Dierkhising, Ross

Background: Prolonged methotrexate (MTX) exposure following high-dose methotrexate (HDMTX; ≥1g/m2) occurs in up to 33% of patients and potentially compromises management through increased renal and systemic toxicities.(Pinedo et al, 1977, Joerger et al, 2012) MTX-associated acute kidney injury (AKI) occurs in 5% to 30% of patients.(May et al, 2014) Rescue leucovorin dose escalation in response to an elevated 48-hour MTX concentration or serum creatinine rise is standard-of-care to reduce adverse events. The practice of preemptive leucovorin dose increases in patients with elevated MTX concentrations or previous AKI during prior MTX doses has unclear outcomes. Methods: This retrospective, single-center, cohort study was approved by the Mayo Clinic IRB and performed in accordance with the ethical standards of the 1964 Declaration of Helsinki. We identified patients newly initiated on HDMTX for management of lymphoma between 1/1/2011 and 10/31/2017 at Mayo Clinic in Rochester, MN. Patients were followed longitudinally until HDMTX was discontinued. The primary endpoint was the proportion of patients with an elevated MTX concentration (MTX > 1.0 mcmol/L) at 48 hours for the initial cycle. Secondary endpoints included the incidence of AKI (Kellum et al, 2012) and whether preemptively increased leucovorin doses during subsequent cycles of HDMTX impacted the incidence of a repeated episode of an elevated 48-hour MTX concentration, decreased incidence of AKI, or decreased hospital length of stay (LOS) compared to patients with standard leucovorin dosing (25mg intravenous every 6 hours until MTX < 0.1 mcmol/L). Results: The 321 included patients had a median (IQR) age of 65 (57, 72) years, 190 (59%) were male, and 293 (91%) were Caucasian. Baseline demographics and clinical characteristics are depicted in table 1 with those who had elevated MTX levels during their initial cycle more likely to be Male, Caucasian, have a higher BSA, have Primary DLBCL of the CNS, have bone marrow involvement, have a higher baseline SCr, higher total bilirubin, and lower albumin. The median (IQR) grams of the initial MTX dose was 6.3 (4.3, 7.5) for 84 patients (26%) receiving MTX for prophylaxis and was 12.8 grams (7.5, 16.8) for the 237 patients (74%) receiving MTX as treatment. Chemotherapy regimen distribution included 43 patients (13%) receiving HDMTX 8 grams/m2 monotherapy, 162 patients (50%) receiving HDMTX 8 grams/m2 with Rituximab and Temozolomide (MRT), and 96 patients (30%) receiving HDMTX 3.5 grams/m2 in combination with R-CHOP. Patients received a median of 3 MTX doses (IQR:2 doses, 6 doses). A total of 83 patients (36%) had an elevated MTX concentration after their first MTX dose, and the overall incidence of elevated MTX concentrations was 22% following a total of 1558 MTX doses. Preemptively increasing the leucovorin dose (based on the prior MTX concentration) was associated with a 34% rate of elevated MTX concentrations (160/466 cycles). Giving standard leucovorin (based on the prior MTX concentration) was associated with a 12% rate of elevated MTX concentration (84/713 cycles). Those with a preemptively increased leucovorin dose were more likely to have an elevated MTX concentration in that cycle (OR=2.84, 95% CI: 2.03-3.97, p<0.001). For the secondary endpoint of AKI, the overall incidence was 18% with 107 patients (33%) experiencing AKI after their first MTX dose. In these first dose AKI episodes, 81 cases (25%) were stage 1, 19 (6%) stage 2, and 7 (2%) stage 3 Preemptive leucovorin dose increase was associated with a greater risk of AKI after MTX (OR=1.52, 95% CI: 1.05-2.19, p=0.027). Overall median hospital LOS was 4.1 (3.8, 5.8) days. Hospital LOS was longer in those with preemptively increased leucovorin doses (Median LOS with preemptively increased leucovorin doses: 5 (4.1, 6.1) days; without preemptively increased leucovorin doses: 4 (3.2, 4.3) days; estimated difference=1.1 days, 95% CI: 0.5-1.7, p<0.001). Conclusion: HDMTX leads to a significant incidence of elevated serum 48hr MTX levels and AKI, 22% and 18%, respectively. Rather than protective, we found that preemptively increased leucovorin doses used during subsequent cycles did not improve the incidence of delayed elimination, reduce the incidence of AKI, or shorten hospital LOS per MTX dose. Further investigation is needed to optimize dosing strategies and supportive measures following MTX administration for management of lymphoma patients. Disclosures Barreto: FAST Biomedical, Inc: Consultancy. Leung:Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Aduro: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding.

Controversy exists regarding the use of dose capping of weight-based unfractionated heparin (UFH) infusions in obese and morbidly obese patients. The primary objective of this study was to compare time to first therapeutic activated partial thromboplastin time (aPTT) in hospitalized patients receiving UFH for acute venous thromboembolism (VTE) among three body mass index (BMI) cohorts: non-obese (< 30 kg/m 2 ), obese (30–39.9 kg/m 2 ), and morbidly obese (⩾ 40 kg/m 2 ). In this single-center, retrospective cohort study, patients were included if they ⩾ 18 years of age, had a documented VTE, and were on an infusion of UFH for at least 24 hours. Weight-based UFH doses were calculated using actual body weight. A total of 423 patients met the inclusion criteria, with 230 (54.4%), 146 (34.5%), and 47 (11.1%) patients in the non-obese, obese, and morbidly obese cohorts, respectively. Median times to therapeutic aPTT were 16.4, 16.6, and 17.1 hours in each cohort. Within 24 hours, the cumulative incidence rates for therapeutic aPTT were 70.7% for the non-obese group, 69.9% for the obese group, and 61.7% for the morbidly obese group (obese vs non-obese: HR = 1.02, 95% CI: 0.82–1.26, p = 0.88; morbidly obese vs non-obese: HR = 0.87, 95% CI: 0.62–1.21, p = 0.41). There was no significant difference in major bleeding events between BMI groups (obese vs non-obese, p = 0.91; morbidly obese vs non-obese, p = 0.98). Based on our study, heparin dosing based on actual body weight without a dose cap is safe and effective.

Abstract Introduction: Clinical tumor lysis syndrome (TLS), which manifests most often as acute kidney injury (AKI) is a common and devastating complication of rapidly proliferating hematologic malignancies. Epidemiologic studies of attributable risk factors for AKI in this setting are small, focus on only aggressive lymphomas rather than the more prevalent intermediate risk disease subtypes, and predate contemporary risk stratification, diagnostic criteria, and supportive care. Additionally, early administration of rasburicase to enhance uric acid (UA) elimination has been adopted without robust evidence in support of its impact on clinical outcomes, specifically, prevention of AKI. Methods: This was a retrospective cohort study of adult lymphoma patients at intermediate or high risk for TLS treated at Mayo Clinic between 2009 and 2017. Patients were excluded if they had AKI at hospital admission, received pre-admission rasburicase, or were on dialysis. Consensus definitions were used to stratify TLS risk and stage AKI. The incidence of new AKI in the setting of TLS was described along with predictors of its development, including early rasburicase use. Results: Of the 461 patients with a new lymphoma diagnosis during the study timeframe at intermediate or high risk of TLS, 78 were excluded, primarily due to prevalent AKI at hospital admission. The 383 included patients were predominantly at intermediate risk for TLS (73%) and had a diagnosis of Diffuse Large B-cell Lymphoma (64%). Incidence of new onset AKI during hospitalization was 6% and 91% of cases were stage 1. All new onset AKI occurred within the first 5 days of hospital admission. Independent predictors of new AKI included age > 60 years, history of chronic kidney disease or cardiovascular disease, and UA >8 mg/dL at any time during hospital admission. Rasburicase was given to 48 patients, 6 (13%) of whom still went on to develop AKI. Rapid UA reduction with rasburicase did not impact the risk of developing AKI (HR 2.3; p = 0.11). Uric acid level at the time of administration did not modify the effect of rasburicase on prevention of AKI (p = 0.36 for the interaction term). Conclusion: In conclusion, for lymphoma patients at intermediate or high risk for TLS, if not present at admission, AKI only infrequently developed during the course of a patient's hospitalization. Predictors of AKI included advanced age, comorbid conditions, and elevated UA levels. Early rasburicase administration, regardless of UA level, did not alter AKI risk. Disclosures No relevant conflicts of interest to declare.

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.

Abstract Background: There is demonstrated benefit when administering fluoroquinolones as infection prophylaxis in neutropenic patients; however, side effects, drug interactions and increasing drug resistance necessitate investigation toward safe and effective alternative therapies. This study investigates the use of oral third generation cephalosporins as antibacterial prophylaxis during chemotherapy-induced neutropenia to establish knowledge on alternative treatment options. Methods: A retrospective chart review was performed to compare incidence of febrile neutropenia and documented infection rates in Acute Myeloid Leukemia (AML) and intermediate to high International prognostic scoring system (IPSS) risk myelodysplastic syndrome (MDS) patients receiving antibacterial chemoprophylaxis at Mayo Clinic between January 2006 and April 2016. Patients were included if they were 18 years or older, had a diagnosis confirmed on bone marrow biopsy, received induction or first relapse induction-remission chemotherapy regimens and then subsequently were prescribed fluoroquinolone or an oral third generation cephalosporin prophylaxis for anticipated profound and prolonged neutropenia. The main regimens prescribed were cytarabine + anthracycline (7+3), daunorubicin + cytarabine + nilotinib, mitoxantrone + etoposide + cytarabine, all-trans-retinoic acid (ATRA) + anthracycline, all-trans-retinoic acid (ATRA) + arsenic, clofarabine + cytarabine, or an investigational trial. After meeting inclusion criteria the treatment arms were matched via Charlson comorbidity index ( ± 3) and age ( ± 5). Patients with a documented infection 48 hours after switching from either broad spectrum antibiotics to antibacterial prophylaxis, or from levofloxacin prophylaxis to an oral third generation cephalosporin were excluded from the study. All patients provided consent for review of their medical records for research purposes. This study was approved by the Mayo Foundations institutional review board. Results: A total of 565 patients admitted to Mayo Clinic inpatient leukemia service for chemotherapy and concurrently prescribed antibacterial prophylaxis with either levofloxacin or an oral third generation cephalosporin were screened between January 1, 2006 and April 1, 2016. Of those screened 397 patients met the inclusion criteria, and subsequently 123 patients were matched via Charlson comorbidity index and age. Patient characteristics are presented in Table I. Of the 123 study patients, 80 (65%) were male, and the median age was 58.6 years (IQR: 53.3-68.5). The population was comprised of 115 (93.5%) patients with AML, and 8 (6.5%) patients with MDS. By 30 days after prophylaxis start 109 of the 123 patients developed febrile neutropenia (89.9%, 95% CI: (82.8-94.1)). There was no difference in the risk of febrile neutropenia between those on levofloxacin and those on an oral third generation cephalosporin (hazard ratio [HR] = 1.057, 95% CI: 0.64-1.75, p=0.83). The mean ANC value at the time of febrile neutropenia was 0.47 (SD: 1.4). Documented reasons that patients did not receive an oral fluoroquinolone were QTc prolongation (34.2%), rash (21.1%), tendonitis (2.6%), anaphylaxis (5.3%), drug interaction with a treatment study drug (23.7%), or other (13.1%). Three patients died 30 days or less after the last dose of chemoprophylaxis (40 day survival: 96.6%, 95% CI: 92.7-100); two of the reported deaths were due to infection. Of the 111 patients who had a documented febrile episode, 40 (36%) had a culture positive infection. Gram positive organisms caused 27 (71.1%) of the infections, 11 (28.9%) were gram negative organisms, and 1 (2.6%) infection was due to an anaerobic organism. There were 3 (7.5%) polymicrobial infections, and 36 (90%) monomicrobial infections. The majority of the patients had bloodstream as the documented site of infection. Of the documented culture positive infections 15 (39.5%) showed resistance to levofloxacin and 6 (15.8%) had resistance to third generation cephalosporins when susceptibility testing was reported. Conclusions: These findings demonstrate comparable safety and efficacy of oral third generation cephalosporins compared to fluoroquinolones and contribute to the growing body of literature surrounding antibacterial prophylaxis during chemotherapy-induced neutropenia. Further prospective, randomized investigation is warranted. Disclosures No relevant conflicts of interest to declare.

Abstract Since its emergence as a novel therapy for cutaneous T-cell lymphoma in 1987, extracorporeal photopheresis (ECP) has gained popularity in the fields of solid organ and stem cell transplantation (Perotti et al Transfus Apher Sci 2015). Though ECP is thought to be associated with few adverse effects, we have anecdotally noted that some patients treated with ECP develop iron deficiency anemia. Anemia has been reported in ECP literature at an incidence of anywhere from 0% to 24.5%, however, the etiology of the anemia has not been described (Quaglino et al Int J Dermatol 2013, Flowers et al Blood 2008, Jaksch et al J Heart Lung Transpl 2012, Dignan et al Bone Marrow Transpl 2014). We performed a retrospective chart review to further investigate the magnitude of this potential adverse effect. Adult patients receiving ECP for any indication at Mayo Clinic Hospital-Rochester were eligible for inclusion. Patients with pre-existing iron deficiency anemia (IDA) or physiologic and/or pharmacologic reasons for altered iron homeostasis were excluded from analysis. The primary endpoint was to describe the cumulative incidence of IDA at one year of ECP therapy, utilizing Kaplan-Meier methodology. We defined IDA as a hemoglobin < 12 g/dL (females) or < 14 g/dL (males), plus any of the following: MCV < 80 fL, ferritin < 11 mcg/L, iron < 35 mcg/dL (females) or < 50 mcg/dL (males), total iron binding capacity > 400 mcg/dL, or percent saturation <14%. Secondarily, we aimed to describe the proportion of patients who underwent further diagnostic evaluation of IDA and those that were initiated on iron supplementation for IDA. Patients were followed for the primary endpoint until diagnosis of IDA, death, or date of last ECP session; those who did not develop IDA were censored at the date of last follow-up. Between January 1, 2006 and July 1, 2015, a total of 120 adult patients were treated with ECP at Mayo Clinic in Rochester, MN; 80 patients met inclusion criteria. For the remaining 40 patients, patients were excluded for recent history of transfusions and/or phlebotomy (n=27), incomplete documentation (n=7), IDA at baseline (n=3), or potentially confounding past medical histories (n=3). Treatment of graft-versus-host disease (GVHD) was the foremost ECP indication in our cohort, accounting for 63.8% of our patients. Patients also received ECP for treatment of cutaneous T-cell lymphoma, treatment of solid organ transplant rejection, and other indications (25%, 7.5%, and 3.8%, respectively). Mean age was 55.6 years, 38.7% were female, and the median duration of ECP therapy was 344 days (IQR 130 - 755 days). At 1 year from the start of ECP therapy, the cumulative incidence of IDA in our cohort was 21.1% (95% CI 9% - 31.6%; Figure 1). At 4 years from the start of ECP therapy, the cumulative incidence of IDA was 49.1% (95% CI 26.4% - 64.8%). Of those that developed an IDA at any time during ECP therapy, 6/20 (30%) underwent invasive diagnostic procedures (colonoscopy and/or upper endoscopy) to evaluate the etiology of the IDA. Iron supplementation was initiated in 18/20 (90%) patients; hemoglobin returned to normal in 8 patients (44.4%) based on available follow-up. These data indicate that a substantial number of patients develop IDA while receiving ECP therapy; a finding which may lead to more prompt recognition and treatment of IDA in patients receiving ECP, and perhaps spare expensive diagnostic procedures. Figure 1. Kaplan-Meier Curve of Cumulative Incidence of IDA During ECP Therapy Figure 1. Kaplan-Meier Curve of Cumulative Incidence of IDA During ECP Therapy Disclosures No relevant conflicts of interest to declare.

INTRODUCTION: Endoscopic surveillance guidelines in Barrett’s esophagus (BE) to detect progression to high grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) are based solely on dysplasia grade. Given low rates of progression, identification of predictors (and scores) of progression may help to focus surveillance or intervention in those at higher risk. We aimed to assess predictors of progression and externally validate the Progression in Barrett’s (PIB) score in an independent multicenter prospective BE and EAC cohort. METHODS: The EA and Barrett’s esophagus (EABE) registry is a prospective cohort of patients recruited from three medical centers. Progressors were defined as those with the development of HGD or EAC more than 12 months after initial diagnosis. Demographic and clinical variables were abstracted. The annual incidence rate and predictors of progression were assessed using univariate and multivariable Cox proportional hazards analysis. The ability of the PIB score (incorporating weighted scores for male gender, smoking (ever versus never), BE length and confirmed LGD) to risk stratify the cohort into low (0-10 points), intermediate (11-20 points) and high risk (> 20 points) groups was assessed. RESULTS: 429 patients were included. 84% were men, with a mean (SD) age of 61.5 (9.9) years. 65% were ever smokers and most (76.7%), had NDBE at diagnosis. Mean (SD) maximal BE segment length was 5.9 (3.2) cm. Eighty-two patients (19.1%) progressed to HGD (n = 65) or EAC (n = 17) over a median (IQR) follow up of 7.5 (3.7, 12.5) years. Annual incidence rates of progression to EAC and EAC/HGD were 0.5% and 2.0% respectively. Univariate and multivariable predictors of progression are displayed in Table 1. The PIB score divided patients into three groups (Table 2) with progressively increasing rates of progression. The risk in the high risk group was three fold higher than the low risk group ( P = 0.024). The risk in the intermediate group was twofold higher but not statistically significantly higher ( P = 0.13). The PIB score had a c-statistic score of 0.76 in the original cohort. In this cohort the c-statistic value was lower at 0.64, suggesting moderate performance. CONCLUSION: Male sex and BE length predicted progression in this independent multicenter cohort. The PIB score was also able to risk-stratify patients in this validation cohort with the high risk cohort being 3x more likely to progress compared to the low risk cohort.

Abstract Background Capsule endoscopy (CE) is frequently hindered by intra-luminal debris. Our aim was to determine whether a combination bowel preparation would improve small-bowel visualization, diagnostic yield, and the completion rate of CE. Methods Single-blind, prospective randomized–controlled study of outpatients scheduled for CE. Bowel-preparation subjects ingested 2 L of polyethylene glycol solution the night prior to CE, 5 mL simethicone and 5 mg metoclopramide 20 minutes prior to CE and laid in the right lateral position 30 minutes after swallowing CE. Controls had no solid food after 7 p.m. the night prior to CE and no liquids 4 hours prior to CE. Participants completed a satisfaction survey. Capsule readers completed a small-bowel-visualization assessment. Results Fifty patients were prospectively enrolled (56% female) with a median age of 54.4 years and 44 completed the study (23 patients in the control group and 21 in the preparation group). There was no significant difference between groups on quartile-based small-bowel visualization (all P &gt; 0.05). There was no significant difference between groups in diagnostic yield (P = 0.69), mean gastric (P = 0.10) or small-bowel transit time (P = 0.89). The small-bowel completion rate was significantly higher in the preparation group (100% vs 78%; P = 0.02). Bowel-preparation subjects reported significantly more discomfort than controls (62% vs 17%; P = 0.01). Conclusions Combined bowel preparation did not improve small-bowel visualization but did significantly increase patient discomfort. The CE completion rate improved in the preparation group but the diagnostic yield was unaffected. Based on our findings, a bowel preparation prior to CE does not appear to improve CE performance and results in decreased patient satisfaction (ClinicalTrials.gov, No. NCT01243736).

AbstractBackgroundExtracorporeal photopheresis (ECP) is associated with few adverse effects. We have anecdotally noted patients treated with long‐term ECP develop iron deficiency anemia (IDA).MethodsWe performed a retrospective chart review of adult patients who received ECP for any indication at Mayo Clinic Rochester and Mayo Clinic Arizona. The primary objective was to describe the cumulative incidence of IDA at 1 year of ECP therapy.ResultsA total of 123 patients were eligible for analysis. Graft‐vs‐host disease was the most common indication for ECP (n = 76, 61.8%). At 1 year of ECP therapy, the cumulative incidence of IDA was 24.1% (95% CI, 14.2%‐32.9%). At 5 years, the cumulative incidence of IDA was 68.3% (95% CI, 38%‐83.8%). Risk factors for the development of IDA included: cumulative number of ECP sessions (HR 1.34, 95% CI, 1.05‐1.73 per 10 additional sessions, P = .022), an indication for ECP of solid organ transplant rejection (compared to cutaneous T‐cell lymphoma, HR 5.46, 95% CI, 2.06‐14.49, P < .001), and proton pump inhibitor use at baseline (HR 2.15, 95% CI, 1.1‐4.21, P = .03). Iron supplementation was initiated in 29 of 37 evaluable patients who developed IDA, with a cumulative incidence of supplementation in 77.2% patients within 3 months of recognition of IDA (95% CI, 55.8%‐88.3%). Hemoglobin normalized in 50.1% of patients started on iron supplementation for IDA within 7 months (95% CI, 25.2%‐66.7%).ConclusionsIron deficiency anemia is common in patients receiving long‐term ECP and occurs throughout ECP therapy. IDA resolved with iron supplementation in half of patients.