Severe Skin Toxicity in Pediatric Oncology Patients Treated with Voriconazole and Concomitant Methotrexate

Abstract

dWe report the occurrence of skin toxicities in pediatric oncology patients on concomitant treatment with voriconazole and methotrexate (MTX). Of 23 patients who received this combination, 11 patients suffered from cheilitis and/or photosensitivity. In contrast, only in 1 of 9 patients who received voriconazole without MTX was photosensitivity observed. A mechanism of action was not able to be identified. We describe two cases with severe skin toxicities. Caution is warranted when using voriconazole and concomitant MTX. Due to an increased risk of fungal exposure (specifically Aspergillus) caused by unavoidable construction activities in our hospital, immunocompromised pediatric patients treated for hematologic malignancies and autologous stem cell transplantation recipients received antifungal prophylaxis with oral voriconazole Strikingly, during the time period of this prophylaxis, increased incidence and severity of skin toxicities were observed in patients treated concomitantly with high-(HD) or low-dose (LD) methotrexate (MTX). This drew our attention, since antifungal prophylaxis with voriconazole was generally not used prior to the construction activities and the nature of skin lesions appeared to be different from that of the typical skin reactions induced by only methotrexate in these patients (1-3).Therefore, we have performed a systematic chart review in all patients treated with prophylactic voriconazole as recorded in the electronic hospital medication registration database within a period of 6 months (January 2011 to June 2011). Toxicities (photosensitivity and cheilitis) were graded according to CTCAE criteria (v4.0) (4). To illustrate our observations, we have described the observed toxicity for two patients in more detail.A total of 32 patients received antifungal prophylaxis with voriconazole, most of whom were treated for acute lymphoblastic leukemia (ALL). In 23 of these patients (17 males, 6 females; 0 to 17 years old; median, 10 years of age), MTX was concomitantly administered as part of their treatment. An overview of all included patients is provided in Table 1. In 11 of 23 patients (48%) receiving prophylactic voriconazole and concomitant MTX, skin toxicities were observed. All of these patients (9 male, 2 female) experienced photosensitivity (grade 1 to 3), whereas 6 patients also experienced cheilitis (grade 2 to 3). In contrast, in patients receiving voriconazole treatment without concomitant MTX, only 1 of 8 patients experienced a skin reaction (photosensitivity grade 3) and no patient experienced cheilitis.The skin reactions most often erupted within a short time period after MTX treatment was given concomitantly (median time after the start of voriconazole, 36 days; range, 5 to 94 days) and typically presented as a painful erythema on sun-exposed areas of hands, face, and neck and with evolution of crustae on the lips. Mucositis, which is a typical high-dose-MTX-associated toxicity, was generally not observed in these patients during the observation period. Some skin reactions of ...

Photosensitivity reactions and skin tumours associated with voriconazole

“…10 In a retrospective analysis of 430 children the incidence of phototoxicity was 20% in all those who took voriconazole and 47% in those who took it for 6 months or more; susceptibility factors included white race, cystic fibrosis, cumulative treatment time, and cumulative dose. 11 Presentation Severe retinoid-like photosensitivity (erythema, desquamation, and ulceration of light-exposed skin) occurred in two children with chronic granulomatous disease who took voriconazole 200 mg twice daily for chronic invasive aspergillosis.…”

Profilaktyka zakażeń grzybiczych u dzieci poddawanych transplantacjom komórek hematopoetycznych

“…Candida sp., n = 6) pojawiły się u pacjentów z czynnikami ryzyka gorszego wchłaniania leku, takich jak stosowanie inhibitorów pompy protonowej, biegunka czy mucositis [27]. Stosowanie worikonazolu jest ograniczone przez potencjalne toksyczności w zakresie skóry czy też układu nerwowego [28]. W niektórych ośrodkach zamiast azoli w profilaktyce u dzieci poddawanych allogenicznej HSCT stosowano mikafunginę [29], kaspofunginę lub liposomalną amfoterycynę B [30,31].…”

Methotrexate ultraviolet reactivation reaction in the setting of voriconazole‐induced phototoxicity

“…who noted an overall increased incidence in skin toxicity reactions in an inpatient pediatric oncology population receiving concomitant voriconazole and methotrexate when compared to voriconazole alone . Two of these cases were described to have recurrence of a photosensitive eruption, described as painful erythema in sun‐exposed areas, after methotrexate administration . Our case illustrates the impressive cutaneous manifestations of UV reactivation and highlights the role that voriconazole may serve as a potential risk factor for methotrexate‐induced UV reactivation.…”

“…Voriconazole is a broad‐spectrum triazole antifungal agent known to induce phototoxicity characterized by erythema, pain, and edema, within 30 min–2 h of sunlight exposure and likely played a role in our patient's pre‐admission sunburn . Precedence in the literature for increased skin toxicity in patients receiving both voriconazole and methotrexate is suggested by van Hasselt et al . who noted an overall increased incidence in skin toxicity reactions in an inpatient pediatric oncology population receiving concomitant voriconazole and methotrexate when compared to voriconazole alone .…”

“…Precedence in the literature for increased skin toxicity in patients receiving both voriconazole and methotrexate is suggested by van Hasselt et al . who noted an overall increased incidence in skin toxicity reactions in an inpatient pediatric oncology population receiving concomitant voriconazole and methotrexate when compared to voriconazole alone . Two of these cases were described to have recurrence of a photosensitive eruption, described as painful erythema in sun‐exposed areas, after methotrexate administration .…”