bluuebunny/crossref_metadata_2025_split huggingface dataset:
PS1289 THE ATYPICAL LYMPHOCYTE COUNT: A NOVEL PREDICTIVE FACTOR FOR SEVERE DENGUE INFECTION
Authors: Abeysuriya V. , Choong C. , de Mel S. , Thilakawardana B.U. , de Mel P. , Shalindi M. , de Mel C. , Chandrasena L. , Seneviratne S.L. , Yap E.‐S. 
Published: June 2019

Background:Dengue haemorrhagic fever (DHF) and Dengue Shock Syndrome (DSS) are life threatening complications of DI which occur in a minority of patients. The early identification of these individuals is critical to guide clinical management. There is currently no validated laboratory test which can predict severe complications of DI. The Atypical lymphocyte count (ALC) is a research parameter generated on Sysmex FBC analysers which has been correlated with the presence of circulating atypical lymphocytes (AL). Pilot studies have suggested that the presence of AL may be associated with severe DI.Aims:We evaluated the utility of the ALC as a predictive factor for severe dengue related thrombocytopaenia as well as DHF and DSS.Methods:We prospectively collected data on patients admitted to Nawaloka Hospital Sri Lanka (NH) with DI between December 2016 and August 2018. DI was diagnosed based on a positive Non‐structural antigen 1 or dengue IgM antibody. ALC data were extracted from the Sysmex XS500i automated FBC analyzer from day of admission to day seven. Clinical data was recorded from medical records and the computerized data base maintained by NH. Statistical analyses were performed using SPSS version 20.Results:201 patients were included in the study. DSS and DHF occurred in 6.5% (n = 13) and 6% (n = 12) of patients respectively. Patients with DHF and DSS as well as those with low Glasgow Coma Scale and respiratory compromise had a higher mean ALC on each day of FBC assessment compared to those without these complications. We detected a statistically significant negative correlation between the ALC on admission and platelet count on days five to seven (the period during which nadir thrombocytopaenia is expected in DI). [Spearmen's correlation; Day 5:‐0.485, Day 6:‐0.428, and Day 7:‐0.344] (P = 0.001) We performed Receiver Operator Curve (ROC) analysis to determine the predictive value of an admission ALC more than 0.5x 103/L for severe thrombocytopaenia (defined as a platelet count less than 50 x 109/l) on day five. We found that this ALC cut off had 90% sensitivity and 70% specificity for severe thrombocytopaenia on day 5. The positive and negative predictive values were 74.4% and 91.2% respectively. We also showed that patients with cardiac and abdominal ultrasonographic abnormalities had a higher mean ALC.Summary/Conclusion:We propose that an admission ALC of greater than 0.5 x 103/L has a strong predictive value for severe thrombocytopaenia on days five to seven of DI. Our data also suggest that a higher ALC on admission maybe predictive for severe DI. ALC on admission maybe a valuable modality for early identification of patients at risk of severe dengue related complications.image
PS1336 DISCREPANCE OF ALLELIC BURDEN CHANGES AND CLINICAL RESPONSE IN PATIENTS WITH HIGHER RISK MYELODYSPLASTIC SYNDROME TREATED WITH HYPOMETHYLATING AGENTS
Authors: Moon J.H. , Cho H.J. , Baek D.W. , Ahn J.‐S. , Ahn S.‐Y. , Choi S.H. , Kim T. , Zhang Z. , Sohn S.K. , Kim D.D. H. , Kim H.‐J. 
Published: June 2019

Background:Hypomethylating agents (HMAs) such as azacitidine (AZA) and decitabine (DEC) are used to treat higher risk myelodysplastic syndrome (HR‐MDS). However, underlying genetics and allelic burden change after HMAs needs to be clarified.Aims:This study investigated the effects of alleleic burden changes on the clinical outcomes after treatment with HMAs.Methods:This study included bone marrow samples from 64 patients (34 AZA and 30 DEC) taken at diagnosis and follow‐up after median 4 cycles. Targeted deep sequencing on a custom myeloid gene panel of 84 genes (Agilent SureSelect) was performed on trios of T‐cell, pre‐HMA, and post‐HMA samples on 64 HR‐MDS patients.Results:At diagnosis, we detected 135 mutations from 54 patients. Most frequently mutated genes were TP53 (n = 9), DNMT3A (n = 7), ASXL1 (n = 7), DDX41 (n = 7) and U2AF1 (n = 6). HMAs were administered median 4 cycles (range 1–14). At follow‐up, allelic burdens were decreased from median 13.7% (range 1.5–87.7) to 1.7% (range 0.0–49.4%), where from median 9.9% to 0.8% in AZA group (p < 0.001) and from median 17.8% to 6.7% in DEC group (p = 0.005). CR/mCR rate were higher in patients with allelic burden reduction <2% (n = 26/43, 60%) than those without (24%, n = 5/21), but not significantly different (p = 0.765). With median follow‐up duration of 19.3 months (range 0.2–99.6 months), 2‐year overall survival (OS) rates were 54.6 ± 8.1% and 44.8 ± 11.3% in patients with and without allelic burden reduction, respectively (p = 0.907). The presence of TP53 mutations did not affect the achievement of CR/mCR (p = 0.379). However, the presence of TP53 mutations were associated with inferior OS rates: 2‐year OS rates of 56.5 ± 7.2% and 22.2 ± 13.9% (p = 0.001). In the multivariate analysis, IPSS high (HR 5.34) and the presence of TP53 mutations (HR 3.42) affected adversely on OS, while the achievement of CR/mCR (HR 0.23) and the performance of allogeneic transplantation (HR 0.33) were favorable factors for OS.Summary/Conclusion:This study showed that allelic burden is decreased after treatment with both azacitidine and decitabine in HR‐MDS patients. However, the allelic burden reduction is independent to the achievement of CR and OS. The presence of TP53 mutation remained independent prognostic factor in HR‐MDS patients treated with HMAs, even with decreased allelic burden.
PS1365 NEXT‐GENERATION OPTICAL MAPPING REVEALS LARGE GENETIC HETEROGENEITY IN MULTIPLE MYELOMA
Authors: Petrackova A. , Fillerova R. , Minarik J. , Mikulkova Z. , Balcarkova J. , Krhovska P. , Pika T. , Gajdos P. , Behalek M. , Papajik T. , Kriegova E. 
Published: June 2019

Background:Genetic heterogeneity in multiple myeloma (MM) affects not only the disease development but also therapeutic response and prognosis. Nowadays, karyotype and FISH are standard diagnostic tools for the detection of genetic aberrations in MM. However, comprehensive analysis of genome architecture, particularly structural variations (SVs), still remain a challenge.Aims:To study the genomic architecture of MM cells using a novel nanochannel technology based on optical mapping of high‐molecular weight DNA in order to refine genomic variability in human MM.Methods:We analysed five samples of bone marrow aspirates from patients with newly diagnosed MM. High‐molecular weight DNA was isolated from sorted MM cells, labelled by DLS chemistry and visualised by Saphyr optical system (BioNano Genomics). Created single molecules were de novo assembled into physical maps spanning whole genome based on known labelled specific motifs. After filtering of structural variants against the database of healthy controls, only rare de novo variants were analysed. Karyotype, FISH, and arrayCGH results were available for the enrolled patients and were compared to the results of optical mapping.Results:For all MM samples, the optical genome maps (480 Gbp) were assembled with an average effective coverage of 124X and aligned to a human reference genome (GRCh38). In our cohort, numerous copy number variations and large somatic SVs, including deletions, insertions, inversions, duplications and translocations, were identified (Table 1) with majority of SVs being deletions (∼60%). All genetic variants detected by arrayCGH were also confirmed by mapping. Additional SVs with novel intra‐ and inter‐chromosomal translocations and copy number variants were found in all patients, not detected by FISH/arrayCGH. Regarding novel translocations, majority were intra‐chromosomal (64%) within chromosomes 3, 4, 6, 14, 16, 17, and 18. Additional translocations (36%), detected only by mapping, involved unusual chromosomes in MM: t(2;8), t(3;6), t(3;12), t(6;8), t(6;17), t(8;9), and t(8;22). All samples carried novel SVs on chromosome 17, including two intra‐ (P1) and one inter‐chromosomal translocations (P2), insertions in four (P2‐P5) and deletions in two (P4‐P5) patients. Although no IGH locus rearrangements were detected by standard methods, monosomy on chromosome 14 within IGH locus was observed in four samples (P2‐P5) by mapping. The analyses of associations of SVs and affected genes with clinical characteristics are ongoing.Summary/Conclusion:A large spectrum of novel genomic rearrangements was detected in MM using next‐generation mapping technology, showing a high potential of optical maps for refinement of genomic variability in human MM.imageGrant support: research grant Celgene, MZ ČR VES16–32339A, NV18–03–00500, MZ ČR – RVO (FNOl, 00098892)
PS1369 AMITRIPTYLINE STRENGTHENS THE EFFECTS OF BORTEZOMIB AND MELPHALAN TREATMENT IN MULTIPLE MYELOMA BY INHIBITING ACID SPHINGOMYELINASE
Authors: Faict S. , Oudaert I. , De Veirman K. , Maes K. , Jacobs L. , De Bruyne E. , Swinnen J. , Schots R. , Fostier K. , Vandebroek I. , Vanderkerken K. , D’Auria L. , Menu E. 
Published: June 2019

Background:Malignant cells can adapt their lipid metabolism to attain higher rates of proliferation, and resist chemotherapy‐induced apoptosis.Aims:In this study, we aimed to identify the changes in lipid metabolism in multiple myeloma (MM) patients, and to further investigate the role of this altered metabolism in vitro.Methods:We performed a lipidomics analysis to compare plasma from MM patients to healthy controls. Based on these results, lipid spike‐in assays enabled us to evaluate effects on MM cell proliferation. Sphingomyelinase (SMase) content of MM cells and their exosomes was measured, before and after treatment with standard‐of‐care drugs, using an AmplexRed assay. We inhibited both neutral and acid SMase (ASM) in MM cells to evaluate effects on drug efficacy. Finally, we investigated whether MM exosomes rich in ASM are able to induce drug resistance in MM cells low in ASM.Results:Lipidomics analysis revealed that several ceramide species were significantly more present in MM patient plasma, while sphingomyelin seemed to be decreased. When adding ceramide in vitro to MM cells, we observed higher viability and proliferation. The increased ceramide/sphingomyelin ratio in plasma lead us to believe that the sphingomyelinase enzyme, which converts sphingomyelin into ceramide, was upregulated in MM cells. This was confirmed in BM samples, comparing CD138+ MM cells to the CD138‐ fraction. In the MM cell lines JJN3, OPM2, LP1 and U266, we observed an increased expression of acid and total SMase when treating these cells with melphalan or bortezomib for 24 h. Furthermore, we investigated whether MM exosomes were involved in the secretion and transfer of acid SMase. Interestingly, amitriptyline, an inhibitor of acid SMase, often prescribed in MM patients for neuropathic pain, increased the efficacy of both drugs in vitro, and also induced apoptosis in primary MM cells as a single agent.Summary/Conclusion:SMase is increased in primary MM cells and cell lines upon treatment with melphalan and bortezomib, while inhibiting this expression using amitriptyline leads to a higher efficacy of drug therapy.
PS1379 SAFETY AND EFFICACY OF ONCE‐WEEKLY CARFILZOMIB DOSING IN FRAIL PATIENTS: A SUBGROUP ANALYSIS FROM THE PHASE 3 A.R.R.O.W. STUDY
Authors: Mateos M.‐V. , Ludwig H. , Kumar S. , Rosenbaum C. , Huang M. , Goldrick A. , Blaedel J. , Dimopoulos M. 
Published: June 2019

Background:A.R.R.O.W. demonstrated superior progression‐free survival (PFS) with once‐weekly carfilzomib (K, 70 mg/m2) and dexamethasone (Kd70) vs twice‐weekly K (27 mg/m2) and dexamethasone (Kd27) in relapsed and refractory (RRMM) patients (pts), regardless of age. For a comprehensive measure of fitness, frailty scales were developed incorporating age, comorbidities, and functional status (Palumbo Blood 2015;125:2068–74; Facon Blood 2015;126:4239).Aims:Here, we assessed post‐hoc pt outcomes by frailty status.Methods:PFS and safety were assessed by treatment arm and a frailty algorithm which incorporated age, Charlson Comorbidity Index derived from medical history, and ECOG performance status; pts with frailty scores of 0, 1, or ≥2 were classified as fit, intermediate, or frail, respectively. PFS was assessed using the Kaplan‐Meier method. Safety was assessed in pts who received ≥1 treatment dose.Results:The distribution of pts by frailty status was generally balanced between treatment arms (Table). Once‐weekly Kd70 vs twice‐weekly Kd27 resulted in median PFS for fit, intermediate, and frail pts of 15.7 vs 5.7 months (hazard ratio [HR] 0.53 [95% confidence interval (CI), 0.33–0.86]), 11.1 vs 7.7 months (HR 0.81 [95% CI, 0.55–1.19]), and 10.3 vs 6.6 months (HR 0.76 [95% CI, 0.49–1.16]), respectively.Rates of grade ≥3 treatment‐emergent adverse events (TEAEs) of interest were similar between treatment arms across frailty subgroups (Table). In the once‐weekly Kd70 subgroups, there was no grade ≥3 peripheral neuropathy and grade ≥3 cardiac failure rates were ≤4%.Summary/Conclusion:Once‐weekly Kd70 resulted in PFS benefits vs twice‐weekly Kd27, regardless of frailty level. These results support weekly Kd70 as a treatment option for fit and frail RRMM pts.image
PS1402 OUTCOME IN TRANSPLANT ELIGIBLE PATIENTS WITH MULTIPLE MYELOMA IN LATIN AMERICA. AN INTERNATIONAL STUDY OF GELAMM
Authors: Peña C. , Schutz N.P. , Bove V. , Villano F. , Osorio R. , Chandía M. , Cardemil D. , Contreras C. , Contreras C.G. , Donoso J. , Espinoza M. , Gabriel L.R. , López‐Vidal H. , Rojas C. , Soto P. , Ochoa P. , Duarte P. , Remaggi G. , Yantorno S. , Corzo A. , Zabaljauregui S. , Shanley C. , Lopresti S. , Orlando S. , Verri V. , Quiroga L. , García C.A. , Fernández V. , Fantl D. , Riva E. 
Published: June 2019

Background:Multiple myeloma (MM) is a frequent hematologic malignancy. Despite the important advances in treatment strategies during the last decades, the gold standard remains being a proteasome inhibitor (PI)‐based induction, followed by autologous stem cell transplant (ASCT).In Latin America (LA) there is great heterogeneity in access to new drugs and ASCT, and there is scarce data regarding patient́s outcomes in the region.Aims:The aim of this study was to describe clinical characteristics and outcomes of MM transplant eligible patients in LA countries.Methods:Retrospective international multicenter cohort study. Unselected consecutive MM transplant‐ eligible patients diagnosed between 2010 and 2018 from participating centers in Chile, Argentina and Uruguay were included. Data was collected from clinical records in a standardized report form. We analyzed clinical characteristics at diagnosis and frontline therapy outcomes, including ASCT.Transplant‐eligible patients were defined as fit patients younger than 66 years old. Response to treatment was defined according to current IMWG criteria.Statistical analysis was performed by using STATA 13.Results:Six hundred and seventy one patients were included in the study, 282 from Chile, 258 from Argentina and 131 from Uruguay. The main characteristics are shown in Table 1. Significant differences in access to PI induction and ASCT were found between private and public institutions, with patients from the latter receiving suboptimal frontline therapy. Optimal response (sCR, CR and VGPR) was achieved in 51% of the patients in the CyBorD group, in 65% in the VTD group, and in 45% in the CTD group, the 3 main induction regimens used. Only 52% of patients finally underwent ASCT. With a median follow up of 33 months (range 1–109), 5 year overall survival (OS) was 58,4%, with a median survival of 73 months in the whole cohort. When analyzed according to induction treatment, 5 year OS was 74% for PI‐based, 48% for thalidomide‐based, and 23% for those not treated with novel agents (P < 0,0001). In the multivariable analysis, not undergoing ASCT (p < 0,001), renal failure (p = 0,004), hypercalcemia (p = 0,001), and achieving less than VGPR (p = 0,001) response were independent factors associated with worse outcome.Summary/Conclusion:Survival in transplant‐eligible patients is lower than the “optimal” described survival in other regions. Unequal access to PI‐based regimens and therefore to ASCT between public and private centers was observed. Reasons for 48% of candidates not being transplanted merit further analysis.image
PS1406 WEEKLY CARFILZOMIB, LENALIDOMIDE AND DEXAMETHASONE UNTIL PROGRESSION IN RELAPSED REFRACTORY MULTIPLE MYELOMA
Authors: Gruchet C. , Richez V. , Guidez S. , Tomowiak C. , Fouquet G. , Machet A. , Moya N. , Sabirou F. , Levy A. , Bobin A. , Gardeney H. , Bouyer S. , Bridoux F. , Javaugue V. , Azais I. , Durand G. , Loiseau H. Avet , Leleu X. 
Published: June 2019

Background:Carfilzomib, Lenalidomide and Dexamethasone association (KRd) has led to approval in early RRMM. On ASPIRE International phase 3 study Carfilzomib was used on a twice a week basis at 27 mg/m2 and limited to 18 months exposure. We have reported already that KRd on a weekly basis at 56 mg/m2 had similar and safe properties. In this abstract we report the long‐term exposure data on KRd weekly given at 56 mg/m2 until progression.Aims:We aimed to evaluate the efficacy of KRd given on a prolong duration beyond 18months, and to validate the safety profile of continuous exposure to Carfilzomib.Methods:28 patients were prospectively recruited. Carfilzomib 20/56 mg/m2 was administered on days 1,8,15 on 28 days cycles. Lenalidomide (25 mg/day) was given 21/28 days and Dexamethasone was administered weekly. Patients were treated until progression.Results:With a median follow‐up at start of KRd of 30 months, 50% of patients relapsed and 39% died. 24/28 patients received 1 prior line of treatment. 8/28 patients are still on treatment with duration > 24 month and 6/28 with duration > 30 months. The median number of cycles was 15. ORR and CBR was 85.7% and 89.3%, whom 46% ≥ CR; with a median DOR of 13 months and 43% having more than 18 months. 6 patients had negative MRD at 10–6 and normalized PET CT. Median of OS is not reached, and the 30 month‐expected OS from the start of KRd was 56%. The median PFS and EFS was at 29 months, and the 30 month‐expected PFS and EFS was 45%. PFS and EFS being superimposable speaks to that there was no safety concern related to prolonged exposure to K. Only 4 patients stopped KRd for safety issues. Hematologic and non‐hematologic adverse events ≥ grade 3 were reported in 16/28 and 10/28 patients. Adverse events ≥ grade 3 seen in ≥10% of patients were neutropenia, thrombocytopenia, vomiting and pyrexia. Of note, 5 patients (18%) were 365 years old and these patients showed similar data compared to the studied cohort.Summary/Conclusion:KRd weekly at 20/56 mg/m2 is effective and safe to early RRMM patients, provides improved safety profile to patients allowing treating patients until progression. Further studies are warranted to confirm this data on a larger early RRMM population and validate the concept of long duration of treatment using Carfilzomib combination.
PS1412 POMALIDOMIDE 3RD LINE VERSUS 4TH LINE FOR IN EARLY RELAPSED REFRACTORY MULTIPLE MYELOMA
Authors: Gruchet C. , Guidez S. , Tomowiak C. , Fouquet G. , Machet A. , Moya N. , Sabirou F. , Levy A. , Bobin A. , Gardeney H. , Bouyer S. , Bridoux F. , Javaugue V. , Azais I. , Durand G. , Loiseau H. Avet , Leleu X. 
Published: June 2019

Background:Pomalidomide in association with dexamethasone is approved for relapsed and refractory Mutiple Myeloma (RRMM) in 3rd line and beyond based on the multicenter international phase 3MM‐003 study that demonstrated greater efficacy for Pomalidomide plus dexamethasone over high dose dexamethasone. However, MM‐003 mainly recruited RRMM with 5 prior lines +, and very few data are available regarding real life Pomalidomide‐based treatment in 3rd and 4th line RRMM.Aims:The aim of this study was to study efficacy and safety of Pomalidomide‐based treatment in 3rd and 4th line for RRMM.Methods:This study is a retrospective, multicenter study based on 108 consecutive RRMM treated with Pomalidomide‐based treatment in 3rd and 4th line. All assessment made according to IMWG.Results:Median age was 62.5 (range, 30–86), with 36% older than 65 years, sex ratio M/F 1.25 and ISS disease stage 2 or 3 in 58%. 100% patients received previous treatment with Bortezomib and Lenalidomide and 34,2% had previously an autologous stem cell transplantation. 52 patients (48%) had pomalidomide‐based therapy as 3rd, and 56 (52%) as 4th line. 74% of patients received a double‐based therapy (Pomalidomide plus Dexamethasone) and 26% received a triple based therapy (Pomalidomide, Cyclophosphamide and Dexamethasone). Overall ORR was 55%, with 25% more than VGPR including 3 complete response with Pomalidomide‐based as 3rd line. ORR was 53% with 16% ≥ VGPR including 1 CR for Pomalidomide‐based as 4th line. With a median follow‐up of 24 months, 58% and 48% at relapsed and died, respectively, in 3rd line, and similarly, 74% and 50% in 4th line. The median TTP was 7 (CI95% 1.4;12.6) and 9 (6.1;11.9) months in 3rd and 4th line, and the median OS 17 (7.8;26.1) and 23 (12.6;33.4) months, respectively. 22% and 30% have discontinued and reduced pomalidomide‐based treatment respectively. No patient died related to adverse events. AEs leading to pomalidomide‐based modification in schema included hematological AEs in 40% and non‐hematological AEs in 12% of patients. Overall, the most common adverse events grade 3 or 4 were neutropenia (22%), anemia (11%), thrombocytopenia (7%) and infectious disease (5%).Summary/Conclusion:Pomalidomide‐based therapy demonstrates efficacy in the real life with a manageable safety profile. Further study ill look into triplet versus doublet pomalidomide‐based regimen, with a benefit expected for the former. Further prospective studies are warranted to confirm this data on a larger MM population.
PS1478 EVALUATION OF COMBINED MEASUREMENT OF IMMATURE PLATELET FRACTION AND SCHISTOCYTES IN PREGNANCY‐ASSOCIATED THROMBOTIC THROMBOCYTOPENIC PURPURA AND SEVERE PREECLAMPSIA/ HELLP SYNDROME
Authors: Fayek M. , Mekawy M. , El‐Gamal R. , Abdelkader A. , Abdelbary H. 
Published: June 2019

Background:The occurrence of thrombotic microangiopathy (TMA) in pregnancy is an unfortunate emergency condition. Proper diagnosis is mandatory which requires the consideration of two overlapping diagnoses: severe preeclampsia/ haemolysis, elevated liver enzymes, and low platelet syndrome (SPE/HELLP) and thrombotic thrombocytopenic purpura (TTP). The long turn‐around times of ADAMTS13 testing precludes the timely distinction between the two conditions.Aims:We aimed at evaluating schistocyte counts and immature platelet fraction (IPF%), as both increase in TMAs, to discriminate between TTP and SPE/HELLP of pregnancy.Methods:IPF% was measured using SysmexXE‐2100 automated hematology analyzer, and schistocyte counts were estimated microscopically as per the International Council for Standardization in Hematology (ICSH)‐Schistocyte Working Group guidelines. The study included 30 pregnant patients with SPE/HELLP, 13 pregnant patients with TTP, and 30 women with normal pregnancy. The discrimination between the two patient categories was based on clinical judgment and TTP cases were identified using the PLASMIC score.Results:TTP patients had higher values of IPF% than SPE/HELLP 19.5 (16.9–27.1) vs 13 (9.5 – 23.25); p <0.001); similar results were revealed regarding schistocyte counts 6.5 (3.9–8.6) vs 2.1 (1.6 – 3.5); p <0.001). IPF% and schistocyte counts were able to discriminate between TMA patients and normal pregnant women, and between and SPE/HELLP and TTP patients. Moreover, the discriminatory function of each was improved when the two parameters were used in combination.Summary/Conclusion:IPF% analysis should be used in conjunction with manual schistocyte counting in TMA cases to distinguish TTP pregnant patients from patients having SPE/HELLP.