bluuebunny/crossref_metadata_2025_split huggingface dataset:
PS978 DISCOVERY OF NOVEL C/D BOX SNORNAS THAT ARE REQUIRED FOR LEUKEMIA CELL PROLIFERATION
Authors: Kienast A. , Rohde C. , Zhou F. , Liu Y. , Gerloff D. , Thiede C. , Pabst C. , Radtke F. , Zoller J. , Müller‐Tidow C. 
Published: June 2019

Background:The vast majority of the human genome is transcribed, but the function of many transcripts remain obscure. It is likely, that cancer specific transcripts exist that are overlooked by conventional pipeline analysis.Aims:We tried to identify novel non coding RNA transcripts with C/D box snoRNA properties based on sequence homology. We specifically analysed AML patient samplesMethods:To understand the role of snoRNAs in leukemogenesis, we analyzed the snoRNA expression pattern in an initial cohort of 63 AML patients (Zhou, 2017) and an additional cohort of 90 AML patients. Abundant regions with coverage were annotated using snoRNABase (LBME), the recently published updated snoRNAome (Jorjani, 2016) and tracks from ENSEMBL, UCSC, RNAcentral and DASHR databases. Regions without annotation were analyzed for C/D box motifs to discover putative C/D box snoRNAs. For further analysis only regions with at least one reads per million (RPM) in at least one patient sample were included.Results:Next generation sequencing data revealed that 248 of the 269 known C/D box snoRNAs (92%) were expressed in one or more patient samples. For the H/ACA box snoRNAs we could identify 103 of 112 (92%). In addition to this established functionally well annotated core‐set of C/D box snoRNA we confirmed another set of 76 C/D box snoRNA to be expressed in AML patient samples. These 76 snoRNA recently have been described as novel C/D‐box snoRNA based on the analysis of ENCODE small RNA‐seq data. Importantly, our in silico analysis identified 45 novel putative C/D box snoRNAs which had not been described so far. All of these putative C/D box snoRNAs contain the box C/D motifs and were mostly located in introns of known genes. In further analyses, we observed increased expression of putative snoRNAs was found in patients with intermediate molecular risk (7 snoRNAs, p≤0.05) and in patients with a poor response to chemotherapy (9 snoRNAs, p≤0.05). The novel snoRNAs were more prominently expressed in in NPM1 wildtype AML compared to NPM1 mutant AML. Overall, 13 putative C/D box snoRNA were downregulated during myeloid differentiation of HL60 cells. To study the function of the snoRNA we performed a CRISPR/Cas9 knockout of five regions in Kasumi1 and U937 cell lines. The knockout of four out of five novel snoRNAs impaired proliferation and colony growth.Summary/Conclusion:Multiple novel C/D box snoRNAs were identified from primary AML specimens. These show a specific expression pattern in myeloid differentiation in distinct AML subtypes. The functional relevance of these snoRNAs suggests that so far overlooked non coding RNA sequences are of high importance in AML.
PS1019 HIGH CYTOMEGALOVIRUS VIRUS LOAD INDUCES A POTENT TUMOR‐SPECIFIC CD8+ T CELL RESPONSE AND PROTECTS PATIENT IN ACUTE MYELOID LEUKEMIA FROM RELAPSE AFTER SINGLE CORD BLOOD TRANSPLANTATION
Authors: Dong M. , Sun Z. , Liu H. 
Published: June 2019

Background:Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality in hematopoietic stem cell transplantation (HSCT). Interestingly, in recent studies, CMV infections have been shown to have potential anti‐leukemia effects in acute myeloid leukemia (AML) patients after HSCT. However, studies of CMV infection on relapse after single cord blood transplantation (CBT) are limited, and the effect of the virus load on relapse has not been assessed.Aims:We hypothesize that the role of MCV on outcomes in CBT are related to virus load. In this study, we retrospectively analyzed the effect of CMV infection on two‐year outcomes in 151 patients with AML after CBT according to the virus load. Additionally, the mechanism of the possible interaction with lymphocyte subsets was also analyzed.Methods:We comparatively analyzed the outcomes of the high virus load group (CMV DNA copies ≥ 1 000/mL) and the low virus load group (CMV DNA copies <1 000/mL or negative CMV DNA copy) of two years after CBT. Furthermore, in order to explore the mechanism of CMV on relapse, a smaller cohort of 26 patients with immune reconstruction data at 1, 3, 6, 9 and 12 months after transplantation were simultaneously studied, and nine healthy physical examination populations were recruited as healthy controls.Results:The results showed that the high CMV virus load group had a lower two‐year cumulative incidence of relapse (Figure A, 2.2% vs. 15.2%, p = 0.008) without an increase in non‐relapse mortality (Figure B, 20.9% vs. 22.4%, p = 0.970) than the low CMV virus load group. Furthermore, the two groups had similar overall survivals (76.8% vs. 72.4%, p = 0.746). Moreover, the proportion and absolute number of CD8+ T cells were increased in the high CMV virus load group in different months after transplantation (Figure C and D).Summary/Conclusion:In conclusion, a high CMV virus load in AML patients after CBT indicated a lower incidence of relapse, and this anti‐leukemic effect might be mediated by the CMV‐driven expansion of CD8+ T cells.image
PS1031 DECITABINE VERSUS INTENSIVE CHEMOTHERAPY IN ELDERLY UNTREATED ACUTE MYELOID LEUKEMIA
Authors: De La Fuente A. , Tormo M. , Beneit P. , Gil C. , Castillo T. Bernal , Lopez J. Serrano , Gonzalez K. Javier , Mayol A. Sampol , Valls J. Davila , Chamorro C. Martinez , Ordoñez S. Suarez , Benavente C. , Bergua J. , de Laguna S. Jimenez Bravo , Espadana A. , Sanchez P. Martinez , Amigo M.L. , LLoris M.J. Sayas , Puente P. Herrera , Boluda B. , Fernandez R. , Brunet S. , Oiartzabal I. , Gama A. Muñoz , Sangerman M. Arnan , Martinez‐Cuadron D. , Polo S. Vives , Jorda R. Coll , Boyero R. Garcia , Figuera A. , Lopez A. Diaz , Gonzalez B. Gonzalez , Montesinos P. 
Published: June 2019

Background:The combination cytarabine + anthracycline (IC) remains the standard of care for 60 year and above AML patients (Lowenberg et al. N Engl J Med 2009). Decitabine (Dec) has been EMA approved for first line AML patients not fit for intensive chemotherapy (Kantarjian et al JCO 2012). IC vs Dec have been not previously compared.Aims:The aim of this study is to analyze effectiveness and tolerability of IC vs Dec as first lines in 60 and above AML patients and to identify risk factors.Methods:We carried out the analysis on previously untreated AML ≥60yrs old patients included in PETHEMA AML epidemiological registry (NCT02607059) and in the MDA‐AML‐2017–05 (AEMPS code). Selection criteria for the study were as follows: Age >60, diagnosis of AML under WHO criteria, treated with IC or Dec during the period 01/01/2012 to 31/12/2016. Response was assessed using the ELN‐2010 criteria, toxicity by the CTCAE v4.0 scale, OS by Kaplan‐Meier, as well as mortality within the first 8 weeks (M8wks).Results:A total of 756 of previously untreated AML patients were analyzed (625 treated with IC and 131 with Dec), baseline characteristics are summarized in table 1. A higher incidence of risk factors was observed in the Dec cohort. Safety: A total of 1051 IC and 716 Dec cycles were analyzed, mean 2.4 and 6.1, febrile neutropenia 74% and 47%, M8wks was 22.5% and 25.5% (p = 0.15) and composite complete response (CCR) 64% and 18% (p < .001). for IC and Dec respectively. In this study serum creatinine>1.3 mg/dL (p = 0.02, p < 0.01), ECOG≥2 (p < 0.01) and adverse cytogenetic (p < 0.01) were adverse prognostic factors for OS in both cohorts, and WBC pre‐Dec >10.000/μL (p < 0.01) in Dec and Secondary AML (p = 0.02) in IC cohort. IC resulted superior for OS (11 vs 8 months p = 0.04) but this was not significant in 70 and above (7 vs 8 months p = 0.94) or after matching by mentioned risk factors.Summary/Conclusion:IC and Dec are not used for the same patients due to physicians judgement. Even the outcome seams superior with IC we observe similar OS after matching by risk factors age, creatinine, ECOG, or cytogenetic. The ongoing EORTC phase III randomized trial (INDACTION) will compare a Dec‐based vs IC front‐line approach for older patients with AML.image
PS1049 COMPARATIVE RANDOMIZED STUDY OF PROTOCOL HAM VERSUS PROTOCOL FLAG IN RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA
Authors: elsergany A.R. , ismaeel M.I. , ibrahim M.A. , Ghazy H.F. , aladle D.A. 
Published: June 2019

Background:Acute myeloid leukemia (AML) is the commonest type of acute leukemias in adults resulting from clonal proliferation of bone marrow precursor cells with disruption of hemostasis. Patients initially respond to induction therapy but the majority of patients suffer relapse and refractoriness with very poor subsequent prognosis.Aims:To compare two widely used salvage regimens in treatment of relapsed/refractory AML, HAM (cytarabine, Mitoxantrone, Colony stimulating factor) versus FLAG (cytarabine, fludarabine, Colony stimulating factor) protocols.Methods:Prospective randomized study included 90 patient diagnosed as relapsed/refractory AML were selected from Oncology Center, Mansoura University, Egypt, from January 2014 to December 2017. Patients received salvage therapy either HAM or FLAG protocol, then outcomes regarding to efficacy, side effects and overall survival were assessed.Results:Ninety patients were included in our study, 43 patients received HAM protocol versus 47 received FLAG protocol. Complete remission (CR) was 42.6% in HAM group versus 48.8% in FLAG group (p = 0.5). On the other hand, hepatic impairment was 46.8% in HAM group versus 30.3% in FLAG group (p = 0.2). Also, renal impairment was 6.4% in HAM group versus 18.6% in FLAG group (p = 0.07). In addition, Event free survival (EFS) was higher in FLAG vs. HAM arms (9 versus 4 months, p = 0.2). Lastly, overall survival (OS) in HAM group was shorter than in FLAG group (3 vs. 5 months, P = 0.09)Summary/Conclusion:Both HAM and FLAG protocols are adequate salvage chemotherapy in relapsed/refractory AML, with different toxicity profile as HAM has more hepatotoxicity while FLAG is more nephrotoxic, CR was slightly higher with FLAG with more survival benefit compared with HAM protocol.
PS1072 SURVIVAL OF B‐CELL LYMPHOMAS IN THE PRE‐ AND POST‐RITUXIMAB ERAS: 30 YEARS REAL‐WORLD DATA
Authors: Gouda M. 
Published: June 2019

Background:Rituximab is an anti‐CD20 monoclonal antibody that has been approved by FDA in 1997 for treatment of B cell lymphomas. Most data about the effect of Rituximab on survival come from either randomized controlled trials or retrospectively from local centers’ experiences.Aims:The aim of this study was to report on the real‐world experience in the United States for patients with B‐cell lymphomas using data available in the SEER (National Cancer Institute Surveillance, Epidemiology, and End Results) program's database. SEER incorporates data from 18 cancer registries all over the United States and includes data dating back to 1973. These nationwide and historical data enabled the comparison between cases diagnosed 1983–1997 (15 years before Rituximab approval) and cases diagnosed 1998–2012 (15 years after Rituximab approval).Methods:Data were obtained using SEER∗Stat version 8.3.5 where (SEER 18 Regs Nov 2017 Submission) database was used as the main data source. B‐cell Non‐Hodgkin lymphoma cases diagnosed between 1983 and 2012 were included. Survival analyses were made using IBM SPSS version 25.0 and SEER∗Stat software. Comparison between groups was done using Log‐rank test while relative survival was calculated using Ederer II method.imageResults:A total number of 230577 cases were included in the analysis. B‐Cell lymphomas showed a median survival of 94 months (95% CI: 93–95) compared to 50 months (95% CI: 48.7–51.3) in the post and pre rituximab eras, respectively. Log rank test showed statstically significant difference in survival between the two groups (p < 0.001) (Figure1). This difference was consistent among all stage groups (Table 1).Summary/Conclusion:Rituximab's approval has led to a dramatic improvement in survival of patients with B‐Cell lymphomas. Data from United States confirms that this improvement was consistent in all disease stages.
PS1079 CLINICAL OUTCOME OF INTENSIFIED CHEMO‐TARGETED THERAPY IN ACTIVATED B CELL NON HODGKIN LYMPHOMA
Authors: Sohaib A. , Hashim T. , Abouelfetouh M. , Elkhouly E. , Alhanafy A. , Samaka R. 
Published: June 2019

Background:Diffuse large B cell lymphoma (DLBCL) accounts for approximately a third of all NHL and is the most common lymphoma subtype in all parts of the world. Advances in DNA array has resulted in further subclassification of DLCBL into germinal center type and activated B cell type (ABC). Activated B cell type has a worse prognosis than germinal center typeAims:To assess the role of intensified chemotherapy for patients with activated B cell type of DLBCL if it would result in better outcome. Primary end point is response rate and secondary end points are PFS and toxicity, OSMethods:This is a randomized phase II study done on 82 patients. Cases are randomized into two arms. Control arm received R‐CHOP (47 patients) and test arm received R‐CHEOP (35 patients). All cases are tested for BCL‐6, MUM‐1 and CD10 to confirm being of ABC type according to Hans algorithm. GCSF was used for prophylaxis in the test arm in the form of daily 1 vial of neupogen for 3 days after the cycle. Evaluation is done by Cheson et. al. criteria. Toxicity was described according to CTCAE V4Results:Both groups were comparable as regard age, gender, performance status, stage and LDH. Median age was 52 years for the control arm and 46 years for the test arm. Results are analyzed at a median follow up of 15 months. Complete remission at end of treatment was 70.2% for the control arm and 91.4% for the test arm (p = 0.019) while interim assessment showed 58% median tumor shrinkage for the control arm and 79% for the test arm (p < 0.001). Median PFS was 25 months for the control arm and not reached for the test arm (p = 0.022) while median overall survival was 28 months for the control group and not reached for the test arm (p = 0.145). At one year of follow up, overall survival was 74.46% for the control arm and 91.4% for the test arm. Toxicity was comparable in both groups regarding neutropenia (p = 0.356), oral mucositis (p = 0.419), diarrhea (p = 0.54), vomiting (p = 0.504), thrombocytopenia (p = 0.308), anemia (p = 0.453), neuropathy (p = 1)Summary/Conclusion:R‐CHEOP showed more tumor shrinkage than R‐CHOP in activated B cell lymphoma with comparable toxicity. PFS was better in the first year of follow up but more time is needed to calculate mature survival dataimage
PS1094 MANAGING CYTOKINE RELEASE SYNDROME (CRS) AND NEUROTOXICITY WITH STEP‐FRACTIONATED DOSING OF MOSUNETUZUMAB IN RELAPSED/REFRACTORY (R/R) B‐CELL NON‐HODGKIN LYMPHOMA (NHL)
Authors: Yoon S.‐S. , Matasar M. , Sehn L.H. , Assouline S. , Bartlett N.L. , Bosch F. , Diefenbach C.M. , Flinn I. , Hong J.Y. , Kim W.S. , Nastoupil L. , Schuster S.J. , Shadman M. , Bender B. , Chu W. , Hernandez G. , Kwan A. , McCall B. , Sison I. , Wang C. , Wei M.C. , Yin S. , Yousefi K. , Budde E.L. 
Published: June 2019

Background:T‐cell directed therapies (e.g. CAR‐T, blinatumomab) are associated with significant risk of Grade (Gr) ≥3 neurotoxicity and CRS/infusion‐related reaction (IRR). Mosunetuzumab is a CD20/CD3 bispecific antibody that directs T‐cells to engage and eliminate malignant B‐cells.Aims:To report safety results from an ongoing Phase 1/1b study (NCT02500407) of mosunetuzumab in patients (pts) with R/R B‐cell NHL.Methods:Pts received ascending doses on Day 1, Day 8, and Day 15 of Cycle 1 (step‐fractionation), then a fixed dose on Day 1 of every 21‐day cycle thereafter, up to a maximum of 17 cycles. Primary outcome measures included safety and efficacy.Results:As of October 23, 2018, 114 pts who received step‐fractionated dosing of mosunetuzumab were evaluable for safety (Table). The majority of adverse events (AE) occurred during Cycle 1 and 2. Neurologic AEs (NAE), defined from Nervous System or Psychiatric System Organ Classes, were mostly low grade, transient (median duration 4 days) and reversible; most common were headache (14%) and dizziness (8%). Gr ≥3 NAEs occurred in 4 pts (4%), with only 1 treatment‐related event (hepatic encephalopathy). CRS/IRR was reported in 25% of pts, with only 1 Gr 3 event. Most common CRS symptoms were pyrexia (86%), chills (38%), tachycardia and headache (14% each). There were no Gr 5 events related to CRS or NAEs. No apparent dose toxicity relationship was observed with step‐fractionation in these pts, despite escalation of the Cycle 1 Day 15 dose to 20 mg, consistent with observed peak IL‐6 levels after a low Cycle 1 Day 1 dose. In these pts, objective responses were observed in 24/73 (33%; complete response [CR], 13 [18%]) aggressive NHL and 17/32 (53%; CR, 10 [31%]) indolent NHL pts.Summary/Conclusion:Step‐fractionation has enabled continued dose escalation of mosunetuzumab with no apparent increases in toxicity, exhibiting a promising risk‐benefit profile.image
PS1101 PERIOPERATIVE MANAGEMENT AND OUTCOMES IN CHILDREN WITH CONGENITAL BLEEDING DISORDERS: A RETROSPECTIVE REVIEW AT A SINGLE HEMOPHILIA TREATMENT CENTER
Authors: Park Y.S. , Chon H.N. 
Published: June 2019

Background:Establishing hemostasis for surgical procedures in children with inherited bleeding disorders is challenging. Providers are often hesitant to undertake surgeries in children with bleeding disorders out of fear of bleeding complications. However, appropriate presurgery/preprocedure factor replacement can decrease pre‐, peri‐, and postoperative bleeding complications and allow almost any necessary surgical procedure to proceed.Aims:We review the results of surgical procedures in children with inherited bleeding disorders at our center and review the preoperative management and hemorrhagic complications.Methods:We conducted a retrospective electronic medical record review from October 2006 to November 2018. Primary focus was review of factor replacement strategies and bleeding complications. Data were collected from patients under 18 years of age.Results:In total, 152 procedures were performed in 99 children at our center. The distribution of bleeding disorders is as follows; hemophilia A 79, hemophilia B 15, Von Willebrand disease 3 and FVII deficiency 2. The median age of the patients was 13 years (range, 0∼18). Duration of hospitalization was median 8 days (range, 0∼44) and period from surgery to discharge was median 7 days (range, 0∼42). Nineteen procedures (12.5%) in 8 children were performed in the presence of high titer inhibitors to coagulation factor. Procedures included synovectomy (84/152, 55.3%), orthopaedic procedures except synovectomy (22/152, 14.5%), central venous catheter placement or revision (9/152, 5.9%), otolaryngology procedures (7/152, 4.6%), circumcision (6/152, 3.9%), laparoscopic appendectomy (5/152, 3.3%) and miscellaneous (19/152, 12.5%). All patients received preoperative factor replacement (100% in hemophilia patients) followed by various factor replacement regimens postoperatively. No deaths or life‐threatening bleeding occurred with any procedure. Seven of 152 procedures (4.6%) were complicated by bleeding. Tonsillectomy was the most common procedure complicated by hemorrhage 3 of 7 (42.9%).The complete list ofall 168 surgical procedures is shown in Table 2.All patients received preoperative factor replacement (100% in hemophilia patients) followed by various factor replacement regimens postoperatively. No deaths or life‐threatening bleeding occurred with any procedure. Seven of 152 procedures (4.6%) were complicated by bleeding. Tonsillectomy was the most common procedure complicated by hemorrhage 3 of 7 (42.9%).Summary/Conclusion:Surgical procedures are safe in children with bleeding disorders with adequate planning and factor replacement. Bleeding remains a problem in a subset of patients and requires ongoing hematological involvement and oversight. Delayed bleeding following tonsillectomy was especially common and suggests a need for close follow‐up and ongoing factor coverage for this group of patients.
PS1149 SECOND CANCER INCIDENCE IN CLL PATIENTS RECEIVING BTK INHIBITORS
Authors: Bond D. , Huang Y. , Fisher J. , Ruppert A. , Owen D. , Bertino E. , Rogers K. , Bhat S. , Jaglowski S. , Grever M. , Byrd J. , Maddocks K. , Woyach J. 
Published: June 2019

Background:Patients (pts) with chronic lymphocytic leukemia (CLL) suffer morbidity and mortality from CLL and increased risk for second primary neoplasia (SPN). BTK inhibitors (BTKi) are highly effective for the treatment of CLL and are associated with partial restoration of immune function with ongoing treatment. The impact of BTKi on the risk for and patterns of SPN is yet to be characterized.Aims:We aimed to determine the incidence of SPN including NMSC in a cohort of CLL pts treated with either ibrutinib or acalabrutinib at a single center, assess for association between baseline clinical characteristics and SPN incidence, and compare the observed with the expected incidence for sex and age matched controls within the Surveillance, Epidemiology, and End Results Program (SEER) database.Methods:CLL pts treated with ibrutinib or acalabrutinib at our center were identified retrospectively. Baseline and outcome data were collected including incidence of Richter's transformation (RT), non‐melanoma skin cancer (NMSC), and SPN.Standard incidence ratio (SIR) with 95% confidence intervals (CI) were calculated using expected incidence rates from the SEER, assuming a Poisson distribution for the observed incidence. Cumulative incidence rate (CIR) of SPN (excluding RT and NMSC) was calculated from BTKi start date to the diagnosis of SPN; death was a competing risk and pts without event were censored at last follow‐up. SPN was correlated with baseline data using the Fine‐Gray model.Results:691 pts were included; the median age was 64 years, median prior lines of treatment was 2 (20% treatment‐naïve, 66% with prior chemo‐immunotherapy), and 56% were never smokers. At a median follow‐up of 44 months, 68 pts (10%) were diagnosed with SPN (SIR 2.4, CI 1.9–3.0) including 13 lung (SIR 3.2, CI 1.7–5.5), 9 melanoma (SIR 6.9, CI 3.1–13), 9 prostate (SIR 1.4, CI 0.6–2.6), 7 bladder (SIR 5.2, CI 2.1–10.6), 4 breast (SIR 1.7, CI 0.5–4.5), and 3 kidney cancers (SIR 2.9, CI 0.6–8.5). CIR of SPN at 3 year was 7.6% (Table). Smoking (hazard ratio (HR) 2.9, CI 1.7–5.0, p < .01) and low baseline CD8 count (HR 0.9 for 2‐fold increase, CI 0.8–0.9, p < .01) were associated with higher incidence of SPN. RT was diagnosed in 58 pts (8%) and NMSC in 138 pts (20%). 179 pts had died with 3 year overall survival of 79% (CI 76–82); the most common causes of death were CLL/RT (57%) and SPN (13%).CIR of Second Cancers
Summary/Conclusion:The incidence of SPN in pts treated with BTKi for CLL is increased relative to the general population. With a 5 year CIR of NMSC and SPN of 23% and 12% respectively, these data support consideration of intensive cancer screening for CLL pts receiving BTKi.image