Severe infusion‐related reaction to crizanlizumab in an adolescent with sickle cell disease
Authors: Kristine Karkoska, Charles T. Quinn, Kelly Clapp, Patrick T. McGann
Journal: American Journal of Hematology (2020)

To the Editor: Crizanlizumab (Adakveo), a humanized monoclonal antibody that binds to P-selectin, was recently approved by the Food and Drug Administration (FDA) in November 2019 for the prevention of painful vasoocclusive crises (VOC) in patients (age ≥ 16 years) with sickle cell disease (SCD). The binding of crizanlizumab to P-selectin interferes with its interaction with P-selectin glycoprotein ligand 1 (PSGL-1) and reduces the adhesion among leukocytes, platelets, erythrocytes, and endothelium that leads to the hallmark painful VOC of SCD.1-3 FDA approval was based upon results from the SUSTAIN study, a phase 2, multicenter, randomized, placebo-controlled trial that assessed the safety and efficacy of crizanlizumab in SCD patients (16-65 years of age) who had 2-10 SCD-related pain crises in the previous 12 months.4 The study reported significant reduction in painful VOC with high-dose crizanlizumab (5 mg/kg) compared to placebo (median 2.98 crises per year vs 1.63, P = .01). There were no significant differences in adverse events (AEs) with crizanlizumab treatment compared to placebo. Results of this phase 2 study of 198 patients allowed crizanlizumab to be designated for Priority Review and Breakthrough Therapy designation by the FDA leading to rapid approval in November 2019. In SUSTAIN, AEs were common, occurring in 85% of patients with an even distribution across study arms.4 The most commonly reported AEs were headache, back pain, nausea, and musculoskeletal pain, occcurring in >10% of patients across all study arms. Serious adverse events (SAEs) were reported in 28% of patients with even distribution across the study arms. There was a high rate of discontinuation of study treatment in all arms (36% high-dose, 32% low-dose and 37% placebo). A secondary analysis concluded that treatment-related AEs and SAEs were higher in patients treated with crizanlizumab than with placebo, but the incidence of AEs leading to discontinuation was low (0-8%).5 The package insert notes that 3% of patients had infusion-related reactions but does not provide details or guidance regarding management. Here, we describe a severe infusion-related event in an adolescent male with SCD. The patient is a 17-year-old male with HbSS disease with a history of frequent VOC, including five hospitalizations in the previous 12 months as his adherence to hydroxyurea waned. After multiple discussions, the patient and family agreed to proceed with crizanlizumab in an attempt to reduce the frequency and severity of his pain. On the infusion day, he presented with his baseline chronic back and shoulder pain, but was otherwise well without fever or other signs of acute illness or infection. His intended dose of crizanlizumab was 300 mg (5 mg/kg) infused over 30 minutes by peripheral IV, according to the package insert. He received acetaminophen as a premedication. Within 10 minutes of the infusion, he experienced sudden and severe pain, rated 10/10, in his back, legs, and head. The infusion rate was slowed by one-half then stopped by 15 minutes with approximately 30% of the intended dose administered. He received IV morphine and a normal saline bolus without improvement, and subsequently received additional doses of morphine, ketorolac, and diphenhydramine. He had expected vital sign changes with acute pain, but remained hemodynamically stable and afebrile. He did not have difficulty breathing, wheezing, or urticaria. He had stabilization but persistence of pain and due to a desire to return home, he was discharged 6 hours from the start of the infusion with an oral pain regimen. Within hours of returning home, his pain again worsened and he presented to the emergency department for further management. Vital signs were notable for fever to 39.3°C with initial oxygen saturations of 94% and subsequent desaturations to 88%. A peripheral blood culture was sent and ceftriaxone was administered IV. He was admitted to the hematology service for further management. Throughout his 7 day hospital course, the patient's pain was difficult to manage; both he and his mother expressed that this was the most severe pain of his life. He required frequent intravenous and oral analgesics including patient-controlled analgesia, short- and long-acting opiates, muscle relaxants, and non-steroidal anti-inflammatory drugs. He had persistent fever to ≥39°C without an identifiable source through hospital day 5 despite scheduled acetaminophen and ketorolac. Blood and urine cultures were negative, as was testing for SARS-CoV-2 (COVID-19). Chest X-ray showed a left basilar opacity consistent with acute chest syndrome, particularly in the setting of an oxygen requirement. Laboratory trends demonstrated worsening anemia with a > 1 g/dL drop in hemoglobin to 6.7 g/dL with evidence of bone marrow stress as noted by a marked increase in nucleated red blood cells, requiring a packed red blood cell transfusion - his first in over 2 years. Additional notable laboratory findings included leukocytosis, mild hyperbilirubinemia, elevated alkaline phosphatase and hepatic transaminases, and hypophosphatemia, requiring supplementation. A workup was performed to evaluate possible complement activation-related psuedoallergy (CARPA), which revealed a mild elevation in sC5b-9 level (Table 1). The patient was discharged on hospital day 8 after slow improvement. He required continued analgesics at home and reported significant psychological distress with associated nightmares related to this event. The family decided to discontinue further crizanlizumab infusions and are hesitant to consider other new treatment options. After decades of limited treatment options, it is exciting that novel treatments for SCD are emerging. While rapid approvals are important to accelerate access to novel medications, it remains critically important to perform postmarketing surveillance of medications such as crizanlizumab that are approved based on data from a limited number of patients enrolled in clinical trials. In reviewing published safety data, there were no expectations that such a severe event could happen with a crizanlizumab infusion. The infusion reaction appears consistent with the CARPA pattern described with other monoclonal antibodies, and this triggered a severe and prolonged painful VOC. This initial crizanlizumab infusion resulted in increased hemolysis, hypertransaminasemia, and renal phosphorous wasting. Since crizanlizumab's approval, Novartis has received multiple reports of painful events within the first 24 hours of an infusion, which prompted the company to release a postmarketing safety statement promising further evaluation and to create a website with updated safety information.6 It will be important to continue to collect and report these cases to better understand the risk profile to educate both providers and patients as the use of this new medication expands. The authors declare no conflicts of interest. Data sharing is not applicable to this article as no new data were created or analyzed in this study.