Management of Immunotherapy Related Toxicities

immune checkpoint inhibitors (ICIs)

PD-1 inhibitors - nivolumab, pembrolizumab, cemiplimab, dostarlimab

PD-L1 inhibitors - atezolizumab, avelumab, durvalumab

CTLA-4 inhibitors - ipilimumab, tremelimumab

chimeric antigen receptor (CAR) T-cell therapies

axicabtagene ciloleucel, brexucabtagene autoleucel, tisagenlecleucel

lymphocyte engager therapies

blinatumomab, tebentatusp-tebn, teclistamab-cqyv

immunotherapy vs. traditional chemotherapy: immunotherapy

action of tumor cells - indirect; NOT cytotoxic

impact on immune system - amplification

onset of SE - delayed

immunotherapy vs. traditional chemotherapy: traditional chemotherapy

action of tumor cells - direct; targets/kills rapidly dividing cells

impact on immune system - suppression

onset of SE - acute

immune checkpoint inhibitors (ICIs): prior to starting therapy

get full pt past medical hx & family hx
• particular focus on autoimmune, infectious disease disorders or vaccination status

physical exam - additional testing to assess baseline cardio & pulmonary fxn

laboratory tests at baseline - CBC, CMP, TSH, T4 repeated q4-6wks during therapy; then q6-12wks afterwards

IF female of reproductive age
• should be ON effective birth control & remain on it for ≥5 mo after finishing therapy
• should refrain from breastfeeding during & for ≥5 mo after finishing therapy

immune checkpoint inhibitors (ICIs): pt education prior to starting therapy

disease state

rationale for immune checkpoint inhibitor & MOA

carrying wallet card → beneficial if admit to hospital

when to alert oncology team
• hospital admissions, new HCP visit
• change in meds or vaccination status → live vaccine NOT recommended during therapy
• SE during & up to 2 years after - severe fatigue, headache, rash, cough/SOB, chest pain, wt loss, vision or mood changes, severe muscle or joint pain/weakness

immune checkpoint inhibitors (ICIs): organ systems impacted

can cause inflammatory disorders essentially ANYwhere in body
• L - lungs (pneumonitis → SOB, cough) / liver (hepatitis, LFTs); least common, most severe
• E - endocrine (thyroid, adrenal, glucose abnormalities → type 1 diabetes)
• G - GI (colitis)
• S - skin (rash); most common, least severe

immune checkpoint inhibitors (ICIs): incidence & timeline

PD-1/PD-L1 = 66% any irAE, 14% severe

anti-CTLA-4 = 72% any irAE, 24% severe

combination = 96% any irAE, 59% severe

skin, rash or pruritus - occurs during 4-6 wks of treatment
colitis - after week 4 to week 10
endocrinopathy & liver toxicity - occurs after week 6 & persists
pneumonitis - after week 10 to after week 14
nephritis - occurs after 14 wks of treatment

immune checkpoint inhibitors (ICIs): grading

most are easily manageable & reversible when caught early

severity often based on common terminology criteria for adverse events (CTCAE)

grade 1 (mild) - asymptomatic or mild symptoms; clinical or diagnostic observations ONLY; NO intervention needed

grade 2 (moderate) - minimal, local OR noninvasive management indicated; limiting instrumental activities of daily living (ADLs) w/ intervention indicated

grade 3 (severe but NOT life threatening) - results in hospitalization; disables/limits self-care & ADLs

grade 4 (life-threatening) - urgent intervention required (ICU)

grade 5 - death related to AE

immune checkpoint inhibitors (ICIs): general management based on grading

grade 1 → continue w/ close monitoring

grade 2 → hold until resolution of symptoms
• toxicity management = prednisone PO 0.5-1 mg/kg/day

grade 3 → hold & consider re-challenging
• toxicity management = prednisone PO or methylprednisolone IV 1-2 mg/kg/day; tapered over 4-6 weeks

grade 4 → permanently d/c
• toxicity management = methylprednisolone IV 1-2 mg/kg/day; tapered over 4-6 weeks

steroid unresponsive (NO response after 72 hrs/3 days) → consult w/ specialist & use immunomodulators (infliximab, vedolizumab or mycophenolate)

immune checkpoint inhibitors (ICIs): organ specific management

colitis → infliximab*, vedolizumab*
*IF steroid refractory

hepatitis → mycophenolate*
*IF steroid refractory

hypothyroid → levothyroxine

skin rxns → PO antihistamines, topical emollients OR corticosteroids

immune checkpoint inhibitors (ICIs): immunosuppressant considerations

pts may require longer steroid tapers (>4-8 wks) to prevent recurrence of irAEs

steroids - NOT recommended as premed

pts may need additional supportive care once on steroid therapy
• hyperglycemia - recommend frequent monitoring, may require drug therapy
• gastritis - recommend prophylaxis w/ H₂ blocker or PPI
• opportunistic infections
➢ recommend pneumocystis jiroveci pneumonia (PJP) prophylaxis IF on daily prednisone >20 mg for ≥4 wks w/ Bactrim
➢ recommend general fungal prophylaxis IF on daily prednisone >20 mg for ≥4 wks w/ fluconazole
• osteoporosis - recommend prophylaxis w/ Ca²⁺ & vitamin D supplementation

chimeric antigen receptor (CAR) T-cell therapy & lymphocyte engager therapies: 2 major toxicities

cytokine release syndrome (CRS) - acute onset & short duration

neurotoxicity - delayed onset & longer duration

chimeric antigen receptor (CAR) T-cell therapy & lymphocyte engager therapies: major toxicity - cytokine release syndrome (CRS)

onset = 2-3 days post infusion

durations = 7-8 days

s/s - fever, hypotension, tachycardia, hypoxia, chills, cardiac/renal/hepatic dysfxn
• grades 1-4

chimeric antigen receptor (CAR) T-cell therapy & lymphocyte engager therapies: major toxicity - neurotoxicity

onset = 4-10 days post infusion

durations = 14-17 days

s/s - encephalopathy, delirium, headache, tremor, dizziness, motor distraction, agitation, psychosis, seizures, cerebral edema
• grades 1-4

CAR T-cell therapy & lymphocyte engager therapies: cytokine release syndrome (CRS) management

use BOTH anti-IL6, corticosteroid & supportive care therapy in ALL cases, dosing & frequencies change w/ severity
• anti-IL6 = tocilizumab 8 mg/kg/dose IV; max 4 doses
• corticosteroids = dexamethasone 10 mg IV q6-24hrs based on grade
• supportive care
➢ sepsis workup → empiric ABX w/ cultures (can present similar, lactate level)
➢ IV fluids → crystalloid
➢ vasopressors
➢ respiratory support PRN
➢ granulocyte-colony stimulating factor (G-CSF) w/ neutropenia

CAR T-cell therapy & lymphocyte engager therapies: neurotoxicity management

corticosteroids & supportive care = mainstay of treatment
• corticosteroids = dexamethasone 10 mg IV q6h OR methylprednisolone 1 mg/kg IV q12h, can ADD anakinra 100 mg SC q6h IF unresponsive
• supportive care
➢ ICU admission due to seizure risk
➢ respiratory support
➢ treat seizures & status epilepticus per institutional protocols → anti-epileptic + BZDP

infusion site rxns: 7 symptoms

fever/chills/rigor
back, head, muscle of joint pain
angioedema
SOB/wheezing
HTN or hypotension
pruritus/urticaria
dizziness
sweating

*will happen while receiving infusion

infusion site rxns: grading

grade 1 (mild or transient) - symptoms resolve on their own after holding infusion

grade 2 (moderate) - symptoms promptly resolve after holding infusion & symptomatic treatment

grades 3-4 (severe) - either prolonged symptoms despite treatment, recurrence of symptoms after initial improvement OR symptoms requiring hospitalization or are life-threatening

infusion site rxns: treatment

grade 1 (mild or transient) - ex: flushing
• hold infusion until resolution of symptoms, may resume as tolerated
• premed w/ APAP, H₂ blockers & antihistamines in future infusions

grade 2 (moderate) - ex: BP ↑ (→ β-blocker) or ↓ (→ fluid)
• follow institutional protocols
• may continue therapy by slowing rate up to ½
• may premed w/ APAP, H₂ blockers, antihistamines OR corticosteroids in future infusions

grades 3-4 (severe) - ex: SOB, anaphylaxis
• follow institutional protocols
• d/c offending therapy; may switch to another agent in same class