d Posaconazole (PCZ), approved for prophylaxis against invasive fungal disease in high-risk patients, is commercially available orally as a suspension formulation (PCZ-susp) and as a delayed-release tablet (PCZ-tab). We evaluated the serum steady-state concentrations (C ss ) of PCZ stratified by the administered formulation for antifungal prophylaxis in patients with myeloid malignancies (n ‫؍‬ 150). The primary outcome was the attainment rate of the target C ss of >700 ng/ml. Secondary outcomes included toxicity assessment (hepatotoxicity and corrected QT [QTc] interval prolongation) and breakthrough fungal infections. Patients who received the PCZ-susp (n ‫؍‬ 118) or PCZ-tab (n ‫؍‬ 32) and had PCZ C ss assessment after at least 7 days of therapy were eligible. The median C ss in the PCZ-susp group was 390 ng/ml (range, 51 to 1,870 ng/ml; mean, 436 ng/ml) compared to 1,740 ng/ml (range, 662 to 3,350 ng/ml; mean, 1,781 ng/ml) in the PCZ-tab group (P < 0.0001). The percentages of patients achieving the target goal of >700 ng/ml were 17% versus 97%, respectively (P < 0.0001). Hepatotoxicity (grade 2 or higher) occurred in 1 patient in each group. QTc interval measurements were available for 32 patients in the PCZ-susp group and for 12 patients in the PCZ-tab group, and prolonged intervals of grade 2 or higher were noted in 9% (n ‫؍‬ 3) and 17% (n ‫؍‬ 2), respectively (P ‫؍‬ 0.6). Breakthrough fungal infections in the PCZ-susp and PCZ-tab groups were 7% (n ‫؍‬ 8) and 3% (n ‫؍‬ 1), respectively (P ‫؍‬ 0.68). We conclude that the use of PCZ-tab was associated with higher C ss and with the probability of achieving therapeutic goals without worsening of adverse effects. P osaconazole (PCZ) is a triazole antifungal agent that is approved for invasive fungal disease prophylaxis in high-risk patients. Oral formulations of PCZ are commercially available as a suspension (PCZ-susp) and as delayed-release tablets (PCZ-tab) (1). Several studies have shown that the gastrointestinal absorption and bioavailability of PCZ-susp are unpredictable and dependent on various factors, including food intake and concomitant acid suppressants (2-7). Due to its superior oral bioavailability, the PCZ-tab can be administered without regard to food intake and seems less likely to be affected by concomitant acid-suppressing medications (8-11).PCZ concentrations follow dose-dependent pharmacokinetics at steady state with saturation of absorption of the PCZ-susp occurring at 800 mg/day (12). The current guidelines recommend as a goal steady-state concentrations (C ss ) of Ն700 ng/ml in the prophylaxis setting (13). Comparative studies evaluating the PCZsusp and the newer PCZ-tab are not available. Herein, we report a retrospective analysis comparing the serum concentrations of the two formulations. MATERIALS AND METHODSPatient population. For this study, 152 consecutive patients with acute myelogenous leukemia (AML) or high-grade myelodysplastic syndrome (MDS) who were admitted to the inpatient hematologic malignancy service at West Virginia Unive...

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Introduction High-risk subtypes of DLBCL, including high-grade B-cell lymphomas (HGBCL) with rearrangements of c-MYC (MYC-R), BCL2 and/or BCL6 [or double hit and triple hit lymphomas (DHL/THL)], double expressor lymphoma (DEL), and patients with International Prognostic Index (IPI) scores of 3-5 have a poor prognosis with standard R-CHOP chemotherapy. Treatment intensification with DA-EPOCH-R did not improve outcomes when compared to R-CHOP in the CALGB 50303 trial (Bartlett et al JCO 2019). However, high-risk patients were underrepresented as 36% of patients had IPI scores of 3-5, 0.61% of patients had DHL or THL, 2.6% of patients had MYC-R, and 8.6% of patients had DEL (Bartlett et al JCO 2019). Our purpose was to retrospectively compare DA-EPOCH-R to R-CHOP in the treatment of high-risk DLBCL. Methods Patients ≥ 18 years old who received either DA-EPOCH-R or R-CHOP at Moffitt Cancer Center between 1/2010 - 9/2019 were included. Patients with a diagnosis of DLBCL with IPI score of 3-5, DHL/THL, and/or DEL were included. Patients with primary mediastinal B-cell lymphoma (PMBCL), DLBCL with testicular or central nervous system (CNS) involvement, grade 3b follicular lymphoma, Richter's transformation or IPI score &lt; 2 were excluded. The primary endpoint was complete response (CR) rate and secondary endpoints included progression-free survival (PFS), overall survival (OS), CNS relapse rate, and adverse events (AE). PFS and OS were estimated using Kaplan-Meier curves and differences were established using the log-rank test. Statistically significant difference was considered if p &lt; 0.05. Results The study included 128 patients: DA-EPOCH-R (n=36) and R-CHOP (n=92). General characteristics were similar between groups and included: median age = 66 years (33-85), stage III/IV = 89%, IPI score 3-5 = 87.6%, non-germinal center B-cell (GCB) = 32.8%, DEL = 26.6%, and DHL/THL = 18%. Of note, more patients in the DA-EPOCH-R group were &lt; 60 years old, had MYC-R, and/or were DHL/THL or HGBCL, NOS cases. The CR rates for DA-EPOCH-R and R-CHOP were 72.2% (95% CI: 54.8, 85.8) vs. 68.5% (95% CI: 57.8,78.0), respectively (p=0.831). In a pre-planned subgroup analysis, the CR rates across subgroups, including IPI score 3-5, DEL, and DHL/THL, were not different. There was no difference in PFS between DA-EPOCH-R and R-CHOP (p= 0.33; Figure 1). The 1-year (y) PFS for DA-EPOCH-R and R-CHOP was 69% (95% CI: 56.0, 86.0) and 62% (95% CI: 52.0, 73.0), respectively. The 3 y PFS for DA-EPOCH-R and R-CHOP was 66% (95% CI: 53.0, 84.0) and 46% (95% CI: 35.0, 59.0), respectively. PFS was higher in the DA-EPOCH-R arm for patients with MYC-R (p=0.0224) and DHL/THL (p=0.045). There was no difference in OS between DA-EPOCH-R and R-CHOP (p=0.83). The 1 y OS was 77% (95% CI: 65.0, 92.0) for the DA-EPOCH-R group compared with 81% (95% CI: 73.0, 90.0) for the R-CHOP group. The 3 y OS was 71% and 65% for the DA-EPOCH-R and R-CHOP groups, respectively. The CNS relapse rate was 6.2% in the DA-EPOCH-R group and 2.4% in the R-CHOP group (p=0.301). Of the 4 patients with CNS relapse, 3 were DHL, THL or DEL. There were more grade ≥ 3 AEs in DA-EPOCH-R vs. R-CHOP (97.2% vs. 77.2%; p=0.003). There was significantly more grade ≥ 3 hematologic toxicity in the DA-EPOCH-R group regarding neutropenia (DA-EPOCH-R 91.7% vs. R-CHOP 69.6%; p=0.017) and thrombocytopenia (DA-EPOCH-R 50% vs. R-CHOP 16.3%; p=0.0003). Neuropathy and mucositis were significantly more common in the DA-EPOCH-R arm. Conclusions R-CHOP remains standard of care for high-risk DLBCL subgroups when compared to DA-EPOCH-R (such as non-GCB DLBCL, DEL, and patients with IPI score &gt; 3). Patients with DHL/THL or MYC-R had greater benefit from DA-EPOCH-R compared to R-CHOP. DA-EPOCH-R was associated with increased rates of AEs, including significantly more hematologic toxicity. Disclosures Chavez: AstraZeneca: Speakers Bureau; Celgene: Consultancy; Bayer: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Novartis: Consultancy; Merck: Research Funding; Morphosys: Consultancy, Speakers Bureau; BeiGene: Speakers Bureau; Karyopharm: Consultancy; Genentech: Speakers Bureau; AbbVie: Consultancy; Verastem: Consultancy; Pfizer: Consultancy; Epizyme: Speakers Bureau; Gilead: Consultancy.

Background: Asparaginase may improve outcomes in chemotherapy resistant malignancy, especially of lymphoid origin. L-asparaginase (L-ASP) was introduced in 1992 and hence has been incorporated in multiple regimens. An effective regimen including steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) was developed by the NK-Cell Tumor Study Group as a unique chemotherapeutic regimen to combat chemo-resistant NK-cell neoplasms (Yamaguchi et al. 2008) and later shown to have efficacy in relapsed and refractory lymphoblastic lymphoma (Chang et al. 2014). The pegylated-asparaginase (PEG-ASP) is the only readily available commercial product as the other forms either have limited availability due to shortages (Erwinia asparaginase) or are no longer available in the United States (E-coli asparaginase). We present retrospective data incorporating PEG-ASP into a modified SMILE (mSMILE) regimen. To our knowledge, no prior comparison between the PEG-ASP and L-ASP based SMILE regimen is available in the literature. Methods: All adult patients treated with mSMILE for either extranodal NK/T-cell leukemia and lymphoma (ENKTL), T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LBL), adult T-cell leukemia/lymphoma (ATLL), or peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) from 12/1/2009-6/30/2019 at Moffitt Cancer Center were included. PEG-ASP replaced L-ASP in SMILE regimen at a dose of 2500 units/m2/dose IV on Day 8 only (maximum dose of 3750 units). Cycles were repeated every 28 days until disease progression, excessive toxicity, or consolidation with hematopoietic cell transplantion (HCT). Patients received appropriate supportive care with peg-filgrastim or filgrastim (until absolute neutrophil count > 1000/ul x 3Days or >3,000/ul) as well as antimicrobial prophylaxis with acyclovir, ciprofloxacin, and fluconazole once methotrexate cleared and post-chemotherapy. Toxicity assessment was analyzed retrospectively and graded based upon Common Terminology Criteria for Adverse Events (CTCAE) version 5. Toxicity profiles of PEG-ASP-based mSMILE in present study were compared to profiles of L-ASP-based SMILE in the recently published literature (Pokrovsky & Vinnikov Expert Rev Anticancer Ther, 2019). Results: A total of 13 patients were treated with mSMILE during the 10-year period (Table 1). Of these patients, the median age was 46 years (range, 19-69), caucasians (46%) and males (70%). Most of the patients were treated for ENKTL (46%). mSMILE was the first line therapy in 3 patients, while the median number of prior therapies was 1 (range 0-3). Toxicity assessment for mSMILE focused on PEG-ASP-induced toxicity as no patients had any hemorrhagic cystitis, neurotoxicity, or renal dysfunction that could be associated with ifosfamide, methotrexate, or etoposide. mSMILE was comparatively associated with more hematologic toxicity, likely related to inclusion of patients with lymphoblastic leukemia (table 2). Grade 3/4 hepatotoxicity rates are low, possibly owing to inclusion of carnitine prophylaxis (Schulte et al. 2018). Thrombosis was not observed. Hypertriglyceridemia was observed in 15% with no cases of pancreatitis. Hypersensitivity and neurotoxicity were not observed. Of the two patients who discontinued therapy due to toxicity, one was related to grade 3 hypofibrinogenemia and the other grade 4 bleeding. Mortality was attributable to disease progression in all cases, with 0% treatment related mortality. Efficacy is comparable, with ORR 54% (7/13), including 30% (4/13) successfully bridged to HCT. Conclusion: In a non-Asian population, modified SMILE regimen with PEG-ASP is a safe alternative to L-ASP-based SMILE regimen. There is increased hematological toxicity, which did not seem to affect chemotherapy delivery. Disclosures Chavez: Genentech: Speakers Bureau; Janssen Pharmaceuticals, Inc.: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Bello:Celgene: Speakers Bureau. Pinilla Ibarz:Sanofi: Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Sokol:EUSA: Consultancy. Shah:AstraZeneca: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria.