背景:全反式维甲酸(ATRA)是治疗急性早幼粒细胞白血病(APL)必不可少的部分。虽然,轻微的皮肤毒性,如粘膜皮肤干燥症,皮疹,瘙痒有很好的报道,与ATRA相关的严重皮肤病毒性极为罕见。ATRA主要由细胞色素P450(CYP450)酶系统代谢,和三唑类抗真菌药因其对CYP450的强抑制作用而臭名昭著。
方法:三名亚洲APL患者经历了罕见的ATRA引起的严重皮肤病毒性:病例1和2的剥脱性皮炎(ED),病例3的坏死性阴囊溃疡。两个病例1(33岁女性),病例2(28岁男性)因脱水进入急诊科,在诱导化疗期间出现全身性皮肤红斑和干燥。这两名患者还发展为侵袭性曲霉病,并在化疗期间需要同时使用三唑抗真菌剂。对于ED,开始静脉输液和广谱抗生素,同时应用局部润肤剂以防止经皮水分流失.尽管他们的一般状况有所改善,但皮肤脱落仍在继续,手掌和鞋底完全脱皮。咨询了皮肤科,建立了ED的临床诊断。停止ATRA导致ED完全消退。病例3(15岁男孩)在诱导化疗期间报告了两个黑色轻度触痛的阴囊病变。他在就诊时还患有皮肤粘膜念珠菌病,并一直服用三唑抗真菌药。当地细菌和真菌培养物,单纯疱疹病毒的血清学检测报告为阴性。尽管有足够的当地护理和最佳的抗生素支持,他的病变持续存在,只有在暂时停止ATRA后才有所改善。经过全面的文献回顾,并考虑到皮肤毒性与三唑抗真菌药的时间关联,我们推测,伴随使用三唑抗真菌药抑制ATRA的肝脏代谢,导致更高的血清ATRA浓度,我们患者的皮肤毒性明显加重。
结论:通过强调这种关键的药代动力学相互作用,我们要提醒其他肿瘤学家注意三唑抗真菌药物对CYP450的抑制作用。因此,我们建议使用ATRA和三氧化二砷的非骨髓抑制组合来治疗APL,消除预防性抗真菌药物的需要。然而,如果发生侵袭性真菌感染(FI),我们建议使用抗真菌药物的替代类。
BACKGROUND: All-trans retinoic acid (ATRA) is an indispensable part of the treatment of acute promyelocytic leukemia (APL). Although, mild cutaneous toxicities like mucocutaneous xerosis, rash, and pruritus are well reported, ATRA associated severe dermatological toxicities are extremely rare. ATRA is primary metabolized by cytochrome P450 (CYP450) enzyme system, and triazole antifungals are notorious for their strong inhibitory effect on CYP450.
METHODS: Three Asian APL patients experienced rare ATRA-induced severe dermatological toxicities: exfoliative dermatitis (ED) in cases 1 and 2, and necrotic scrotal ulceration in
case 3. Both
case 1 (33-year-old female), and
case 2 (28-year-old male) landed in emergency department with dehydration, generalized skin erythema and xerosis during their induction chemotherapy. Both of these patients also developed invasive
aspergillosis and required concomitant triazole antifungals during their chemotherapy. For ED, intravenous fluids and broad-spectrum antibiotics were started along with application of local emollients to prevent transdermal water loss. Although their general condition improved but skin exfoliation continued with complete desquamation of palms and soles. Dermatology was consulted, and clinical diagnosis of ED was established. Discontinuation of ATRA resulted in complete resolution of ED.
Case 3 (15-year-old boy) reported two blackish mildly tender scrotal lesions during induction chemotherapy. He also had mucocutaneous candidiasis at presentation and was kept on triazole antifungal. Local bacterial & fungal cultures, and serological testing for herpes simplex virus were reported negative. Despite adequate local care and optimal antibiotic support, his lesions persisted, and improved only after temporary discontinuation of ATRA. After a thorough literature review and considering the temporal association of cutaneous toxicities with triazole antifungals, we speculate that the concomitant use of triazole antifungals inhibited the hepatic metabolism of ATRA, resulting in higher serum ATRA concentration, and markedly accentuated cutaneous toxicities in our patients.
CONCLUSIONS: By highlighting this crucial pharmacokinetic interaction, we want to caution the fellow oncologists to be mindful of the inhibitory effect of triazole antifungals on CYP450. We propose using a non-myelosuppressive combination of ATRA and arsenic trioxide for management of APL hence, obliterating the need of prophylactic antifungals. However, in the event of invasive fungal infection (IFI), we suggest using alternative class of antifungals.