Crizanlizumab-Associated Painful Febrile Reaction in Sickle Cell Disease Patients
Authors: Li Valery J , Adesina Oyebimpe O. , Fertrin Kleber Yotsumoto 
Published: November 2021

Abstract
Background: P-selectin expressed on endothelium and platelets has been implicated in the pathophysiology of vaso-occlusive crises (VOCs) in sickle cell disease (SCD) patients. Crizanlizumab is a humanized monoclonal anti-P-selectin antibody approved by the FDA to reduce the frequency of VOCs. While severe adverse events (AEs) are rare, over 80% of patients most commonly have headache, back pain, nausea, or arthralgia; infusion-related reactions occurred in 3% according to the package insert. We report on 2 patients whose crizanlizumab-associated reactions help shed light on how to manage such events and possible mechanisms.
Case reports: Case 1, a 48-year-old woman with hemoglobin SC disease, history of left shoulder replacement due to avascular necrosis and left knee avascular necrosis, pending surgical replacement. Given her frequent pain episodes, she was initiated on crizanlizumab after being intolerant to hydroxyurea (watery diarrhea). She received the first dose of crizanlizumab uneventfully, but at the end of her second infusion, she developed acute bilateral groin pain that radiated to both legs. She was eventually admitted to the hospital with a fever of 38-39°C without evidence of infection. She also received one unit of RBC transfusion for a drop in Hct from 32% to 25%. For her third infusion, we premedicated her with acetaminophen 650mg, diphenhydramine 50mg, ketorolac 1g along with concurrent IV hydration. She tolerated an initial infusion at 20ml/h for the first 15 minutes after which we ramped it up to the regular rate of 200ml/h. Within minutes of that rate increase, the patient developed chest pain and dyspnea, so infusion was stopped immediately. Blood samples taken right after the event revealed tryptase and IgE levels within normal limits, and she chose to discontinue the medication.
Case 2, a 20-year-old woman with sickle cell anemia with frequent painful episodes despite hydroxyurea at 25mg/kg/day. The patient preferred to start crizanlizumab over increasing oral medication. She reported having had fever and chills at home after her first crizanlizumab infusion and improved with acetaminophen. About 10 minutes into her second infusion, she developed acute severe migratory pain in her back, moving to her lower limbs, associated with tachycardia. Infusion was immediately discontinued, and she was medicated with diphenhydramine 25mg and methylprednisolone 125mg with no improvement. She progressed with abdominal pain moving into her arms and needed meperidine 25mg and hydromorphone 1mg to achieve pain resolution. She completed the infusion successfully at 50% reduced rate but still reported subjective high fevers and chills again the next day, medicated with acetaminophen. She continues monthly infusions with a slower rate.
Discussion: As of October 2020, Novartis (manufacturer of crizanlizumab) informed that, out of 3,500 patients, there have been 22 postmarketing reports of severe pain during or within 24 hours of the infusion. Seven cases reported complications, all of which resolved. Immediate hypersensitivity reactions to monoclonal antibodies can be a cytokine release syndrome, IgE-mediated, or IgG-mediated. One case report has suggested this may be a complement activation-related pseudoallergy (CARPA) as sC5b-9 was mildly elevated in a 17-year-old male patient who developed sudden and severe pain in his back, legs and head within 10 minutes of the infusion, despite having been premedicated with acetaminophen, later developing a fever and need for admission. Differently from that case, our patients developed severe pain with a second exposure of the drug, arguing in favor of an antibody-mediated process. We did not find evidence of mast cell activation or increased IgE production in our patient who needed to discontinue the medication. We therefore hypothesize that crizanlizumab-associated painful febrile reaction may be IgG-mediated. Premedication in our experience was unsuccessful, and symptomatic treatment with acetaminophen was appropriate, but slower infusion rates may prove useful for some patients.
Conclusion: While rare, crizanlizumab-associated painful febrile reactions may be observed after a first uneventful infusion and are possibly IgG-mediated. Patients experiencing this reaction may require symptomatic treatment with acetaminophen despite premedication and can be tried on slower infusion rates.

Disclosures
Fertrin: Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.