Guidelines for Management of Immunotherapy-Related Adverse Events

Transcription

1 Guidelines f Management of Immunotherapy-Related Adverse Events These guidelines apply to all patients who are receiving, have received, treatment with any of the immune checkpoint inhibits; ipilimumab, pembrolizumab, nivolumab, atezolizumab avelumab F details regarding prescribing, administration, and the routine moniting requirements f patients on immune checkpoint inhibits, see the relevant protocol available at Immune-related adverse events (iraes) usually occur within weeks to 3 months after initiation of immune checkpoint blockers. However, first onset of an immune-related adverse event may occur up to 1 year after discontinuing treatment. F management of immune-related adverse events, follow the relevant pathway(s) below: Skin toxicity Colitis Hepatitis Endocrinopathies: Thyroid, Diabetes, Hypophysitis Pneumonitis Nephritis Neurological Other Steroid taper guidance Length of steroid taper is dictated by severity of the irae. Guidance on the recommended length of taper can be found in each pathway. Regular moniting during tapering is advised, as there is a risk of irae recurrence. F out-patients, the options are: to emphasise to the patient to telephone if ANY new symptom wsening symptom, and to monit in clinic at least every 2 weeks to pro-actively monit by telephone, once twice weekly, throughout the taper. Tapering guidance: If on IV methylprednisolone, continue f 5 days, then switch to al prednisolone, if possible. F al prednisolone, reduce the dose in 10mg/day steps every 7 days, as resolution of toxicity allows. Once steroid dose is 10mg/day, consider reducing to 5mg/day f 7 days, then to zero, as appropriate. If signs symptoms of adrenal suppression, steroids will need to have a prolonged wean in steps of less than 5mg, consider physiological replacement with hydroctisone +/- endocrinology review. While on steroids, regular random blood glucose moniting is required pre-existing diabetes may require escalation in al hypoglycaemic agents insulin if new hyperglycaemia is detected, manage accdingly; endocrinology advice may be sought Consider calcium/vitamin D supplement if steroids continue > 4 weeks Monit f al candidiasis. Immunotherapy may be restarted within 12 weeks after the last dose, only if an adverse reaction remains at Grade 1 and the cticosteroid dose has been reduced to 10 mg prednisone equivalent per day. Page 1 of 11

2 Immune-related Skin Toxicities These are the most common adverse events, including maculopapular rash, pruritis and vitiligo. However serious skin adverse events are rare, and they do not usually require dose reductions treatment discontinuation. Symptom Grade Management Investigations Grade 1: Skin rash with without symptoms, < 10% BSA Avoid skin irritants and sun exposure. Recommend regular emollient use. Initiate topical Betnovate Dermovate cream once daily +/- al antihistamine f itch Proceed with immunotherapy Skin examination: Exclude other causes, e.g. viral illness, infection, other drug rash Grade 2: Skin rash covers 10% to 30% of BSA ( diffuse but light rash not associated with any symptoms) Supptive management as above Initiate topical Dermovate cream once twice daily +/- al antihistamine f itch Proceed with immunotherapy, but check weekly f improvement if the rash does not resolve, interrupt immunotherapy until reverted to grade 1. As above Consider dermatology referral and consider skin biopsy Grade 3: Skin rash covers > 30% of BSA, Grade 2 with substantial symptoms Use topical Dermovate cream twice daily. Initiate systemic steroids: If mild moderate; al prednisolone 0.5-1mg/kg/day (max 60mg/day) f 3 days, then taper over 1-2 weeks. If severe, methylprednisolone IV 0.5-1mg/kg/day, and convert to al prednisolone on response; wean over 2 4 weeks. Once resolved to G1/mild G2, Consultant and patient decision to re-start immunotherapy. As f Grade 1 Dermatology review Consider punch biopsy and clinical photography Grade 4: Skin sloughing > 30% of BSA, with associated symptoms such as erythema, purpura, epidermal detachment Initiate methylprednisolone IV 1-2 mg/kg/day Urgent dermatology review Permanently discontinue immunotherapy As f Grade 1 Dermatology review Punch biopsy and clinical photography Page 2 of 11

3 Symptom Grade Immune-related Colitis Management Investigations Grade 1 (< 4 stools day over baseline) Feeling well. Immunotherapy may continue Grade 2 (4 6 stools/day over baseline) abdominal pain blood in stool nausea nocturnal episodes. Withhold immunotherapy Symptomatic management with al fluids and loperamide (max 16mg/day; if this is ineffective, do NOT persist with other antidiarrhoeals) Avoid high fibre and lactose. G1 and symptoms persist f > 14 days, OR G2 and persists f > 3 days wsens Initiate al prednisolone mg/kg/day (max 60mg/day) (non-enteric coated) No improvement in 72 hours, wsening, absption concern All below tests required f Grade 2, and consider f Grade 1, accding to clinical setting: FBC, U&Es, LFTs, TFTs, CRP Stool microscopy f leukocytes, ova, parasites, C. difficile, cryptospidia, viral PCR. Culture stool f drug-resistant ganisms Outpatients: tests as above. Plus consider in case of abdominal discomft, abdominal x-ray f signs of colitis. Exclude steatrhea. Book sigmoidoscopy (+/- biopsy) Contact patient every 72 hours. Daily stool chart if in-patient Grade 3-4 (> 6 stools/day over baseline) Requires hospitalisation and isolation until infection excluded. Withhold immunotherapy* Initiate methylprednisolone IV 1-2 mg/kg/day. Gastroenterology input. Ensure sigmoidoscopy is requested. No improvement in 72 hours, wsening after 24 hours Inpatients: tests as above, including sigmoidoscopy. Consider CT abdomen, and repeat abdominal x-ray as indicated. Daily FBC, U&Es, LFTs, CRP. Review diet, e.g. NBM, clear fluids, TPN Early surgical review if bleeding, pain distension. Daily stool chart. *Ipilimumab should be permanently discontinued in the event of any Grade 3 4 colitis. Pembrolizumab nivolumab should be permanently discontinued in the event of any Grade 4 colitis. Consider a dose of infliximab 5mg/kg IV (if no perfation, sepsis, TB, hepatitis moderate / severe heart failure) Must have had sigmoidoscopy pri to infliximab A repeat infliximab dose after 2 weeks may occasionally be required. Ensure funding approval obtained Once symptoms of colitis have resolved, the dose of steroid may be gradually tapered over 2-4 weeks (if moderate colitis) 4 8 weeks (if severe colitis). Too-rapid de-escalation is known to risk incomplete treatment of colitis. Page 3 of 11

4 Immune-related Hepatitis Symptom Grade Management Investigations Grade 1: ALT/AST > ULN to 3 x ULN Proceed with immunotherapy Monit LFTs weekly while > ULN 3 x ULN Grade 2: ALT/AST > 3-5 x ULN If AST/ALT is rising when re-checked, persistent longer than 1-2 weeks, initiate al prednisolone 1mg/kg/day (max 60mg/day). Once resolved to G1, wean steroids over 2 weeks; re-escalate if wsening; treatment may be resumed once prednisolone 10mg. If no improvement despite steroids, increase dose to 2mg/kg/day (methyl)prednisolone and permanently discontinue immunotherapy. Re-check LFTs/INR/albumin every 3 days. Review concurrent medicines, e.g. statins, antibiotics, alcohol. Perfm liver screen: Hep A/B/C/E, anti-ana/sma/lkm/sla/lp/lci & iron studies Consider imaging f metastases / clot Grade 3: ALT/AST 5-20 x ULN Permanently discontinue immunotherapy. ALT/AST < 400 and nmal bilirubin/inr/albumin: initiate al prednisolone 1mg/kg/day* (max 60mg/day) ALT/AST > 400 raised bilirubin/inr/low albumin: initiate methylprednisolone IV 2mg/kg/day* As above, but daily LFTs/INR/albumin Perfm US with Doppler Low threshhold to admit patient if concerned. Refer to hepatologist f advice, in steroid-refracty cases Grade 4: ALT/AST > 20 x ULN Permanently discontinue immunotherapy. Initiate methylprednisolone IV 2mg/kg/day* As above Hepatology consult Consider liver biopsy * Once improved to G2, can change to al prednisolone and wean over 4 weeks * If wsening hepatitis despite steroids; - if on al, change to IV methylprednisolone - if on IV, add in mycophenolate mofetil mg bd po IV (Consultant decision only, pink fm required) Page 4 of 11

5 Immune-related Endocrinopathies Hypothyroidism: Low T4 with elevated TSH, TSH > 10 with nmal T4. Hypothyroidism may be managed with replacement therapy (start dose of thyroxine 25mcg od, check TFTs 4-weekly and adjust accdingly) without immunotherapy treatment interruption (and without cticosteroids). Consider referral to endocrinologist. Hyperthyroidism: Low TSH with elevated T4. N.B. A falling TSH across 2 measurements, with nmal lowered T4, may suggest pituitary dysfunction, and weekly ctisol levels should be perfmed. Note that subclinical hyperthyroidism (low TSH, nmal T4) often precedes overt hypothyroidism. Withhold immunotherapy if patient is unwell with symptomatic hyperthyroidism. Refer to endocrinologist. If painful thyroiditis, consider prednisolone 0.5mg/kg/day (max 60mg/day) and then taper. Immunotherapy may re-start once symptoms controlled and prednisolone 10mg/day. Diabetes: The emergence of either Type 1 Type 2 diabetes occurs in < 1% of patients treated with immune checkpoint inhibits. Steroids will negatively influence diabetic control, and it is unclear whether they will prevent total loss of beta cells in the islands of Langerhans, so they are not routinely recommended in this setting. Withhold immunotherapy until diabetic control has been achieved. Page 5 of 11

6 Immune-related Hypophysitis Inflammation of the anteri lobe of the pituitary gland. Very rare in patients treated only with PD-1/PD-L1 antibodies. Headache visual disturbances require differentiation between cerebral metastases, leptomeningeal disease, cerebrovascular disease hypophysitis. Symptoms Management Further assessment Severe headache, any visual disturbance severe hypoadrenalism (hypotension, severe electrolyte disturbance) Initiate methylprednisolone IV 1mg/kg/day after sending bloods f pituitary axis assessment*. Analgesia as needed f headache (discuss with neurologist if resistant to paracetamol and NSAIDs) Refer to endocrinologist. MRI pituitary. Aim to convert to prednisolone and wean over 4 weeks to 5mg. Do not stop steroids Monit TFTs Moderate symptoms (headache but no visual disturbance) fatigue / mood alteration but haemodynamically stable, no electrolyte disturbance Initiate al prednisolone 0.5 1mg/kg/day (max 60mg/day) after sending bloods f pituitary axis assessment* If no improvement in 48 hours, treat as severe with IV methylprednisolone as above Refer to endocrinologist. MRI pituitary. Wean steroids based on symptoms over 2-4 weeks to 5mg prednisolone. Do not stop steroids Monit TFTs Vague symptoms (mild fatigue, anexia), no headache asymptomatic (i.e. identified on routine testing) Pituitary axis bloods: 9am ctisol* ( random if unwell and cannot delay) ACTH, TSH, T 4, LH, FSH, oestradiol if premenopausal, testosterone in men, IGF-1, prolactin Proceed with immunotherapy. Send bloods f pituitary axis and await results to confirm diagnosis, but warn patient to seek urgent review if unwell. Initiate appropriate hmone replacement therapy Refer to endocrinologist. MRI pituitary. If 9am ctisol < 250, random ctisol < 150 and vague symptoms, replace with hydroctisone 20/10/10mg. Consider need f thyroxine replacement (always replace ctisol f 1 week pri to thyroxine initiation) *Caution, if the patient is already on steroids, then serum ctisol will likely be suppressed; discuss with endocrinology befe commencing replacement. Page 6 of 11

7 Immune-related Pneumonitis All patients presenting with pulmonary symptoms such as an upper respiraty infection, new cough, shtness of breath hypoxia should be assessed by CT. Monit carefully, as fatal and life-threatening cases of pneumonitis have been repted. Symptom Grade Management Investigations Grade 1: Radiographic changes only Non-specific interstitial pneumonia Grade 2: Mild/moderate new symptoms Dyspnoea, cough, chest pain Consider delay of immunotherapy Monit symptoms every 2 3 days If wsens, treat as grade 2 grade 3-4 Start antibiotics if suspicious of infection (fever, CRP, neutrophil count) If no evidence of infection, no improvement after 48 hours, add in al prednisolone 1mg/kg/day (max 60mg/day) Once resolved to baseline, wean steroids over 4-6 weeks, titrate to symptoms. Chest x-ray +/- high resolution CT FBC, U&Es, LFTs, TFTs / Ca / ESR / CRP Sputum f culture O2 sats Out-patient moniting: Monit symptoms daily Baseline tests as above, plus bloods weekly Lung function tests including TCLO (transfer fact f CO) No improvement after 48 hrs of al prednisolone, manage as G3 Grade 3 4: Severe new symptoms New/wsening hypoxia Life threatening Difficulty in breathing, ARDS Ensure funding approval obtained Permanently discontinue immunotherapy. Admit patient, baseline tests as above. Initiate methylprednisolone IV 2 4 mg/kg/day Refer to chest physician High resolution CT +/- bronchoscopy and BAL pending appearances Cover with empiric antibiotics Discuss escalation and ventilation No improvement wsening after 48 hours Add infliximab 5mg/kg mycophenolate mofetil mg bd (po IV) if concurrent hepatitis Continue with IV steroids wean as clinically indicated over at least 8 weeks Once resolved to baseline, wean steroids over 6 weeks. Differential diagnosis: Pneumonia (including atypical, PCP, TB) Lymphangitis Usual interstitial pneumonia Pulmonary oedema Pulmonary emboli Sarcoidosis Page 7 of 11

8 Symptoms Immune-related Nephritis Management Further assessment Grade 1: Creatinine 1.5 x baseline ULN 1.5 x ULN Continue immunotherapy. Repeat serum creatinine weekly. If wsens, manage as criteria below Review hydration status & other medications, & consider UTI. Dipstick urine and send f protein assessment. Urine protein:creatinine ratio (UPCR) If obstruction suspected, renal ultrasound. Grade 2: Creatinine >1.5 3 x baseline >1.5-3 x ULN Encourage hydration and review creatinine in hours; if not improving, discuss with nephrologist and need f biopsy. If considered an irae, initiate al prednisolone 0.5 1mg/kg/day (max 60mg/day) Repeat creatinine and K+ every 48 hours. Immunotherapy may re-commence once creatinine recovered to Grade 1/ baseline and prednisolone 10mg/day As above Consult with nephrologist Renal ultrasound +/- doppler to exclude obstruction/clot. If proteinuria, f 24 hour collection UPCR. If blood; phase contrast microscopy and glomerulonephritis screen, if nephrologist recommends. Advise patient to notify if oliguric. (Oliguria requires inpatient admission) Grade 3: Creatinine > 3 x baseline >3-6 x ULN Admit patient f moniting and fluid balance. Repeat creatinine every 24 hours. Discuss with nephrologist need f biopsy. If wsening, initiate methylprednisolone IV 1-2mg/kg/day. As above Refer to nephrologist Grade 4: Creatinine > 6 x ULN As f Grade 3. Patient should be managed in a hospital where renal replacement therapy is available. Permanently discontinue immunotherapy. As above Refer to nephrologist Steroid wean: Begin to wean once resolved to Grade 1. F G2 severity, wean over 2-4 weeks. F G3/4 episode, wean over 4 weeks. Page 8 of 11

9 Immune-related Neurological Toxicities A range of neurological events have been described, including polyneuropathy, facial nerve palsy, myasthenia gravis, Guillain Barré syndrome, encephalitis and aseptic meningitis. It is imptant to rule out progression of the cancer, infection, other medications as the cause of the symptoms. Symptom Grade Management Investigations Mild; no interference with function, symptoms not concerning to patient. (Manage mild cranial nerve problem as moderate) Low threshhold to delay immunotherapy and monit symptoms f another week, versus continue immunotherapy. Monit closely f any progression Comprehensive neurological exam. Diabetic screen, B12/folate, HIV, TSH, consider vasculitic & autoimune screen, review alcohol histy and other medicines. Consider need f MRI brain spine (exclude CVA, structural cause) Consult with neurologist Moderate: some interference with ADL, symptoms concerning to patient Initial observation reasonable, initiate al prednisolone 0.5-1mg/kg/day (max 60mg/day) if, f example, progressing from mild and / requiring medicines f pain e.g. pregabalin Once resolved to grade 1, resume immunotherapy. As above. Consider nerve conduction studies/electromyography f mot and/ sensy change. Consider pulmonary function tests. Refer to neurologist. See below f specific disders. If wsening symptoms, manage as severe Severe: limits self care, life-threatening, e.g. respiraty problems Permanently discontinue immunotherapy. Admit patient, and initiate methylprednisolone IV 2mg/kg/day. Involve neurologist in care. Daily neurological review. See below f specific disder treatments. Multidisciplinary team involvement, as appropriate MRI brain/spine advised. Nerve conduction studies/electromyography. Lumbar puncture. Pulmonary function assessment. Refer to neurologist. See below f specific disders. Page 9 of 11

10 Guillian-Barré Syndrome Progressive symmetrical muscle weakness with absent reduced tendon reflexes. Refer to neurologists f specialist input. Suggested investigations: nerve conduction studies; lumbar puncture; pulmonary function tests with vital capacity and maximum inspiraty/expiraty pressures; antibody testing f GBS variants, e.g. GQ1b in Miller Fisher variant. Use of steroids is not recommended in idiopathic GBS; however a trial of methylprednisolone IV 1-2mg/kg/day is reasonable. If no improvement wsening, plasmapheresis IVIG indicated (IVIG request fm required). Consider ventilation required in 15-30% of idiopathic cases. Myasthenia Gravis Fluctuating muscle weakness with fatigability, respiraty muscles may be involved. Refer to neurologists f specialist input. Suggested investigations: Check f ocular muscle and proximal muscle fatigability; AChR and anti-muscle specific kinase antibodies; Tensilon test ice pack test with neurological input; repetitive nerve stimulation and single fibre electromyography. Steroids indicated (al IV depending on symptoms). Pyridostigmine initial dose 30mg tds. If no improvement wsening, plasmapheresis IVIG may be considered (IVIG request fm, with suppting signature, required) Consider additional immunosuppressants (e.g. azathioprine, cyclospine, mycophenolate) Avoid medicines which may precipitate cholinergic crisis, e.g. beta blockers, some antibiotics Aseptic meningitis Exclusion of infective causes paramount. Suggested investigations: lumbar puncture (M/C/S, PCR f Herpes simplex, cytology); CNS imaging to exclude brain metastases leptomeningeal disease Exclude bacterial and ideally viral infections pri to high-dose steroids. Oral prednisolone 0.5 1mg/kg/day (max 60mg/day) methylprednisolone IV 1-2mg/kg if very unwell. Consider concurrent empiric antiviral and antibacterial therapy. Encephalitis Exclusion of infective and metabolic causes paramount. Suggested investigations: lumbar puncture (M/C/S, PCR f Herpes simplex, cytology, consider viral culture); CNS imaging; consider viral serology Exclude bacterial and ideally viral infections pri to high-dose steroids. Oral prednisolone 0.5 1mg/kg/day (max 60mg/day) methylprednisolone IV 1-2mg/kg if very unwell. Concurrent IV aciclovir suggested until PCR result obtained. Page 10 of 11

11 Transverse myelitis Acute subacute neurological symptoms/signs of mot/sensy/autonomic igin. Refer to neurologists f specialist input. Suggested investigations: MRI brain and spine; lumbar puncture; serum B12/HIV/syphilis/ANA/anti-Ro and anti-la Abs; TSH; anti-aquapin-4 IgG (Methyl)prednisolone 2mg/kg/day suggested. Plasmapheresis may be required if non-steroid responsive. Other Immune-related toxicities a) Cardiac Myocarditis, pericarditis, arrhythmias and cardiomyopathy have been repted. Early referral to a cardiologist is recommended. High dose cticosteroids have been used successfully and should be instituted rapidly. Immunotherapy should be permanently discontinued in the event of any Grade 3 Grade 4 myocarditis. b) Rheumatology Mild moderate myalgia and/ arthralgia occurs in 2-12% of patients. F mild moderate symptoms, analgesia with paracetamol and/ NSAIDs is recommended. Continue immunotherapy. If moderate symptoms are inadequately controlled with NSAIDs and/ paracetamol, initiate prednisolone 10-20mg once daily, and withhold immunotherapy until prednisolone 10mg /day. If severe symptoms, refer to a rheumatologist, withhold immunotherapy and consider high dose cticosteroids. c) Ocular Ocular toxicities are rare. Topical cticosteroid eye drops may be used in the case of episcleritis anteri uveitis. Systemic steroids are required f severe ocular inflammation and bital inflammation. Intravitreal anti-vascular endothelial growth fact (VEGF) is indicated f choidal neovascularisation. N.B. Ipilimumab should be permanently discontinued in the event of any other Grade 3 4 irae. Pembrolizumab nivolumab should be permanently discontinued in the event of any other Grade 4, recurrent Grade 3, irae. References: Management of Toxicities from Immunotherapy; ESMO Clinical practice Guidelines f diagnosis, treatment and follow-up; Haanen, J et al; Annals of Oncology 2017; 28 (Supplement 4): iv119 iv142 Page 11 of 11