Daily Continuous Infusion Research Articles

Efficacy and Safety of Intensive Etoposide Aracytine Consolidation Following Rituximab Methotrexate Temozolomide Induction in Newly Diagnosed Primary Central Nervous System Lymphoma

Primary central nervous system lymphoma (PCNSL) is reported as having a dismal prognosis, due to the limited blood-brain barrier crossing capacity of lymphoma chemotherapies. Long-term remission and even cure could be achieved for a significant proportion of PCNSL patients using methotrexate-based chemotherapy regimens and intensive consolidation strategies. We report our single center experience of 27 consecutive patients with newly diagnosed PCNSL treated with Rituximab Methotrexate Temozolomide (RMT) regimen, and high-dose Etoposide Aracytine (EA) consolidation, with particular consideration for safety data.Methods: All patients consecutively diagnosed with PCNSL from November 2013 to December 2016 at Cochin hospital (Paris, France) were retrospectively included. Primary vitro-retinal lymphoma without cerebral involvement (n=1) and immunodeficient patients (n=1) were excluded. Contrast-enhanced magnetic resonance imaging (MRI) was performed at diagnosis for all patients. Slit lamp evaluation and cerebrospinal fluid examination were performed at the diagnosis or during therapy. Induction therapy consisted of four cycles of 375mg/m² Rituximab and 8g/m² Methotrexate (with folinic acid rescue) at day 1 and 14, and Temozolomide 150mg/m² days 7 through 11, repeated every four weeks (the RMT regimen). Patients under 75 year-old without significant comorbidities and achieving a complete response (CR) or a partial response (PR) were treated with intravenous Etoposide 40mg/kg on a continuous 96h infusion days 1 through 4 and Aracytine 2g/m² twice a day days 1 through 4 (the EA regimen). MRI was performed after the second and fourth cycle of RMT and after treatment completion. Response was evaluated according to international PCNSL cooperative group (IPCG) criteria.Results: Median age was 68 and 26% of the patients were under 60. Median Karnofsky performans status was 60 (range, 40-100). After induction, we observed 16 (59.3%) CR/CRu, 6 (22.2%) progressive disease (PD), 2 (7.4%) unrelated lymphoma death and 3 (11.1%) were not evaluated but were in PR after 2 cycles. Nineteen patients achieved CR/PR and were eligible for subsequent consolidation therapy. Four patients received whole brain radiotherapy (30.6 Gy n=1, 23.4 Gy n=3), and two patients had a watchful waiting strategy. Thirteen (48.1%) patients received EA. Median age of EA cohort was 60. After 29 months (range, 8-43 months) of follow-up, 19 (70.4%) patients were alive in CR. Eight patients deceased, 4 (14.8%) from progressive disease and 4 (14.8%) from lymphoma-unrelated cause. Median of progression free survival (PFS) and overall survival (OS) were not reached. The two-year PFS and OS were 57% (CI 95%, 36-74%) and 67% (CI 95%, 44-82%), respectively when considering the whole cohort; and 82% (CI 95%, 44-95%) and 92% (CI 95%, 54-99%), respectively when focusing on patients who received EA consolidation (Figures 1a and 1b). Main toxic side-effects of RMT regimen, evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events V4.0 were infections (30% of grade 3-4) and liver enzymes modifications (37% of grade 3-4). We observed a single-case of fully-resolved grade 3 renal dysfunction. Regarding EA consolidation, median hospital stay and neutrophil recovery (neutrophil count over 0.5x109/l) was 22 (range, 20-183 days) and 11 days (range, 9-14 days), respectively. All patients developed grade 4 neutropenia and thrombocytopenia. Sixty one percent of patients experienced grade 3 anemia. Neutropenic fever was observed in 92.3% of patients. Grade 3-4 mucositis developed in 22.2% of patients. Sixty one percent of EA-treated patients experienced grade 3-4 infections, including documented bacterial infection in 6 patients (central venous catheter infection, n=3; septicemia, n=2 and Clostridium difficile colitis, n=1) and fungal infection in two patients (probable aspergillosis, n=1 and documented mucormycosis, n=1). We observed one case of vancomycine-induced grade 4 renal failure during febrile aplasia that fully recovered.Conclusion : The RMT regimen allowed a near 60% complete response rate with limited toxicity. Intensive Etoposide Aracytine consolidation is feasible but more toxic than previously reported. The high survival rate observed in patients receiving RMT induction and then EA consolidation support further comparative evaluation of this strategy in prospective trials. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Budget Impact Analysis of CPX-351 in the Treatment of Patients with Treatment-Related Acute Myeloid Leukemia (tAML) or AML with Myelodysplasia-Related Changes (MRC) from a US Payer Perspective

AML is a rapidly progressing and life-threatening blood cancer that disproportionately affects older adults. The treatment paradigm in AML has seen little change in the past 4 decades, with intensive chemotherapy with a 7-day continuous infusion of cytarabine plus an anthracycline such as daunorubicin on Days 1-3 (ie, “7+3” regimen) remaining the standard-of-care induction therapy for AML. CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic drug ratio into leukemia cells. In a phase 3 study (NCT01696084), CPX-351 demonstrated superior overall survival (9.56 vs 5.95 months; HR = 0.69; P= 0.005) and significantly improved complete remission rate (38% vs 26%; P= 0.040) compared with 7+3 in the treatment of elderly patients with newly diagnosed tAML or AML-MRC (Lancet JE, et al. ASCO 2016. Abstr 7000). Additionally, CPX-351 is administered as a 90-minute infusion on Days 1, 3, and 5 (induction cycle 1 only), and offers the potential for outpatient administration. The aim of this study was to estimate the budget impact associated with the introduction of CPX-351 for the treatment of patients with tAML or AML-MRC from a US payer perspective.A decision analytic model was developed to estimate the budget impact of using CPX-351 compared with 7+3 for induction and consolidation treatment of AML patients with tAML and AML-MRC. The decision algorithm was developed based on clinical practice guidelines from the National Comprehensive Cancer Network and validated by an oncologist. Epidemiology estimates were from SEER 2017. Clinical outcomes (response rate and incidence of adverse events [AE]) and site of care were from the CPX-351 phase 3 pivotal trial. In that study, CPX-351 was administered in the outpatient setting for 51% of patients in consolidation cycle 1 and 61% in cycle 2, compared with 6% and 0% of 7+3 patients in consolidation cycles 1 and 2 (Kolitz JE, et al. ASCO 2017. Abstr 7036). Administration costs were from CMS for Medicare and InGauge Healthcare Solutions for commercial costs. Hospital costs were from the CMS Limited Data Set. H-CUP National Inpatient Sample was used to estimate the AE costs by payer type. Drug costs were wholesale acquisition costs. The model did not include costs for hematopoietic cell transplant.For a hypothetical 1 million-member plan, it is estimated that there are approximately 12 patients with tAML and AML-MRC each year. Increasing the use of CPX-351 from year 1 to 3 (assumption of year 1 = 20%, year 2 = 50%, and year 3 = 80%) resulted in cost increases compared with 7+3 (year 1 = $7,471 to year 3 = $29,884, or <$0.01 per member per month increase in each year). Over the same time period, the estimated number of responders increased from 3.06 with 7+3 to 4.19 with CPX-351. The increased level of responses with CPX-351 reduced the cost/responder from $358,695 with 7+3 to $269,106 by year 3 following introduction of CPX-351. Of note, outcomes are derived from a phase 3 randomized, controlled trial of CPX-351 versus 7+3, the model did not account for potential regimen changes, and costs may not be generalizable across all settingsThis model predicted that the use of CPX-351 may be associated with improved patient outcomes and limited budget impact from the payer perspective. DisclosuresJensen:Celator/Jazz: Consultancy. Wu:Celator/Jazz: Consultancy. Sacks:Celator/Jazz: Consultancy. Cyr:Celator/Jazz: Consultancy. Chung:Baxter: Equity Ownership; Shire: Equity Ownership; Baxalta: Equity Ownership; Amgen: Equity Ownership; Gilead: Equity Ownership; Bayer: Equity Ownership; Gilead: Employment; Jazz Pharmaceuticals: Employment, Equity Ownership.

Short-course IL-15 given as a continuous infusion led to a massive expansion of effective NK cells: implications for combination therapy with antitumor antibodies

BackgroundFull application of cytokines as oncoimmunotherapeutics requires identification of optimal regimens. Our initial effort with intravenous bolus recombinant human interleukin-15 (rhIL-15) was limited by postinfusional reactions. Subcutaneous injection and continuous...

The improved survival rate and cost-effectiveness of a 7-day continuous subcutaneous insulin infusion set

Aims The purpose of this article is to compare the insulin cost-savings of the Medtronic Extended Infusion Set (or EIS, a.k.a. Extended Wear Infusion Set) designed and labeled for up to 7-day use with rapid-acting insulins to the current standard of care, 2- to 3-day infusion sets. Methods There are three major improvements (reducing insulin waste, plastic waste, and adverse events) with the extended duration of infusion set wear. This analysis focuses on cost savings from reduced insulin wastage during set changes. Studies published on insulin infusion set survival and EIS clinical trial data (NCT04113694) were used to estimate device lifetime performance using a Markov chain Monte Carlo model, including the assessment of adverse effects and device failure. Total costs associated with infusion set change or failure were systematically found in published literature or estimated based on physical usage, and the direct impact on insulin costs was calculated. Results Based on the model and clinical data, EIS users can expect to change their infusion sets about 75 fewer times than standard set users each year. The costs related to unrecoverable insulin during an infusion set and reservoir change in the US were estimated to range from $19.79 to $22.48, resulting in approximately $1324 to $1677 in annual cost-savings for the typical user from minimizing insulin wastage. Limitations The study only assessed devices used within a monitored setting, that is, clinical trials. In addition, the variability associated with healthcare standards and costs and individual treatment variability including insulin dosages, contribute to the uncertainties with the calculations. Conclusions Our analysis demonstrates that by extending the duration of infusion set wear, there may be substantial cost savings by reducing insulin wastage.

Insulin, Not the Preservative m-cresol, Instigates Loss of Infusion Site Patency Over Extended Durations of CSII in Diabetic Swine.

Insulin infusion sets worn for more than 4-5 days have been associated with a greater risk of unexplained hyperglycemia, a phenomenon that has been hypothesized to be caused by an inflammatory response to preservatives such as m-cresol and phenol. In this cross-over study in diabetic swine, we examined the role of the preservative m-cresol in inflammation and changes in infusion site patency. Insulin pharmacokinetics (PK) and glucose pharmacodynamics (PD) were measured on delivery of a bolus of regular human insulin U-100 (U-100R), formulated with or without 2.5mg/mL m-cresol, to fasted swine following 0, 3, 5, 7, and 10 days of continuous subcutaneous insulin infusion (CSII). In a subsequent study with the same animals, biopsies were evaluated from swine wearing infusion sets infusing nothing, saline, or U-100R either with or without 2.5mg/mL m-cresol, following 3, 7, and 10 days of CSII. Exposure to m-cresol did not impact any PK or PD endpoints. PK and PD responses dropped markedly from Days 7-10, regardless of the presence of m-cresol. Histopathology results suggest an additive inflammatory response to both the infusion set and the insulin protein itself, peaking at Day 7 and remaining stable beyond.

Adjunction of a Fish Oil Emulsion to Cytarabine and Daunorubicin Induction Chemotherapy in High-Risk AML. the Famyly Pilot Study from the French Innovative Leukemia Organization (FILO)

Background. Acute myeloid leukemia (AML) with unfavorable cytogenetics remains a therapeutic challenge. We previously established that ex vivo exposure of AML blasts to eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or fish oil emulsion (FO) induces Nrf2 pathway activation, metabolic switch and cell death (Picou et al., Pharmacol Res 2018;136:45-55). Objectives. The FILO group launched a pilot clinical study to evaluate the feasibility, safety and efficacy of the adjunction of a commercial FO emulsion (OMEGAVEN) to 3+7 in untreated AML with unfavorable cytogenetics. Patients and methods. The FAMYLY trial was a multicenter single-arm phase II study. Eligible patients had a diagnosis of untreated AML with unfavorable cytogenetics, 18 years old or above. For patients with WBC &amp;lt; 30 G/L, FO was administered at 2 mL/kg/d IV 2 days before 3+7 induction chemotherapy (daunorubicin 60 mg/m² days 1-3 and cytarabine 200 mg/m²/d as a continuous infusion days 1-7), until day 7 of induction. For patients with WBC &amp;gt;= 30 G/L, FO and 3+7 were started concomitantly, and FO was administered until day 9. The primary objective was complete response (CR) on the BM aspirate at the end of induction. Data from 75 patients with adverse cytogenetics and treated with daunorubicin and cytarabine in LAM2001 study (Lioure et al., Blood 2012) was used as a historical control. Serial blood samples were collected before treatment, and on days 1 and 3 after start of treatment, to evaluate the expression of NRF-2 target genes and antioxidant enzymes by RT-qPCR. Results. Thirty patients were included. The median age was 54 years (range: 30-64 years), and only 3 patients were hyperleukocytic. FO administration raised the plasma levels of EPA and DHA (p&amp;lt;0.05). The Cmax of daunorubicin was 92.2 µg/L (Q1; Q3: 44.8; 105.1), and the AUCꚙ 414.9 ng.h, representing a mean clearance Cl=358.5 mL/h and a half-life T1/2=3.5h. The cytarabine clearance was highly variable with a mean of 1.628 L/h. A historical comparison to the LAM2001 trial found no unexpected toxicity. The CR rate was 76%, similar to the daunorubicin arm of the previous study in patients with unfavorable cytogenetics (72%). No survival improvement was observed in a historical comparison. RT-qPCR analysis of NRF-2 target genes and antioxidant enzymes (particularly HMOX1 and NQO1) in sequential blood samples did not show a significant in vivo response. Conclusions. Altogether, FO emulsion adjunction to 3+7 is feasible and safe. Although CR rate improvement was not shown in this cohort of high-risk patients, further research aiming at finding the sufficient dose to trigger an NRF-2 response in vivo should be considered. ClinicalTrials.gov identifier: NCT01999413. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: OMEGAVEN (fish oil emulsion) in Acute Myeloid Leukemia

High Dose Ifosfamide in Relapsed and Unresectable High-Grade Osteosarcoma Patients: A Retrospective Series.

Background: The evidence on high-dose ifosfamide (HD-IFO) use in patients with relapsed osteosarcoma is limited. We performed a retrospective study to analyze HD-IFO activity. Methods: Patients with osteosarcoma relapsed after standard treatment [methotrexate, doxorubicin, cisplatin +/− ifosfamide (MAP+/−I)] with measurable disease according to RECIST1.1 were eligible to ifosfamide (3 g/m2/day) continuous infusion (c.i.) days 1–5 q21d. RECIST1.1 overall response rate (ORR) (complete response (CR) + partial response (PR)), progression-free survival at 6-month (6m-PFS), duration of response (DOR), and 2-year overall survival (2y-OS) were assessed. PARP1 expression and gene mutations were tested by immunohistochemistry and next-generation sequencing. Results: 51 patients were included. ORR was 20% (1 CR + 9 PR). Median DOR was 5 months (95%CI 2–7). Median PFS, 6m-PFS, OS, and 2y-OS were 6 months (95%CI 4–9), 51%, 15 months (10–19), and 30%, respectively. A second surgical complete remission (CR2) was achieved in 26 (51%) patients. After multivariate analysis, previous use of ifosfamide (HR 2.007, p = 0.034) and CR2 (HR 0.126, p < 0.001) showed a significant correlation with PFS and OS, respectively. No significant correlation was found between outcomes and PARP1 or gene mutations. Conclusions: HD-IFO should be considered as the standard first-line treatment option in relapsed osteosarcoma and control arm of future trial in this setting.

Abrogation of atypical neurogenesis and vascular-derived EphA4 prevents repeated mild TBI-induced learning and memory impairments

Brain injury resulting from repeated mild traumatic insult is associated with cognitive dysfunction and other chronic co-morbidities. The current study tested the effects of aberrant neurogenesis in a mouse model of repeated mild traumatic brain injury (rmTBI). Using Barnes Maze analysis, we found a significant reduction in spatial learning and memory at 24 days post-rmTBI compared to repeated sham (rSham) injury. Cell fate analysis showed a greater number of BrdU-labeled cells which co-expressed Prox-1 in the DG of rmTBI-injured mice which coincided with enhanced cFos expression for neuronal activity. We then selectively ablated dividing neural progenitor cells using a 7-day continuous infusion of Ara-C prior to rSham or rmTBI. This resulted in attenuation of cFos and BrdU-labeled cell changes and prevented associated learning and memory deficits. We further showed this phenotype was ameliorated in EphA4f./f/Tie2-Cre knockout compared to EphA4f./f wild type mice, which coincided with altered mRNA transcript levels of MCP-1, Cx43 and TGFβ. These findings demonstrate that cognitive decline is associated with an increased presence of immature neurons and gene expression changes in the DG following rmTBI. Our data also suggests that vascular EphA4-mediated neurogenic remodeling adversely affects learning and memory behavior in response to repeated insult.

Prediction of exposure-driven myelotoxicity of continuous infusion 5-fluorouracil by a semi-physiological pharmacokinetic\u2013pharmacodynamic model in gastrointestinal cancer patients

PurposeTo describe 5-fluorouracil (5FU) pharmacokinetics, myelotoxicity and respective covariates using a simultaneous nonlinear mixed effect modelling approach.MethodsThirty patients with gastrointestinal cancer received 5FU 650 or 1000 mg/m2/day as 5-day continuous venous infusion (14 of whom also received cisplatin 20 mg/m2/day). 5FU and 5-fluoro-5,6-dihydrouracil (5FUH2) plasma concentrations were described by a pharmacokinetic model using NONMEM. Absolute leukocyte counts were described by a semi-mechanistic myelosuppression model. Covariate relationships were evaluated to explain the possible sources of variability in 5FU pharmacokinetics and pharmacodynamics.ResultsTotal clearance of 5FU correlated with body surface area (BSA). Population estimate for total clearance was 249 L/h. Clearances of 5FU and 5FUH2 fractionally changed by 77%/m2 difference from the median BSA. 5FU central and peripheral volumes of distribution were 5.56 L and 28.5 L, respectively. Estimated 5FUH2 clearance and volume of distribution were 121 L/h and 96.7 L, respectively. Baseline leukocyte count of 6.86 × 109/L, as well as mean leukocyte transit time of 281 h accounting for time delay between proliferating and circulating cells, was estimated. The relationship between 5FU plasma concentrations and absolute leukocyte count was found to be linear. A higher degree of myelosuppression was attributed to combination therapy (slope = 2.82 L/mg) with cisplatin as compared to 5FU monotherapy (slope = 1.17 L/mg).ConclusionsBSA should be taken into account for predicting 5FU exposure. Myelosuppression was influenced by 5FU exposure and concomitant administration of cisplatin.

Sexual Differences in response to Mid- or Low-Premixed Insulin Analogue in Patients with Type 2 Diabetes.

Objective To observe whether there are sexual-related differences in response to mid- or low-premixed insulin in type 2 diabetic patients. Methods This was an analysis of CGM data of a previous study. After screening, patients with longstanding T2D receive a 7-day continuous subcutaneous insulin infusion (CSII) therapy, and then subjects were randomly assigned 1 : 1 into two groups receiving Novo Mix 30 or Humalog Mix 50 regimen for a 2-day phage, followed by a 4-day cross-over period. A 4-day continuous glucose monitoring (CGM) was performed during the cross-over period. The primary endpoint was the differences in glycemic control between male and female patients receiving mid- or low-premixed insulin therapy. Results A total of 102 patients (52 men and 50 women) completed the study. Our data showed that male patients had significant decrease in mean glucose levels monitored by CGM after three meals during Humalog Mix 50 treatment period compared to those received Novo Mix 30 regimen (0900: 11.0 ± 2.5 vs. 12.2 ± 2.8, 1000: 9.9 ± 2.9 vs. 11.3 ± 3.1, 1200: 8.0 ± 1.9 vs. 9.1 ± 2.5, 1400: 9.2 ± 2.3 vs. 10.3 ± 2.5, and 2000: 7.3 ± 2.1 vs. 8.2 ± 2.4 mmol/L, p < 0.05, respectively). In addition, male patients receiving Novo Mix 30 experienced a significantly increased hypoglycemic duration compared to those of receiving Humalog Mix 50 (0 (0, 4.8) vs. 0 (0, 0), p < 0.05, respectively). In addition, male patients receiving Novo Mix 30 experienced a significantly increased hypoglycemic duration compared to those of receiving Humalog Mix 50 (0 (0, 4.8) vs. 0 (0, 0), Conclusion Our data indicate that male patients with T2D receiving mid-premixed insulin analogue regimen may have a potential benefit of improvement in glycemic control compared to female patients. This trial is registered with ClinicalTrials.gov ChiCTR-IPR-15007340.

Modified 3-weekly cisplatin or cisplatin-5-fluorouracil 5-day infusion as the concurrent chemoradiotherapy regimen in locally advanced squamous cell carcinoma of the head and neck: Comparison of efficacy and toxicity

Background: Concurrent chemoradiotherapy (CCRT) is an important therapeutic strategy in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). We evaluated the efficacy and toxicity of two CCRT regimens in treating LA-SCCHN. Materials and Methods: LA-SCCHN patients receiving CCRT with either a modified 3-weekly cisplatin 75 mg/m2 (Group A, n = 86) or 5-day continuous infusion of cisplatin 12 mg/m2 plus 5-fluorouracil (5-FU) 600 mg/m2 (Group B, n = 87) were enrolled. The Kaplan−Meier method was used to estimate overall survival (OS), progression-free survival (PFS), and locoregional recurrence-free survival (LRFS). Univariate and multivariate analyses were performed using Cox proportional hazard models to assess correlations between clinical parameters and survival. Results: With a median of 35.8 months' follow-up, the median OS and PFS in Group A and Group B were 65.9 versus 55.0 months (P = 0.546) and 34.6 versus 33.3 months (P = 0.948), respectively. LRFS was not reached in either group. Group B patients had more Grade 3−4 mucositis (53.7% vs. 32.28%, P= 0.001) and dermatitis (49.8% vs. 21.5%, P= 0.0001). Trends of higher incidence rates of Grade 3−4 hematologic and renal toxicity were observed in Group A. After statistical adjustment, higher disease stage (Stage IVb) (hazard ratio [HR] = 6.657, 95% confidence interval [CI] 1.786−24.81, P= 0.005) and pretreatment anemia (hemoglobin

A Phase I/II Study of AZD2811 Nanoparticles (NP) As Monotherapy or in Combination in Treatment-Naïve or Relapsed/Refractory AML/MDS Patients Not Eligible for Intensive Induction Therapy

A Phase I/II Study of AZD2811 Nanoparticles (NP) As Monotherapy or in Combination in Treatment-Naïve or Relapsed/Refractory AML/MDS Patients Not Eligible for Intensive Induction Therapy

Blinatumomab/Lenalidomide in Relapsed/Refractory Non-Hodgkin's Lymphoma: A Phase I California Cancer Consortium Study of Safety, Efficacy and Immune Correlative Analysis

Blinatumomab/Lenalidomide in Relapsed/Refractory Non-Hodgkin's Lymphoma: A Phase I California Cancer Consortium Study of Safety, Efficacy and Immune Correlative Analysis

High-Dose Cytarabine Is Indispensable for the Survival of Children with Myeloid Leukemia of Down Syndrome Despite Negative Minimal Residual Disease Post-Induction

Introduction. Myeloid leukemia in children with Down syndrome (ML-DS) is a unique subtype of acute myeloid leukemia, distinguished by an earlier age of onset (under 4 years of age); somatic mutations of GATA1; hypersensitivity of leukemic blasts to cytarabine and other chemotherapeutic agents; lack of CNS involvement; and superior event-free survival (EFS, 85-90% at 5 years). Due to these excellent outcomes, successive protocols by the Children's Oncology Group (COG) have aimed for a reduction of treatment intensity but continue to include a course containing high-dose cytarabine (HD-AraC) for all patients, which is associated with the bulk of infectious toxicity. COG AAML1531 is the first study to evaluate differential treatment for ML-DS patients based on risk-stratification. We report the outcomes for patients with Standard Risk (SR) ML-DS enrolled on AAML1531, who were treated without inclusion of HD-AraC (https://clinicaltrials.gov/ct2/show/NCT02521493?term=AAML1531&amp;rank=1). Methods. Patients older than 90 days and younger than 4 years of age with ML-DS were eligible, including those presenting with myelodysplastic syndrome (&amp;lt; 20% blasts in the bone marrow) and trisomy 21 mosaicism. Pathological and cytogenetic data were reviewed centrally. All patients received the same first course of induction therapy (cytarabine 200 mg/m2/24h IV as continuous infusion, day 1-4; daunorubicin 20 mg/m2IV, day 1-4; thioguanine 50 mg/m2/dose PO twice daily, day 1-4; and a single dose of age-based intrathecal cytarabine on day 1). After this first course, measureable residual disease (MRD) in the bone marrow by multi-dimensional flow cytometry in a reference laboratory was used for risk stratification. Patients with negative MRD (&amp;lt;0.05%) were assigned to Standard Risk (SR) therapy, which was modeled after the AAML0431 predecessor study, but with further reduction of treatment by omission of the course containing HD-AraC/E. coli asparaginase (Induction II of AAML0431). Courses #2 and #3 of SR therapy were identical to the first course except that no further intrathecal chemotherapy was administered. Courses #4 and #5 (cytarabine 100 mg/m2/24h IV as continuous infusion day 1-7; etoposide 125 mg/m2 IV, day 1-3) were identical to the corresponding courses of AAML0431. For patients younger than 36 months, chemotherapy doses were calculated based on weight. Use of dexrazoxane during anthracycline-containing courses was at the discretion of the treating center but was captured by the data collection of the study. Patients with positive MRD (&amp;gt;0.05%) after the first course were assigned to the High Risk (HR) Arm and received intensified therapy (equivalent to that used for non-DS AML). Accrual to the HR arm is ongoing. Results. Interim analysis of SR therapy was performed after 50% of expected EFS events had occurred as of June 30, 2018. The observed EFS was 89.3 +/- 6.1% at 2 years from study entry and significantly lower than expected for comparable MRD-negative patients whose treatment in predecessor study AAML0431 included a course of HD-AraC/E. coliasparaginase (p=0.0002). OS at 2 years was 88.7 +/- 6.8%. Among a total of 114 SR ML-DS patients, 11 developed a relapse, all within the first year from study entry (range 136-327 days). OS at 1 year from relapse was 9.1 +/- 17.3%. Based on the results of interim analysis, the SR arm of AAML1531 was closed to accrual due to lack of efficacy. Cytogenetic analysis showed that complex karyotypes (defined as &amp;gt;3 independent abnormalities including &amp;gt;1 structural one) were significantly more frequent in SR patients who relapsed (40%, n=10) compared to SR patients who did not (9%; n=100; p=0.017). The most common abnormalities were trisomies (61% of cases) of chromosomes 3 and 8, and a gain of a fourth copy of chromosome 21. Monosomy 7 was present in 20% of relapsed vs. 5% of patients without a relapse (p=0.122). Conclusions. MRD measured by multi-dimensional flow cytometry is insufficient to identify a subset of ML-DS patients for whom HD-AraC/E.coliasparaginase can be eliminated from treatment. Cytogenetic profiling may aid in further refining risk-based subsets of ML-DS patients. Additional approaches to risk stratification of ML-DS should be pursued, which take into account the emerging genetic events that co-operate with mutant GATA1 in the development of ML-DS. At this time, HD-AraC/E.coli asparaginase should be included in the treatment of ML-DS, regardless of MRD. Disclosures Druley: Washington University: Employment; ArcherDX Inc.: Employment, Equity Ownership. Loken:Hematologics, Inc: Employment, Equity Ownership. Eidenschink Brodersen:Hematologics, Inc: Employment.

Phase 1 Trial of Human IL-15 (rhIL-15) and Obinutuzumab for Relapsed and Refractory Chronic Lymphocytic Leukemia

Background: Of the several drugs and drug combinations approved for treatment of relapsed and refractory chronic lymphocytic leukemia (CLL), the reported complete response rates are no greater than 30%. Obinutuzumab is a glycoengineered, humanized type 2 anti-CD20 monoclonal antibody thought to engage the immune system by directly activating antibody- dependent, cell-mediated cytotoxicity (ADCC); it is approved for treatment of chronic lymphocytic leukemia in combination with chlorambucil. The key mediators of ADCC are polymorphonuclear neutrophils, monocytes, and natural killer (NK) cells. Recombinant human Interleukin-15 (rhIL-15) is a stimulatory cytokine that promotes the differentiation and activation of NK cells, monocytes, and long-term CD8+ memory T-cells. In a Phase I trial, administration of rhIL-15 as a 5-day continuous intravenous infusion (civ) was associated with up to 45-fold increase in the number of NK cells at well- tolerated dose levels. Preclinical murine lymphoid malignancy models have shown increased efficacy of monoclonal antibodies when administered together with rhIL-15; BL/6 mice inoculated with EL4-CD20 cells (a syngeneic lymphoma line); including significant prolongation of survival with the IL-15/Rituximab combination compared to either drug given as single agent (90% v. 30% alive at 75 days). We hypothesized that rhIL-15-associated increase in NK cell number and activity would improve efficacy of obinutuzumab in treatment of relapsed and refractory CLL, and would increase the duration and depth of response; this phase I trial is testing the safety of the combination. Primary objective: determine the safety, toxicity profile, dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of civ rhIL-15 administration in combination with obinutuzumab treatment Secondary objectives: 1) evaluate the potential antitumor activity of the combination of rhIL-15 and obinutuzumab by assessing the clinical response rate, minimal residual disease (MRD) status, progression-free survival, and overall survival in patients with relapsed and refractory CLL; 2) define the effects of rhIL-15 on the ADCC mediated by obinutuzumab using ex vivo peripheral blood mononuclear cells (PBMCs); 3) characterize the biological effects of rhIL-15 administered with obinutuzumab on the percentages and absolute numbers of circulating lymphocytes (T and NK cells) and the T- cell subsets (including naïve, central, and effector memory subsets) by flow cytometry Exploratory objectives: identify biomarkers predictive of response to rhIL-15 and obinutuzumab treatment, such as circulating tumor DNA (ctDNA) and baseline cytokine levels Eligibility criteria: 1) age ≥ 18 years; 2) ECOG ≤ 1; 3) Diagnosis of CLL or small lymphocytic lymphoma (SLL) with ≥ 50% of B cells expressing CD20; 4) measurable or evaluable disease that is refractory or relapsed following therapy with a BTK inhibitor OR have relapsed/refractory CLL and are intolerant to BTK inhibitor therapy; patients with del(17p) must also be refractory or relapsed after, or intolerant to, therapy with venetoclax; 5) adequate organ function parameters as defined within the protocol; 6) active disease requiring treatment, as defined within the protocol. Study design: a single institution non-randomized phase I dose escalation study evaluating increasing doses of civ rhIL-15 in combination with obinutuzumab using a 3 + 3 dose escalation design. On days 1-5 of each 4-week cycle, rhIL-15 will be administered by civ at dose levels 0.5, 1, and 2 mcg/kg/day. During the first cycle, obinutuzumab will be administered at a dose of 100 mg by IV on day 4, 900 mg on day 5, 1,000 mg on day 11, and 1,000 mg on day 18; then 1,000 mg on day 4 of each subsequent cycle. Infusion reaction, antimicrobial, and tumor lysis syndrome prophylaxis will be administered per manufacturer's recommendations. Treatment will continue up to 6 cycles, or until unacceptable toxicity or progressive disease. Up to 24 patients will be enrolled in the study. Correlative studies: 1) optional lymph node biopsy at baseline and after the first week of treatment (C1D8) for tissue immune cell subsets and quantifying antibody penetration; 2) lymphocyte subset testing, ctDNA, and cell and plasma banking on days 1, 4, 8, and 11 of cycle 1, and days 1 and 8 of cycles 2-6; 3) ADCC capacity of ex vivo NK cells on C1D1, 4, and 8. One patient has started treatment to date. Enrollment is ongoing. Figure Disclosures Wiestner: Acerta: Research Funding; Pharmayclics: Research Funding; Merck: Research Funding; Nurix: Research Funding. Waldmann:Bioniz: Membership on an entity's Board of Directors or advisory committees.

PF257 GEMTUZUMAB OZOGAMICIN COMBINED WITH CYTARABINE FOR ACUTE MYELOID LEUKEMIA PATIENTS IN FIRST RELAPSE

Background:Although the majority of adult acute myeloid leukemia (AML) patients achieve complete remission (CR), a relapse still occurs in 35–80% of cases mostly depending on baseline clinical and cytogenetic characteristics. The prognosis of patients with AML relapse remains very poor with 10–20% long‐term survival rates. At relapse, the common admitted strategy is to reach a second CR (CR2) and to bridge eligible patients to allogeneic hematopoietic stem cell transplantation (HSCT). Gemtuzumab ozogamicin (GO, anti‐CD33 linked to calicheamicin) was recently approved to treat frontline AML patients in combination with daunorubicin and cytarabine. GO has also shown some activity in relapse AML, particularly in the core binding factor (CBF) subgroup (Hospital MA, Blood 2014). Whether the use of standard anthracyclines is required when combined to anthracycline‐like calicheamicin remains to be explored.Aims:To assess the efficacy and safety of GO combined with cytarabine (GO+AraC) to treat AML patients in first relapse.Methods:We conducted a retrospective monocentric study of relapsed AML patients in Saint‐Louis Hospital (Paris, France). Between Jan 2008 and Dec 2018, all consecutive patients with AML in first relapse treated with GO (3 mg/sqm/d for 3 days or 6 mg/sqm for 1 day) plus AraC (1–3 g/sqm/bid for 3–5 days or 200 mg/sqm/d for 7 days in continuous infusion) were included. GO was provided through the French compassionate use program (ATU). Patients and disease characteristics, safety, and outcome are reported.Results:A total of 71 patients with a median age of 46 years old (range, 17–77) were included. ELN‐2010 classification was favorable in 42 patients (59%, including 31 CBF‐AML), intermediate in 19 patients (27%), and unfavorable in 10 patients (14%). Median percentage of CD33 expression on blast cells was 87% (range, 22–100). Five patients (7%) had been transplanted in first CR. Median time to relapse was 10 months (range, 5–140). Median follow up was 1.5 years (range, 0.1–10.1). Overall Response Rate (ORR) after salvage was 77% (N = 55) with 52 patients (74%) achieving CR. Time to relapse &gt;12 months (p = .04) and CD33 expression &gt;70% (p = .05) (Olombel G., Blood 2016) were the only factors significantly associated with increased ORR. Among patients with OR, 18 (33%) were consolidated with HDAC alone (38%) and 26 with HDAC+GO (55%). Thirty‐two patients (58%) were bridged to HSCT in CR2. During salvage, a grade 3/4 hepatic toxicity was found in 16 patients (22%) including 6 sinusoidal obstruction syndromes (SOS). A total of 11 patients (15%) experienced SOS with 1/5 patients with previous HSCT and 4/32 after subsequent HSCT (13%). Non‐relapse mortality at 3 years was 12% (95%CI, 6–23) with 2 SOS, 2 sepsis, and 2 hemorrhage. The 3‐year cumulative Incidence of relapse (CIR) was 55% (95%CI, 40–71). In univariate and multivariate analyses, factors significantly associated with increased CIR were a short time to relapse (&lt;12 months), unfavorable ELN classification, and the use of continuous AraC during induction. The 3‐year overall survival (OS) was 43% (95%CI, 30–56). Factors associated with decreased OS were a shorter time to relapse and unfavorable ELN status (Figure). In patients bridged to HSCT, 3‐year OS was 61% (95%CI, 40–77), with no difference between ELN favorable and intermediate subgroups.Summary/Conclusion:In patients with AML in first relapse, GO+Arac is a safe and efficient salvage regimen, especially in patients with ELN favorable/intermediate profile and time to relapse of more than 12 months.image

Retrospective Review of the Use of High-Dose Cyclophosphamide, Bortezomib, Doxorubicin, and Dexamethasone for the Treatment of Multiple Myeloma and Plasma Cell Leukemia

BackgroundMultiple myeloma (MM) usually follows a clinical course leading to refractoriness and limited treatment options in advanced stages, which might need bridge therapies to either autologous stem cell transplantation or novel therapies. We report our experience with the high-dose chemotherapy mCBAD (modified cyclophosphamide, bortezomib, doxorubicin, and dexamethasone) regimen in newly diagnosed MM (NDMM), relapsed/refractory MM (RRMM), and plasma cell leukemia (PCL) patients. Patients and MethodsWe searched our electronic records database for MM patients who received mCBAD from 2010 to 2016 for 28-day cycles of cyclophosphamide 350 mg/m2 intravenously (I.V.) twice daily with mesna 400 mg/m2 I.V. daily (days 1-4), bortezomib 1.3 mg/m2 subcutaneously/I.V. (days 1, 4, 8, 11), doxorubicin 9 mg/m2 daily continuous infusion (days 1-4), dexamethasone 40 mg orally daily (on days 1-4, 9-12, 17-20). International Myeloma Working Group (IMWG) criteria were used for response assessment and diagnosis. Descriptive statistics, Fisher exact test, χ2, Wilcoxon rank sum, and Kaplan–Meier were used for statistical purposes. ResultsOne hundred forty patients met the inclusion criteria. A median of 2 cycles of therapy was administered. The overall response rate was 85% in patients with RRMM (n = 116) and 100% in NDMM (n = 13) and PCL (n = 11) patients. Respective median progression-free survival (mPFS) for NDMM, PCL, and RRMM were 19.61 months (95% confidence interval [CI], 5.26 to not applicable [NA]), 7.56 months (95% CI, 4.7 to NA), and 4.64 months (95% CI, 3.75-6.73). Patients with RRMM who used mCBAD as a bridge to autologous transplant (36.2%) had mPFS (11.48 months; 95% CI, 7.52-15.9 months) compared with those who did not (mPFS: 3.19 months; 95% CI, 2.4-3.75 months). Cytopenias occurred in more than 90% of patients, and febrile neutropenia was noted in 26%. All cases of treatment-related mortality (8%) occurred in patients with RRMM, except for 1 patient with PCL. ConclusionmCBAD results in high response rates in myeloma and PCL, however, with high treatment-related mortality. Its use in RRMM should be limited to patients who have immediate need for therapy without other treatment options and who have good performance status (score of 0-1) or NDMM if novel agents are not available depending on practice setting. mCBAD can be a treatment option for patients with PCL.

Effects of intravenous AICAR (5-aminoimidazole-4-carboximide riboside) administration on insulin signaling and resistance in premature baboons, Papio sp.

Premature baboons exhibit peripheral insulin resistance and impaired insulin signaling. 5’ AMP-activated protein kinase (AMPK) activation improves insulin sensitivity by enhancing glucose uptake (via increased glucose transporter type 4 [GLUT4] translocation and activation of the extracellular signal-regulated kinase [ERK]/ atypical protein kinase C [aPKC] pathway), and increasing fatty acid oxidation (via inhibition of acetyl-CoA carboxylase 1 [ACC]), while downregulating gluconeogenesis (via induction of small heterodimer partner [SHP] and subsequent downregulation of the gluconeogenic enzymes: phosphoenolpyruvate carboxykinase [PEPCK], glucose 6-phosphatase [G6PASE], fructose- 1,6-bisphosphatase 1 [FBP1], and forkhead box protein 1 [FOXO1]). The purpose of this study was to investigate whether pharmacologic activation of AMPK with AICAR (5-aminoimidazole-4-carboximide riboside) administration improves peripheral insulin sensitivity in preterm baboons. 11 baboons were delivered prematurely at 125±2 days (67%) gestation. 5 animals were randomized to receive 5 days of continuous AICAR infusion at a dose of 0.5 mg·g-1·day-1. 6 animals were in the placebo group. Euglycemic hyperinsulinemic clamps were performed at 5±2 and 14±2 days of life. Key molecules potentially altered by AICAR (AMPK, GLUT4, ACC, PEPCK, G6PASE, FBP1, and FOXO1), and the insulin signaling molecules: insulin receptor (INSR), insulin receptor substrate 1 (IRS-1), protein kinase B (AKT), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) were measured using RT-PCR and western blotting. AICAR infusion did not improve whole body insulin-stimulated glucose disposal in preterm baboons (12.8±2.4 vs 12.4±2.0 mg/(kg·min), p = 0.8, placebo vs AICAR). One animal developed complications during treatment. In skeletal muscle, AICAR infusion did not increase phosphorylation of ACC, AKT, or AMPK whereas it increased mRNA expression of ACACA (ACC), AKT, and PPARGC1A (PGC1α). In the liver, INSR, IRS1, G6PC3, AKT, PCK1, FOXO1, and FBP1 were unchanged, whereas PPARGC1A mRNA expression increased after AICAR infusion. This study provides evidence that AICAR does not improve insulin sensitivity in premature euglycemic baboons, and may have adverse effects.

A Phase I/II, Open-Label, Multicentre 2-Part Study to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of AZD2811 Nanoparticle As Monotherapy or in Combination in Treatment-Naïve or Relapsed/Refractory Acute Myeloid Leukaemia/Myelodysplastic Syndrome Patients Not Eligible for Intensive Induction Therapy

Background: Aurora kinases represent potential targets for anticancer therapy in solid tumors and hematological malignancies. In a phase I/II study, the aurora B kinase inhibitor AZD1152 (barasertib) showed benefit (35% CR/CRi) in patients (pts) with untreated AML when given as a 7-day continuous infusion (Lowenberg B et al, Blood 2011, Kantarjian HG et al., Cancer 2013). AZD2811 nanoparticle is a novel, encapsulated slow-release inhibitor of Aurora kinase B offering several advantages compared with AZD1152, including prolonged drug release in vivo. AZD2811 nanoparticle mimics the AZD1152 7-day continuous infusion when given as a 2-hr infusion on Day 1 and 4, and resulted in increased efficacy and decreased toxicity in vivo. We report the first-in-man dose-escalation of AZD2811 nanoparticle in pts with relapsed AML/MDS or treatment-naïve patients not eligible for intensive induction therapy. The objectives were to determine the safety profile, MTD, PK, dosing schedule and preliminary efficacy of AZD2811 nanoparticle. Methods: Patients received a single 2-hour IV infusion on Day 1 and 4 of each 28-day cycle. Based on the previous experience with AZD1152 in the same patient population, the expected MTD is in a range of 1,200 mg per cycle. In the ongoing dose escalation, cohorts of 3-6 patients have been sequentially enrolled in 4 cohorts ranging from 100 mg to 600 mg per infusion on Day 1 and 4 every 28 days, i.e. from 200 mg to 1,200 mg per cycle. Patients were allowed to continue to receive AZD2811 until disease progression, tolerability, or discontinuation criteria have been met. The study uses a Bayesian adaptive design approach to dose escalation to improve the efficiency and precision of the MTD estimation compared to a traditional 3+3 design. Results: Currently, 10 pts with age ranges from 56 to 86 years have completed DLT assessment period for the first 3 cohorts. 9 patients had relapsed/refractory secondary AML/MDS after failure of hypomethylating agents and 1 patient had a relapsed, therapy-related AML. Cohort 4 (600 mg per infusion D1 and D4) is currently under evaluation. Of the 10 pts in cohorts 1-3, 7 pts discontinued due to disease progression, 1 discontinued due to subject decision/consent withdrawal, 1 discontinued due to physician decision, and 1 pt is active and ongoing. AEs assessed as related to AZD2811 that occurred in one or more patients were Grade 3/4 neutropenia/thrombocytopenia, Grade 3 anemia and Grade 1 fatigue, rash and stomatitis. Thus far, no DLTs and no fatal AEs related to AZD2811 have been observed. 2 deaths have been reported, 1 due to the underlying disease and 1 due to a Serious Adverse Event of Gr 5 Sepsis (not related to study drug). AZD2811 total blood PK appears dose proportional with a t1/2 of 30-50 hours. Conclusion: AZD2811 nanoparticle is safe and well tolerated at a dose up to 400 mg on Day 1 and 4 every 28-days. The monotherapy dose escalation is ongoing and updated results including preliminary efficacy data and supporting preclinical data will be presented. Additional dose finding and expansion cohorts of AZD2811 nanoparticle in combination with azacytidine and venetoclax are planned. DisclosuresAtallah:Novartis: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Jazz: Consultancy; Pfizer: Consultancy. Charlton:AstraZeneca: Employment. MacDonald:AstraZeneca: Employment. Young:AstraZeneca: Employment. Sainsbury:AstraZeneca: Employment. Overend:AstraZeneca: Employment. Adelman:AstraZeneca: Employment. Travers:AstraZeneca: Employment. Smith:AstraZeneca: Employment. Pease:AstraZeneca: Employment. Brugger:AstraZeneca: Employment.

Zella 201: A Biomarker-Guided Phase II Study of Alvocidib Followed By Cytarabine and Mitoxantrone in MCL-1 Dependent Relapsed/Refractory Acute Myeloid Leukemia (AML)

BackgroundMultiple studies have shown the clinical activity of alvocidib followed by cytarabine and mitoxantrone in newly diagnosed and relapsed/refractory (R/R) AML. Alvocidib's anti-leukemic pharmacologic activity appears to be predominantly due to the inhibition of transcriptional regulator, CDK9, resulting in suppression of CDK9-regulated genes, such as the BCL-2 family member, MCL-1. Pre-treatment bone marrow samples from newly diagnosed AML patients revealed an increased sensitivity to alvocidib in those with MCL-1 dependence of ≥40% as measured by a BH3 profiling biomarker assay (J Clin Oncol 33, 2015 suppl; 7062). Thus, we hypothesized that alvocidib, followed by cytarabine and mitoxantrone, may be preferentially active in those with MCL-1 dependence (≥ 40%). Here, the findings from stage 1 of the Zella 201 trial in which this biomarker assay is used to select for patients with MCL-1 dependence, are reported.AimsTo evaluate the efficacy and safety of alvocidib, in combination with cytarabine and mitoxantrone, in MCL-1 dependent R/R AML patients.MethodsThe key eligibility criteria were: ages 18-65 years; refractory to 1-2 cycles of induction therapy, or in first relapse AML with complete remission (CR) duration ≤ 2 years; ≥ 40% myeloblast MCL-1 dependency determined by BH3 profiling; ECOG PS 0-2; and no major organ dysfunction. Patients who received prior allogeneic stem cell transplant (alloSCT) were eligible, if it was greater than two months after SCT and there was no active GVHD. Treatment consisted of alvocidib 30 mg/m2 as a 30-minute IV bolus followed by 60 mg/m2 over 4 hours on Days 1-3, cytarabine 667 mg/m2/day by continuous IV infusion days 6-8, and mitoxantrone 40 mg/m2 IV on day 9 starting 12 hours after completing cytarabine. Up to 3 additional cycles of the same regimen (with or without mitoxantrone) were permittedin responders. The primary endpoint was the rate of CR+CR with incomplete recovery (CRi). Stage I was determined to be positive if ≥13 CRs were seenin the first 23 evaluable patients. Key secondary endpoints were overall survival, event-freesurvival, the combinedresponse rate and safety assessed by adverse events and laboratory results.ResultsA total of 163 patients were screened, of which 47 (29%) were determined to be MCL-1 dependent. Of these, 25 patients were enrolledin Stage 1 (Table 1), with 21 evaluable for response. Median MCL-1 dependence score was 55% (range: 41-98%). Of the 21 evaluable patients, 11 (52%) were refractory to frontline therapy (resistant disease or CR < 90d). The overall CR/CRi rate in evaluable patients was 62% (13/21) meeting the primary endpoint of stage 1. Seven out of 11 (64%) patients with primary refractory disease achieved a CR and five of these patients proceeded to an alloSCT. Overall, 10 patients received a post-study alloSCT. The most common NCI CTCAE ≥Grade 3treatment-emergent nonhematologic AEs noted in >1 patient in the safety population (n=25) were tumor lysis syndrome (20% Grade 3, 8% Grade 4); diarrhea (24% Grade 3); increased AST (12% Grade 3, 8% Grade 4), sepsis (16% Grade 5, 4% Grade 4); and peripheral edema, (8% Grade 3). To date, overall 30- and 60-day mortality rates were 16% and 20%, respectively, due to sepsis (n=4), and mitral valve rupture (n=1).ConclusionOur findings indicate that alvocidib given beforecytarabine and mitoxantrone in MCL-1-dependent AML has clinical activity, particularly in those refractory to frontline therapy. Given these findings, stage 2 of the Zella 201 trial has been initiated,randomizing patients to alvocidib, cytarabine, and mitoxantrone versus cytarabine and mitoxantrone alone in MCL-1 dependent R/R AML. Furthermore, a Phase Ib study of alvocidib followed by 7+3 induction in newly diagnosed AML (Zella 101) is being conducted. DisclosuresZeidner:Rafael Pharmaceuticals: Other: Travel Fees; Takeda: Other: Travel fees, Research Funding; Merck: Research Funding; Asystbio Laboratories: Consultancy; Tolero: Honoraria, Other: Travel Fees, Research Funding; Celgene: Honoraria. Lin:Jazz Pharmaceuticals: Honoraria. Wang:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Amgen: Consultancy. Levy:Takeda (Millennium Pharmaceuticals, Inc.): Consultancy. Montesinos:Daiichi Sankyo: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Anthony:Tolero Pharmaceuticals, Inc: Employment. Bearss:Tolero Pharmaceuticals, Inc: Employment.