bluuebunny/crossref_metadata_2025_split huggingface dataset:
PS1330 VARIABILITY IN THE EXTENT OF DEL(5Q) AND ITS CLINICAL IMPLICATION IN MYELODYSPLASTIC SYNDROMES (MDS)
Authors: Zemanova Z. , Brezinova J. , Michalova K. , Svobodova K. , Lhotska H. , Vesela D. , Izakova S. , Sarova I. , Lizcova L. , Ransdorfova S. , Pavlistova L. , Belickova M. , Vesela J. , Siskova M. , Neuwirtova R. , Cermak J. , Stopka T. , Jonasova A. 
Published: June 2019

Background:The interstitial deletion of the long arm of chromosome 5—del(5q)—is the most common cytogenetic abnormality in MDS occurring either as a sole aberration or as a part of complex karyotypes (CK). MDS with isolated del(5q) are associated with a favorable outcome while MDS with CK relate to poor prognosis. Extent of deleted segment is highly variable. However, it remains unclear whether its size matters for the different MDS phenotypes.Aims:The aim was to compare the extent of deletion in 264 MDS patients [116 with isolated del(5q) and 148 with del(5q) involved in CK] and to assess the relationship of del(5q) extent and TP53 gene mutation.Methods:Extent of del(5q) was analyzed using I‐FISH (Abbott, MetaSystems), mBAND (MetaSystems) and array CGH/SNP (CytoChip Cancer SNP 180K, Illumina or SurePrint G3 Cancer CGH+SNP 4x180K, Agilent). CK were analyzed with mFISH (MetaSystems). Sequence analysis of TP53 gene was performed in 84 cases using amplicon deep sequencing (exons 4–11) on a 454 GS Junior system (Roche) or with TruSight Myeloid Panel Kit on MiSeq sequencing instruments (Illumina).Results:In the group with isolated del(5q), the most frequently deleted segment ranged between the bands 5q14 and 5q33.3, with the smallest deletion encompassing the 5q31.1–5q31.3 region (18.527 Mb). The TP53 mutation was proved in 19.4% cases. The size of the deletion did not significantly differ in patients with and without TP53 mutation. In the group with CK, the deletion often involved entire long arm including the telomeric region. In some cases, a part of short arm was also deleted, but we never observed the loss of the entire chromosome 5. The commonly conserved region (CCR) was localized in bands 5p12 to 5p14.1. In this group, the mutation of TP53 and/or LOH17p was detected in 49% of patients. The commonly deleted regions (CDR) were in the band 5q31.1 (5.522 Mb) in cases with isolated del(5q) and between the bands 5q31.1 and 5q31.3 (18.527 Mb) in patients with CK.Summary/Conclusion:Patients with isolated del(5q) had a smaller size of the deleted segment. More extensive 5q deletion was associated with higher karyotype complexity, increased frequency of TP53 aberrations and worse prognosis. Accurate analysis of breakpoints and range of del(5q) points out to the correlation of deletion size with increasing genomic instability in MDS and contributes to a better understanding of the MDS pathogenesis.Supported by RVO‐VFN64165, GACR P302/12/G157, ProgresQ28/LF1, MHCR 00023736.
PS1338 TEMPORAL TRENDS IN TRANSFUSION BURDEN AMONG NEWLY DIAGNOSED PATIENTS WITH MYELODYSPLASTIC SYNDROMES: A U.S. CLAIMS DATABASE STUDY
Authors: Slabaugh S.L. , Mearns E.S. , Copher R. , Johnson J. , Buzinec P. , Mukherjee S. 
Published: June 2019

Background:Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematologic stem cell disorders characterized by ineffective hematopoiesis resulting in peripheral cytopenias. Anemia is the most prevalent of all cytopenias and is often treated with red blood cell transfusion (RBCT). There is a paucity of data on how the transfusion requirements of MDS patients change early in their clinical course. Understanding the temporal changes in transfusion needs in patients with MDS can provide data on the clinical need of MDS‐specific therapies based on the pace and burden of transfusion dependency.Aims:This retrospective study assessed the status and temporal trends in RBCTs among newly diagnosed patients with MDS in the United States, using a large administrative claims data set, Optum Research Database.Methods:All patients aged ≥ 18 years with newly diagnosed MDS (≥ 2 medical claims with an International Classification of Diseases, 9th or 10th Revision [ICD‐9 or ICD‐10] diagnosis codes ≥ 30 days apart) and in continuous health plan enrollment for ≥ 6 months pre‐ and 3 months post‐index date between January 2012 and May 2018 were included. Index was defined as date of first diagnosis. Transfusion status was evaluated during the 6‐month pre‐, and at 3‐month, 6‐month, and 9‐month post‐index periods for patients managed with observation alone, or with RBCT with or without erythropoiesis‐stimulating agents (ESAs). Transfusion independence (TI) was defined as patients receiving no transfusions; transfusion users (TU) was defined as 1 transfusion episode; and transfusion dependence (TD) was defined as patients receiving ≥ 2 transfusions during the observation periods.Results:Among the 3,803 patients identified, 56.3% were male, 85.4% were ≥ 65 years old (median age was 76), 78.0% were enrolled in a Medicare Advantage with Part D plan, and mean Quan‐Charlson Comorbidity Index was 1.98. Most patients (61.7%) were diagnosed with MDS, unspecified (ICD‐9‐CM 238.75, ICD‐10‐CM D46.9) on index date. Anemia was the presenting cytopenia in 78.8% of patients and 24.4% needed ≥ 1 RBCT (11.5% were TD and 12.9% were TU) preceding the MDS diagnosis. Common comorbidities observed in the pre‐index period were: hypertension (69.6%), cardiac diseases (58.1%), and dyslipidemia (54.8%). ESAs were administered to 40.7% of patients during the post‐index period. During the 9 months following diagnosis, a steady increase in TD was observed (Table).Summary/Conclusion:Disease burden in patients with MDS remains considerable. Considering that RBCT needs increased steadily despite ESA use with up to 37% still reliant on RBCT at 9 months post diagnosis indicates a critical unmet need for newer therapies for MDS patients who have TD anemia and for whom limited therapies exist beyond ESAs and RBCT.image
PS1347 PHF19 INDUCES EZH2 PHOSPHORYLATION AND PROMOTES DRUG RESISTANCE IN MULTIPLE MYELOMA
Authors: Du C.‐X. , Yu T.‐T. , Liu L.‐T. , Xu J. , Li Z.‐Q. , Yu Z. , Zhan F.‐H. , Ma X.‐K. , Qiu L.‐G. , Hao M. 
Published: June 2019

Background:Multiple myeloma (MM) is a plasma cell malignancy characterized by consecutive progression and increased invasion. It is becoming increasingly evident that tumor development and the acquisition of drug resistance involves the alteration of epigenetic regulation. PcG (polycomb group) proteins are key to epigenetic repression through two main complexes, PRC1 (Polycomb repressive complex 1) and PRC2. PHF19, also known as PCL3, combines with histone methyltransferase EZH2 (Enhancer of Zeste 2) and participates in the formation of PRC2 complex. Our study is the first report that depicts the role of PHF19 in the drug resistance of MM, providing new therapeutic choices for these patients.Aims:To disclose the role of PHF19 in promoting drug resistance of multiple myeloma and explore the therapeutic strategy based on the mechanism research.Methods:RNA‐seq data from 351 newly‐diagnosed patients, 44 MGUS, 12 SMM and 22 healthy plasma cells reported the role of PHF19 as an independent risk predictor for survival. We then studied the functional role of PHF19 by overexpression or shRNA knockdown in ARP1 and OCI‐My5 MM cell lines, conducting cell proliferation counting, Annexin V/7AAD assay for apoptosis, and mouse xenograft experiments. Gene expression profile was performed in ARP1 MM cell line. Western blot was used to investigate the expression of the potential targets of PHF19. Dual luciferase assay was used to reveal the relation between miR‐15a and PHF19 mRNA.Results:PHF19 was associated to high‐risk and dismal outcome of MM patients. It promoted cell growth and resistance to bortezomib both in vitro and in vivo. PHF19 activated the bypass of canonical PRC2 function by recruiting AKT to phosphorylate EZH2, which released the expression of HIF‐1α, Bcl‐xL and Mcl‐1. PI3K inhibitor LY294002 reversed the upregulation of the mentioned pro‐survival proteins. miR‐15a bound to 3’UTR of PHF19 mRNA to negatively regulate its expression.Summary/Conclusion:PHF19 is correlated to disease progression and drug resistance of MM. In vitro and in vivo experiments reveal PHF19 significantly promotes cell survival and inhibites apoptotic activity. PI3K/AKT signaling pathway is highly involved in the function of PHF19, indicating inhibition of PI3K/AKT may be an effective strategy to treat those patients with high level of PHF19.
PS1368 IGH AND IGK REARRANGEMENT AND IGH SOMATIC HYPERMUTATION ANALYSIS USING NEXT‐GENERATION SEQUENCING FOR THE DETECTION OF CLONALITY IN HIGH‐RISK KOREAN MULTIPLE MYELOMA PATIENTS
Authors: Lee J. , Lee Y.K. , Kim M. , Kim H.J. 
Published: June 2019

Background:Clonality assessment in patients with multiple myeloma (MM) is important both for initial diagnosis and detecting minimal residual disease. Next‐generation sequencing (NGS)‐based immunoglobulin gene rearrangement assays may be useful for assessing clonality, although their applicability has not been convincingly demonstrated.Aims:We intended to evaluate the primer set most widely used with the only commercially available NGS‐based clonality assay in high‐risk MM patients for the first time.Methods:Thirty bone marrow aspirate samples were included in the study. The samples were evaluated for IGH rearrangements and IGH somatic hypermutation using the LymphoTrack®
IGH‐FR1 assay (InVivoScribe, San Diego, CA) on a MiSeqDx instrument (Illumina, San Diego, CA). When kappa‐type cases showed negative IGH rearrangement (and somatic hypermutation), LymphoTrack®
IGK assay (InVivoScribe) was performed.Results:IGH‐FR1 and/or IGK assay detected clonality (demonstrated by rearrangements) in 22 out of 26 MM cases (84.6%) who were not lambda‐type light chain disease. Detailed analysis on IGH clonality/somatic hypermutations and IGK clonality is presented in Table 1. IGH clonality were observed in 20 of the 26 samples (76.5%), and among them 17 cases (85.0%) showed IGH somatic hypermutations. By testing IGK clonality on 5 kappa‐type samples which did not show any IGH clonality including 1 kappa‐type light chain disease, 2 samples (40.0%) showed IGK clonality. One out of 2 kappa‐type light chain disease cases and 1 out of 3 lambda‐type light chain disease cases showed IGH clonality, suggesting that the heavy chain clonality could have been missed in immunofixation electrophoresis assay. The IGH or IGK clonality was not statistically associated with heavy chain type or light chain type, even though all the 10 IgA‐type cases showed either IGH or IGK clonality. Neither the existence of IGH clonality nor its quantity (expressed as a percentage) was associated with the percentage of plasma cells in the specimens.Table 1. IGH clonality, IGH somatic hypermutation and IGK clonality according to the heavy chain and light chain types in 30 high‐risk Korean multiple myeloma samples.Summary/Conclusion:By combining the IGH‐FR1 assay and/or IGK assay, we detected clonality in approximately 85% of high‐risk Korean MM patients. Somatic hypermutations of IGH gene was observed in 85% cases with IGH clonality. Different sets of primers of immunoglobulin genes might increase the clonality detection rate in MM.image
PS1430 INTEGRATION OF FOUR COLOUR FLOW TO PREDICT RELAPSE/PROGRESSION AND TIME TO NEXT TREATMENT IN MULTIPLE MYELOMA AFTER UPFRONT AUTOLOGOUS STEM CELL TRANSPLANT
Authors: Chorão P. , Maia T. , Bergantim R. , Aguiar E. , Pires J. Cancela , Trigo F. , Guimarães J.E. 
Published: June 2019

Background:Four colour multiparameter flow cytometry (4MFC) is widely available and easier to apply than conventional minimal residual disease methods, although less sensitive.Aims:Our objective was to integrate 4MFC results in a clinical model to predict relapse/progression free survival (R/PFS) and time to next treatment (TNT) after upfront autologous stem cell transplant (ASCT) in a resource limited setting.Methods:Single center retrospective review of 146 consecutive MM patients with 4MFC bone marrow (BM) evaluation at day 100 after upfront ASCT with melphalan conditioning between 2008 and 2016. The 4MFC panel included CD38, CD138, CD45, CD19 and CD56. CD38+, CD138+ plasmocytes (PC) with (CD45 ± )CD19‐CD56+ or CD45‐CD19‐(CD56 ± ) were considered abnormal. Baseline PC 4MFC was only available in 50% of patients and was not considered for this analysis. Multivariate Cox regression analysis was performed to elect statistically significant variables to integrate R/PFS (either biochemical or clinic) and TNT clinical models at 3 years (y) after ASCT.Results:Median follow‐up after ASCT was 43 months (interval 2–126). At diagnosis, median age was 58y (interval 36–70), 56% were male, 23% had hypercalcemia, 15% renal insufficiency, 41% anemia, 67% lytic lesions and 33% plasmacytomas. Induction regimens included a proteasome inhibitor (PI) in 62%, immunomodulator (IMiD) in 6%, IP and IMiD in 24% and neither in 8%. At day 100 after ASCT, 57% had a complete remission, 32% a very good partial remission (VGPR) and 11% had <VGPR. BM evaluation at day 100 detected a median of 0.3% PC, with 17% of patients having abnormal PC. For all follow‐up, relapse/progression was documented in 75%, 69% was biochemical and 31% clinic.In multivariate analysis, kidney insufficiency at diagnosis, >0.25% BM PC at day 100 and detection of abnormal BM PC at day 100 impacted on R/PFS at 3y. Different risk groups for relapse/progression were defined according to the presence of 0, 1 or >1 of these characteristics (median R/PFS not reached versus (vs) 24 vs 14 months, respectively; p < 0.001; Figure 1A). In multivariate analysis, the three characteristics above and also age >58y impacted on TNT at 3 years. Three groups with distinct timings for second line treatment were defined according to the presence of 0–1, 2 or >2 of these risk factors (median TNT not reached vs 24 vs 16 months, respectively; p < 0.001; Figure 1B).Summary/Conclusion:The addition of BM 4MFC PC analysis at day 100 after upfront ASCT to clinical characteristics identifies subgroups of MM patients with increased risk for relapse/progression and need for second line treatment, which may require different post‐ASCT observation. Further efforts are needed in order to validate and integrate affordable end of treatment disease burden evaluation in resource limited settings.image
PS1432 3‐WEEKLY DARATUMUMAB‐IMID‐DEXAMETHASONE IS HIGHLY EFFICACIOUS, HENCE FINANCIALLY AFFORDABLE WITH ENORMOUS ECONOMIC IMPACT FOR RELAPSED/REFRACTORY MULTIPLE MYELOMA IN LESS AFFLUENT COUNTRIES
Authors: Chim C.S. , Wong V.K. C. , Au Y.L. E. , Kwong Y.L. 
Published: June 2019

Background:Daratumumab (dara) with immunomodulatory agents (IMiD) and dexamethasone (dex) is highly effective in relapsed multiple myeloma (MM). The recommended schedule of dara is weekly for 8 doses, followed by 2‐weekly for 8 doses, and then every 4‐weekly thereafter. Given the high cost and the long half‐life as an antibody, a 3‐weekly dosing of dara was used together with IMiD/dexamethasone.Aims:Dara at 16 mg/kg was used every 3‐weekly with lenalidomide or pomalidomide. Patient achieving best response received single agent IMiD maintenance until disease progression.Methods:Fourteen relapsed MM patients were enrolled. One had received weekly dara from a private oncologist, hence was excluded from analysis. Thirteen patients at a median age of 63 years (range: 50–84 years) were studied. The median number of previous therapies was 2 (range: 1–5), with nine patients (69.2%) having undergone autologous stem cell transplantation. Three patients (23.1%) were refractory to bortezomib, seven patients (53.8%) to lenalidomide, and eight patients (61.5%) to last treatment. At relapse, two (15.4%) had high LDH, eight (61.5%) impaired renal function, and three (23.1%) extramedullary disease. Treatment was dara‐lenalidomide‐dex in six (46.2%), and dara‐pomalidomide‐dex in seven (53.8%).Results:Responses after four cycles included CR in 5 patients (38.5%), VGPR in five patients (38.5%), and PR in three patients (23.1%). After a median of four dara infusions (range: 3–10), the best responses included CR in seven patients (53.8%), nCR in two patients (15.4%), VGPR in two patients (15.4%), and PR in two patients (15.4%). Median time to VGPR was one month. At 10 months, the OS was 90%, and PFS 54.7%. Three patients progressed, one of whom died of ruptured hepatic plasmacytoma. The most frequent toxicity was haematological especially neutropenia (all grades: 92.3%, Grade 3/4: 76.9%), infusion reaction (38.5%, all grade 1/2), neuropathy (38.5%, all grade 1/2), gastrointestinal (all grades: 38.5%, grade 3/4 : 7.7%), and sepsis (all grades: 30.8%; grade 3/4: 23.1%). Neutropenia was effectively prevented with prophylactic G‐CSF.Summary/Conclusion:In conclusion, a 3‐weekly dara‐IMiD‐dex regimen is highly efficacious, inducing deep and rapid responses, hence cost‐effective for less affluent countries. In view of prevalent grade3/4 neutropenia despite less frequent dara, 3‐weekly dara might be more suitable for Asian patients.image
PS1433 RESULTS OF AUTOLOGOUS STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA PATIENTS WITH RENAL FAILURE
Authors: Tuğlular A. Tülin , Elibol T. , Uzunoğlu C. , Aldağ B. , Dedeoğlu Ö. , Ercan T. , İpek Y. , Arıkan F. , Yılmaz A.F. , Atagündüz I. Kaygusuz , Toptaş T. 
Published: June 2019

Background:Multiple Myeloma (MM) is a hematological malignancy in which renal involvement is common. Almost half of MM patients have increased creatinine levels at the time of diagnosis. In 20% of these patients, creatinine level is above 2 mg/dl. Kidney damage can be reversible in 50% of these patients.Aims:In this retrospective study, we evaluated the outcomes of autologous stem cell transplantation (ASCT) which was done in our center in multiple myeloma patients with renal failure. We compared the outcomes of these patients with patients with normal renal functions and who underwent ASCT. In patients with renal failure, melphalan 140 mg/m2 was used as conditioning regimen.Methods:We retrospectively analyzed the files of 574 patients with multiple myeloma in our center. We identified 106 patients who had ASCT between 2007–2018. We calculated creatinine clearances (CrCl) with Modification of Diet in Renal Disease (MDRD) formula at diagnosis. Patients were divided into 2 categories according to their CrCl results: patients with CrCl above 60 ml/min (n = 41), patients with CrCl below 60 ml/min (n = 28).Demographic data, laboratory results, pre‐transplant treatment and response to treatments were presented in Table 1.Results:Median follow‐up of the patients was 54 months. Median progression‐free survival (PFS) in patients with CrCl<60 ml/min and ≥60 ml/min was 56 months and 62 months, respectively. Three‐year PFS in these patients was 56.4% and 58%, respectively (p = 0.859). Median overall survival in patiens CrCl<60 ml/min was 69 months; median OS was not reached in patients with CrCl≥60 ml/min (p = 0.001). Median OS of all patients was 90 months. Four‐year OS of patients with CrCl<60 ml/min and≥ 60 ml/min was 69.9% vs. 97%, respectively (p = 0.001).We found that patients who had an improvement after ASCT in their renal functions had a better OS than compared to patients who had no improvement after ASCT (49 vs 73 months, respectively, p = 0.095). Four of the 7 patients with dialysis‐dependent renal failure at the time of diagnosis became dialysis independent. Median creatinine clearences of patients with CrCl <60 ml/min before and after ASCT was 25.45 ml/min and 54.39 ml/min respectively. CrCl increased above 60 ml/min in 11 patients. CrCl increased %50 above baseline in 18 patients.Summary/Conclusion:In conclusion treatment response rates and progression‐free survival rates were not affected by renal failure. Treatment of patients with renal insufficiency should not be different than those of patients who do not have renal failure. Standard myeloma treatment and ASCT should be used in these patients; melphalan dose can be reduced to 140 mg/m2 in patients with CrCl <60 ml/min.image
PS1452 GLI‐1, EFFECTOR OF CANONICAL HEDGEHOG SIGNALING PATHWAY, DOES NOT SEEM TO BE DYSREGULATED IN PATIENTS WITH MYELOFIBROSIS
Authors: Lucijanic M. , Livun A. , Stoos‐Veic T. , Pejsa V. , Jonjic Z. , Dzankic A. Fazlic , Ivic M. , Kusec R. 
Published: June 2019

Background:Although activation of Hedgehog signaling pathway was reported to be present in murine bone marrow transplant model of primary myelofibrosis (PMF) and increased expression of Hedgehog target genes was reported in granulocytes isolated from unselected patients with myeloproliferative neoplasms, therapeutic Hedgehog inhibition showed only limited results in myelofibrosis so far. Also, inconsistent effects of such therapy on Gli1 (effector of hedgehog signaling) were observed.Aims:We aimed to investigate Gli‐1 expression in bone‐marrow tissues of patients with primary and secondary myelofibrosis (SMF) and to assess its clinical correlations.Methods:We retrospectively investigated Gli‐1 mRNA expression in 32 diseased (28 PMF, 4 SMF) and 16 healthy (limited stage agressive Non‐Hodgkin lymphoma) bone marrow samples using real‐time‐polymerase‐chain‐reaction (GLI1 Hs01110766_m1 Thermo Fischer Scientific TaqMan assay). Expression was normalized to Abl and expressed as a ΔCT value. Correlations with clinical parameters were made. Study was approved by the institutional review board. All procedures were in accordance with the Helsinki Declaration. All patients provided written informed consent.Results:Median age of our patients was 70 years, there were 21 (66%) males and 11 (34%) females. Gli‐1 expression did not significantly differ between PMF, SMF and controls (median ΔCT 7.2, 7.3 and 6.9 respectively; P = 0.864).Higher Gli‐1 bone marrow expression was not significantly associated with neither age, gender, JAK2, CALR, MPL mutational status nor degree of bone marrow fibrosis (P>0.05 for all analyses). Only statistically significant associations were present between higher Gli‐1 expression and higher transferrin saturation (P = 0.039; Rho = 0.4) and higher absolute lymphocyte count (P = 0.032; Rho = 0.4).Gli‐1 expression separated at median (ΔCT 7.25) had neutral effect on overall survival in our cohort of patients (P = 0.651) as shown in a Figure.Summary/Conclusion:Our findings indicate Gli‐1 mRNA expression might not be dysregulated in patients with myelofibrosis and has neutral impact on prognosis of these patients. Although limited by small number of patients, retrospective study design and single center experience, our results are in line with previous observations of modest clinical effects of Hedgehog inhibition in patients with myelofibrosis.image