Continue ICPI and monitor

Colitis – Grade 2 - Low Risk

 

Treat ambulatory

 

  • Initiate oral methylprednisolone at a dose of 2x 32 mg per day, start first dose in hospital.
  • Initiate oral antibiotics (e.g. ciproxin 250 mg BID) in case of suspected infectious origin and adapt according to result of coproculture

Colitis – Grade 3 or 4

 

Assessment and Investigations

  • Perform anamnesis
  • Physical examination
  • Blood analysis (H, S, CRP)
  • Coproculture
  • Perform CT-scan and rectosigmoidoscopy (if no risk of perforation)
  • Check CMV on bowel biopsy

 

Management escalation pathway

Hospitalize:
  • Consult with abdominal surgeon: consider laparotomy in case of bowel perforation
  • Consult ICU physician: manage shock
  • Manage dehydration, malnutrition and anemia according to standard practice.
  • Start Solumedrol 125 mg iv 1x/day for 3 consecutive days
  • Initiate oral antibiotics (e.g. ciproxin 250 mg BID) in case of suspected infectious origin and adapt according to result of coproculture

Colitis – Grade 2 - Low Risk -

 

Yes, the diarrhea stopped within 72h and no recurrence on day 4 and 5

 

  • Taper steroids every 5 days (provide taper plan on paper to the patient)
  • Control blood tests weekly until normal or return to baseline
  • In case or recurrence, treat according to medium risk management guidelines

ICPi might be resumed >1 week after stopping steroid therapy and in the absence of diarrhea/colitis recurrence (https://www.ncbi.nlm.nih.gov/pubmed/31163011)

Colitis – Grade 2 - Low Risk

 

No, the diarrhea did not stop within 72h or had recurrence on day 4 and 5

 

Treat according to medium risk management guidelines

Colitis – Grade 2 – Medium risk

 

Yes, the diarrhea stopped within 72h

 

Initiate oral methylprednisolone at a dose of 2x 32 mg per day.

Colitis – Grade 2 – Medium risk

 

No, the diarrhea did not stopped within 72h

 

Administer infliximab 5 mg/kg + methylprednisolone 40mg iv BID (consider consultation gastroenterologist)

Arthralgia – Grade 1

 

Management escalation pathway

  • Initiate analgesia with paracetamol and/or NSAID (If not contraindicated)
  • Continue ICPI

Assessment and Investigations

  • Complete rheumatological history
  • Examination of all joints and skin
  • Consider imaging to exclude metastases
  • Consider ultrasound to exclude artritis

Arthralgia – Grade 2

 

Management escalation pathway

  • Escalate analgesia and use NSAID (if not contraindicated) or low dose corticoids (≤10mg prednisone)
  • Benefits of corticoids may be reevaluated by a rheumatologist after 2 weeks; in case of doubt contact rheumatologist before
  • Discuss witholding ICPi until resolution of pain (if corticoids are required, restart of ICPi should be discussed in a multidisciplinary team)

Assessment and Investigations

  • Perform X-rays to assess inflammatory pathology, always consider other imaging to exclude possible metastasis
  • Complete rheumatological history
  • Examination of all joints and skin
  • Consider ultrasound to exclude arthritis
  • Autoimmune panel:
    – ACPA
    – RF
    – ANA (by indirect immunofluorescence) followed by more specific analysis if positive result (according to local practice)

Arthritis

 

Management escalation pathway

  • Severity of pain is not a criterium for escalating treatment, treatment will rather be defined by the type and amount of joints affected
  • Escalate analgesics and use NSAID (if not contraindicated)
  • Prednisone (10-20mg) to be started ideally after consultation with rheumatologist
  • Withhold ICPI until resolution of symptoms and tapering of corticoids
  • Intra-articular injections only if infection was ruled out (usually done by treating rheumatologist and to be considered if only one joint is affected)
  • Consider methotrexate/leflunomide/salazopyrine/TNF blocker if steroid refractory or for steroid sparing purposes (experience and not evidence based)

Assessment and Investigations

  • Evaluate pain with visual analogue scale
  • Always do X-ray (consider arthropathy, pre-existing arthropathy, metastasis or baseline evaluation)
  • If possible, try to objectify arthritis (eg by ultrasound or arthrocentesis) and always consider joint aspiration especially when fever or severe inflammation is present (to rule out septic arthritis and crystalarthropathies)
  • Complete rheumatological history regarding differential diagnosis
  • Clinical examination of all joints

Autoimmune panel:

  • ACPA
  • RF
  • ANA (by indirect imunofluorescence) followed by more specific analysis if positive result (according to local practice)
  • ANCA (to be discussed with rheumatologist)
  • Joint biopsy can be done in collaboration with certain centres for scientific purposes

Rheumatology department where joint biopsy is done for scientific purposes

  • Ghent University Hospital
  • Hopital St-Pierre, Brussels
  • Hopital St-Luc, UCL, Brussels
  • Hopital Universitaire de Liège, ULG
  • University Hospital Leuven

Skin toxicity – Grade 2-4 – Low risk

Assessment and investigations

  • Perform anamnesis, clinical assessment, and basic lab test

 

Management escalation pathway

  • Treat ambulatory
  • Apply topical steroids as indicated
  • Apply symptomatic treatment to associated symptoms (e.g. itching, dry skin) as indicated second-generation antihistamines
  • If symptoms persist > 6 days consult dermatologist

Symptoms resolved to grade 0 or 1?

Yes:

  • Stop topical therapy
  • Restart ICPI

No:

  • biopsy should be done

Skin toxicity – Grade 2-4 – High risk

Assessment and investigations

  • Perform biopsy
  • Perform blood analysis

Management escalation pathway

  • Hospitalize in ICU/burn unit
  • Apply electrolyte and fluid control
  • Apply nutritional control initiated antibiotic therapy as indicated
  • Apply general burn unit measures (e.g. sterile handling, antiseptic solution, repeated cultures, pain management …)
  • Withhold ICPI and consider other causes (treatment related, paraneoplastic, …)
  • Instore systemic immunosuppression (corticoids and beyond)

Skin toxicity – Grade 2-4 – Medium risk

 

Assessment and investigations

  • Biopsy should be done

Management escalation pathway

  • Treat ambulatory or hospitalize
  • Apply topical steroids as indicated
  • Apply symptomatic treatment to associated symptoms (e.g. itching, dry skin) as indicated second-generation antihistamines
  • Initiate oral/iv methylprednisolone at a dose of 1mg/kg BW per day in case of steroid responsive toxicity
  • Treat with antibiotics as indicated after taking swaps

Symptoms resolved to grade 0 or 1

Yes:

  • restart ICPI (can be combined with topical corticoids but not with oral corticoids)
  • Taper oral steroids over >1 month
  • For bullous dermatitis, a long corticosteroid taper is indicated followed by a period of low dose corticosteroids (3-4 months with 4-8 mg/d)

No:

  • Hospitalize patient
  • Consider increasing the dose of steroids to 2 mg/kg BW
  • For bullous dermatitis resistant to corticoids Omalizumab (anti-IgE) might be considered (experience and not evidence based)

Hepatitis – Grade 1

 
 
 

Management escalation pathway

  • Continue ICPI
  • If bilirubin is increasing or in case of doubt: postpone 1 week:
    • if hereafter it remains stable or lowers: ICPI can be restarted
    • if hereafter it becomes grade II either for AST, ALT or bilirubin: perform serology and imagery to exclude other causes

Hepatitis – Grade 2

 

Management escalation pathway

  • Withhold ICPI treatment until normalisation of ALT/AST to grade I
  • If rising ALT/AST when re-checked wait until normalisation unless grade III or bilirubin increases: start methylprednisolone 1mg/kg (https://www.ncbi.nlm.nih.gov/pubmed/29427729)

Assessment and Investigations

  • Re-check LFTs/INR/albumin every 3 days
  • Review medications, e.g. statins, antibiotics and alcohol history
  • Perform liver screen: – Hepatitis A/B/C serology – Hepatitis E PCR – Anti-ANA/SMA/LKM/SLA/LP/LCI – Iron studie
  • Consider imaging for metastases/portal trombosis
 
More information

Steroid wean:

-G2: once G1, wean over 2 weeks; re-escalate if worsening; treatment may be resumed once prednisolone < 10 mg

-G3/4: once improved to G2, can change to oral prednisolone and wean over 4 weeks; for G3, rechallenge only at consultant discretion

Worsening despite steroids:

– If on oral change to i.v. (methyl)prednisolone

– If on i.v. add MMF 500-1000 mg b.d.

– If worse on MMF, consider addition of tacrolimus

– A case report has described the use of anti-thymocyte globulin in steroid + MMF-refractory fulminant hepatitis

Hepatitis – Grade 3

 

Management escalation pathway

  • Suspend ICPI
  • If ALT/AST < 10 x ULN and normal bilirubin/INR/albumin: wait and see (https://www.ncbi.nlm.nih.gov/pubmed/29427729)
  • If bilirubin > 3ULN or if patient was treated with anti-CTLA4/anti-PD(L)1 treatment: oral prednisolone 1 mg/kg
  • Low threshold to admit if clinical concern (hypoglycaemia, increasing bilirubin, lowering INR or albumin) treat intravenously: i.v. (methyl)prednisolone 2 mg/kg

Assessment and Investigations

  • Daily LFTs/INR/albumin
  • Perform US with Doppler with liver biopsy if no bleeding diathesis (should be discussed with specialised anatomopathologist)
  • If refractory after 3 days to corticoids or bleeding diathesis: consult hepatologist

More information

Steroid wean:

-G2: once G1, wean over 2 weeks; re-escalate if worsening; treatment may be resumed once prednisolone < 10 mg

-G3/4: once improved to G2, can change to oral prednisolone and wean over 4 weeks; for G3, rechallenge only after multidisciplinary discussion

Worsening despite steroids:

– If on oral change to i.v. (methyl)prednisolone or higher dose of i.v. (methyl)prednisolone

– If on i.v. add MMF 500-1000 mg b.d. (after discussion with hepatologist)

– If worse on MMF, consider addition of tacrolimus

Hepatitis – Grade 4

 

Management escalation pathway

  • Suspend ICPI
  • If bilirubin < 3ULN: oral prednisolone 1 mg/kg
  • If bilirubin > 3ULN or one of the following hypoglycaemia, increasing bilirubin, lowering INR or albumin: admit patient treat intravenously: i.v. (methyl)prednisolone 2 mg/kg

Assessment and Investigations

  • Daily LFTs/INR/albumin
  • Perform US with Doppler with liver biopsy if no bleeding diasthesis (should be discussed with specialised anatomopathologist)
  • If refractory after 3 days to corticoids or bleeding diasthesis: consult hepatologist

Worsening despite steroids:

– If on oral change to i.v. (methyl)prednisolone

– If on i.v. add MMF 500-1000 mg b.d. after discussion with hepatologist

 

Steroid wean and ICPI rechallenge

Steroid wean:

-G2: once G1, wean over 2 weeks; re-escalate if worsening; treatment may be resumed once prednisolone < 10 mg

-G3/4: once improved to G2, can change to oral prednisolone and wean over 4 weeks

-Only resume ICPI if steroids are fully tapered; ideally this is discussed at a multidisciplinary meeting

Nephritis – Grade 1

Management escalation pathway

  • Continue ICPI
  • Repeat creatinine weekly
  • When worsening treat as grade II

Assessment and Investigations

  • Review hydration status, medications, urine test, culture if urinary tract infection symptoms
  • Dipstick urine and send for protein assessment UPCR
  • If obstruction suspected: renal US +/- doppler to exclude obstructions or a clot

Nephritis – Grade 2

Management escalation pathway

  • Withhold ICPI
  • Hydration and review creatinine in 48-72h; if not improving, discuss with nephrologist the need for biopsy and if attributed to irAE, initiate steroids (oral prednisolone 1mg/kg)
  • When returning to Grade 1, or baseline: restart ICPI might be discussed upon corticoid stop

Assessment and Investigations

    • Renal ultrasound +/- doppler to exclude obstructions or a clot
    • If proteinuria: 24h collection or UPCR
    • Advise patient to notify if oliguric

Nephritis – Grade 3

Management escalation pathway

  • Withhold ICPI
  • Admit patient for monitoring and fluid balance
  • Repeat creatinine every 24h
  • Early discussion with nephrologist and need for biopsy and initiation of i.v. (methyl)prednnisolone 2 mg/kg
  • Restart ICPI only when steroids are completely stopped and after multidisciplinary discussion

Assessment and Investigations

  • Consider renal biopsy
  • Perform UPCR

Nephritis – Grade 4

Management escalation pathway

  • As per Grade 3
  • Patient should be managed in hospital where renal replacement therapy is available

Assessment and Investigations

  • As for Grade 3

Transversal myelitis

Signs & Symptoms

  • Acute or subacute neurological signs/symptoms of motor/sensory/autonomic origin
  • Most have sensory symptoms
  • Often bilateral symptoms

Evaluation

  • Always MRI to exclude compression
  • Lumbar puncture after brain imaging: analysis of CSF for white blood cell analysis (ideally including flowcytometry analysis), proteinorraghy, glucose level, presence for neoplastic cells
  • infectious workup (incl. viral and bacterial analysis in CSF and blood according to local practice (incl. viral and bacterial analysis in CSF and blood: eg varicella, hepatitis E, HSV1, HSV2, VZV, EBV, syphilis, HIV, CMV …):
  • Blood analysis for: lactate, copper levels in the blood, TSH, B12
  • Autoimmune serology: anti-MOG, anti-aquaporin-4 IgG, ANF

Management

  • IV 500mg-1gr methylprednisolone during 3-5 days followed by oral steroid tapering
  • Plasmapheresis might be indicated if no response to corticoid therapy upon 1 week of treatment
  • ICU admission should be considered if autonomic instability
  • Neurological consult

Encephalitis

Signs & Symptoms

  • Coma – Acute neurological deficit (aphasia, paralysis etc)
  • Epilepsy – Confusion
  • Might be rapidly worsening

Evaluation

  • Brain MRI
  • Lumbar puncture after brain imaging: analysis of CSF for white blood cell analysis (ideally including flowcytometry analysis), protein level, glucose level, presence for neoplastic cells
  • Infectious workup (incl. viral and bacterial analysis in CSF and blood: according to local practice and epidemiology (eg varicella, hepatitis E, HSV1, HSV2, VZV, EBV, HIV,…):
  • Lactate
  • EEG
  • Autoimmune serology: neuronal surface antibodies and/or intracellular neuronal antibodies according to clinical presentation in the serum (except anti-NMDA R Ab are done on CSF (can be done later, therefore keep CSF)
  • ICPi-related encephalitis is an exclusion diagnosis

Management

Treat with following combination:

  • 1-2mg/kg methylprednisolone IV
  • 10mg/kg 3 x pd acyclovir until PCR for viral infections is negative
  • 2gr 3 x pd ceftriaxone, 500mg 3 x pd metronidazole, 2gr 6x pd ampicilline until negative cultures
  • ICU admission should be considered and cases should be discussed with a neurologist

Hyperthyroidism – Asymptomatic

Management

  • Pursue ICPI
  • No treatment

Assessment and Investigations

  • Repeat thyroid function tests
  • Medication history: amiodarone or lithium therapy

Hyperthyroidism – Severe

Management

  • Hold ICPi, restart when downgraded to grade 2
  • Treat same as grade 2 – Symptomatic
  • Discuss with endocrinologist

 

 

See 'Hyperthyroidism - Symptomatic'

 

 

 

Hyperthyroidism – Symptomatic

Management

Pursue iCPI

  • In the hyperthyroid phase, patients may benefit from beta blockers if symptomatic (e.g., atenolol 25-50 mg daily, titrate for HR < 90 if BP allows). Monitor closely with regular symptom evaluation and fT4 testing every 2 weeks
  • Introduce thyroid hormones (see hypothyroidism management) if the patient becomes hypothyroid (low T4/T3, even if TSH is not elevated)

Assessment and Investigations

  • Thyroid function tests (fT3, fT4, TSH)
  • Anti-TPO, TSI
  • Thyroid echography (nodule?)
  • Medication history: amiodarone or lithium therapy
  • Suspect Graves’ disease if :
    – pretreatment by anti-CTLA-4
    – persistant hyperthyroidism beyond 6 weeks

Hypothyroidism – Subclinical

Management

  • Pursue ICPI
  • Start standard thyroid hormone replacement therapy if TSH > 10 mIU/L with normal free T4

Assessment and Investigations

  • Repeat TSH and free T4 testing after 6-8 weeks and adjust thyroid hormone dose accordingly.
  • If TSH is above reference range, increase thyroid hormone dose by 12,5 mcg to 25 mcg.
  • After identification of the appropriate maintenance dose, further evaluation is required every year, or sooner if patient’s

Hypothyroidism – Severe

Management

  • Hold ICPI, restart when downgraded to grade 2
  • Treat same as grade 2 – Clinical
  • Discuss with endocrinologist

See also Hypothyroidism – Clinical

 

Hypothyroidism – Clinical

Management

  • Pursue ICPI
  • Start standard thyroid hormone replacement therapy: initial dose can be the full dose (1.6 mcg/kg) in young, healthy patients, but a reduced dose of 25 -50 mcg should be initiated in elderly patients or known cardiovascular disease.

Assessment and Investigations

  • Repeat TSH and free T4 testing after 6-8 weeks and adjust thyroid hormone dose accordingly.
  • If TSH is above reference range, increase thyroid hormone dose by 12.5 mcg to 25 mcg
  • After identification of the appropriate maintenance dose, further evaluation is required every year, or sooner if patient’s status changes

Aseptic meningitis – Mild

Signs & Symptoms

Headache, fever and meningeal symptoms

Evaluation

  • Brain MRI to exclude brain metastasis and leptomeningeal involvement
  • Lumbar puncture after brain imaging: analysis of CSF for white blood cell analysis (ideally including flowcytometry analysis), protein level, glucose level, presence for cancer cells
  • Infectious workup (incl. viral serologies and (myco)bacterial analysis in CSF and blood according to local practice)
  • blood analysis for lactate
  • Open pressure measurement (done during lumbar puncture)

Management

  • Suspend ICPi untill clear diagnosis
  • Exclude infectious cause before start of steroids
  • Prednisone according to local practice: symptoms should disappear within 1 week if not: treat as severe aseptic meningitis
  • Symptomatic treatment (paracetamol and NSAID)
  • Restart of ICPi can be discussed in a multidisciplinary team if symptomatology was mild and steroids are stopped for some time
  • Evacuating lumbar punctures to lower elevated ICP, consider other measures to lower elevated ICP

Aseptic meningitis – Severe

Signs & Symptoms

Presence of complications such as seizures, paralysis or impaired consciousness

Evaluation

  • Brain MRI to exclude brain metastasis and leptomeningeal involvement
  • Lumbar puncture after brain imaging: analysis of CSF for white blood cell analysis (ideally including flowcytometry analysis), protein level, glucose level, presence for cancer cells
  • Infectious workup (incl. viral serologies and (myco)bacterial analysis in CSF and blood according to local practice)
  • blood analysis for lactate
  • Open pressure measurement (done during lumbar puncture)

Management

  • Suspend ICPi
  • Patient should have neurological consultation
  • Exclude infectious causes before start of steroids
  • ICU transfer for symptom management and exclusion of other causes
  • High dose prednisone according to local practice
  • No response within 1 week: consider second line immune suppressants

Uncomplicated Peripheral neuropathy – Mild

Management escalation pathway

  • Low threshold to withhold ICPI
  • Close monitoring for any progression

Assessment and Investigations

  • Comprehensive neurological examination
  • Autoimmune anamnesis alcohol history, medication – diabetic screen – B12/folate – HIV – TSH – autoimmune serology – alcohol stigmata
  • MRI brain or spine (exclude CVA, structural cause)
  • Lumbar puncture to exclude tumor invasion (after brain CT scan)
  • Contact neurologist.

Uncomplicated Peripheral neuropathy – Moderate

 

Management escalation pathway

  • Withhold ICPI
  • Initial observation reasonable vs direct iniation of prednisolone 0.5 to 1 mg/kg (if progressing, e.g. from mild)
  • Pregabalin or duloxetine might be introduced for pain
  • If no clinical improvement after 48h, manage as severe
  • Consider Myasthenia Gravis, GBS or CIDP
  • Only consider resuming ICPI after multidisciplinary discussion

 

Advice on steroid wean:

  • Conversion from i.v. to oral steroids at clinician discretion once improvement is noted
  • Suggested oral prednisolone taper for 4-8 weeks
  • Consider PJP prophylaxis, vitamin D if > 4-weeks duration

Assessment and Investigations

  • Consider EMG for lower moter neuron and/or sensory change
  • Neurological consult
  • Perform imagery to exclude local compression due to cancer progression

Uncomplicated Peripheral neuropathy – Severe

 

Management escalation pathway

  • Withhold ICPI and admit patient Initiate (methyl) prednisolone 2mg/kg i.v.
  • Involve neurologist in care
  • Respiratory function should be checked 6 x pd
  • Daily or more frequent neurological review according to severity

 

Multidisciplinary team involvement:

  • Physiotherapy, occupational therapy and speech therapy as appropriate, opthalmology review for ocular/cranial nerve issues
  • Orthopedic devices (e.g. for foot drop) should be considered

Assessment and Investigations

  • MRI brain/spine advised
  • EMG
  • Lumbar puncture
  • Consider pulmonary function or diafragmatic function tests
  • Neurological consult

Peripheral neuropathy Guillain Barré Syndrome

 

Signs & Symptoms

Symptomatology may be very atypical: eg. cranial nerve involvement, dyspnea, swallowing impairment, pain syndrome -weakness may worsen within hours

Evaluation

  • GBS is a clinical diagnosis! Don’t wait with treatment untill all assessments have been done
  • EMG
  • Lumbar puncture after brain imaging: typically elevated protein with normal white blood cell count
  • CMV, mycoplasma, hepatitis E, campylobacter jejuni serology, check presence of anti-GQ1b antibodies
  • Swallowing analysis
  • Pulmonary function tests with vital capacity and maximum inspiratory/expiratory pressures; respiratory function should be evaluated 6 x pd
  • ECG

Management

  • IVIg therapy
  • Plasmapheresis or IVIg therapy might be repeated
  • FU in accordance with local neurologists
  • Corticoid treatment discussion
  • Consider location of care where ventilatory support is available (required in 15-30% of idiopathic cases)
  • Close FU of patient: monitoring of respiratory function at least 6 x pd + (ECG) monitoring in order to detect autonomic dysfunction
  • DVT prevention

 

Corticoid treatment discussion

Not indicated for idiopathic GBS, however some case reports show interesting results with ICPI induced GBS with methylprednisolone 1-2mg/kg (check literature). Among the neurology community discussion is ongoing if ICPI induced GBS is similar to chronic inflammatory demyelinating polyneuropathy (CIDP). The latter has a similar symptoms as GBS but has a slower onset and in contrast to GBS, for CIDP corticoids are indicated.
  •  

Pneumonitis – Grade 1

 

Management escalation pathway

Consider delay of treatment

  • Monitor Symptoms every 2-3 weeks
  • When worsening: treat as grade 2 or 3-4

Assessment and Investigations

  • Chest X-Ray
  • Regular blood analysis including CRP
  • Consider sputum sample and screening for viral, opportunistic or specific bacterial infections (mycoplasma, legionella) depending on the clinical contact

 

Check in medical history

  • Underlying cardiac or respiratory disease: pulmonary hypertension, connective tissue disease (eg preexisting interstitial lung disease)
  • Past or ongoing infectious diseases: HIV, Influenza, Mycobacterium Tuberculosis exposure
  • Smoking, travel and allergens history (including exposure to home occupational aeroallergens)

 

Differential Diagnosis

  • Other causes of pneumonia (including atypical pneumonia, Pneumocystis Jirovicei, Tuberculosis, …)
  • Carcinomatous lymphangitis
  • Pulmonary oedema
  • Pulmonary emboli
  • Sarcoidosis

 

Steroid weaning upon symptom control

  • Grade 2: wean oral steroids over at least 6 weeks, titrate to symptoms
  • Grade 3/4: wean steroids over at least 8 weeks, check evolution with CT scan

Caution during steroid treatment:

  • Calcium & vitamin D supplementation as per local guidelines
  • Pneumocystis prophylaxis to be considered: Cotrimoxazol 480mg 3 times a week

 

 

Restart immunotherapy

  • Should be discussed multidisciplinary among oncologist and pneumologist  patient should be included in risk assessment (only 7 out 10 cases of pneumonitis had a relaps of pneumonitis upon ICPI restart https://www.ncbi.nlm.nih.gov/pubmed/28798088)
  • Only indicated once steroids are completely weaned and CT lung is completely cleared

Pneumonitis – Grade 2

 

Management escalation pathway

Withhold ICPi

  • Monitor symptoms: hospitalize patient in case of doubt
  • Start antibiotic if suspicion of infection (fever, CRP, neutrophil counts, purulent sputa)
  • If no evidence of infection or no improvement with antibiotics after 48h add (methyl)prednisolone 1 mg/kg/day orally
  • If no improvement after 48h of oral prednisolone, manage as per Grade 3
  • Consider Pneumocystis prophylaxis depending on the clinical context (especially in immunosuppressed and lymphopenic patients)

Assessment and Investigations

  • High resolution CT
  • Regular blood analysis including CRP
  • Analyse sputum sample (incl screening for viral, opportunistic or specific bacterial infections (mycoplasma, legionella))
  • Discuss bronchoscopy and BAL with pneumologist
  • Perform lung function tests, including TCLO

 

Check in medical history

  • Underlying cardiac or respiratory disease: pulmonary hypertension, connective tissue disease (eg preexisting interstitial lung disease)
  • Past or ongoing infectious diseases: HIV, Influenza, Mycobacterium Tuberculosis exposure
  • Smoking, travel and allergens history (including exposure to home occupational aeroallergens)
  • Discuss previous exposure to thoracic radiotherapy with radiotherapist

 

Differential Diagnosis

  • other causes of pneumonia (including atypical pneumonia, Pneumocystis, Tuberculosis, …)
  • Carcinomatous lymphangitis
  • Pulmonary oedema
  • Pulmonary emboli
  • Sarcoidosis

 

Steroid weaning upon symptom control

  • Grade 2: wean oral steroids over at least 6 weeks, titrate to symptoms
  • Grade 3/4: wean steroids over at least 8 weeks (evaluate with CT scan)

Caution during steroid treatment:

  • Calcium & vitamin D supplementation as per local guidelines
  • Pneumocystis prophylaxis to be considered: Cotrimoxazol 480mg 3 times a week

 

 

Restart immunotherapy

  • Should be discussed multidisciplinary among oncologist and pneumologist  patient should be included in risk assessment (only 7 out 10 cases of pneumonitis had a relaps of pneumonitis upon ICPI restart https://www.ncbi.nlm.nih.gov/pubmed/28798088)
  • Only indicated once steroids are completely weaned and CT lung is completely cleared

Pneumonitis – Grade 3

 

Management escalation pathway

Discontinue ICPi

  • Hospitalize patient, consider ICU care
  • Start (methyl)prednisolone i.v. 2 mg/kg/day + cover with empiric antibiotics
  • consider treatment with cotrimoxazole for Pneumocystis (until PCR comes out negative)

Assessment and investigations

  • Perform blood test
  • Analyze sputum for bacteria, viral and other opportunistic infections
  • High resolution CT
  • Bronchoscopy and BAL as well as lung function tests to be discussed with pneumologist

If no improvement or worsening after 48h

  • Discuss addition of Infliximab 5 mg/kg or other secondary immunosuppressant with pneumologist or in multidisciplinary board
  • Continue with i.v. steroids
  • Exclude other diagnosis including diaphragm paralysis due to concurrent immune related (cardio)myositis

 

Check in medical history

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  • Underlying cardiac or respiratory disease: pulmonary hypertension, connective tissue disease (eg preexisting interstitial lung disease)
  • Past or ongoing infectious diseases: HIV, Influenza, Mycobacterium Tuberculosis exposure
  • Smoking, travel and allergens history (including exposure to home occupational aeroallergens)
  • Discuss previous exposure to thoracic radiotherapy with radiotherapist

Differential Diagnosis

Steroid weaning

  • Other causes of pneumonia (including atypical pneumonia, Pneumocystis, Tuberculosis, …)
  • Carcinomatous lymphangitis
  • Pulmonary oedema
  • Pulmonary emboli
  • Sarcoidosis

Steroid considerations

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  • Grade 2: wean oral steroids over at least 6 weeks, titrate to symptoms
  • Grade 3/4: wean steroids over at least 8 weeks (evaluate with CT scan)

Caution during steroid treatment:

  • Calcium & vitamin D supplementation as per local guidelines
  • Pneumocystis prophylaxis to be considered: Cotrimoxazol 480mg 3 times a week

 

Restart immunotherapy

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  • Should be discussed multidisciplinary among oncologist and pneumologist  patient should be included in risk assessment (only 7 out 10 cases of pneumonitis had a relaps of pneumonitis upon ICPI restart https://www.ncbi.nlm.nih.gov/pubmed/28798088)
  • Only indicated once steroids are completely weaned and CT lung is completely cleared

Diabetes Mellitus – Normal

Evaluation

  • Screen for new-onset diabetes
  • Or worsening of pre-existing diabetes

Assessment and Investigations

  • Repeat fasting glycemia within one week

Management

  • Subcutaneous Insulin therapy
  • Continue ICPI once adequate glycemic control

Diabetes Mellitus – Severe

Evaluation

  • Fulminant diabetes mellitus, with or without diabetic ketoacidosis
  • Rule out sepsis, adrenal insufficiency

Assessment and Investigations

  • Urea & Electrolytes/CRP/Full Blood Count
  • Ketones on capillary blood, urine or blood
  • Random serum cortisol/ACTH
  • Cultures, imaging as indicated

Management

  • ICPI can be resumed when glycemia and general status has recovered
  • Intravenous hydration, correction of electrolytes
  • Intravenous Insulin therapy

Adrenalitis – Asymptomatic or Mild

Assessment and Investigations

 Adrenalitis Unlikely
  • 8 am or random cortisol >160 µg/L
Possible
  • 8 am cortisol 70-160 µg/L
  • Or random cortisol 30-160 µg/L
Likely
  • 8 am cortisol <70 µg/L
  • Or random cortisol <30 µg/L

Management

  • Await hormonal assessment (<24h)
  • Start physiological substitution with hydrocortisone 10-5-5mg if adrenalitis possible or likely
  • Continue ICPI once adequately substituted

Adrenalitis – Severe

Assessment and Investigations

Adrenal crisis, rule out sepsis
Adrenalitis Unlikely
  • Random cortisol >160 µg/L
Likely
  • Random cortisol <160 µg/L

Management

  • Urgent hydrocortisone stress dose of hydrocortisone 100mg IV (or IM)
  • Intravenous hydration
  • Hold ICPI
  • Taper to physiological substitution in consultation with Endocrinology
  • Measure renin-aldosterone and start fludrocortisone in consultation with Endocrinology
  • Restart ICPI once adequately substituted

Silent Hypophysitis

Assessment and Investigations

Hypophysitis Unlikely
  • 8 am or random cortisol >160 µg/L
Possible
  • 8 am cortisol 70-160 µg/L
  • Or random cortisol 30-160 µg/L
Likely
  • 8 am cortisol <70 µg/L
  • Or random cortisol <30 µg/L

Management

  • Await hormonal assessment (<24h)
  • Start physiological substitution with hydrocortisone 10-5-5mg if hypophysitis possible or likely
  • Continue ICPI once adequately substituted

Hypophysitis

Assessment and Investigations

Hypophysitis Unlikely
  • Random cortisol >160 µg/L
Likely
  • Random cortisol <160 µg/L

Rule out mass-effect symptoms of hypophysitis, adrenal crisis, rule out sepsis
Perform MRI of the pituitary gland + whole brain imaging (exclude metastasis)

Management

  • Urgent hydrocortisone stress dose of hydrocortisone 100mg IV (or IM)
  • Intravenous hydration
  • Hold ICPI
  • Taper to physiological hydrocortisone substitution in consultation with Endocrinology
  • If low fT4 and low/normal TSH, first await 72h of hydrocortisone substitution before starting thyroxine replacement therapy
  • Restart ICPI once adequately substituted

Polymyalgia rheumatica

Management escalation pathway

  • Diagnosis and treatment (corticoid therapy) can be done by oncologist/GP except when diagnosis is not clear or when there is lack of respons to corticoids (which suggests an alternative diagnosis)
  • Corticoid treatment: 20 mg predni and tapering over 9-12 months (https://www.ncbi.nlm.nih.gov/pubmed/26352874)

Assessment and Investigations

  • Blood sample: often elevated ESR/CRP (should be done before starting corticoids); CKs should be normal (in contrast to myositis)
  • Check for symptoms of giant cell arteritis in order to avoid sudden blindness (discuss temporal artery biopsy with rheumatologist/internist)

Myastenia gravis

Management escalation pathway

  • Steroids indicated (oral or i.v.)
  • Pyridostigmine initial dose 30 mg
  • Neurological consult If no improvement, or worsening, plasmapheresis or IVIG may be considered
  • Avoid certain medications, that may precipitate cholinergic crisis (e.g. ciprofloxacin, beta blockers, amikacin, benzodiazepines and above all curares during general anesthesia)’)

Assessment and Investigations

  • Check for ocular muscle and proximal muscle fatigability AChr and MuSK antibodies
  • Bedsides tests, e.g. Tensilon test or ice pack test with neurological input
  • Repetitive nerve stimulation and single fibre EMG
  • Exclude myocarditis with cardiac enzymes (and cardiac MRI in case of doubt) (cave pseudo myasthenic myositis)

Myositis – Grade 1

Management escalation pathway

  • In case of doubt withhold ICPI
  • Initiate paracetamol/NSAID
  • If symptom severity increases despite NSAID consider treatment cfr grade 2
  • Control CK after one week, if increasing: discuss with local myositis specialist

Assessment and Investigations

  • Complete history of all organ systems
  • Perform examination of joints and skin
  • Exclude cardiac origin (CKMB/troponin/pro-BNP and ECG) and in case of doubt perform cardiac MRI
  • ! Troponin I is more specific of cardiac involvement than troponin T
  • Exclude other causes of elevated CK: IM injection, physical activity, …

Myositis – Grade 2

Management escalation pathway

  • Stop ICPI
  • Start corticoids 1mg/kg after discussion with internist/rhumatologist/neuromuscular specialist, continue for at least 1 month even if clinical imporvement after 1 week. If needed add other immunsuppressants so corticoids can be tapered after one month
  • If no improvement after 48h (pain or CK): increase to 2 mg/kg; if still no improvement 48h later, other immunosuppressants should be discussed with experienced organ specialist
  • Consider IVIG (no reimbursment in Belgium) or bolus steroids if severe life threatening weakness, less evidence for plasma exchange

Assessment and Investigations

  • In addition to analysis for grade I:
    • Perform EMG to evaluate myopathic features
    • Assesment of diaphragm motion: X ray and perform respiratory tests both in upright and horizontal position.
  • Perform MRI of affected muscle
  • Consider muscle biopsy before start steroids (should be done by experienced specialist)
  • Analyze serology before start of steroids (ANF (+further subanalysis), myositis specific antibodies / myositis associated antibodies: according to local practice)
  • Perform spirometry in order to assess restrictive syndrom (due to paralysis of intercostal muscles)

AE possibly related to both ICI and TKI

 

G≤1 or tolerable G2

  • continue both agents
  • supportive care
  • monitor for signs of worsening

Intolerable G2 or G≥3

  • hold both ICI and TKI
  • if improvement in ≤7 days (in case of axitinib) or ≤14 days (in case of cabozantinib): suspect TKI; restart ICI as indicated
  • if no improvement in 14 days: suspect ICI; restart TKI as indicated

CTCAE grading
grade 1: mild (a/paucisymptomatic)

grade 2: moderate (minimal symptoms)

grade 3: severe (hospitalisation often required)

grade 4: life threatening

AE considered related to TKI

 

G≤1 or tolerable G2, thyroid or adrenal dysfunction:

  • continue TKI
  • supportive care
  • endocrine replacement therapy

Intolerable G2, G≥3, ONJ or AST/ALT >3-10xULN and/or bilirubin <2xULN:

  • hold TKI
  • when resolved to G≤1 or baseline: restart TKI at reduced dose
  • if recurrent/intolerant at lowest dose: discontinue TKI

Consider discontinuation TKI in case of:

  • ONJ
  • severe hemorrhage
  • GI perforation/fistula
  • acute cardiovascular events
  • severe uncontrollable hypertension
  • ALT/AST >10x ULN or >3x ULN with bili ≥2x ULN
  • nephrotic syndrome
  • RPLS

Abbrevations

ACPA: Anti Citrullinated Antibody
ANCA: Anti Neutrophil Cytoplasmic Antibody
ANF: Anti Nuclear Factor
ICPi: Immune Checkpoint Blockade Inhibition
NSAID: Non Steroidal Anti-Inflammatory Drugs
RF: Rheuma Factor

Abbrevations

H: Hematology
C: Chemistry
ICPi: Immune Checkpoint Blockade Inhibition
Hb: Hemoglobin
CRP: C Reactive Protein
BP: Blood Pressure

Abbrevations

AE: Adverse Event
ICPi: Immune Checkpoint Blockade Inhibition
BSA: Body Surface Area

Abbrevations

ICPi: Immune Checkpoint Blockade Inhibition
ALT: Alanine Transaminase
AST: Aspartate Transaminase
ANA: Anti Nuclear Antibodies
ULN: Upper Limit of Normal
LFT: Liver Function Test
SMA: Smooth Muscle Antibody
LKM: Liver/Kidney Microsome type 1
SLA: Soluble Liver Antigen
LP: Liver/Pancreas
US: Ultra Sound

Abbrevations

US: Ultra Sound
ULN: Upper Limit of Normal
ICPi: Immune Checkpoint Blockade Inhibition
UPCR: Urine Protein to Creatinine Ratio
ACPA: Anti Citrullinated Antibody
ANCA: Anti Neutrophil Cytoplasmic Antibody
CRP: C Reactive Protein
RF: Rheuma Factor

Abbrevations

CMV: Cytomegalovirus
CIDP: Chronic Inflammatory Demyelinating Polyneuropathy
GBS: Guillain Barré Syndrome
PJP: Pneumocystis Jirovei Pneumopathy

Abbrevations

CMV: Cytomegalovirus
DVT: Deep Venous Thrombosis
EEG: Electro EncephaloGram
GBS: Guillain Barré Syndrome
ICPi: Immune Checkpoint Blockade Inhibition
EMG: ElectroMyoGram
IVIg: IntraVeneous Immunoglobulins

Abbrevations

ANF: Anti Nuclear Factor
Anti-MOG Ab: Anti Myelin Oligodendrocyte Glycoprotein Antibody
CMV: Cytomegalovirus
CSF: Cerebrospinal fluid
EBV: Epstein-Barr Virus
EEG: Electro EncephaloGram
HSV: Herpes Zoster Virus
ICPi: Immune Checkpoint Blockade Inhibition
ICU: Intensive Care Unit
HIV: Human Immunedeficiency Virus
MRI: Magnetic Resonance Imaging
PCR: Polymerase Chain Reaction
VZV: Varicella Zoster Virus

Abbrevations

Anti-NMDA R Ab: Anti-N-Methyl-D-Aspartate Receptor Antibody
CSF: Cerebrospinal fluid
EBV: Epstein-Barr Virus
EEG: Electro EncephaloGram
HSV: Herpes Zoster Virus
ICPi: Immune Checkpoint Blockade Inhibition
ICU: Intensive Care Unit
HIV: Human Immunedeficiency Virus
MRI: Magnetic Resonance Imaging
PCR: Polymerase Chain Reaction
VZV: Varicella Zoster Virus

Abbrevations

CMV: Cytomegalovirus
CIDP: Chronic Inflammatory Demyelinating Polyneuropathy
GBS: Guillain Barré Syndrome
PJP: Pneumocystis Jirovei Pneumopathy

Abbrevations

ICPi: Immune Checkpoint Blockade Inhibition
ARDS: Acute Respiratory Distress Syndrome
CRP: C Reactive Protein
ULN: Upper Limit of Normal
TFT: Thyroid Function Test
TCLO: Transfer Factor for Carbon Monoxide
MMF: Mycophenolate mofetil

Abbrevations

ICPi: Immune Checkpoint Blockade Inhibition
TSH: Thyroid-Stimulating Hormone
FT4: Free Thyroxin
TSI: Thyroid Stimulating Immunoglobulins

Abbrevations

ICPi: Immune Checkpoint Blockade Inhibition
TSH: Thyroid-Stimulating Hormone
FT4: Free Thyroxin

Abbrevations

ACPA: Anti Citrullinated Antibody
ANF: Anti Nuclear Factor
C3/C4: Complement Factor 3 or 4
CK: Creatine Kinase
CK MB: Creatine Kinase Muscle
ECG: ElectroCardioGram
EMG: ElectroMyoGram
ICPi: Immune Checkpoint Blockade Inhibition
MRI: Magnetic Resonance Imaging
PD: Per Day
PO: Per Os
Pro-BNP: Pro-Brain Natriuretic Peptide
RF: Rheuma Factor
ULN: Upper Limit of Normal

Note: This is not a diagnosis/management tool for patients: patients should always consult their treating specialist