Wojenski, Daniel

Abstract Background Voriconazole 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 voriconazole with the development of squamous cell carcinoma (SCC) post-transplant, but its association with SCC in allo-HSCT patients is unknown. We sought to determine this association. Methods After IRB approval, Mayo Clinic’s transplant database (2007-2012) was accessed and electronic charts of allo-HSCT patients were retrospectively reviewed. Voriconazole exposure was defined as exposure to voriconazole at any time during treatment of primary disease, prior to or following HSCT. Cumulative voriconazole exposure was defined as total days of voriconazole use following HSCT; days were not required to be consecutive. Two time-dependent voriconazole exposure variables were defined: (1) history of voriconazole exposure (yes/no) over time, and (2) cumulative days on voriconazole over time. Results 404 patients underwent allo-HSCT during this timeframe, and 381 patients (table 1) were included in the final analysis. 23 patients were excluded (8 patients received multiple transplants, 9 patients were treated under pediatric protocols, 6 patients lacked research consent). 312/381 received voriconazole; other antifungal therapy included fluconazole (n=40), posaconazole (n=23), anidulafungin (n=1), and caspofungin (n=5). Median duration of cumulative days of voriconazole was 214 (range 2 -1553). SCC developed in 26/312 exposed to voriconazole 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 voriconazole 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 conditioning regimen, skin cancer pre-HSCT, chronic GVHD) as covariates (HR 1.859 for each 180 days of use, p<0.001). History of prior voriconazole exposure was not associated with an increased risk of SCC after covariate adjustment (HR 2.436, p=0.2369). Conclusion This is the first study to establish cumulative days of voriconazole 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. Disclosures: No relevant conflicts of interest to declare.

572 Background: There is limited data regarding chemotherapy dosing in obese mCRC patients. Methods: A retrospective, single institution, cohort study of mCRC patients receiving mFOLFOX6 (fluorouracil (5-FU) bolus omitted) was conducted between January 2002 and January 2011. Patients were stratified into: obese (BMI > 30) full dose, obese dose reduced (oxaliplatin (OX) and/or 5-FU), non-obese (BMI 18-29.9) full dose, and non-obese dose reduced. The primary endpoint was incidence of grade 3/4 myelosuppression within the first 12 wks of therapy. Secondary endpoints included incidence of any grade diarrhea and neuropathy, progression free (PFS) and overall survival (OS). Results: Of the 236 patients (72 obese, 164 non-obese), 15 obese and 37 non-obese received a dose reduction. Grade 3/4 myelosuppression occurred in 0 obese OX dose reduced, 3 (7.5%) obese full dose, 1 (8.3%) non-obese dose reduced, and 7 (7.8%) non-obese full dose patients (p=0.93). Grade 3/4 myelosuppression occurred in 0 obese 5-FU dose reduced, 3 (7.5%) obese full dose, 2 (12.5%) non-obese dose reduced, and 6 (7%) non-obese full dose patients (p=0.8). There were no statistically significant differences in the incidence of neuropathy or diarrhea between groups. PFS was longer in OX full dose patients (obese dose reduced, 8.8 mos; obese full dose, 10 mos; non-obese dose reduced, 3.7 mos; non-obese full dose, 10.4 mos; p=0.0094). No difference in PFS was found with 5-FU dosing (p=0.0615). OS favored OX full dose patients (obese dose reduced, 1.6 yrs; obese full dose, 2.4 yrs; non-obese dose reduced, 0.7 yrs; non-obese full dose, 2 yrs; p=0.0006) and 5-FU full dose patients (obese dose reduced, 1.6 yrs; obese full dose, 2.2 yrs; non-obese dose reduced, 1.6 yrs; non-obese full dose, 1.9 yrs; p=0.0287). Conclusions: There is no difference in the incidence of grade 3/4 myelosuppression, diarrhea or neuropathy in obese versus non-obese patients, dose reduced or not. OX dose reductions were associated with reduced PFS and OS. 5-FU dose reductions were associated with reduced OS. Our study supports ASCO recommendations against dose reductions in obese patients receiving chemotherapy.

AbstractBackgroundVoriconazole is a commonly used antifungal medication in allogeneic hematopoietic stem cell transplantation (allo‐HSCT) patients. In solid organ transplantation, voriconazole use has been associated with the development of cutaneous squamous cell carcinoma (SCC). We sought to determine if voriconazole use was associated with SCC in patients undergoing allo‐HSCT.MethodsWe retrospectively reviewed consecutive adult patients who underwent allo‐HSCT at Mayo Clinic from January 2007 through July 2012. Multivariable Cox models were created to assess the relationship of SCC with two time‐dependent voriconazole exposure variables: (i) history of voriconazole exposure (yes/no), and (ii) cumulative days of voriconazole use.ResultsIn our cohort of 381 allo‐HSCT patients, SCC developed in 26 of 312 patients exposed to voriconazole (25 post‐voriconazole) and in 1 of 69 patients who received alternative antifungal agent(s). Cumulative incidence of SCC was estimated to be 19% at 5 years post allo‐transplant. Cumulative days of voriconazole use was found to be a risk factor for SCC, and this relationship persisted in a multivariable model using previously identified risk factors as covariates (hazard ratio 1.859 for each 180 days of use, P < 0.001).ConclusionThis is the first study, to our knowledge, to identify cumulative days of voriconazole use as a risk factor for SCC development following allo‐HSCT, and may help guide appropriate antifungal use in this patient population.