INTRODUCTION:Cefepime is a fourth-generation cephalosporin and is a workhorse for the empiric treatment of febrile neutropenia (FN). Beta-lactam therapeutic drug monitoring (TDM) has emerged as a dose optimization strategy in patient populations with altered kinetics. Prior literature has demonstrated that patients with FN exhibit augmented renal clearance which may lead to subtherapeutic drug concentrations with standard dosing regimens. The aim of this study was to evaluate pharmacokinetic/pharmacodynamic (PK/PD) target attainment and clinical outcomes in patients with hematologic malignancies and FN who were treated empirically with cefepime. METHODS:This was a prospective, single-center study of adults with hematologic malignancies and FN admitted to the inpatient unit. The primary outcome was PK/PD target attainment (defined as 100% free time greater than minimum inhibitory concentration (100% fT > MIC)). Secondary clinical outcomes were time to defervescence, time to ANC recovery, in-hospital mortality, and cefepime failure. RESULTS:There were 55 patients in our study. Forty-three (78%) patients achieved the primary outcome of PK/PD target attainment. The mean time to defervescence was similar between those that achieved PK/PD target attainment and those that did not (95% CI -0.75 to 1.25, p = 0.62). CONCLUSIONS:This study showed that standard cefepime dosing in patients with hematologic malignancies and FN does not result in achievement of 100% fT > MIC in all patients. Patients in the group that did not achieve PK/PD target attainment were younger with increased creatinine clearance, indicating that cefepime TDM may be especially beneficial in these patients.

e19053 Background: Recent advances and approval of multiple targeted and non-targeted agents have significantly transformed care for Acute Myeloid Leukemia (AML) over the past 5 years, particularly for older/unfit patients. While this has provided clinicians with several treatment options in both upfront and relapsed/refractory setting, it has also increased the complexity of clinical decision making. Although several trials have shown immense promise of these therapies, the real-world outcomes have not been reported. The primary aim of this study is to compare survival outcomes in newly diagnosed and relapsed AML before and after the introduction of the novel AML treatments that were granted FDA approval over the past 5 years. Methods: We performed a retrospective single-center analysis on adult patients (≥ 18 years) with newly diagnosed and relapsed AML treated at University of Florida Cancer Hospital between January 2012 and December 2020. Patients were stratified according to the time of diagnosis and Overall survival (OS) was estimated using Kaplan Meier method. Survival between groups was compared using log-rank test. Results: A total of 1617 patients were included in this analysis. Median age was 61 years (range 18-83) and 54.4% of patients were men. 71.4% patients were of white race. Median OS was 71.5 months with 1-year OS of 67.4%. Women had significantly better survival than men (1-year OS: 72% vs 63.6%, p=0.0043). 1-year OS for patients diagnosed in 2012-14, 2015-17 and 2018-20 was 73.5%, 67.6% and 58.1% respectively (p < 0.0001). There were no significant differences in survival based on race. 21.4% (n=347) patients had relapse of AML. Median OS for AML relapse was 9.8 months with 1-year survival of 45.1%. There were no significant differences in survival of patients based on race, sex and year of diagnosis. Conclusions: Our study reports decline in 1-year survival of patients with AML in the modern era despite introduction of several novel therapies in recent years. Additionally, relapsed AML continues to have dismal outcomes despite the availability of multiple novel agents for R/R AML. These results are surprising given the reported good efficacy of these agents in clinical trials. Possible explanations include under-representation of real-life patients in clinical trials, poor tolerability of these therapies by the average patient, and/or barriers to access to these novel therapies in healthcare due to prohibitive high cost, inadequate insurance coverage, or limited availability. Larger-scale real-life population-based studies are needed to further investigate the validity of these findings. [Table: see text]

Background Engraftment syndrome (ES) is a common complication of autologous hematopoietic cell transplantation (HCT). The difference in incidence of ES between melphalan formulations has not been widely reported throughout the literature and would allow for a more comprehensive understanding of the advantages and disadvantages of both melphalan formulations. Patients and methods This retrospective, single-center, observational study evaluated 83 adult multiple myeloma and immunoglobulin light chain amyloidosis patients who received either propylene glycol-containing (PG) or propylene glycol-free (PG-free) melphalan 140 mg/m(2) as single-agent conditioning chemotherapy for autologous HCT from May 31, 2015 to May 31, 2019. The primary outcome was to assess the incidence of ES, as defined using the Maiolino criteria, with both melphalan formulations. Secondary outcomes included an analysis of potential risk factors for the development of ES, as well as an evaluation of overall length of stay (LOS). Results The incidence of ES for PG and PG-free melphalan did not differ significantly, 14/39 (35.9%) and 12/44 (27.3%) (P = 0.4), respectively. No potential risk factors for ES were identified on multivariate logistic regression analysis. A statistically significant difference in number of days to engraftment was identified for PG and PG-free melphalan, 15.56 vs. 13.82 days (P = 0.01), respectively; although, this did not translate to a decrease in LOS, 19.9 vs. 18.59 days (P = 0.14). Conclusions The incidence of ES did not differ significantly between melphalan formulations. Future research is needed to determine whether the faster time to engraftment seen with PG-free melphalan may translate to a decrease in LOS.

Weight-based dosing of intravenous busulfan is widely used in hematopoietic cell transplantation. However, a variety of dosing weights have been described. The objective of this retrospective study was to determine the pharmacokinetic impact of using ideal body weight as the initial dosing weight in obese as compared to non-obese transplant recipients. The secondary objectives were to describe the use of alternative dosing weights, the impact on survival, and the rates of toxicities. The mean steady-state concentration was 779.3 ng/mL (n = 82) in the non-obese cohort and 673.7 ng/mL (n = 63) in the obese cohort (p < 0.001). A smaller proportion of concentrations were below goal in the non-obese cohort (10% vs. 41%, p < 0.001). Ideal body weight and adjusted body weights with a 25 and 40% correction factor are appropriate in nonobese patients; adjusted body weights with a 25 and 40% correction factor are appropriate in obese patients. There was no difference in overall survival (p = 0.18); there was a difference in median progression-free survival (1078 vs. 500 days, p = 0.045) in the non-obese compared to obese cohorts. The use of ideal body weight to dose busulfan resulted in lower steady-state concentrations, a larger proportion of subtherapeutic concentrations, and worse progression-free survival in obese patients.

Objectives Voriconazole, a first-line agent for the treatment of invasive fungal infections (IFIs), is metabolized by CYP2C19. A significant proportion of patients fail to achieve therapeutic trough concentrations with standard weight-based voriconazole dosing, placing them at increased risk for treatment failure, which can be life threatening. We sought to test the association between the CYP2C19 genotype and subtherapeutic voriconazole concentrations in adults with IFIs. Patient and methods Adults receiving weight-based voriconazole dosing for the treatment of IFIs were genotyped for the CYP2C19*2, *3, and *17 polymorphisms, and CYP2C19 metabolizer phenotypes were inferred. Steady-state voriconazole trough plasma concentrations and the prevalence of subtherapeutic troughs (<2 mg/l) were compared between patients with the CYP2C19*17/*17 (ultrarapid metabolizer, UM) or *1/*17 (rapid metabolizer, RM) genotype versus those with other genotypes. Logistic regression, adjusting for clinical factors, was performed to estimate the odds of subtherapeutic concentrations. Results Of 70 patients included (mean age 52.5±18 years), 39% were RMs or UMs. Compared with patients with the other phenotypes, RMs/UMs had a lower steady-state trough concentration (4.26±2.2 vs. 2.86±2.3, P=0.0093) and a higher prevalence of subtherapeutic troughs (16 vs. 52%, P=0.0028), with an odds ratio of 5.6 (95% confidence interval: 1.64–19.24, P=0.0044). Conclusion Our findings indicate that adults with the CYP2C19 RM or UM phenotype are more likely to have subtherapeutic concentrations with weight-based voriconazole dosing. These results corroborate previous findings in children and support the potential clinical utility of CYP2C19 genotype-guided voriconazole dosing to avoid underexposure in RMs and UMs.

Paroxysmal nocturnal hemoglobinuria (PNH) is a hematologic disorder characterized by an acquired somatic mutation in the phosphatidylinositol glycan class A gene which leads to a higher risk for increased venous and arterial thrombosis. Current treatment for PNH includes eculizumab. Pregnant patients who have PNH have higher risk for thrombosis and hemorrhage with both pregnancy and their underlying PNH. Treatment frequently poses conundrum. The safety and efficacy of eculizumab during pregnancy and breast feeding have not been extensively studied and contraception has been recommended due to potential for teratogenicity. We present a case of a patient who was safely on both eculizumab and modest prophylactic anticoagulation for 6 weeks post-partum.

Abstract Abstract 4301 Background: Currently, there is no standard reinduction regimen for relapsed and refractory (RR) AML. In order to evaluate responses to reinduction regimens we present a retrospective side-by-side comparison frequently used AML salvage regimens at our institution: CECA, HiDAC and CLAG-M. Method: From April 2007 to May 2011, 74 consecutive patients with RR AML received CECA (n=44), HiDAC (n=18) or CLAG-M (n=12). The primary outcome was complete remission (CR) rates and secondary outcomes were overall survival (OS) and relapse free survival (RFS). Additional variables such as toxicity and transplant data were also examined. Result: Baseline characteristics among the three groups were similar except for relapse status, with a greater proportion of AML patients receiving CECA after first relapse and HiDAC and CLAG-M after multiple relapses (Table 1). The mean age was 55.6 (range, 24–70), 53.8 (range, 25–71) and 49.5 (range, 23–68) years for CECA, HiDAC and CLAG-M respectively (P=0.38). For CECA, HiDAC and CLAG-M, respectively, 29.5%, 27.7% and 50% of patients were classified with therapy-related AML (P=0.85) and 11.4%, 11.1% and 16.7% of patients were classified with AML transformed from MDS (P=0.62). There was no difference in cytogenetic risk groups between the cohorts with the majority of the patients classified as intermediate risk. The mean blast percentage at the start of treatment was equivalent between the three groups at 39.8%, 27.4% and 26.7% for CECA, HiDAC and CLAG-M respectively (P=0.25). Median follow-up for all patients was 3.5 months. CR rates for CECA, HiDAC and CLAG-M were similar (20.5%, 16.7%, 41.7%; P=0.44). Median OS was 5 months for patients receiving CECA, 5 months for HiDAC and 3.5 months for CLAG-M (P=0.91) (Figure 1A). RFS was also similar among the three groups (p=0.91) (Fig. 1B). Of patients treated with CECA, HiDAC and CLAG-M, 27.2%, 38.8% and 41.6% proceeded to allogeneic hematopoietic cell transplant (P=0.71). Of the 8 patients who achieved CR with CECA but did not proceed to transplant, 5 patients had a CR of less then 3 months, 1 refused further care, 1 was lost to follow up and 1 received further consolidation therapy then relapsed. The mean length of stay in the hospital was 33.6±3.4, 99.7±60.3 and 45.4 ±35.7 days respectively for CECA, HiDAC and CLAG-M (P=0.19). The 30-day treatment related mortality rate was 2.3%, 16.7% and 16.7% respectively (P=0.13). Patients who received CECA had a higher number of total adverse events than patients who received HiDAC and CLAG-M (Table 1), with higher rates of pulmonary edema, sepsis, fungal pneumonia and C. difficle colitis. However, due to the small number of patients per cohort, only descriptive statistics are reported. Conclusion: CECA, HiDAC and CLAG-M are equivalent AML salvage regimens in terms of CR, OS, and RFS. Although each resulted in different adverse event profiles. These data provide a basis for designing prospective clinical studies and sample size estimates to formally compare three common reinduction regimens in RR AML. Disclosures: No relevant conflicts of interest to declare.

Summary. A serious adverse effect that can limit the utility of ifosfamide is neurotoxicity, known as ifosfamide-induced encephalopathy (IIE). Information regarding the usefulness of prophylactic administration of methylene blue, thiamine, and albumin to reduce the incidence of IIE is scarce. We present the results of a retrospective chart review evaluating the incidence of IIE in adult patients who received ifosfamide to treat sarcoma at the University of Washington within a 2-year period. Patients who received methylene blue, thiamine, and/or albumin were compared to patients who did not receive these prophylactic agents concurrently with ifosfamide. The primary objective was to evaluate if prophylaxis is associated with a reduced incidence of IIE. Identifying risk factors associated with IIE was a secondary objective. The cost of using prophylaxis with ifosfamide administration was reviewed. Results. A total of 166 cycles were included. For the primary endpoint, more cycles in the prophylaxis group had patients with symptoms of IIE (21.1% in the prophylaxis group vs. 8.4% in the nonprophylaxis group); p = 0.026. The average number of risk factors per cycle was the same in each group; however, the type of risk factors differed. Conclusions. Prophylaxis was not associated with a reduced incidence of IIE, and it does not appear to delay time to onset of symptoms at our institution. Results of this study provide no support for using methylene blue, thiamine, and/or albumin as routine prophylaxis when administering ifosfamide to adults with sarcoma.