Table 2.

IL-2 toxicity management guidelines for TIL cell therapy

Toxicity	Management
Fevers/chills/rigors	Fever above 100.5°C Acetaminophen 650 mg PO q4h scheduled. Indomethacin 50–75 mg q6h or equivalent (stop if sCr>2 mg/dL, decreased UOP, or platelets <50 000 x10ˆ9/L). Meperidine 25 mg with option to repeat another dose within 30 mins as needed for rigors (25–50 mg IV q4h PRN). Hydromorphone 0.5 mg IV every 15 min as needed for rigors, may repeat×3 total doses.* Preparation should be made beforehand, so intervention is possible in a timely fashion. Appropriate infectious workup and antibiotics as warranted.
Blood pressure	Target blood pressure set on admission and assessed prior to each dose—assess ~2 hours prior to dose If not meeting target, administer NS or LR 250–500 mL IV bolus over 30–60 min. Repeat blood pressure 30 min post IV bolus, if not meeting target, then may repeat another 250 mL IV bolus. If hypotension persists despite IV fluid bolus, we recommend IL-2 discontinuation; select centers with IL-2 experience use dopamine 2 µg/kg/min or initiate phenylephrine 0.1 µg/kg/ min (may be titrated up to obtain target blood pressure); when phenylephrine can be weaned to 0.5 µg/kg/min or less, these centers reassess if it is safe to proceed with additional IL-2 dosing. In general, we recommend discontinuation of IL-2 in the setting of fluid-refractory hypotension.
Urine output	To assess renal function, monitor serum creatinine prior to beginning IL-2 and then two times per day during administration urine output of at least 0.5 mL/kg/hour—assess two times per day, including about 2 hours prior to dose If not meeting target, administer NS or LR 500 mL IV bolus over 30 min. Check urine output 1 hour post IV bolus, if <50–80 mL/hour, then may repeat another 500 mL IV bolus. Persistent low urine output despite IV fluid boluses, urine output <4 mL/kg over 8 hours, or serum creatinine 2.5–2.9 mg/dL are indications to hold IL-2. If persistent low creatinine clearance, we generally recommend discontinuation of IL-2. If creatinine clearance is persistently low, select centers with IL-2 experience initiate dopamine at renal perfusion doses of 2 µg/kg/min. If dopamine is initiated, urine output of 50 cc/hour must be established while off dopamine before additional IL-2 doses may be considered. NSAIDs and nephrotoxic agents should be withheld in the setting of renal injury.
Pulmonary	Physical exam with auscultation: check for rales in lung bases. Chest X-ray should be obtained to assess for pleural effusions or pulmonary edema. O2 saturation should be maintained above 92%; may initiate oxygen therapy if O2<95%. IL-2 doses should be permanently discontinued when patients require supplemental O2 (<92% on room air) at timing of next dose (see table 3). If blood pressure can be maintained, diuresis can be tried to alleviate O2 requirement.
Cardiovascular	Sinus tachycardia >130 beats per min sustained for 1 hour Assess fluid status and may administer NS or LR 500 mL IV fluid bolus. Assess telemetry/EKG for arrhythmias; continuously monitor and manage any new arrhythmias. Replete electrolytes. If arrhythmia or sustained tachycardia despite correction of reversible factors (hypotension, fever, dopamine), then may need to hold dose or stop IL-2 therapy
Gastrointestinal	Nausea/vomiting: scheduled ondansetron 8 mg IV q8h 30 min prior to each dose, prochlorperazine 10 mg IV q6h PRN, or lorazepam 0.5 mg IV q6h PRN. Diarrhea: PRN loperamide 2 mg every 2 hours as needed after ruling out gastrointestinal infection; diphenoxylate/atropine two tablets PO q6h PRN for diarrhea refractory to loperamide. Gastrointestinal prophylaxis: pantoprazole 40 mg PO/IV daily or famotidine 20 mg PO/IV two times per day (steroid use is prohibited for prevention of gastrointestinal symptoms). Transient cholestasis is reversible after discontinuation of IL-2 therapy.
Neurologic	IL-2 therapy should be withheld until the course of neurotoxicity can be established. Usually temporary. Anti-psychotic drugs may be required if there is progressive development of personality changes, hostility, confusion, disorientation, and hallucinations.
Dermatologic	Macular erythema, pruritus, desquamation. Itching: Diphenhydramine 25 mg PO q6h PRN or hydroxyzine 10 mg PO q6h PRN. Aveeno or Lubriderm (or equivalent) lotion TID. If rash is persistent/severe despite above measures, consider dermatology consult and use of topical steroid agents.
Endocrine	Hypothyroidism may need supplementation with levothyroxine if it persists after completion of therapy.
Infectious	10%–30% incidence of staphylococcus bacterial infections. Prophylaxis as per institutional guidelines. Appropriate infectious workup and antibiotic coverage.
Edema/capillary leak	Closely monitor daily weights and rate of weight increase. Intravenous diuretics may be needed and are commonly administered >24 hours after completion of IL-2.

*Either meperidine or hydromorphone is given initially depending on institutional protocol, and if refractory to one, then the other is administered.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; CTCAE, Common Terminology Criteria for Adverse Events; IL-2, interleukin-2; IL-2, interleukin-2; IV, intravenous; LFT, liver function test; LR, lactated Ringer’s; NS, normal saline; PO, per orally (by mouth); PO, per oral (by mouth); PRN, pro re nata (take as needed); q4h, every 4 hours; q6h, every 6 hours; sCr, serum creatinine; sCr, serum creatinine; ULN, upper limit of normal; UOP, urinary output.