Immunotherapy toxicity management

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Meghan Mooradian, MD Boston, MA

Grading toxicity

CTCAE

• Common Terminology Criteria for Adverse Events (CTCAE) and Common Toxicity Criteria (CTC) - Adverse event grading for clinical trials

• CTCAE 5x7" small booklet format local backup
• CTCAE 8.5x11" letter size format local backup

Skin, dermatologic

Maculopapular rash: the most frequent event with checkpoint inhibitors, the fourth version of the CTCAE classification proposes:

• Grade 1: macules/papules covering < 10% the body surface area (BSA) with or without symptoms (e.g. pruritus, burning, tightness);

MGMT: avoid skin irritants; topical steroids, anti-histamines; continue ICI;

• Grade 2: macules/papules covering 10%–30% BSA with or without symptoms (e.g. pruritus, burning, tightness); limiting instrumental activities of daily living (ADL);

MGMT: avoid skin irritants; topical steroids, anti-histamines +/- oral agents if needed; continue ICI;

·      Non-urgent dermatology referral; consider skin biopsy

• Grade 3: macules/papules covering > 30% BSA with or without associated symptoms; limiting self-care ADL;

MGMT: avoid skin irritants; if mild – moderation systemic steroids 0.5-1mg/kg prednisone daily for 3 days then taper off; if more severe wean consider IV methylpred (1-2mg/kg) and slower taper over 2-4 weeks; can consider re-trial of ICI depending on severity of rash and dermatology recommendation;

·      Dermatology referral with biopsy

Pruritus: a frequent event with checkpoint inhibitors, often can be treated supportively with topicals, anti-histamines with continuation of ICI

·      Topical lotions/emollients – menthol containing hydrate skin and provide pruritus relief in mild cases (i.e. Gold Bond)

·      Topical steroids (clobestasol propionate, betasmethasone dipropionate)

·      Oral anti-histamines: cetirizine/loratidine daily, hydroxyzine

·      If intense, limiting quality of life: oral corticosteroid – prednisone 0.5-1mg/kg/day tapered over 1-2 weeks; and dermatology referral

Guidelines

• ESMO: Management of Toxicities from Immunotherapy: ESMO Clinical Practice Guidelines (2017)
• SITC: Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group
• ASCO: Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline
• Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, Postow MA, Wolchok JD. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015 Dec;26(12):2375-91. link to original article correction of Figure 2 PubMed

Evaluation

Monitoring guidelines for identification of immune-related adverse events (irAEs)

·      Patients should receive timely and up-to-date education about immunotherapies, their mechanism of action, and the clinical profile of possible irAEs prior to initiating therapy and throughout treatment and survivorship.

·      There should be a high level of suspicion that new symptoms are treatment related.

·      Recommend weekly toxicity visits for patients on combination CTLA-4/PD-1 inhibition while on therapy; every 2 or 3 week visits are reasonable for patients on single agent PD-1/L1 or CTLA-4 inhibitors

Pre-treatment evaluation

Detailed physical examination, including dermatologic assessment

Detailed history including personal and family history of auto-immune disease

History of bowel habits

Baseline lab evaluation: CBC, CMP, TSH

o  Consider hepatitis serologies (HBsAg, HBsAb, HBcAb, hCAb), T-spot 

o  Consider baseline troponin, BNP

General organ agnostic recommendations

The following are general recommendations that should be followed irrespective of affected organs. For organ-specific management,

Per the ASCO guidelines, clinicians should manage toxicities as follows:

• In general, ICI therapy should be continued with close monitoring for grade 1 toxicities, with the exception of some neurologic, hematologic, and cardiac toxicities.
• Hold ICI for most grade 2 toxicities and consider resuming when symptoms and/or laboratory values revert to grade 1 or less.
  • Corticosteroids (initial dose of 0.5 to 1 mg/kg/d of prednisone or equivalent) may be administered.
• Hold ICI for grade 3 toxicities and initiate high-dose corticosteroids prednisone 1 to 2 mg/kg/d or methylprednisolone IV 1 to 2 mg/kg/d).
  • Corticosteroids should be tapered over the course of at least 4 to 6 weeks. If symptoms do not improve with 48 to 72 hours of high-dose corticosteroid, should consider additional immune modulatory agents (such as infliximab for ICI-induced colitis)
• When symptoms and/or laboratory values revert to grade 1 or less, re-challenging with ICIs may be offered; however, caution is advised, especially in those patients with early-onset irAEs.
  • Dose adjustments are not recommended.
• In general, grade 4 toxicities warrant permanent discontinuation of ICI with rhe exception of endocrinopathies that have been controlled by hormone replacement.

Endocrinopathy

• ACTH
• AM cortisol with cosyntropin stimulation test
• TSH
• FSH
• LH
• Prolactin
• Testosterone

Liver, hepatic

• Liver function tests (LFTs) or comprehensive metabolic panel (CMP)
• Hepatitis B & C serologies
• Liver/abdominal CT/MRI/ultrasound imaging

Kidney, renal

• BUN/creatinine, basic metabolic panel (BMP)
• Renal imaging (CT/MRI/ultrasound imaging)
• Urine sodium, urine urea, urine creatinine (for calculating FeNa and FeUrea)
• Kidney biopsy

Neurologic

• Electromyography (EMG)

Ocular

• Ophthalmology exam

Pancreas

• Amylase
• Lipase