Voriconazole Exposure and the Risk of Cutaneous Squamous Cell Carcinoma in Allogeneic Hematopoietic Stem Cell Transplant Patients

Background Voriconazole (Vori) is a common antifungal medication used in allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients. In solid organ transplantation, multiple studies have associated the use of vori with the development of squamous cell carcinoma (SCC) post-transplant, but its association with SCC in allo-HSCT patients is unknown.

Methods Mayo Clinic's transplant database (2007-2012) was accessed and electronic charts of allo-HSCT patients were reviewed. Vori exposure was defined as its exposure at any time during treatment of primary disease, prior to or following HSCT.  Cumulative vori exposure was defined as total days of voric use following HSCT; days were not required to be consecutive.  Two time-dependent vori exposure variables were defined: (1) history of vori exposure (yes/no) over time, and (2) cumulative days on vori over time. 

Results 404 patients underwent allo-HSCT during this timeframe, and 381 patients (table 1) were included in the final analysis. 312/381 received vori; other antifungal therapy included fluconazole (n=40), posaconazole (n=23), anidulafungin (n=1), and caspofungin (n=5).  Median duration of cumulative days of vori was 214 (range 2 -1553). SCC developed in 26/312 exposed to vori and in 1/69 who received alternative antifungals. Cumulative incidence of SCC at 1 year was 3%, 2 years was 8%, 3 years was 13%, 4 years was 14%, and at 5 years was 19% (figure 1). Cumulative days of vori use was found to be a risk factor for the development of SCC, and this relationship persisted in a multivariate model using previously identified risk factors (gender, age at transplant, TBI , skin cancer pre-HSCT, GVHD) as covariates (HR 1.859 for each 180 days of use, p<0.001). History of prior vori exposure was not associated with increased risk of SCC after covariate adjustment (HR 2.436, p=0.2369). 

Conclusion This is the first study to establish cumulative days of vori use as a risk factor for SCC development following allo-HSCT, and may help guide appropriate antifungal prophylaxis in this patient population which is already at an increased risk of developing skin cancers.

Table 1: Baseline Characteristics of 381 patients undergoing allogeneic HSCT
Characteristic	HSCT Patients (N = 381)
Age (years)    Median    Range	53 19-71
Gender    Male	58.3%
Race    Caucasian	94.0%
Primary malignancy    ALL    AML    MDS    CLL    CML    Lymphoma    Plasma-Cell-Disorders    Non-Malignant-Disorders	13.1% 36.0% 18.6% 11.5% 6.0% 4.5% 7.9% 2.4%
Graft type    Peripheral-Blood    Bone-Marrow    Umbilical-Cord-Blood	86.9% 10.5% 2.6%
Total body irradiation    Myeloablative    Reduced Intensity/Nonmyeloablative	36.0% 14.4%