Barreto, Jason N.

Abstract Introduction L-asparaginase therapy results in systemic depletion of antithrombin (AT) and fibrinogen (FG), resulting in thrombotic (TE) and hemorrhagic events (HE). Prophylactic correction of coagulation disturbances have been inconclusive with regard to cost effectiveness, and specifically cost effectiveness of antithrombin concentrate (ATC) replacement has not been evaluated. (Abbott et al, 2009, Mitchell et al, 2003). Currently, AT repletion is recommended for levels less than 60%. (Stock et al, 2012) Several treatment protocols with distinctly different L-asparaginase (LAS) or pegaspargase (PEG) doses complicate the frequency and intensity of ATC replacement. We carried out this study to evaluate the cost effectiveness of ATC replacement, based on our institutional practice. Methods This single center, retrospective, observational study was approved by the Institutional Review Board and conducted at Mayo Clinic, Rochester, MN. Consecutive adult patients with a confirmed diagnosis of ALL receiving LAS or PEG between January 2000 and October 2012 were evaluated. Patients with hereditary or acquired thrombophilias or pre-existing TE or HE, were excluded. Per institutional guidelines, ATC was administered if levels were less than 70%. The Centers for Medicare & Medicaid (CMS) single drug historical pricing guide was utilized for 2000-2004. ATC cost beginning January 1, 2005, was derived from the CMS average sales price, reported quarterly. To adjust for price differences due to regimen utilization trends, each dose was also calculated at the final 2012 cost of 3.05/unit. ATC repletion practices and estimated expenditures were compared between regimens. Results Fifty four patients were treated with LAS or PEG containing regimens. Of these, 47 (87%) received ATC. Twenty-eight patients received LASP, 22 received PEGASP and 4 received both. Distribution across protocols was; CALGB 9111 (n=20, Larson et al, 1998), E2993 (n=13, Goldstone et al, 2008), C10403 (n=9, NLM: NCT00558519), CCG 1941 (n=7, Gaynon et al, 2006) and Augmented HyperCVAD (n=5, Faderl et al, 2005). PEG and LAS dosing schemes are outlined in table 1 . LAS doses were converted to PEG upon specific protocol revision or at discontinuation of LAS availability in 2012. Regimens specified a dose cap with the exception of C10403. A total of 399 LAS and PEG doses resulted in 378 instances of ATC repletion. The reimbursement price of ATC in 2000 was estimated at 1.50/unit U.S. dollars (USD) and 3.04/unit USD by the fourth quarter of 2012. The total estimated average sales price was 2,471,745 USD over the study period. C10403 resulted in the highest median number of PEG doses per patient (n = 5) and a median of 17 ATC doses per dose of PEG. This resulted in C10403 being the most expensive regimen with the median expense for ATC replacement being 118,064 USD (chart 1). This conclusion was also seen after comparing different regimens using the most recent 2012 cost estimates. The overall incidence of TE or HE was 17% and equally distributed between regimens (please see accompanying abstract). Conclusions Repletion of ATC in patients receiving asparaginase containing chemotherapy regimens is very expensive and continues to add to costs at many centers, without clear benefit, especially with regards to TE and HE. A prospective, randomized, multicenter clinical trial looking to answer this question is the need of the hour. Disclosures: No relevant conflicts of interest to declare.

Background: Corticosteroid therapy is a well-recognized risk factor for Pneumocystis pneumonia (PCP); however, it has also been proposed as an adjunct to decrease inflammation and respiratory failure. Objective: To determine the association between preadmission corticosteroid use and risk of moderate-to-severe respiratory failure at the time of PCP presentation. Methods: This retrospective cohort study evaluated HIV-negative immunosuppressed adults diagnosed with PCP at Mayo Clinic from 2006 to 2016. Multivariable regression models were used to evaluate the association between preadmission corticosteroid exposure and moderate-to-severe respiratory failure at presentation. Results: Of the 323 patients included, 174 (54%) used preadmission corticosteroids with a median daily dosage of 20 (interquartile range: 10-40) mg of prednisone or equivalent. After adjustment for baseline demographics, preadmission corticosteroid therapy did not decrease respiratory failure at the time of PCP presentation (odds ratio: 1.23, 95% confidence interval: 0.73-2.09, P = .38). Additionally, after adjusting for inpatient corticosteroid administration, preadmission corticosteroid use did not impact the need for intensive care unit admission ( P = .98), mechanical ventilation ( P = .92), or 30-day mortality ( P = .11). Conclusions: Corticosteroid exposure before PCP presentation in immunosuppressed HIV-negative adults was not associated with a reduced risk of moderate-to-severe respiratory failure.

The clinical utility of ganciclovir therapeutic drug monitoring (TDM) is unknown. We retrospectively analyzed adult patients treated for cytomegalovirus (CMV) infection with ganciclovir with TDM between 2005 and 2015.

High-dose methotrexate (MTX; ≥1 g/m2) is a renally eliminated and nephrotoxic first-line therapy for central nervous system (CNS) lymphoma. Creatinine-based estimation of renal function is the recommended approach to dosing MTX in these cases, but nonrenal determinants of creatinine production and elimination in cancer patients such as malnutrition and cachexia lead to overestimation of glomerular filtration rate (GFR) by this method and a heightened risk for drug toxicity. Serum cystatin C is one of the first readily available, relatively inexpensive, endogenous biomarkers to emerge as a practical adjunct to creatinine for estimation of renal function for drug dosing. In this report, we describe two cases where cystatin C was used in conjunction with creatinine to inform MTX dosing for CNS lymphoma. In both cases, the estimated GFR was nearly 40% lower with the combination of the two biomarkers compared to creatinine-only estimates. Empiric MTX dose reductions as a product of these results likely spared the patients sustained exposure to toxic drug concentrations and facilitated earlier administration of supportive care interventions. Further prospective investigations with validated dosing regimens including cystatin C are warranted for high-dose MTX.

Recent literature has demonstrated concern over the risk of Pneumocystis jirovecii pneumonia (PJP) when administering rituximab with combination chemotherapy such as in R‐CHOP; however, the exact risk and potential need for prophylaxis is unknown. We sought to determine the incidence of PJP infection following R‐CHOP administration in patients with B‐cell lymphoma. Consecutive patients diagnosed with B‐cell lymphoma receiving R‐CHOP were evaluated from chemotherapy initiation until 180 days after the last administration. The primary outcome was cumulative incidence of PJP infection. Secondary endpoints included the association of rituximab, prednisone and subsequent chemotherapy with PJP infection risk. A total of 689 patients (53% male, median age 66 years) were included. Seventy‐three percent of patients completed at least 6 cycles of R‐CHOP treatment. Median rituximab and prednisone cumulative doses were 3950 mg and 5325 mg, respectively. Median daily prednisone dose through end of treatment was 45 mg (range 7.6 mg to 119 mg). The cumulative incidence of PJP was 1.51% (95% CI 0.57–2.43, at maximum follow‐up of 330 days), below 3.5%, the conventional threshold for prophylaxis. Univariate analysis did not detect a statistically significant association between PJP and rituximab, steroids, or receipt of additional chemotherapy in this patient population. Our results demonstrate a low occurrence of Pneumocystis pneumonia during R‐CHOP treatment of B‐cell lymphoma and argue against universal anti‐Pneumocystis prophylaxis in this setting. Further investigations should focus on targeted anti‐Pneumocystis prophylaxis for patients presenting with high‐risk baseline characteristics or when receiving rituximab‐inclusive intensive combination chemotherapy regimens as treatment for other aggressive lymphoma subtypes. Am. J. Hematol. 91:1113–1117, 2016. © 2016 Wiley Periodicals, Inc.

ABSTRACT While posaconazole prophylaxis decreases the risk of invasive fungal infection compared to fluconazole, low bioavailability of the oral-suspension formulation limits its efficacy. A new delayed-release tablet formulation demonstrated an improved pharmacokinetic profile in healthy volunteers. However, serum levels for the two formulations have not been compared in clinical practice. This study compared achievement of therapeutic posaconazole levels in patients taking the delayed-release tablet to those taking the oral suspension. This retrospective cohort study included 93 patients initiated on posaconazole between 2012 and 2014 and had at least one serum posaconazole level measured. The primary measure was the proportion of patients achieving an initial therapeutic level (>700 ng/ml). An initial therapeutic posaconazole level was seen in 29 of 32 (91%) patients receiving tablets and 37 of 61 (61%) patients receiving suspension ( P = 0.003). Among patients with a steady-state level measured 5 to 14 days after initiation, a therapeutic level was observed in 18 of 20 (90%) patients receiving tablets and 25 of 43 (58%) patients receiving suspension ( P = 0.01). In these patients, the median posaconazole level of the tablet cohort (1655 ng/ml) was twice that of the suspension cohort (798 ng/ml) ( P = 0.004). In this cohort study, the improved bioavailability of delayed-release posaconazole tablets translates into a significantly higher proportion of patients achieving therapeutic serum levels than in the cohort receiving the oral suspension. The results of this study strongly support the use of delayed-release tablets over suspension in patients at risk for invasive fungal infection.