How are immunotherapy toxicities graded?

Grading of Immunotherapy Toxicities

Immunotherapy toxicities are graded using the Common Terminology Criteria for Adverse Events (CTCAE) system, which classifies immune-related adverse events (irAEs) from Grade 1 (mild) to Grade 5 (death), with grading based on severity of symptoms, extent of organ involvement, and impact on activities of daily living. 1

General Grading Framework

The CTCAE grading system provides a standardized approach across all organ systems affected by immunotherapy:

• Grade 1: Mild symptoms requiring minimal or no intervention; asymptomatic or mild symptoms; clinical or diagnostic observations only 1
• Grade 2: Moderate symptoms requiring minimal, local, or noninvasive intervention; limiting instrumental activities of daily living (preparing meals, shopping, managing money) 1
• Grade 3: Severe or medically significant symptoms that are not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living (bathing, dressing, feeding self, using toilet) 1
• Grade 4: Life-threatening consequences requiring urgent intervention 1
• Grade 5: Death related to the adverse event 1

Organ-Specific Grading Examples

Dermatologic Toxicities (Rash)

The grading incorporates both body surface area (BSA) involvement and symptom severity 1:

• Grade 1: Rash covering <10% BSA with or without symptoms 1, 2
• Grade 2: Rash covering 10-30% BSA, may have mild to moderate symptoms (pruritus, discomfort) 1, 2
• Grade 3: Rash covering >30% BSA OR Grade 2 rash with substantial symptoms (severe pruritus, pain, interference with daily activities) 1, 2
• Grade 4: Skin sloughing >30% BSA with associated systemic symptoms (erythema, purpura, epidermal detachment suggesting Stevens-Johnson syndrome or toxic epidermal necrolysis) 1, 2

Important caveat: The ESMO guidelines note that when rash is diffuse but light without additional symptoms, Grade 2 may be more appropriate than Grade 3, and version 5 of CTCAE provides more appropriate classification for skin adverse events 1

Gastrointestinal Toxicities (Diarrhea/Colitis)

Grading combines stool frequency increase and presence of colitis symptoms 1:

• Grade 1: Increase of <4 bowel movements per day above baseline; mild increase in ostomy output; no colitis symptoms (no watery diarrhea, cramping, urgency, abdominal pain, blood/mucus in stool, fever, nocturnal bowel movements) 1
• Grade 2: Increase of 4-6 bowel movements per day above baseline; moderate ostomy output increase; mild to moderate colitis symptoms present; limiting instrumental activities of daily living 1
• Grade 3: Increase of >6 bowel movements per day above baseline; severe ostomy output increase; severe colitis symptoms (watery diarrhea, incontinence, severe cramping, blood/mucus in stool, fever, ileus); limiting self-care activities of daily living; hemodynamic instability; hospitalization indicated 1
• Grade 4: Life-threatening complications (ischemic bowel, perforation, toxic megacolon); urgent intervention required 1

Critical distinction: Blood or mucus in stool, fever, or other colitis symptoms should prompt immediate thorough workup for infection and consideration of higher grade classification, as diarrhea/colitis can rapidly escalate in severity 1

Clinical Application Principles

Timing Considerations

Very severe (Grade 4-5) irAEs occur significantly earlier than milder toxicities, with median time to occurrence of 41 days versus 91 days for Grades 1-3 3. This earlier onset pattern should heighten vigilance during the first 6-8 weeks of therapy 1.

Agent-Specific Severity Patterns

The grading severity distribution varies by immunotherapy class 1:

• Anti-CTLA4 (ipilimumab): 10-27% develop Grade 3-4 toxicities at 3 mg/kg; increases to 30% at 10 mg/kg; Grade 5 rate 1.1-2.1% 1
• Anti-PD-1/PD-L1: 12-20% Grade 3-4 toxicities, generally lower severity than anti-CTLA4 1
• Combination therapy (ipilimumab + nivolumab): Higher rates of severe toxicities than monotherapy 1

Management Implications by Grade

Treatment decisions are directly tied to toxicity grade 1, 2:

• Grade 1: Continue immunotherapy with symptomatic management 1, 2
• Grade 2: Continue immunotherapy with close monitoring (weekly); hold if not improving 1, 2
• Grade 3: Hold immunotherapy immediately; initiate systemic corticosteroids (0.5-1 mg/kg prednisone); resume only after improvement to Grade 1 1, 2
• Grade 4: Permanently discontinue immunotherapy; urgent hospitalization; IV methylprednisolone 1-2 mg/kg 1, 2

Common pitfall: Underestimating Grade 2 toxicities that have significant symptoms—these should be managed more aggressively as Grade 3, particularly when symptoms substantially impact quality of life despite not meeting strict BSA or frequency criteria 1.