ALBERT

Description: Serious congestion and delay problems exist in most of the busiest airports worldwide because of imbalance between scarce airport slot resources and increasing traffic demand. Various factors, especially weather conditions, exacerbate the demand–capacity imbalance. This paper presents a robust model for simultaneous slot allocation on an airport network in multiple calendar days, considering airport capacity uncertainty. The idea of robust optimization is conducive to sustainable and stable decision-making. Robustness is represented through reducing the potential scheduling conflicts in the worst case. Then the model links the strategic decisions and pre-tactical decisions in air traffic management (ATM) through the tradeoff between strategic discrepancy cost and operational congestion cost. Under the support of the Cplex solver, numerical analyses are taken to validate the characteristics and effectiveness of the proposed model. The results show that the proposed model effectively eliminates the existing and potential scheduling conflicts, and makes effective tradeoffs between airline preference and potential airport congestion risk.

Description: BACKGROUND: Ibrutinib is an irreversible inhibitor of BTK in the B-cell receptor signaling cascade and is widely used to treat chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Ibrutinib also inhibits the tyrosine kinase Tec in platelets, which may be one of the mechanisms of its bleeding toxicity. This makes concomitant use of anticoagulation (AC) or antiplatelet agents challenging, which is a common delimma as many patients taking ibrutinib are elderly and have increased risks of venous and arterial thromboses. The incidence of thrombosis in patients taking ibrutinib is unknown, and we hypothesized that the risk of thrombosis may be reduced during ibrutinib treatment. Therefore, we conducted a single-institution retrospective cohort study to determine the incidence and type of both arterial and venous thromboses during ibrutinib treatment and their management. METHODS: We reviewed medical records of all patients treated with ibrutinib for a hematological malignancy at the Ohio State University between 6/1/2010 and 3/31/2016. Baseline patient and disease characteristics were captured at time of starting ibrutinib. All thrombotic events occurring at any time during treatment with ibrutinib and within three days of its discontinuation were recorded. Time to thrombosis was calculated from the date of starting ibrutinib to the date of thrombosis or censored at the last assessment date, treating discontinuation of ibrutinib or death prior to thrombosis as competing risks. The cumulative incidence of thrombosis was estimated and the Fine and Gray regression models accounting for competing riskes were used to examine the association between patient characteristics and risk of thrombosis. RESULTS: The cohort included 565 patients. Median age was 65 (range 23-〉89) years and 70.3% (397/565) were men. The majority of patients had CLL (73.6%, 416/565). Other diagnoses included mantle cell lymphoma (9.9%, 56/565), indolent B-cell malignancies (8.1%, 46/565), and aggressive lymphomas (8.3%, 47/565). Median number of prior treatments was 3 (range 0-18) and 6.5% (37/565) of patients were treatment naïve. Prior to ibrutinib, 144 of 565 patients (25.5%) had a history of thrombosis. Sixty-four (11.3%, 64/565) patients had only venous thromboses, 66 (11.7% 66/565) had only arterial thromboses, and 14 patients had both. Concurrently with ibrutinib, 193 (34.2%) patients received antiplatelet agents, 16 (2.8%) patients received AC, and 31 (5.5%) patients received both. Total ibrutinib exposure for the cohort was 1,429 person-years with a median exposure of 2.39 (range 0-7.36) years per patient. A second antineoplastic agent was given with ibrutinib in 30.8% (174/565) of cases, including an immunomodulatory drug in 24 (4.2%, 24/565) patients. During ibrutinib treatment, 22 of 565 (3.9%) patients experienced 24 acute thrombotic events, mostly arterial (Table 1). The incidence of thrombosis was 1.7 (95% CI 1.1-2.5) per 100 person-years of ibrutinib exposure. Of the venous thromboses, 87.5% (7/8) were deep vein thromboses and developed at a median of 7.5 (range 0.5-75.3) months after starting ibrutinib. Of the arterial thromboses, the majority were acute cerebrovascular accidents (37.5%, 6/16) and developed at a median of 27.4 (range 0.4 - 56.6) months after starting ibrutinib. Thrombosis treatment is summarized in Table 1. After thrombosis, ibrutinib was discontinued or held in the majority of cases (75%, 18/24). One patient developed a recurrent thrombosis while on ibrutinib and AC. There were six bleeding events, 3 major (based on ISTH criteria) and 3 minor: all were taking ibrutinib and most were on AC (2 patients on antiplatelet, 1 on AC, 2 on both, 1 on neither). On univariable analysis, the only factors associated with significant (p2) increased risk of venous thrombosis were prior venous (HR 4.73, CI: 1.06-21.11) and arterial (HR 15.66, CI: 3.07-79.87) thromboses. Antiplatelet use was not significantly associated with either thrombus type. CONCLUSIONS: The cumulative incidence of thrombosis during ibrutinib treatment was low (1.7 per 100 person-years), with the majority being arterial. Prior thrombosis was associated with increased venous thrombosis risk. There are more bleeding than thrombotic complications after patients develop thromboses on ibrutinib, and optimal treatment strategies for this population requires further investigation. Disclosures Kander: AstraZeneca: Consultancy. Wang:Daiichi Sankyo: Consultancy, Other: Travel.

Description: Introduction: Hairy Cell Leukemia (HCL) is a rare, chronic hematological malignancy that makes up approximately 2% of all leukemias. HCL patients are at a markedly increased risk for infection related to a combination of disease-related and treatment-related immunosuppression which has been well described in the literature. However, the significance of infection prior to initiation of HCL therapy and its impact on the subsequent selection of HCL treatment, or outcomes, is not well described. Using the HCL patient data registry, we report here the impact of antecedent infection on the treatment patterns and outcomes of HCL patients. Methods: We evaluated adult (≥18 years) patients with HCL who had information regarding antecedent infections and subsequent HCL treatment during 1984-2018. The primary endpoint was progression-free survival (PFS-1). Secondary endpoint included time to next treatment (TTNT). PFS-1 was measured from the date of first HCL treatment to date of progression/death or last follow-up. TTNT was defined as the time from first HCL treatment to initiation of second HCL treatment. The study population was stratified into 3 groups based on the presence or absence of antecedent infections: no infection prior to first HCL treatment (no infection group), infection within 30 days prior to first HCL treatment (infection1 group) and infection 〉30 days prior to first HCL treatment (infection2 group). Fisher's exact test or Kruskal-Wallis test was used to compare the characteristics among the no infection and infection groups and the Cox proportional hazard model was used to evaluate the association with PFS-1 and TTNT. Results: A total of 205 HCL patients who had information regarding antecedent infections and subsequent HCL treatment were eligible for the study. Among these, 144 (70%) belonged to the no infection group, while 26 patients (13%) belonged to infection1 group and 35 (17%) to infection2 group. Patient characteristics are shown in Table 1 with a breakdown between the three groups. The majority of the patients were Caucasian with a male preponderance and had classic HCL. The patients in the infection1 group had a lower median WBC (K/uL) (1.9 vs 3.1 vs 2.9), particularly the absolute neutrophil count (K/uL) (0.4 vs 0.7 vs 0.8) and significantly lower median hemoglobin (gm%) (10.1 vs 12.2 vs 12.4) relative to the no infection and infection2 groups, respectively (p=0.01). Similarly, a greater proportion of patients in the infection1 group had significant comorbidities (including pulmonary, gastrointestinal and hepatic disease) relative to no infection and infection2 groups as shown in Table 1. The majority of patients received purine nucleoside analogs as their first HCL treatment (no infection group=92%, infection1 group=85%, infection2 group=94%). The median PFS-1 (in years) was better in the no infection group compared to the infection1 group but was not statistically significant (17.0 [95% CI=7.9-not reached (NR)] vs 8.8 [95% CI=4.2-NR], respectively, p=0.98, Figure 1). However, the median TTNT (in years) was significantly longer for HCL patients with no infection versus the infection1 group (6.3 [95% CI=5.4-7.8] vs 3.6 [95% CI=0.7-NR], respectively, p=0.001, Figure 1). On subgroup analysis, relative to the no infection group, median PFS-1 (in years) was not significantly different in infection1 group treated with Pentostatin (10.7 [95% CI=3.53-NR] vs NR [95% CI=1.38-NR], respectively, p=0.43), however, the median PFS-1 (in years) was shorter in the infection1 group treated with Cladribine (17.0 [95% CI=7.67-NR] vs 4.0 [95% CI=2.00-NR], respectively), although not reaching statistical significance (p=0.09) probably due to small sample size. Conclusion: In this large series of HCL patients who received treatment, we show that the patients who had infections at the time of HCL treatment have a significantly shorter TTNT. The reasons for this are unclear but may indicate that patients were unable to receive treatment in a timely manner because of the infection, or were unable to complete treatment because of complications. The significant difference in hemoglobin between the infection1 and other groups indicates the possibility that these patients had more advanced HCL at the time of diagnosis. These findings indicate the potential long term negative impact of infections in patients who need treatment for HCL and reinforce the need for careful management in this setting. Disclosures Lozanski: Beckman: Research Funding; Coulter: Research Funding; Stem Line: Research Funding; Genentech: Research Funding; Novartis: Research Funding; BI: Research Funding. Andritsos:HCLF: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy.

Description: Alterations in global DNA methylation patterns are a major hallmark of cancer and represent attractive biomarkers for personalized risk stratification. Chronic lymphocytic leukemia (CLL) risk stratification studies typically focus on time to first treatment (TTFT), time to progression (TTP) after treatment, and overall survival (OS). Whereas TTFT risk stratification remains similar over time, TTP and OS have changed dramatically with the introduction of targeted therapies, such as the Bruton tyrosine kinase inhibitor ibrutinib. We have shown that genome-wide DNA methylation patterns in CLL are strongly associated with phenotypic differentiation and patient outcomes. Here, we developed a novel assay, termed methylation-iPLEX (Me-iPLEX), for high-throughput quantification of targeted panels of single cytosine guanine dinucleotides from multiple independent loci. Me-iPLEX was used to classify CLL samples into 1 of 3 known epigenetic subtypes (epitypes). We examined the impact of epitype in 1286 CLL patients from 4 independent cohorts representing a comprehensive view of CLL disease course and therapies. We found that epitype significantly predicted TTFT and OS among newly diagnosed CLL patients. Additionally, epitype predicted TTP and OS with 2 common CLL therapies: chemoimmunotherapy and ibrutinib. Epitype retained significance after stratifying by biologically related biomarkers, immunoglobulin heavy chain mutational status, and ZAP70 expression, as well as other common prognostic markers. Furthermore, among several biological traits enriched between epitypes, we found highly biased immunogenetic features, including IGLV3-21 usage in the poorly characterized intermediate-programmed CLL epitype. In summary, Me-iPLEX is an elegant method to assess epigenetic signatures, including robust classification of CLL epitypes that independently stratify patient risk at diagnosis and time of treatment.

Description: Introduction: Exportin-1 (XPO1), a nuclear transport protein critical for the export of tumor suppressor proteins (TSPs) and select mRNAs to the cytoplasm, is highly expressed in acute myeloid leukemia (AML) and correlates with poor survival. Selinexor, an oral, first-in-class, selective inhibitor of nuclear export, blocks XPO1 function. We previously reported that sequential treatment of AML blasts using the hypomethylating agent decitabine followed by selinexor exhibited strong anti-leukemic effects in vivo by inducing the expression of silenced TSPs that are kept in the nucleus by XPO1 inhibition (Ranganathan, Blood 2015). Methods: Based on these findings, a phase I dose-escalation study was initiated to evaluate the safety, feasibility, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and preliminary clinical activity of selinexor in combination with decitabine in poor-risk AML pts (NCT02093403). Adults with relapsed or refractory (R/R) AML and older (age ≥60) unfit pts with untreated AML were eligible. Pts received 10-day decitabine induction(s) at 20mg/m2 on days 1-10 for up to four 28-day cycles in combination with selinexor once daily, twice weekly beginning on day 11. Pts with

Description: Background: Patients undergoing allogeneic hematopoietic stem cell transplant with reduced-intensity conditioning (RIC-alloSCT) rely primarily on the graft-versus-tumor (GVT) effect to prevent relapse. Although relapse remains high in this setting, previous data suggest modifications of allograft composition could produce enhanced GVT effect and improve outcomes. Prior retrospective studies suggested higher total nucleated cell (TNC) and CD8 dose correlate with improved overall survival (OS) and a reduction in relapse among all patients undergoing RIC-alloSCT. The aim of our study was to further investigate this association by comparing transplant outcomes with detailed graft immunophenotyping data including T-cell and NK-cell activation and maturation status and CD34 cell doses in patients with AML and MDS undergoing RIC-alloSCT. Methods: We performed a retrospective analysis using data from consecutive patients with AML and MDS who underwent RIC-alloSCT at a single center from 2010-2015 who had graft immunophenotyping data available. We compared transplant outcomes with TNC per kilogram (kg) and dose of CD3, CD4, CD8, CD34, and NK cells along with selected activation and maturation subsets. A competing risk regression analysis was conducted to examine the association between cell dose/kg and risk of relapse and graft versus host disease (GVHD). Overall survival and relapse free survival (RFS) were assessed utilizing the Cox proportional hazard model. Estimates of survival probability were determined by the Kaplan-Meier survival function. The log-rank test was used to compare OS and RFS among patients. Univariable and multivariable regression analyses were performed. Disease Risk Index (DRI) was used to stratify risk among patients. To identify optimal cutoffs (OC) of continuous variables for a specific outcome, a Classification and Regression Tree (CART) algorithm was utilized. Results: Our study included 142 patients who underwent RIC-alloHSCT for AML (n=97, 68%) and MDS (n=45, 32%). The vast majority of patients (98%) received fludarabine and busulfan conditioning with 65% receiving anti-thymocyte globulin. All patients received tacrolimus-based GVHD prophylaxis. Overall relapse rate was 37% at 3 years. Overall survival was 49% with median follow-up of 3.2 years. Total Nucleated Cell Dose: In multivariable analysis controlling for disease, comorbidity index, and performance status, a high infused TNC dose (10.6 - 16.8 x 108 cells/kg) correlated with improved overall survival (HR 0.27, 95% CI [0.12 - 0.59], p=0.001) and relapse free survival (HR 0.31, 95% CI [0.15 - 0.64], p=0.002). However, a very high TNC dose (OC 〉16.8 x 108 cells/kg) correlated with significantly worse OS (HR 2.84, 95% CI [1.16 - 6.98], p=0.023) and trended toward worse RFS (HR 2.09, 95% CI [0.88 - 4.93], p=0.093). Higher TNC doses were also correlated with an increased risk of chronic GVHD (HR 2.16, 95% CI [1.28 - 3.67], p=0.004, OC 9.8 x 108 cells/kg). Cell Subsets: Very low CD3 cell doses (OC

Description: Background: Consolidation therapy with allogeneic hematopoietic stem cell transplant (HSCT) is recommended to prevent relapse and improve survival in patients with intermediate and poor risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Due to toxicity, older patients with comorbidities were historically not candidates for HSCT. The development of reduced-intensity conditioning (RIC) regimens has allowed more patients to proceed to HSCT by reducing toxicities associated with myeloablative conditioning (MAC).The cornerstone of reducing conditioning regimen intensity is modification of busulfan exposure, expressed as an area under the curve (AUC). This can be achieved by the use of patient-specific pharmacokinetic targets. Previous studies (including BMT CTN 0901) have demonstrated RIC regimens were associated with less toxicity at the cost of potentially decreased survival relative to weight-based MAC regimens. At OSU, we have utilized an AUC target of 4,000 μmol-min/L per day x 4 days in a subset of patients to balance reduced toxicity with risk of relapse. Here we compare outcomes of AUC 4,000 to weight-based RIC Flu/Bu2. Methods: To compare the two regimens, a retrospective, IRB-approved cohort study was conducted. The inclusion criteria were as follows: age 18-89 years, HSCT for a diagnosis of AML or MDS, and fludarabine + busulfan conditioning regimen ± antithymocyte globulin. In the AUC 4,000 group, the target busulfan exposure was 16,000 μmol-min/L divided over 4 daily doses. In the RIC group, patents received busulfan 0.8 mg/kg/dose for 8 doses (Flu/Bu2). The primary outcome was relapse free survival (RFS). Secondary outcomes included overall survival (OS); time to neutrophil recovery; time to platelet recovery; incidence of acute and chronic graft vs host disease (GVHD); sinusoidal obstructive syndrome; febrile neutropenia; graft failure; and grade 3-5 mucositis, acute kidney injury, or hepatic dysfunction. The log-rank test was used to compare RFS and OS, and Cox proportional hazard regression model was used to estimate the hazard ratio. Gray's test was used for competing risks analysis of relapse, acute GVHD, and chronic GVHD. Fine and Gray regression models were used to estimate the hazard ratio. Results: Seventy-four patients who received conditioning from 2015-2018 with either AUC 4,000 or RIC were identified. Disease type was similar between groups with 61.8% AML in the AUC 4,000 group and 52.5% in the RIC group. There were no significant differences in disease risk status. In the AUC 4,000 group, 17.6% had either AML with myelodysplastic changes or therapy-related AML/MDS, compared to 17.5% in the RIC group. The percent of patients with HCT-Comorbidity Index score of ≥ 3 was 52.9% for AUC 4,000 and 77.5% for RIC. At 18 months, RFS was not significantly different, at 66.9% with AUC 4,000 compared to 57.5% with RIC (p=0.37) (A). Eighteen-month overall survival was also not significantly different with 66.9% alive in the AUC 4,000 group and 60% in the RIC group (p=0.63) (B). Cumulative incidence of acute and chronic GVHD were not significantly different (p=0.82, p=0.18, respectively) (C,D). There was, however, a statistically significant difference in the cumulative incidence of relapse over 18 months in favor of the AUC 4,000 regimen (hazard ratio 4.08, 95% confidence interval 1.15-14.5) (E). Grade 2-4 mucositis was more common in the AUC 4,000 group (85.3% vs 30%, p