First case of <scp>DRESS</scp> (drug reaction with eosinophilia and systemic symptoms) associated with voxelotor
Authors: Matthew Lee, Thomas Stringer, Jack Jacob, Elana M. Friedman, Caterina Minniti, Henny H. Billett, Susanna A. Curtis
Journal: American Journal of Hematology (2021)

Sickle cell disease (SCD) is a group of inherited diseases that includes sickle cell anemia, an autosomal recessive disorder caused by a single amino acid substitution within the β-globin gene of hemoglobin (Hb). This mutation can result in polymerization of the Hb α2βs2 tetramer, causing red cell sickling, erythrocyte membrane damage and red cell destruction.1, 2 Until recently, there were few therapies which directly targeted red cell sickling. However, a novel agent, voxelotor, has demonstrated its ability to increase hemoglobin levels by bonding with the α chain of the α2βs2 tetramer and shifting the hemoglobin oxygenation dissociation curve to the left, which increases oxygen binding and decreases hemoglobin polymerization.3 Voxelotor was granted accelerated approval and breakthrough therapy designation by the FDA based on the HOPE trial (NCT 03036813) with the most common adverse reactions being headache, diarrhea, arthralgia, upper respiratory tract infection and rash.4 Studies examining new medications for rare diseases may be too small to demonstrate risk of rare adverse outcomes and so reports of any such outcomes post approval are critical for patient care. To our knowledge there have been no reported incidents of DRESS (drug rash with eosinophilia and systemic symptoms) due to voxelotor usage. We present here the first case of this. We report a 53-year-old African American woman with homozygous HbSS complicated by pulmonary hypertension and chronic kidney disease stage IV (baseline creatinine 2.5 mg/dl) with a baseline around Hb of 5.0 g/dl, on long-standing epoetin alfa since 2019 and requiring red cell transfusions approximately every 3 months for the treatment of symptomatic anemia. She had been hydroxyurea since 2017 but it had been held since March 2020 for reticulocytopenia and she was started on voxelotor 1500 mg once daily on October 10, 2020. On November 5, 2020, she developed acute kidney injury (AKI) with a creatine (Cr) of 5.32 mg/dl along with eosinophilia at an absolute count of 1.1 thousands per cubic milliliter (15% on complete blood count differential). Given concerns of a drug reaction voxelotor was held. It was restarted 2 weeks later on November 20 2020 at a reduced dose of 1000 mg daily after resolution of her AKI and decrease in eosinophilia to 0.9 thousands per cubic milliliter, and subsequently her hemoglobin improved to 10.4 g/dl. Five weeks later on December 30 she was admitted for fevers, fatigue, cough, facial swelling and a pruritic rash along her face, neck, chest, shoulders, back and lower extremities (Figure 1(A)) with no lymphadenopathy on physical exam. Her labs were significant for a drop in Hgb from 10.1 to 7.6 g/dl and an increase in white blood cell count of 13,900 per cubic milliliter with an absolute eosinophil count of 5200 per cubic milliliter, an AKI with Cr of 3.96 mg/dl and transaminitis with maximum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of 129 units per litre and 82 units per litre, respectively, along with alkaline phosphatase (ALP) of 243 units per litre and total bilirubin of 2.0 mg/dl. Infectious workup was negative and computed tomography (CT) of the chest revealed diffuse ground-glass opacities and mosaic attenuation without lymphadenopathy. The patient was evaluated by dermatology and underwent a punch biopsy of the left upper arm which revealed spongiosis and an interstitial, perivascular, and interface dermatitis with histiocytes, lymphocytes, and eosinophils. These histologic findings were felt to be compatible with a drug reaction (Figure 1(B)) and given the clinical picture, it was concluded this was an attenuated drug reaction with eosinophilia and systemic symptoms (DRESS) caused by voxeletor. The patient's skin findings resolved with emollients and high potency topical hydrocortisone 2.5% ointment and amlactin 12% lotion. Her liver and renal function tests improved and the patient was discharged 2 weeks later with stabilization of Hb and eosinophilia (Figure 1(C)). She required only one more additional transfusion 3 months after discharge. Her rash has fully resolved and renal and liver function tests have returned to baseline with decrease in eosinophilia to 600 per cubic milliliter on most recent visits in August 2021. While rash is a common adverse event seen in patients started on voxelotor, DRESS has not previously been reported. In the initial phase 1 and 2 trials of voxelotor, (NCT02285088 and NCT03041909) of the 41 participants studied up to 6 months, 12% reported rashes with only one patient on a dose of 1000 mg daily discontinuing voxelotor after developing a grade 2 rash.5 In the phase 3 study cutaneous adverse events (e.g., generalized, urticaria, maculopapular, vesicular or pruritic) were reported in 12%, 10% and 9% of patients of the voxelotor 1500 mg daily, 900 mg daily, and placebo groups respectively but no cutaneous events with systemic manifestations, eosinophilia, or DRESS syndrome were reported.4 Currently, there is a warning for serious hypersensitivity reactions in < 1% of patients treated with voxelotor. Note, DRESS is commonly associated with medications such as allopurinol, sulfonamides, vancomycin, minocycline, or antiepileptics.6 In most cases of visceral involvement, treatment is prednisone 0.5 to 1 mg/kg/d.7 Relapses occur after resolution in 25% of cases after a median of 4.5 months, often manifesting as eosinophilia or transaminitis. Relapses may be triggered by medications other than the initial causative drug and should be monitored closely.8 In our patient, no relapses have been seen yet and patient did well on high potency topical corticosteroids only and systemic corticosteroids were withheld in her case given the clinical improvement with topical treatment alone as well as concerns of the increased risk of severe vaso-occlusive events following systemic steroids in a person with SCD.9 In summary, this highlights the need for heightened awareness whenever a patient on voxelotor presents with a new rash along with an increase in eosinophils and signs of new or worsening organ damage. Early diagnosis of DRESS could be particularly critical in patients with sickle cell disease, as they commonly have pre-existing end organ damage which could predispose them to an even higher mortality risk than that reported in the general population. Importantly, since voxelotor was approved as rare disease therapy, even phase 3 studies may be too small to identify rare life-threatening adverse events such as DRESS. This makes post marketing studies and case reports critically important. There is an ongoing open label extension study of the HOPE trial examining treatment-related adverse effects over a 5-year time period (NCT 03573882) and a phase 2 open label dose escalation study of doses of 1500 to 3000 mg/d of voxelotor (NCT 04247594).10 This case highlights the importance of prompt recognition of possible DRESS in patients started on voxelotor in order to mitigate or prevent long term effects in this vulnerable population as well as the need for long-term studies of the safety profiles of voxelotor and any new medications approved in rare diseases. Would like to acknowledge the support of Montefiore Medical Center and in particular the hematology, dermatology and pathology departments and the verbal consent given by the patient to multiple authors included on this report and in accordance of Declaration of Helsinki. The authors have no interests to declare or disclose and no competing financial interests. All authors were involved in the clinical management of the reported patient, and contributed to the writing of the manuscript and approved the final version.