BMS-recommended management guidelines for skin2
For suspected irAEs, first exclude other causes
| Grade 1–2 | Grade 3–4 | |
|---|---|---|
| Definition | Covering ≤30% BSA | Covering >30% BSA
life-threatening consequences |
| Dual NIVO + IPI
or NIVO alone1,3,4 |
Continue treatment
hold if bullous dermatosis |
Grade 3: Withhold treatment
Grade 4: Permanently discontinue treatment |
| Consultations | If bullous dermatosis, consider dermatology | Dermatology
Rare cases of SJS and TEN have been observed. If symptoms and signs of SJS or TEN appear, treatment should be withheld If confirmed, the treatment should be discontinued and patient should be referred to a specialised unit for assessment and treatment |
| Medication | Administer antihistamines and topical steroids for symptomatic treatment | 1–2 mg/kg/day methylprednisolone or equivalent |
| Skin test | – | Consider biopsy |
| Follow-up | If symptoms persist >1 to 2 weeks or recur:
Consider skin biopsy Withhold treatment Consider 0.5–1.0 mg/kg/day methylprednisolone or equivalent.* Once improving, taper steroids over at least 1 month and resume treatment |
If improved to Grade <2
Taper steroids over at least 1 month before resuming treatment** |
| If symptoms worsen:
Treat as Grade 3–4 |
– |
*Consider prophylactic antibiotics for opportunistic infections, ** Add prophylactic antibiotics
BSA, body surface area; IPI, ipilimumab; irAE, immune-related adverse event; NIVO, nivolumab; SJS, Stevens–Johnson syndrome; TEN, toxic epidermal necrolysis
International guideline (ASCO, ESMO and NCCN) recommendations for skin irAEs4–6^
^ For detailed guidelines, please refer to original publications
| Grade 1 | Grade 2 | Grade 3 | Grade 4 | |
|---|---|---|---|---|
| Immunotherapy | Continue immunotherapy4–6 | Continue immunotherapy, consider holding4–6 | Hold immunotherapy4–6 | Immediately hold6 or permanently discontinue immunotherapy5 |
| Medication | Mild- to moderate-potency topical steroids4–6 | Moderate- to high-potency topical steroids4–6 | High-potency topical steroids4–6 | – |
| – | Consider prednisone/
(methyl)prednisolone4–6* |
Prednisone/(methyl)prednisolone4–6* | ||
| For Grade 1–2, oral/topical antihistamines for itch4–6
For Grade 1–3, topical emollients4–6 |
||||
| Admission | – | – | Consider admitting patient4 | Admit patient5,6 |
| Consultation | – | – | Urgent dermatology consult4–6 | |
| Others | Advise to avoid irritants/sun exposure5,6 | – | – | |
*Consult steroid dosing information below for recommendations
Physical examination, history, total body skin exam including mucosa, skin biopsy, eosinophil count, peripheral blood smear and liver function tests.4–6 For grade 1, physical examination and exclude other causes5. For grade 2, consider dermatology referral and skin biopsy and clinical photography.5,6 For grade 3, implement dermatology review and consider punch biopsy and clinical photography in addition to steps for earlier grades.5,6 For grade 4, conduct dermatology review, punch biopsy and clinical photography and all earlier steps5,6
| ASCO | ESMO | NCCN | |
|---|---|---|---|
| Grade 1 | Rash covering <10% BSA, which may or may not be associated with symptoms of pruritus or tenderness6 | Lesions covering <10% BSA with or without symptoms5 | Macules/papules covering <10% BSA with or without symptoms4 |
| Grade 2 | Rash covering 10%–30% BSA with or without symptoms; limiting instrumental ADL; rash covering >30% BSA with or without mild symptoms6 | Lesions covering 10–30% BSA with or without symptoms; or limiting instrumental ADL; or lesions covering >30% BSA with or without mild symptoms, without limiting self-care ADL5 | Macules/papules covering 10–30% BSA4 with or without symptoms; limiting instrumental ADL4 |
| Grade 3 | Rash covering >30% BSA with moderate or severe symptoms; limiting self-care ADL6 | Lesions covering >30% BSA with moderate or severe symptoms; limiting self-care ADL5 | Macules/papules covering >30% BSA4 with or without symptoms; limiting self-care ADL4 |
| Grade 4 | Severe consequences requiring hospitalisation or urgent intervention indicated or life-threatening consequences6 | Life-threatening consequences, urgent intervention needed5 | Macules/papules covering >30% BSA with or without symptoms; limiting self-care ADL4 |
ADL, activities of daily living; ASCO, American Society of Clinical Oncology; BSA, body surface area; ESMO, European Society for Medical Oncology; NCCN, National Comprehensive Cancer Network
| ASCO6 | ESMO5 | NCCN4 | |
|---|---|---|---|
| Grade 2 | Consider prednisone (or equivalent) 0.5–1 mg/kg tapering over 4 weeks | If refractory, initiate (methyl)prednisolone/prednisolone (or equivalent) 0.5–1 mg/kg tapering over >4 weeks | Consider 0.5 mg/kg/day prednisone if unresponsive to topical treatments within 1 week |
| Grade 3 | Initiate oral prednisone (or equivalent) 1 mg/kg/day tapering over at least 4 weeks | If refractory, initiate prednisone (or equivalent) 0.5–1 mg/kg tapering over >4 weeks | 0.5–1 mg/kg/day prednisone, up to 2 mg/kg/day if no improvement, tapering over 4–6 weeks once symptoms are Grade ≤1 |
| Grade 4 | IV methylprednisolone (or equivalent) 1–2 mg/kg with slow tapering when the toxicity resolves | IV (methyl)prednisolone (or equivalent) 1–2 mg/kg tapering over >4 weeks once reaction is controlled | Prednisone 0.5–1 mg/kg/day, up to 2 mg/kg/day if no improvement, tapering over 4–6 weeks once symptoms are Grade ≤1 |
ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; IV, intravenous; NCCN, National Comprehensive Cancer Network
| Grade 1 | Grade 2 | Grade 3 | |
|---|---|---|---|
| Immunotherapy | Continue immunotherapy | Continue immunotherapy or consider holding in select cases
Intensify antipruritic therapy |
Hold immunotherapy |
| Intervention | – | Consider:
|
Prednisone/methylprednisolone 0.5–1 mg/kg/day*
Consider:
|
| Moderate–potency topical steroids to affected areas for localized pruritus | High-potency topical steroids | ||
| Oral antihistamines can be used across all grades of pruritus | |||
| Consultation | – | Dermatology consultation | Urgent dermatology consultation |
*Continue until symptoms improve to Grade ≤1, then taper over 4–6 weeks.
UVB, ultraviolet B
Assess pruritus through a total body skin exam including the mucosa, and assess for history of prior inflammatory dermatological diseases.
|
NCCN4 |
||
|---|---|---|
| Grade 1 | Grade 2 | Grade 3 |
| Mild or localized | Intense or widespread, intermittent; skin changes from scratching; limiting instrumental ADL | Intense or widespread; constant; limiting self-care ADL or sleep |
ADL, activities of daily living; NCCN, National Comprehensive Cancer Network
| Grade 1 | Grade 2 | Grade 3–4 | |
|---|---|---|---|
| Immunotherapy | Consider holding4 or continue6 immunotherapy if asymptomatic | Hold immunotherapy until Grade <1 | Grade 3: Hold6 or discontinue4 immunotherapy Grade 4: Permanently discontinue4,6 immunotherapy |
| Medication | High-potency topical corticosteroids4 | Class 1 high-potency topical steroid (clobetasol, betamethasone or equivalent)6 | – |
| Prednisone6/(methyl)prednisolone 0.5–1 mg/kg/day4*
If no improvement after 3 days, consider adding rituximab4 |
Prednisone/(methyl)prednisolone 1–2 mg/kg/day4,6*
IVIG† can be considered as an adjunct to rituximab4** |
||
| Consultation | – | Consult dermatology6 | Urgent dermatology consultation4 Consider infectious disease consultation6 |
| Other | – | – | Inpatient care required4 |
*Until symptoms resolve to Grade ≤1, tapering over 4–6 weeks; **Rituximab at 1,000 mg every 2 weeks for two doses in combination with tapering of glucocorticoids, followed by 500 mg maintenance rituximab at 12 and 18 months; †IVIG 1 g/kg/day x 2 days with monthly cycle until clear.
IVIG, intravenous immunoglobulin
Physical examination, ruling out other aetiologies. Dermatology consultation, skin biopsy, serology.
|
ASCO & NCCN4,6 |
|||
|---|---|---|---|
| Grade 1 | Grade 2 | Grade 3 | Grade 4 |
| Asymptomatic, blisters covering <10% BSA and no associated erythema | Blistering that affects quality of life and requires intervention based on diagnosis not meeting criteria for Grade >2. Blisters covering 10–30% BSA | Skin sloughing covering >30% BSA with associated pain and limiting self-care ADL | Blisters covering >30% BSA with associated fluid or electrolyte abnormalities |
ADL, activities of daily living; ASCO, American Society of Clinical Oncology; BSA, body surface area; NCCN, National Comprehensive Cancer Network
NCCN guidelines4
| All grades | |
|---|---|
| Immunotherapy | Permanently discontinue immunotherapy |
| Medication | Prednisone/(methyl)prednisolone 1–2 mg/kg/day
Consider IVIG* |
| Consultation | Urgent dermatology, ophthalmology and urology consultation |
| Other | Inpatient care required |
*IVIG 1 g/kg/day in divided doses per product information for 3–4 days. Other immunosuppressive therapies (i.e., etanercept, cyclosporine) can be considered. After a patient has widespread skin separation (blisters or erosions), the risk of infection should be weighed against the potential benefits of immunosuppression.
ASCO guidelines6
| Grade 1–2* | Grade 3 | Grade 4 | |
|---|---|---|---|
| Immunotherapy | – | Hold immunotherapy | Permanently discontinue immunotherapy |
| Topical therapies | – | Topical emollients, oral antihistamines, high-potency topical corticosteroids
Dimethicone may be considered |
– |
| Medication | – | IV (methyl)prednisolone 0.5–1 mg/kg
Convert to oral corticosteroids on response and taper for ≥4 weeks |
IV (methyl)prednisolone 1–2 mg/kg, tapering when toxicity resolves
For corticosteroid-unresponsive cases, consider IVIG or cyclosporine |
| Admission | – | Admit to burn unit or consult wound care services
Implement supportive care |
Admit to burn unit/ICU, consult dermatology and wound care services Implement supportive care |
| Consultation | – | Consult widely, as appropriate, for management and preventing sequelae For patients with DRESS, consider pain/palliative consultation and/or admission |
|
*For the SCAR adverse reactions, there are no Grade 1 or 2 categories. If limited BSA is involved with bullae or erosions, there should remain high concern that this reaction will progress to grade 3 or 4.6
Although rare, SCARs, comprising SJS, TEN, DIHS and DRESS, are serious and potentially life-threatening AEs. They may occur independently or overlap, and are characterised by flaccid blister formation, rapidly progressing extensive necrosis and separation of the dermis.4 SJS involves <10% BSA; TEN involves <30% BSA.4–6
AE, adverse event; ASCO, American Society of Clinical Oncology; BSA, body surface area; DIHS, drug-induced hypersensitivity syndrome; DRESS, drug reaction with eosinophilia and system symptoms; ICU, intensive care unit; IV, intravenous; IVIG, intravenous immunoglobulin; NCCN, National Comprehensive Cancer Network; SCAR, severe cutaneous adverse reaction; SJS, Stevens–Johnson syndrome; TEN, toxic epidermal necrolysis
An urgent dermatology consultation is required at the first signs or symptoms of SJS or TEN. Patients should undergo total body skin and mucous membrane examinations, ruling out other aetiologies, serology/biologic check-ups, and skin biopsy.
|
ASCO |
|||
|---|---|---|---|
| Grade 1–2* | Grade 3 | Grade 4 | |
| – | Skin sloughing covering <10% BSA with mucosal involvement-associated signs (e.g. erythema, purpura, epidermal detachment, mucous membrane detachment) | Skin erythema and blistering/sloughing covering ≥10% BSA with associated signs (e.g. erythema, purpura, epidermal detachment, mucous membrane detachment) and/or systemic symptoms and concerning associated bloodwork abnormalities (e.g. liver function test elevations in the setting of DRESS/DIHS) | |
*For the SCAR adverse reactions, there are no Grade 1 or 2 categories. If limited BSA is involved with bullae or erosions, there should remain high concern that this reaction will progress to grade 3 or 4.6
ASCO, American Society of Clinical Oncology; BSA, body surface area; DIHS, drug-induced hypersensitivity syndrome; DRESS, drug reaction with eosinophilia and system symptoms; SCAR, severe cutaneous adverse reaction; SJS, Stevens–Johnson syndrome; TEN, toxic epidermal necrolysis
ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; irAE, immune-related adverse event; NCCN, National Comprehensive Cancer Network
References:
- OPDIVO® (nivolumab) Product Information, BMS Hong Kong.
- Bristol-Myers Squibb. Immune-Related Adverse Reaction (irAR) Management Guide. 1506AU2002148-01. April 2020.
- YERVOY® (ipilimumab) Product Information, BMS Hong Kong.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Management of immunotherapy-Related Toxicities. Version 1.2022. Available: https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Accessed February 2023.
- Haanen J, et al. Ann Oncol 2022;33:1217–1238. Available at: https://www.annalsofoncology.org/article/S0923-7534(22)04187-4/fulltext. Accessed March 2023.
- Schneider BJ, et, al. J Clin Oncol 2021;39:4073–4126. Available at: https://ascopubs.org/doi/full/10.1200/JCO.21.01440. Accessed March 2023.
