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First case of DRESS (drug reaction with eosinophilia and systemic symptoms) associated with voxelotor
American Journal of Hematology ( IF 12.8 ) Pub Date : 2021-09-03 , DOI: 10.1002/ajh.26342
Matthew Lee 1 , Thomas Stringer 2 , Jack Jacob 3 , Elana M Friedman 4 , Caterina Minniti 1 , Henny H Billett 1 , Susanna A Curtis 1
Affiliation  

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.

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FIGURE 1
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The initial clinical presentation including labs and histopathology of the patient's rashes. (A) The patient had presented with multiple erythematous, confluent plaques of superficial desquamative scale throughout the scalp, head and neck, back, chest (A), abdomen and lower extremities as seen above. (B) Punch biopsy (40x) of patient's left arm, revealed spongiotic and an interstitial, perivascular, interface dermatitis with mixed infiltrate including lymphocytes, histiocytes, and numerous intraepidermal and dermal eosinophils consistent with a drug. Background pigment incontinence is also noted. (C) The time course of the patient with the incorporation of the values of hemoglobin and the absolute eosinophil count along with when voxelotor was started and held and the subsequent effects this had on these lab values

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.



中文翻译:

与voxelotor相关的首例DRESS(嗜酸性粒细胞增多和全身症状的药物反应)

镰状细胞病 (SCD) 是一组遗传性疾病,包括镰状细胞性贫血,这是一种常染色体隐性遗传病,由血红蛋白 (Hb) 的 β-珠蛋白基因内的单个氨基酸取代引起。这种突变可导致 Hb α 2 β s 2四聚体聚合,导致红细胞镰状化、红细胞膜损伤和红细胞破坏。1, 2

直到最近,很少有直接针对红细胞镰状细胞的疗法。然而,一种新型药物 voxelotor 已证明其能够通过与 α 2 β s 2四聚体的 α 链结合并将血红蛋白氧合解离曲线向左移动来增加血红蛋白水平,从而增加氧结合并减少血红蛋白聚合。3 Voxelotor 获得 FDA 基于 HOPE 试验(NCT 03036813)的加速批准和突破性治疗指定,最常见的不良反应是头痛、腹泻、关节痛、上呼吸道感染和皮疹。4检查罕见疾病新药的研究可能太小,无法证明罕见不良结果的风险,因此批准后任何此类结果的报告对于患者护理至关重要。据我们所知,目前还没有因使用 voxelotor 引起的 DRESS(伴有嗜酸性粒细胞增多和全身症状的药疹)事件的报告。我们在这里介绍第一个案例。

我们报告了一名 53 岁的非洲裔美国女性,患有纯合子 HbSS,并发肺动脉高压和慢性肾病 IV 期(基线肌酐 2.5 mg/dl),基线 Hb 约为 5.0 g/dl,自使用 α-epoetin 以来2019 年,需要大约每 3 个月输注一次红细胞以治疗症状性贫血。她自 2017 年以来一直服用羟基脲,但自 2020 年 3 月起因网织红细胞减少症而停药,她于 2020 年 10 月 10 日开始服用 voxelotor 1500 毫克,每天一次。2020 年 11 月 5 日,她因肌酸出现急性肾损伤 (AKI) ( Cr)为 5.32 mg/dl,同时嗜酸性粒细胞增多,绝对计数为 1.100/mL(全血细胞计数差异为 15%)。鉴于对药物反应的担忧,voxelotor 举行。2 周后于 2020 年 11 月 20 日重新开始,在 AKI 缓解且嗜酸性粒细胞减少至每立方毫升 0.9 万后,每天减少 1000 毫克的剂量,随后她的血红蛋白改善至 10.4 克/分升。五周后的 12 月 30 日,她因发烧、疲劳、咳嗽、面部肿胀和面部、颈部、胸部、肩部、背部和下肢的瘙痒性皮疹(图 1(A))入院,体检未发现淋巴结肿大。她的实验室显示 Hgb 从 10.1 降至 7.6 g/dl,白细胞计数增加 13,900/ml,嗜酸性粒细胞绝对计数为 5200/ml,AKI 与 Cr 为 3.96 mg/dl 和最大天冬氨酸氨基转移酶 (AST) 和丙氨酸氨基转移酶 (ALT) 129 单位/升和 82 单位/升的转氨酶,分别与每升 243 单位的碱性磷酸酶 (ALP) 和 2.0 毫克/分升的总胆红素一起。感染性检查结果为阴性,胸部计算机断层扫描 (CT) 显示弥漫性磨玻璃影和马赛克衰减,无淋巴结肿大。对该患者进行了皮肤科评估,并对左上臂进行了穿刺活检,结果显示海绵组织增生和间质性、血管周围和界面性皮炎,包括组织细胞、淋巴细胞和嗜酸性粒细胞。这些组织学发现被认为与药物反应相符(图 1(B)),并且根据临床情况,可以得出结论,这是由体素引起的嗜酸性粒细胞增多和全身症状(DRESS)减弱的药物反应。使用润肤剂和高效外用氢化可的松 2 解决了患者的皮肤问题。5% 的软膏和 12% 的 amlactin 乳液。她的肝肾功能检查有所改善,2 周后患者出院,Hb 和嗜酸性粒细胞稳定(图 1(C))。出院后 3 个月,她只需要再输一次血。在 2021 年 8 月的最近一次就诊中,她的皮疹已完全消退,肾功能和肝功能测试已恢复到基线水平,嗜酸性粒细胞减少至 600/mL。

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图1
在图形查看器中打开微软幻灯片软件
最初的临床表现,包括患者皮疹的实验室和组织病理学。(A) 如上图所示,患者在整个头皮、头颈部、背部、胸部 (A)、腹部和下肢出现多处融合的表层脱屑性鳞屑红斑。(B) 对患者左臂进行穿刺活检 (40x),发现海绵状和间质性、血管周围、界面性皮炎,伴有混合浸润,包括淋巴细胞、组织细胞和大量表皮内和真皮内嗜酸性粒细胞,与药物一致。还注意到背景色素失禁。(C) 患者的时间过程,包括血红蛋白值和绝对嗜酸性粒细胞计数,以及 voxelotor 何时开始和保持以及随后对这些实验室值的影响

虽然皮疹是开始使用 voxelotor 的患者中常见的不良事件,但以前没有报道过 DRESS。在 voxelotor 的初始 1 期和 2 期试验(NCT02285088 和 NCT03041909)中,研究了长达 6 个月的 41 名参与者,12% 的参与者报告了皮疹,只有一名患者在出现 2 级皮疹后停用 voxelotor,每天服用 1000 毫克。5在 3 期研究中,voxelotor 每天 1500 毫克、每天 900 毫克和安慰剂组分别有 12%、10% 和 9% 的患者报告了皮肤不良事件(例如,全身性、荨麻疹、斑丘疹、水疱或瘙痒)但没有报告伴有全身表现、嗜酸性粒细胞增多或 DRESS 综合征的皮肤事件。4目前,在接受 voxelotor 治疗的患者中,<1% 的患者会出现严重超敏反应的警告。

请注意,DRESS 通常与别嘌醇、磺胺类药物、万古霉素、米诺环素或抗癫痫药等药物有关。6在大多数内脏受累病例中,治疗是泼尼松 0.5 至 1 mg/kg/d。7中位 4.5 个月后,25% 的病例在缓解后复发,通常表现为嗜酸性粒细胞增多症或转氨炎。复发可能由最初的致病药物以外的药物引发,应密切监测。8在我们的患者中,尚未发现复发,患者仅使用高效外用皮质类固醇治疗效果良好,鉴于单独局部治疗的临床改善以及对严重血管闭塞事件风险增加的担忧,她的病例未使用全身性皮质类固醇在患有 SCD 的人中使用全身性类固醇。9

总之,这强调了每当使用 voxelotor 的患者出现新的皮疹、嗜酸性粒细胞增加和新的或恶化的器官损伤迹象时,需要提高认识。DRESS 的早期诊断对镰状细胞病患者尤其重要,因为他们通常有预先存在的终末器官损伤,这可能使他们比一般人群报告的死亡风险更高。重要的是,由于 voxelotor 被批准为罕见病治疗,即使是 3 期研究也可能太小而无法识别罕见的危及生命的不良事件,例如 DRESS。这使得营销后研究和案例报告变得至关重要。10

该案例强调了迅速识别开始使用 voxelotor 的患者可能的 DRESS 的重要性,以减轻或预防对这一弱势群体的长期影响,以及对 voxelotor 和任何新批准药物的安全性进行长期研究的必要性在罕见病中。

更新日期:2021-10-12
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