bluuebunny/crossref_metadata_2025_split huggingface dataset:
PS1151 PHASE 2 STUDY OF ACALABRUTINIB IN IBRUTINIB‐INTOLERANT PATIENTS WITH RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: Rogers K. , Thompson P.A. , Allan J.N. , Coleman M. , Sharman J.P. , Cheson B.D. , Izumi R. , Frigualt M.M. , Quah C. , Raman R.K. , Wang M.H. , Kipps T.J. 
Published: June 2019

Background:In patients with chronic lymphocytic leukemia (CLL) treated with the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, intolerance was the most common reason for discontinuation (50% to 63%; Mato AR, et al. Haematologica. 2018).Aims:This Phase 2 trial evaluated acalabrutinib, a highly selective, potent, covalent BTK inhibitor, in ibrutinib‐intolerant patients with relapsed/refractory CLL.Methods:Patients with relapsed/refractory CLL (≥1 prior therapy) who discontinued ibrutinib due to Grade 3/4 adverse events or persistent/recurrent Grade 2 adverse events and had progressive disease after ibrutinib discontinuation were eligible. Acalabrutinib was given orally at 100 mg twice daily in 28‐day cycles until progressive disease or unacceptable toxicity. The primary endpoint was overall response rate (ORR).Results:Sixty patients were treated. The median age was 70 years (range, 43 to 88). Patient characteristics included bulky disease ≥5 cm (33%), Rai stage III/IV (47%), del17p (28%), del11q (23%), and unmutated IGHV (79%). Fifty‐two of 55 patients (95%) with available baseline samples were wild type for BTK and PLCG2. The median number of prior therapies was 2 (range, 1 to 10). The median duration of prior ibrutinib therapy was 6 months (range, <1 to 55); common adverse events that led to ibrutinib discontinuation were atrial fibrillation/flutter (25%), diarrhea (12%), arthralgia (10%), and rash (12%). At a median follow‐up of 19 months (range, 1 to 31), 67% of patients remain on acalabrutinib; discontinuations were mostly due to progressive disease (13%) and adverse events (10%; pneumonia [n = 2], diarrhea, headache, ascites, arthralgia, subdural hematoma [all n = 1]). Efficacy outcomes are in the Table. Common adverse events (any grade) were diarrhea (48%), headache (40%), contusion (35%), and dizziness (32%). Serious adverse events (≥2 patients) were pneumonia (10%), anemia (3%), and syncope (3%). Atrial fibrillation occurred in 3 patients (5%; all Grade 1/2) and major hemorrhage in 2 (3%; Grade 3 hematuria and Grade 2 subdural hematoma). Grade 5 adverse events were pneumonia (n = 2), bronchopulmonary aspergillosis (n = 1), and ventricular fibrillation (n = 1); all were considered not related to treatment.Summary/Conclusion:Acalabrutinib is tolerable and effective in ibrutinib‐intolerant patients, providing a viable strategy for continuing BTK inhibitor therapy.image
PS1199 SCREENING FOR HEREDITARY SPHEROCYTOSIS IN DAILY PRACTICE: WHICH IS THE BEST ALGORITHM USING ERYTHROCYTE AND RETICULOCYTE PARAMETERS?
Authors: Adam A.‐S. , Gulbis B. , Cotton F. 
Published: June 2019

Background:Hereditary spherocytosis (HS) is the most common inherited chronic haemolytic anemia in Northern Europe. Its prevalence is estimated to 1 in every 2000 births. The actual guidelines for the screening and diagnosis of HS are based on clinical and family histories, physical examination and laboratory findings. Additional parameters based on complete blood count (CBC) and reticulocyte parameters have been developed on haematology analyzers leading to many publications about their effectiveness as HS screening tool.Aims:We evaluated and compared the effectiveness of four published algorithms for the screening of HS using two haematology analyzers i.e. the UniCel DxH800 (DxH; Beckman‐Coulter, Miami, FL) and the XN‐9000 (XN; Sysmex, Kobe, Japan) and determined which algorithm could be the most suitable in our daily clinical practice.Methods:A total of 96 EDTA samples obtained for HS screening were analyzed prospectively on both haematology analyzers and a CBC with extended reticulocyte parameters were collected. These included 12 confirmed HS patients and 84 non‐HS patients. The diagnosis of HS was based on clinical and family histories, cryohaemolysis test, eosin‐5’‐maleimide (EMA) dye binding test, ektacytometry and identification of the defective protein. The specific reticulocyte parameters used on the DxH800 were mean reticulocyte volume (MRV), immature reticulocyte fraction (IRF) and mean sphered cell volume (MSCV), and on the XN‐9000 were hypohaemoglobinized erythrocytes (Hypo‐He), microcytic erythrocytes (MicroR) and IRF. For each algorithm, we established sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV).Results:The results are reported in Table 1. The only algorithm that provided a sensitivity of 100% was the algorithm published by Lazarova et al. in 2014 using the DxH800. The three algorithms published based on the Sysmex parameters showed much lower performances than the one based on the DxH800 parameters i.e. out of the 96 patients with HS, between 2 to 6 patients were screened as negative for HS. Three of the published algorithms were evaluated on a previous XE model i.e. XE‐5000, mode of HS diagnosis is not always comparable as well as the amount of patients involved in the different studies.Table 1: Performance characteristics of the different algorithms (original stated performance characteristics) tested prospectively on 12 HS and 84 non‐HS patients.Summary/Conclusion:To screen for HS in the daily practice, the extended reticulocyte parameters provided by the Sysmex analyzers seem promising but the clinical cut‐offs on the XN‐9000 should be reevaluated on a larger number of patients.image
PS1210 DEVELOPMENT OF A NEXT GENERATION ALLOGENEIC CAR‐T CELL PLATFORM WITHOUT GENE EDITING
Authors: Sotiropoulou P.A. , Michaux A. , Raitano S. , Bornschein S. , Bolsée J. , Lenger S.R. , Machado H.B. , Moore J.D. , Gilham D.E. 
Published: June 2019

Background:Autologous CAR‐T cell therapy is now a proven breakthrough technology in the treatment of B cell malignancies and holds promise in the therapy of all types of cancer. However, autologous CAR‐T cell therapy does have significant challenges relating to logistics and product consistency. Allogeneic CAR‐T therapeutic products could allow treatment of multiple patients with cells from the same healthy donor, increasing product consistency, likely reducing manufacturing costs and avoiding the time delay required to generate an autologous T cell product.Aims:Allogeneic CAR‐T cell therapy is dependent upon eliminating the activity of the endogenous T Cell Receptor (TCR) within the engineered T cell, thereby preventing the induction of a graft versus host response and resultant potentially life‐threatening toxicity. We have explored RNA interference to modulate the TCR and to assess the potential of short hairpin RNA (shRNA) as a platform technology for Allogeneic CAR T cell therapy.Methods:shRNAs targeting the CD3ε and CD3ζ chains of the TCR complex were expressed in primary T cells where the efficacy of the individual shRNAs to downregulate the CD3 component and subsequent impact upon TCR expression assessed. The optimal shRNAs were tested in a head to head fashion against the state‐of‐the‐art gene editing technology, CRISPR‐Cas9, in vitro for response against mitogenic stimulation and in animal models for control of xenoGvHD.Results:shRNAs specific for CD3ε and CD3ζ reduced the transcriptional expression of their relevant targets, as well as the cell surface expression of the TCR. Downregulation of TCR expression and inhibition of the in vitro mitogenic response when challenged with anti‐CD3 antibodies was similar between shRNAs and CRISP‐Cas9 targeting CD3ζ. Importantly, in vivo experiments with T cells adoptively transferred to NSG mice showed that shRNAs targeting CD3ζ protected animals from GvHD, while T cell persistence was significantly higher compared to T cells genetically engineered with CRISP‐Cas9 targeting CD3ζ.Summary/Conclusion:This work demonstrates that the expression of shRNA in a standard retroviral vector provides a one‐step solution to produce cells suitable for Allogeneic CAR T cell therapy. Our testing continues, involving the examination of the anti‐tumor potency of such shRNA‐Allo CAR‐T cells. Importantly, this approach provides a one vector solution that offers an alternative to strategies such as gene editing to eliminate the TCR, while also requiring no major alteration to current CAR‐T cell manufacturing, that should enable the rapid adoption of the approach into clinical testing.
PS1249 EXTRANODAL AND SPLEEN DISEASE DETECTED BY FDG‐PET/CT IS ASSOCIATED WITH EARLY CLINICAL FAILURE IN UNTREATED FOLLICULAR LYMPHOMA
Authors: St‐Pierre F. , Broski S. , Laplant B. , Ristow K. , Maurer M. , Macon W. , Habermann T. , Ansell S. , Thompson C. , Micallef I. , Nowakowski G. , Witzig T. 
Published: June 2019

Background:Predicting early clinical failure in patients with untreated follicular lymphoma (FL) is important but difficult. Lymphoma involvement of extranodal (EN) sites is better detected by FDG‐PET/CT than CT alone, but PET parameters are not part of the usual predictive indices.Aims:We aimed to determine the incidence and patterns of EN and spleen disease, and learn if they were useful in predicting early clinical failure.Methods:PET/CT images from 613 cases of newly diagnosed FL between 2003 – 2016 were retrospectively reviewed for EN and spleen involvement. The location, number, and pattern of EN sites, as well as splenic involvement, were recorded. Associations with outcomes were assessed using event‐free survival (EFS), overall survival (OS), and early clinical failure at 24 months (EFS24).Results:49% (301/613) of patients had PET/CT‐detected EN involvement, and 28% (171/613) had spleen involvement. Presence of ≥2 EN sites, spleen, bone or soft tissue involvement all predicted failure to achieve EFS24. These factors, as well as pattern of bone involvement by imaging, were predictors of EFS on univariate analysis; presence of ≥2 EN sites and bone involvement pattern were also predictive of OS. In a multivariate analysis with FLIPI‐2 factors, spleen involvement, pattern of bone involvement, and soft tissue involvement independently predicted a lower EFS (Table 1). When the multivariate analysis was performed using PRIMA‐PI factors (marrow and B2 M), the presence of ≥2 EN sites was an adverse independent prognostic factor for OS (HR 2.28; 95% CI 1.01–5.18; p = 0.05).Table 1: Extranodal and spleen involvement by PET/CT as predictors of event‐free survival
Summary/Conclusion:Baseline PET/CT identifies EN and spleen sites of disease that can predict early clinical failure in FL. These results, when combined with other factors, may better identify high‐risk patients and guide appropriate therapy.imageimage
PS1271 PREDICTORS, RATES AND COSTS ASSOCIATED WITH READMISSION FOR CLOSTRIDIUM DIFFICILE INFECTION WITHIN 90 DAYS OF HEMATOPOIETIC STEM CELL TRANSPLANTATION: INSIGHT FROM THE NATIONWIDE READMISSION DATABASE
Authors: Elsabbagh E.M. , Hageman J. 
Published: June 2019

Background:Clostridium difficile infection (CDI) is a common and serious disease attributable to substantial morbidity, and mortality following the bone marrow transplant in pediatric population. Rates of readmission, during the first 3‐month follow‐up are poorly characterized.Aims:We aimed to identify rates, predictors and hospitalization cost of CDI readmission after Hematopoietic Stem Cell Transplant (HSCT) using the Nationwide Readmission Database (HCUP‐NRD)Methods:Using administrative claim codes for CDI in the 2014 Nationwide Readmission Database, pediatric patients admitted after HSCT with at least 3 months of follow‐up were included for analysis. Patients were stratified according to HSCT type, either Umbilical Cord Blood Transplant (UCBT) or Bone Marrow Transplant (BMT) which was further stratified into autologous and allogenic transplantation, then evaluated for CDI readmission through day 90.Results:A total of 2057 pediatric patients met the inclusion criteria, including 2.2 % that received UCBT, 97.8% that received BMT. All‐causes readmission rate was 65% (1338/2057) and CDI readmission rate was 4.7% (63/1338). The mean age was 4 years, 71.4% were male, mean length of stay was 12.9 days and the median time lapsed after transplant discharge and CDI readmission was 52 days. Medicaid was the most common payer at 54.7%. The median cost per CDI admission was $67999 with net total cost $12.2 million. The respective rates of CDI 90‐day readmission according to transplant type were 11.5% for UCBT and 88.5% for BMT (p < 0.001). The most frequent diagnosis associated with CDI readmission in the first 90 days was neuroblastoma (19.5%; p < .001)Summary/Conclusion:Conclusion(s): (1) Among pediatric patients treated with HSCT, CDI 90‐day readmission rate is significant and associated with significant high cost. (2) The most common diagnosis associated with high burden of CDI 90day readmission was neuroblastoma. (3) Additional study is warranted to evaluate factors that may lead to decreased rate of CDI readmissions following HSCT
PS1280 FUNGAL INFECTIONS IN ACUTE MYELOID LEUKEMIA IN THE POSACONAZOLE ERA
Authors: Marini C. , Baldaia A. , Chorão P. , Bergantim R. , Aguiar E. , Cancela J. , Trigo F. , Guimarães J.E. 
Published: June 2019

Background:Posaconazole prophylaxis in patients with acute myeloid leukaemia (AML) changed the paradigm of fungal infections (FI).Aims:Description of FI and analysis of factors that might predispose to this type of infection in non‐allotransplant AML patients in the posaconazole era.Methods:Retrospective analysis of 144 consecutive non‐M3 AML patients diagnosed between January 2012 and June 2018 in a tertiary center and treated with intensive chemotherapy regimens with posaconazole prophylaxis, including autologous transplantation when performed in these patients. Multivariate regression analysis was performed to identify characteristics related to FI.Results:Median age at diagnosis was 52 years [19;71], 52% were females and 90% had an age‐adjusted Charlson score ≤3. Genetic risk group according to the European Leukemia Net 2017 classification was favourable in 28%, intermediate in 41% and adverse in 22%. Fourteen percent of patients (n = 20) had secondary AML. Patients were included since diagnosis and if completed remission‐induction intensive therapy up to transplant referral, the latter which occurred in 52% of patients (n = 75), with a median follow‐up of 7 months [1;81]. Only 7 patients had 1 episode of prophylaxis interruption, 3 due to mucositis and 4 out of our protocol. Median time of neutropenia per cycle was 26 days [5;180] and 10% of patients had >2 episodes of prolonged neutropenia (defined as ≥28 consecutive days of <500 neutrophils/microliter).Fungal infections were identified in 25 patients (17.4%) and classified according to EORTC criteria, with 5 proven, 13 probable and 7 possible infections. In 32% of patients FI occurred during remission‐induction (n = 8) of which 3 were diagnosed in the first week of neutropenia, 20% during consolidation treatment in first remission and 48% during relapse treatment. Of the confirmed infections, 3 were aspergillosis and 2 candidemia. Probable infections had pulmonary origin with no microbiology isolate or serologic positivity but identified by typical radiologic evidence; of these, broncho‐alveolar lavage and/or pulmonary biopsy was performed in 4 patients (31%) with negative results. For possible infections, antifungal therapy was initiated in a pre‐emptive manner for high risk patients with persistent fever despite large spectrum antibiotics.In a multivariate analysis, patients with FI had a higher odds of having relapsed AML and >2 episodes of prolonged neutropenia during treatment (p = 0.049 and p = 0.011, respectively). There was no mortality related to FI in this cohort of patients.Summary/Conclusion:Despite posaconazole prophylaxis, FI is still prevalent in AML patients. Infection during salvage treatment for relapsed disease and >2 previous periods of neutropenia exceeding 4 weeks should raise awareness for an increased risk of FI.
PS1295 IRON IN THE HUMAN HEARTS: DISTRIBUTION AND ASSOCIATION WITH R2∗ VALUES BY CMR
Authors: Meloni A. , Maggio A. , Positano V. , Angelini A. , Putti M.C. , Maresi E. , Pucci A. , Basso C. , Leto F. , Perazzolo M. , Pistoia L. , Pepe A. 
Published: June 2019

Background:T2∗ (or R2∗ = 1000/T2∗) cardiac magnetic resonance (CMR) allows the non‐invasive and reproducible measurement of myocardial iron and has been established as fundamental to the best practice management of iron loaded patients to improve morbidity and mortality.Aims:In the present study we calibrated cardiac R2∗ values against myocardial tissue ‐measured iron concentration by using a segmental approach and we assessed the distribution and regional variations in iron distribution.Methods:Five hearts of patients with thalassemia were donated after death (N = 4) or cardiac transplantation (N = 1) to the CoreLab of the MIOT (Myocardial Iron Overload in Thalassemia) Network. A multislice multiecho T2∗ approach was adopted. After CMR, used as guidance, the heart was cut in three short‐axis slice and each slice was cut into different equiangular segments accordingly with AHA segmentation and differentiated into endocardial and epicardial layer, the same ones in which the T2∗ was assessed. Tissue iron concentration in the segments was measured with an atomic absorption spectrometer.Results:55 samples were used since it was possible to analyze all the 16 samples only from two hearts due to medical‐forensic reasons. The mean iron concentration in all samples was 4.71 ± 4.67 mg/g dw. Segmental iron levels ranged from 0.24 to 13.78 mg/g dw. Mean iron concentration was significantly higher in the epicardial than in the endocardial layer (5.99 ± 6.01 mg/g dw vs 4.84 ± 4.87 mg/g dw; P = 0.042).The coefficient of variability (CoV) of iron for myocardial segments ranged from 8.08% to 24.54%, with a mean value for all patients of 13.49 ± 6.93%. Four different main circumferential regions (anterior, septal, inferior and lateral) were defined. A circumferential heterogeneity was noted, with more iron observed in the anterior region, followed by the inferior region. The heterogeneity in circumferential iron concentration expressed as percentage deviation of the regions from the global value is shown in the Figure 1A.A strong linear correlation (R‐square = 0.956) was found by plotting ln(R2∗‐ROI) and ln[Fe] with a slope s = 0.654 (95% confidence intervals‐CI = 0.616–0.693) and intercept i = 4.216 (95% CI = 4.150–4.281) (Figure 1B). The linear relation was converted to the calibration curve: [Fe] = 0.001591 X (R2∗)1.529.Summary/Conclusion:Our data suggests an heterogeneous pattern of cardiac iron distribution with higher epicardial layer involvement. Heart R2∗ provided a robust calibration against chemically assayed cardiac iron, further validating the current clinical practice of monitoring cardiac iron in vivo by CMR.image
PS1298 TISSUE IRON DISTRIBUTION IN PATIENTS WITH LOW‐RISK MDS
Authors: Grosse R. , Asemissen A.M. , Ganster C.G. , Starekova J. , Schafhausen P. , Schoennagel B. , Nielsen P. , Yamamura J. , Haase D. , Fischer R. 
Published: June 2019

Background:Iron accumulation occurs in MDS patients by upregulated iron absorption due to ineffective erythropoiesis with decreased hepcidin levels (Santini et al, 2011) and by chronic blood transfusion therapy. Elevated liver iron concentration (LIC) is regularly found in transfusion dependent patients. Abnormal cardiac iron (50–1) was observed in few studies and severe cardiac iron overload was almost not present although cardiac death appeared in 8% of deceased patients (Nachtkamp et al, 2016). Little is known about corresponding pancreatic iron and iron accumulation in the bone marrow. The release of NTBI in the bone marrow may directly affect hematopoiesis by oxidative stress (Porter et al, 2016).Aims:To compare the relationship of iron concentration and fat content in different organs in low ‐ risk MDS patients.Methods:We studied the iron accumulation in bone marrow, liver, spleen, pancreas and septal heart muscle in 14 mainly low‐risk MDS patients (age 39–87 y), partly transfused and chelated. Tissue iron concentration and fat content were assessed by magnetic resonance imaging (MRI ‐ R2∗) with 3D data acquisition at 3 Tesla using chemical shift relaxometry (Pfeifer et al, 2015).Results:About 50% of patients showed iron overload in the spleen, pancreas and vertebral bone marrow (VBM). Mean LIC (±SD) was found as 1.709 ± 0.914 mg/gliver (10.3 ± 5.5 mg/gdry weight). Patients with iron overload in the pancreas showed as well abnormal pancreatic fat contents (11–32%) and fasting glucose values (101–186 mg/dL). As expected, septal cardiac iron was normal for all patients. Bone marrow (VBM) iron was elevated in 8/14 patients (R2∗ = 149–330 s−1) with the highest R2∗ in a non‐chelated patient.Summary/Conclusion:The feasibility of multi‐organ iron and fat measurements by MRI in heart, liver, spleen, pancreas and bone marrow was shown in a small group of elderly MDS patients within a reasonable scan time (30 min).The iron concentration and fat content in different organs will contribute further information about disease process in low ‐ risk MDS patients, as well as success of iron chelation therapy.
PS1322 ASTX660, A NON‐PEPTIDOMIMETIC ANTAGONIST OF CIAP1/2 AND XIAP, INDUCES APOPTOSIS IN T CELL LYMPHOMA BY ENHANCING IMMUNE MEDIATED AND DEATH RECEPTOR DEPENDENT KILLING
Authors: Sims M. , Ward G. , Munck J. , Jueliger S. , Davis M. , Gewinner C. , Ferraldeschi R. , Lyons J. 
Published: June 2019

Background:ASTX660 is a potent, non‐peptidomimetic antagonist of the cellular and X‐linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), which is currently being tested in a first in human phase I‐II study in patients with advanced solid tumors and lymphomas (NCT02503423). IAP antagonists enhance tumor necrosis factor (TNF) receptor superfamily mediated apoptosis and are potent anti‐tumor immune enhancers.Aims:Herein, we describe the profile of ASTX660 in a range of T cell lymphoma (TCL) cell lines and evaluate ASTX660's ability to enhance immune mediated killing of tumor cells.Methods:A panel of human and mouse T‐cell lymphoma cell lines were tested in proliferation (Alamar blue or CellTiterGlo) or apoptosis assays (activated caspase‐3 substrate assays by IncuCyte or FACS) for sensitivity to ASTX660 alone or in combination with recombinant Death Receptor ligands (TNFα, FASL or TRAIL). Additionally, we used a novel co‐culture system of tumor cell lines with anti‐CD3 activated human peripheral blood mononuclear cells (PBMC) to assess ASTX660 effects on immune mediated cell killing. Target engagement and induction of apoptosis markers were analysed by Western blotting.Results:ASTX660 antagonises IAPs in TCL cell lines, as indicated by a decrease in cIAP1 protein levels. This ASTX660‐dependent decrease in cIAP was associated with an increase in TNFα‐dependent apoptosis in the EL4 and L5178 TCL cell lines. Several T‐cell lymphoma models, including HuT‐78, HH and My‐La expressed low levels of TNFR1 and therefore did not respond to ASTX660 in the presence of TNFα. However, in these cell lines, ASTX660 conferred a significant increase in FASL or TRAIL‐dependent apoptosis, indicating that ASTX660 sensitises TCL cells to various death receptor ligands and response correlates with receptor expression levels. In addition to this direct effect on TCL cell lines, ASTX660 also enhances anti‐CD3 stimulated PBMC‐dependent killing of multiple tumour cell lines, including TCL lines, via induction of caspase activity. Additional preclinical experiments (both in vitro and in vivo) are underway to further characterise the mode of action of ASTX660 in TCL.Summary/Conclusion:The combination of both direct and indirect effects of ASTX660 on TCL lines, described here, supports the ongoing clinical testing of ASTX660 in TCL (NCT02503423). Preliminary clinical efficacy and safety data of ASTX660 in relapsed/refractory (r/r) peripheral T cell lymphoma and cutaneous T cell lymphoma is the subject of a separate abstract.