bluuebunny/crossref_metadata_2025 huggingface dataset:
PF631 HEALTH‐RELATED QUALITY OF LIFE WITH POMALIDOMIDE + LOW‐DOSE DEXAMETHASONE + DARATUMUMAB IN PATIENTS WITH RELAPSED REFRACTORY MULTIPLE MYELOMA AFTER LENALIDOMIDE TREATMENT
Authors: Reece D. , Bahlis N.J. , Samaras C. , Sebag M. , Berdeja J. , Ganguly S. , Matous J. , Song K. , Seet C.S. , Talamo G. , Acosta‐Rivera M. , Bar M. , Quick D. , Anz B. , Fonseca G. , Agarwal A. , Chung W. , Zafar F. , Siegel D.S.
Published: June 2019

Background:

Treatment of relapsed refractory multiple myeloma (RRMM) is complex and requires evaluation of disease and patient factors to maximize efficacy and minimize toxicity. As survival has improved with therapeutic advances, maintaining quality of life has become an important aspect of multiple myeloma treatment. Results from cohort B of the ongoing phase 2 MM‐014 trial (NCT01946477) have demonstrated that pomalidomide (POM) + low‐dose dexamethasone (LoDEX) + daratumumab (DARA) is safe and effective in patients with RRMM after first‐ or second‐line lenalidomide (LEN)‐based treatment.

Aims:

To evaluate the impact of POM+ LoDEX + DARA on health‐related quality of life (HRQoL) in patients with RRMM who received this regimen after first‐ or second‐line LEN.

Methods:

Patients with RRMM and 1 to 2 prior lines of treatment, LEN‐based treatment as their most recent regimen, and progressive disease during or after their last treatment line were eligible for inclusion in cohort B. In 28‐day cycles, patients received POM 4 mg/day on days 1–21 + LoDEX 40 mg/day (20 mg/day if aged > 75 years) on days 1, 8, 15, and 22, and DARA 16 mg/kg IV on DEX dosing days of cycles 1 and 2, then on days 1 and 15 of cycles 3–6, and then on day 1 of cycle 7 and beyond. Thromboprophylaxis was mandatory. The primary endpoint was overall response rate. HRQoL, an exploratory endpoint for cohort B, was assessed via EQ‐5D.

Results:

As of 15 October 2018, 108 patients were evaluable for HRQoL. Baseline characteristics were similar to those of the ITT population (N = 112). EQ‐5D completion rates for each cycle (1–6) were ≥ 88%. Through 6 treatment cycles, mean change from baseline in the EQ‐5D index and VAS health score was stable. At cycle 6, minimum clinically important improvement in the EQ‐5D index (≥ 0.1) and VAS health score (≥ 6) was achieved by 28.8% and 39.0% of patients, respectively. EQ‐5D index values were stable; however, a trend toward improvement was observed in usual activities, pain/discomfort, and anxiety/depression (Figure).

Summary/Conclusion:

In patients with RRMM who received POM + LoDEX + DARA after first‐ or ‐second‐line LEN based treatment, HRQoL was maintained or trended toward improvement, despite the combination of 3 drugs with distinct toxicity profiles. In context with the previously reported safety and efficacy data from cohort B of MM‐014, the results of this HRQoL analysis further support the earlier use of POM‐based treatment in RRMM immediately following treatment with LEN.

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PF725 REAL WORLD ASSESSMENT OF PRACTICE EFFICIENCY WITH THE INTRODUCTION OF SUBCUTANEOUS RITUXIMAB
Authors: Qiu A. , Shapouri S. , Drill E. , Schade J. , Ravelo A. , Ni A. , Tu‐My T. , Dawson K. , Matasar M.
Published: June 2019

Background:

Rituximab (R), available as an intravenous (IV; R‐IV) infusion or subcutaneous (SC; R‐SC) injection, is used in the treatment of follicular lymphoma (FL), diffuse large B‐cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL).

Aims:

This study evaluated real‐world practice efficiency changes associated with the adoption of R‐SC by studying differences in chair time by route of administration.

Methods:

We conducted a retrospective analysis of practice care delivery measures before and after adoption of R‐SC at Memorial Sloan Kettering Cancer Center (MSKCC). Data for patients (pts) with FL, DLBCL, or CLL receiving R‐based therapy from September 2016 to September 2018 were extracted from the electronic medical record. A linear mixed effect multivariate model with random intercept was used to analyze the association between treatment type (R‐IV vs R‐SC) and chair time (defined as the difference in pt room‐in and room‐out times) in the year prior to and following R‐SC adoption at MSKCC. Model covariates included treatment time and location, therapy type (monotherapy vs combination), and pt demographics. Given the prolonged infusion time, patients’ first dose of R‐IV was excluded from the analysis.

Results:

Data were collected during 6744 visits (3018 visits prior to R‐SC adoption and 3726 after) for 1503 pts receiving R. Pts receiving R‐IV combination therapy had a mean chair time of 203 minutes (min); overall, R‐SC injection reduced chair time by a mean of 92 min (p < 0.001 vs R‐IV). Monotherapy, regardless of route, reduced chair time by a mean of 30 min (p < 0.001) compared with combination therapy, and mean chair time was further reduced by 39 min (p < 0.001) for R‐SC pts receiving monotherapy. Reductions in chair time increased over time following initial adoption of R‐SC (p = 0.042), and were greater at the lymphoma‐specific site than multispecialty oncology infusion centers (p < 0.001).

Summary/Conclusion:

Adoption of R‐SC results in substantial time savings for both the pt and health system as measured by reduced chair time and improved pt throughput. Given increasing constraints on infusion chair space, increased utilization of R‐SC may improve practice efficiency and pt access to care.
PS927 PHOSPHOCHROMATOME ANALYSIS UNCOVERS UNEXPECTED ROLES OF CDK6 IN REGULATING TRANSCRIPTION
Authors: Nebenfuehr S. , Bellutti F. , Kollmann K. , Farlik M. , Müller A.C. , Sexl V.
Published: June 2019

Background:

Cyclin‐dependent kinase 6 (CDK6) together with its close homologue CDK4 enables the progression of cells through the early G1 phase of the cell cycle. CDK4/6‐cyclin D complexes phosphorylate members of the retinoblastoma (Rb) protein family, allowing for the release of E2F transcription factors that induce genes required for cell cycle progression and DNA replication. Alterations of the CDK4/6‐Rb pathway are frequently observed in human malignancies. Recent studies focusing on acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML) have uncovered a novel role for CDK6 in regulating transcription. Our group has identified CDK6 as part of chromatin‐bound complexes which drive transcription of disease–relevant genes including the cell cycle inhibitor p16INK4a, the angiogenesis‐promoting factor VEGF‐A (vascular endothelial factor A) and the proto‐oncogene FLT3 (Fms like tyrosine kinase 3).

Aims:

The aim of this study is to identify novel binding partners of CDK6 on chromatin and to investigate their target gene sets. A better understanding of CDK6 functionality in tumor formation and promotion may help in the design and selection of adequate treatment options.

Methods:

For further investigation of CDK6́s role in transcription, we transduced murine Cdk6
+/+ and Cdk6
−/− primary bone marrow with the oncogene Bcr/Abl
p185. To systematically gain insights on how CDK6 takes influence on chromatin‐binding and activity of transcription factors we performed RNA‐seq paralleled by mass spectrometry‐based phosphoproteomics of chromatin‐bound proteins (Phospho‐Chromatome).

Results:

RNA‐seq analysis of Cdk6
+/+ and Cdk6
−/− BCR‐ABL transformed cells identified more than 1700 genes that are differentially expressed. Phospho‐Chromatome studies performed in parallel revealed significant changes in the phosphorylation status of the transcription factors ZBTB7A, EBF1 and YY1. In vitro kinase assays verified a direct phosphorylation of ZBTB7A and EBF1 by active CDK6/CyclinD3 complexes.

Summary/Conclusion:

We show that CDK6 is broadly associated with chromatin where it fulfils different tasks: beside its well‐known role in the E2F‐release it enhances the phosphorylation of various transcription factors and chromatin‐regulating enzymes. This results in pronounced changes in associated gene expression. Therefor our data indicate that the function of CDK6 is not limited to cell cycle progression but regulates a plethora of tumor‐relevant transcriptional programs. Future therapies may consider this unexpected role and even exploit it to improve personalized and cancer‐specific treatment protocols.
PS982 THE ROLE OF STAT3 ISOFORMS IN ACUTE MYELOID LEUKEMIA
Authors: Aigner P. , Mizutani T. , Horvath J. , Just V. , Sill H. , Grebien F. , Moriggl R. , Casanova E. , Stoiber D.
Published: June 2019

Background:

Signal transducer and activator of transcription 3 (STAT3) plays a central role in proliferation, differentiation and oncogenic transformation. It is expressed in two alternatively spliced isoforms, STAT3α and truncated STAT3β, which lacks the C‐terminal transactivation domain and instead carries seven unique amino acids. Interestingly, STAT3β recently gained attention as a powerful anti‐tumorigenic molecule and protective prognostic marker. This has been shown in patients with esophageal squamous cell carcinoma as well as in mouse models for breast, skin and colon cancer. Deregulated STAT3 signaling is frequently observed in leukemogenesis and generally associated with a poor clinical outcome in patients with acute myeloid leukemia (AML). In addition, it has been shown that the expression ratios of STAT3α and STAT3β change upon myeloid differentiation. However, the exact role of STAT3β in AML patients and during disease progression remains unknown.

Aims:

The goal of our study is to analyze the contribution of the two STAT3 isoforms to leukemogenesis with a particular focus on STAT3β in AML development.

Methods:

We analyzed more than 50 AML patient samples for STAT3β/STAT3α mRNA expression levels and its correlation with clinical prognosis and overall survival. Furthermore, we generated an inducible Stat3β transgenic mouse model and crossed it with Pten‐deficient mice, a previously described model for AML. In addition, we used fetal liver‐derived stem cells from Stat3β transgenic mice, transduced with a retrovirus encoding for the MLL‐AF9 translocation, in a transplant model for AML.

Results:

We observed a correlation between clinical prognosis and STAT3β/STAT3α expression ratio. A higher STAT3β/STAT3α ratio was further associated with a favorable clinical prognosis and a significantly increased overall survival. In both in vivo mouse models we could demonstrate that the expression of STAT3β impairs leukemogenesis and leukemic cell infiltration into hematopoietic organs. The STAT3β‐dependent delay in disease progression and leukemic infiltration resulted in a significant increase of overall survival.

Summary/Conclusion:

In summary, the results of our study demonstrate STAT3β as an anti‐tumorigenic molecule in AML mouse models and the STAT3β/STAT3α ratio in AML patient derived blasts positively correlates with survival.
PS1103 NOVEL COMPOUND HETEROZYGOUS MUTATIONS CAUSING FACTOR XI DEFICIENCY IN UNRELATED TWO CHINESE PATIENTS
Authors: Li Q. , Zhou R.
Published: June 2019

Background:

Coagulation factor XI deficiency is a rare bleeding disorder, whose molecular mechanism is not well understood.

Aims:

To investigate the molecular pathogenesis of coagulation factor XI (FXI) deficiency in two unrelated Chinese patients

Methods:

The diagnosis was validated by coagulant assays: APTT and correct test, PT and coagulation factors activities. The patients’ DNA were extracted and all exons and flanking sequences of FXI gene were amplified using PCR. After purified, the products were sequenced directly, the mutations were detected by comparing with wild sequences and analysed using some bioinformatics software.

Results:

The two patients were diagnosed as coagulation factor XI deficiency due to prolonged APTT, corrected APTT and low activities of coagulation factor FXI. The results of APTT, corrected APTT and FXI:C were 88.1 s, 32.9 s,1.1% and 107.1 s, 31.5 s, 3.8% for patient1 and patient2, respectively. Genetic analysis showed compound heterozygous mutations g.1251–1G>A and g.1271delT in patient1 and the sequencing results of TA plasmid clones found that the two mutations were located on different single strands of chromosomes. Double heterozygous mutations g.1070A>G and g.1446C>G were detected in patient2 resulting in Lys357Arg and Cys482Stop. Software analysis suggested the mutations probably brought amino acid sequence changed, protein features affected and splice site changed.

Summary/Conclusion:

Double heterozygous mutations g.1251–1G>A, g.1271delT and g.1070A>G, g.1446C>G had been identified in unrelated two coagulation factor XI deficiency Chinese patients, which might be the reasons for their prolonged APTT and low FXI:C. To the best of our knowledge, the four mutations are reported firstly in literature.
PS1126 JNK1: AN EMERGING THERAPEUTIC TARGET IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) DOWNSTREAM OF THE B‐CELL RECEPTOR, WHICH OVERCOMES IBRUTINIB RESISTANCE
Authors: Decker S. , Saleem S. Khaja , Kissel S. , Duyster J. , Dierks C.
Published: June 2019

Background:

B‐cell receptor (BCR) inhibitors like ibrutinib are highly effective in the treatment of CLL, but frequent occurrence of resistance mutations limits treatment duration and causes relapses in many patients. The C‐Jun NH2‐terminal protein kinases 1 (JNK 1) belongs to the family of serine/threonine kinases, is involved in cell proliferation, survival and differentiation, and is located downstream of the BCR in CLL.

Aims:

Therefore, we aimed to validate JNK1 as crucial mediator of BCR signaling in CLL. Further, we wanted to validate JNK1 as a therapeutic target in ibrutinib‐resistant CLL.

Methods:

Patient derived xenograft mice from CLL patients and ibrutinib‐resistant CLL patients, and Eμ‐TCL1 tg mice were daily treated with the JNK1 inhibitor SP600125 using oral gavage. After 2 and 3 weeks of treatment, mice were sacrificed, and spleen and bone marrow cells were harvested and stained for CLL cells (BD).

Results:

In this study, we found that JNK1 is overexpressed and highly activated especially in IgVH unmutated B‐CLL lymphocytes with adverse prognosis, and overactive BCR signaling. JNK inhibition with the kinase inhibitors SP600125 and CC‐930, the substrate binding inhibitor protein L‐JNKi or siRNA mediated silencing all lead to apoptosis induction in IgVH unmutated primary human CLL samples. JNK1 inhibition was effective even in the presence of protective stroma cells, and resulted in down‐regulation of the anti‐apoptotic proteins BCL2 and MCL1, and the oncogenic transcription factor c‐JUN. By performing knockdown experiments and kinase inhibition of essential upstream BCR‐signaling mediators in CLL like SYK, BTK and PI3K, we identified JNK1 as a crucial downstream kinase in the BCR signaling pathway. In vivo treatment studies in patient derived xenograft mouse models and the Eμ‐TCL1 tg mouse model with the JNK1 inhibitor SP600125 confirmed our results and strongly reduced CLL cell numbers in the peripheral blood and spleen of both mouse models. JNK1 inhibition was even effective in a CLL xenograft model of a patient being resistant to ibrutinib treatment. In addition to direct effects on CLL cells, we found that JNK1 inhibitors in vivo also improve T‐cell responses, and reduce the frequency of immunosuppressive Tregs, while increasing the activity of CD4+ and CD8+ T‐cells.

Summary/Conclusion:

In conclusion, our studies revealed JNK1 as a promising novel therapeutic target in CLL downstream of the BCR, which can overcome ibrutinib resistance, and additionally improve immune responses against CLL cells.
PS1144 TARGETING IRAK4 DISRUPTS INFLAMMATORY PATHWAYS AND DELAYS TUMOR DEVELOPMENT IN CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: Moya L. Rosich , Gimenez N. , Schulz R. , Higashi M. , Aymerich M. , Villamor N. , Delgado J. , Juan M. , Lopez‐Guerra M. , campo E. , Seiffert M. , Colomer D.
Published: June 2019

Background:

Interleukin‐1 receptor‐associated kinase 4 (IRAK4) plays a critical role in Toll‐like receptor (TLR) signal transduction and innate immune responses. Recruitment and subsequent activation of IRAK4 upon TLR stimulation is mediated by the myeloid differentiation primary response 88 (MYD88) adaptor protein. Around 3% of chronic lymphocytic leukemia (CLL) patients have activating mutations of MYD88, a driver mutation in this disease.

Aims:

Here, we studied the effects of TLR activation and the pharmacological inhibition of IRAK4 with ND2158, an IRAK4 competitive inhibitor, as a therapeutic approach in CLL.

Methods:

TLR stimulation was performed with an agonist mix of Pam3CSK4, HKLM, FSL1 and ODN2006. Cytokine secretion and CLL proliferation were assessed by Luminex system and carboxyfluorescein succinimidyl ester staining, respectively. For in vivo studies, the Eμ‐TCL1 adoptive transfer mouse model was used.

Results:

Our in vitro studies demonstrated that ND2158 preferentially killed CLL cells in a dose‐dependent manner. We further observed a decrease in NF‐κB and STAT3 signaling, cytokine secretion, proliferation and migration of primary CLL cells from MYD88‐mutated and –unmutated cases. In the Eμ‐TCL1 adoptive transfer mouse model of CLL, ND2158 delayed tumor progression and modulated the activity of myeloid and T cells.

Summary/Conclusion:

Our findings show the importance of TLR signaling in CLL development and suggest IRAK4 as a therapeutic target for this disease.
PS1191 PROGNOSTIC SIGNIFICANCE OF REGULATORY T CELLS (TREGS) IN CHRONIC MYELOID LEUKEMIA PATIENTS TREATED WITH GENERIC IMATINIB
Authors: Saj F.
Published: June 2019

Background:

It has been observed that the proportion of regulatory T cells (Tregs) is elevated in untreated Chronic Myeloid Leukemia (CML) patients that curtail tumor‐specific immune response. The degree of imatinib‐related Treg inhibition correlates with CML prognosis. There is limited information on the dynamics of Tregs in CML patients treated with generic imatinib. We studied Treg proportions in newly‐diagnosed CML patients (at baseline and 3 months of treatment with generic imatinib).

Aims:

To evaluate Tregs in periperal blood of newly diagnosed patients of CML‐Chronic phase and their association with disease progression.

Methods:

Newly‐diagnosed adult CML patients in chronic phase were prospectively studied from July 2017 to March 2018. At baseline, a peripheral blood sample for Treg analysis was collected from CML patients before starting imatinib and from healthy controls. At 3 months, in addition to quantitative RQPCR for BCR‐ABL, a repeat peripheral blood sample was collected for Treg analysis. Treg percentage in peripheral blood was assessed by flowcytometry (triple laser BD FACS Canto II flow cytometer). Following sample acquisition on flow cytometer, the data was analysed using BD FACSDIVA software (Becton Dickinson, USA). Tregs were calculated as percentage of CD4+ T lymphocytes.

Results:

Fifty‐seven newly‐diagnosed CML patients and 30 age‐ and sex‐matched healthy controls were prospectively enrolled. The median age of the CML patients was 39 years (range 16 – 64years); 47.3% were males. The BCR‐ABL (IS) % at 3months was <1%, 1–10% and >10% in 15 (26.3%), 26 (45.6%) and 16 (28.1%) patients, respectively. The mean baseline Treg% of CML patients (3.61 ± 0.32%) was significantly higher than the mean Treg % of controls (1.58 ± 0.21%) (p < 0.001). The mean Treg% at 3 months in CML patients (1.73 ± 0.35%) was significantly lower than baseline Treg% (3.61 ± 0.32%) (p < 0.001). Baseline Treg% in CML patients showed significant positive correlation with Sokal score (r = 0.29), Hasford score (r = 0.33) and EUTOS score (r = 0.28) (p < 0.05). The baseline Treg% correlated significantly with the BCR‐ABL% at 3months (p = 0.03).

Summary/Conclusion:

We found a significantly higher proportion of Tregs in CML patients in chronic phase vis‐a‐vis healthy controls which significantly decreased with generic imatinib treatment at 3 months. The study results add evidence to the hypothesis that imatinib‐related Treg suppression is another novel mechanism through which it targets CML. Our findings lend support to the fact that generic imatinib is reasonably efficacious in restoring immunological milieu in CML patients.
PS1279 A PRACTICAL UPDATE ON THE EPIDEMIOLOGY AND RISK FACTORS FOR THE EMERGENCE AND MORTALITY OF BLOODSTREAM INFECTIONS IN 3014 PATIENTS WITH HEMATOLOGICAL MALIGNANCY RECEIVING CHEMOTHERAPY
Authors: Hu J. , Chen S. , Yang T.
Published: June 2019

Background:

The pathogenic epidemiology, antibiotic resistance, and risk factors of bloodstream infections (BSIs) in patients with hematologic malignancies (HMs) receiving chemotherapy is importment for clinican.

Aims:

To investigate the pathogenic epidemiology and antibiotic resistance of bloodstream infections (BSIs) in patients with hematologic malignancies (HMs) receiving chemotherapy, and to determine the risk factors for BSIs.

Methods:

Retrospective chart review of patients diagnosed with HMs (n = 3014) was performed (1/2013–12/2016), and patients classified as having BSIs (n = 725) or not (n = 2289). Clinical characteristics and pathogens were evaluated, and risk factors for BSIs identified by univariate and multivariate Logtistic and COX regression analyses.

Results:

BSI frequency was 24.1%, with 744 different isolated strains in 725 cases. Gram‐negative (G‐) represented 64.7% of the 744 isolated strains, while Gram‐positive (G+) and fungi were 27.7% and 7.7%, respectively. The most common isolates were Klebsiella pneumoniae (19.2%), and 90% of extended‐spectrum beta‐lactamases (ESBL)‐producing enterobacteria were multidrug‐resistant. Methicillin‐resistant Coagulase‐negative Staphylococci and Methicillin‐resistant Staphylococcus aureus accounted for 87.16% and 37.93% of the cases, respectively. Multivariate analysis revealed that male, age ≥ 45 and <65 yr, hospital length of stay (LOS) ≥ 9d, neutropenia ≥ 7d before BSIs, ≥ 2 antibiotics, gastrointestinal, perirectal and urinary tract infections independently predicted BSIs emergence. Furthermore, age ≥ 65, neutropenia ≥ 7d before BSIs, no HM remission, lower white blood cell count, ≥ 3 antibiotics, respiratory infections, and Acinetobacter baumannii and Stenotrophomonas maltophilia BSIs were independent predictors of 30‐day mortality.

Summary/Conclusion:

Antibiotic resistance was high, outcome was poor, and mortality due to BSIs was high in this patient cohort. Therefore, close attention should be paid to the risk factors identified here during management of these patients with BSIs.

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PS1510 FLUPENTIXOL MELITRACEN COMBINED WITH ONDANSETRON IN PREVENTION OF NAUSEA AND VOMITING INDUCED BY CONDITIONING IN PATIENT TO UNDERGO HSCT
Authors: Lu Y. , Fan R. , Kuang L. , Feng B. , Shan Y.
Published: June 2019

Background:

Nausea and vomiting are the most common complaints for patients with haematological neoplasia during conditioning. The risk of hematopoiesis stem cell transplantation (HSCT) always cause people in anxiety and depression, which add patients’ discomforts.

Aims:

The aim of this study is to observe the effect of lupentixol melitracen combined with ondansetron on nausea and vomiting.

Methods:

160 patients with hematological neoplasia in the state of complete remission were included in this study. The patients were randomly divided into control group and lupentixol melitracen group. For patients in control group, they received recommended‐dose of ondansetron during conditioning each day. For patients in lupentixol melitracen group, they received lupentixol melitracen 10.5 mg combined with ondansetron each day. The incidence of nausea and vomiting was evaluated before, during and after chemotherapeutics infusion in the first day of conditioning.

Results:

Totally 158 patients, 78 in control group and 80 in lupentixol melitracen group could be evaluated. The difference of chemotherapy drug intensity in the two groups has no statistical significance (P > 0.05). The incidence of nausea before, during and immediately after chemotherapeutics infusion was respectively 5.2%, 72.5%, 60.6% in the control group and 1.6%, 53.3%, 45.5% in the lupentixol melitracen group, and the difference was significant between the two groups (P < 0.05). While the incidence of vomiting in the two groups has no significant difference (P > 0.05).

Summary/Conclusion:

Flupentixol melitracen combined with ondansetron is more effective to prevent nausea than single ondansetron in patients during the first day of conditioning but no more effect on vomiting in our study.
PS1559 EFFICACY AND TOXICITY OF SEAM (SEMUSTINE, ETOPOSIDE, CYTARABINE, AND MELPHALAN) CONDITIONING REGIMEN FOLLOWED BY AUTOLOGOUS STEM CELL TRANSPLANTATION IN LYMPHOMA
Authors: Zhang L. , Chen X. , Liu S. , Zhu Q. , Wu D. , Huang H.
Published: June 2019

Background:

BEAM (carmustine, etoposide, cytarabine, and melphalan) is considered the gold standard conditioning regimen for autologous stem cell transplantation (auto‐SCT) in lymphoma. However, a shortage of old drugs is a worldwide problem, and carmustine (BCNU) is on this list. Alternative regimens are therefore being developed and used by many institutions. Semustine (Me‐CCNU), an alternative oral nitrosourea agent, has been chosen as a potential substitute. In China, we substituted BCNU by Me‐CCNU to provide the modified conditioning regimen SEAM (semustine, etoposide, cytarabine, and melphalan).

Aims:

The aim of this study was to evaluate the safety and efficacy of the SEAM regimen followed by auto‐SCT for malignant lymphoma patients.

Methods:

We retrospectively reviewed the records of patients with lymphoma who underwent auto‐SCT with SEAM regimen (n = 97) from January 2010 to June 2018 in our center. We evaluated the safety and efficacy of the SEAM regimen by comparing with previous studies using BEAM as conditioning regimen.

Results:

The median age of patients (n = 97) was 42 years (range, 15–65). The median time to neutrophil engraftment was 9.5 days (range, 7–15 days), and the median time to platelet engraftment was 12 days (range, 7–25 days). Grade 3–4 nausea/vomiting, mucositis and diarrhea were observed in 21.6%, 36.1%, and 11.3% of patients, respectively. Veno‐occlusive disease (VOD) and idiopathic pulmonary syndrome (IPS) were not observed. Treatment‐related mortality (TRM) at 100 days occurred in 2 patients (2.1%). After a median follow‐up time of 53.9 months, 31 patients (32.0%) showed progression over a median duration of 4.87 months (range, 1.1–40.53) after transplantation. In addition, the 3‐year incidence of disease relapse or progression (CIR) was 34%. The estimated progression‐free survival (PFS) and overall survival (OS) at 3 years were 62% and 75%, respectively. Compared with previous studies using BEAM as the conditioning regimen, this study shows that the SEAM conditioning regimen has a comparable efficacy and safety profile.

Summary/Conclusion:

The incidence and severity of non‐hematological regimen‐related toxicities of the SEAM conditioning regimen in this study were almost identical to that of BEAM conditioning regimen as reported in the previous studies. The SEAM conditioning regimen followed by auto‐SCT was well tolerated and had an efficacy and safety profile comparable to BEAM. Therefore, SEAM conditioning regimen is feasible whether in efficacy, safety or sources of drugs and might be an ideal alternative to BEAM conditioning regimen for auto‐SCT in lymphoma.

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PS1576 ADENOSINE DIPHOSPHATE RECEPTOR GENE (P2Y12) SEQUENCE VARIANTS AMONG SWEDISH, PALESTINIAN AND CONGOLESE INDIVIDUALS
Authors: Asees M. , Seir R. Abu , Hesse C. , Reza A.
Published: June 2019

Background:

The P2Y12 receptor plays a central role in platelet aggregation and thrombus formation. Recently, inter‐individual variations in platelet response of healthy untreated individuals were established which was explained by genetic variations in the P2Y12 receptor gene. Several single nucleotide polymorphisms (SNPs) in the P2Y12 receptor have been associated with increased platelet reactivity and risk of cardiovascular diseases.

Aims:

This study aimed to evaluate the pathological H2 haplotype (using G52T as a tag‐SNP) and 18C>T polymorphisms in three different ethnic groups; Palestinians, Swedish and Congolese. in addition to that, to investigate the effect of H2 haplotype pn palatelt aggregation induced by ADP/TRAP agonists.

Methods:

The H2 haplotype and 18C>T SNPs were determined in conveniently selected healthy individuals from different ethnic groups (n = 254). The whole exon‐3 of P2Y12 was sequenced and analyzed by using ABI PRISM 310 Genetic Analyzer. The major and the minor allele frequencies of the P2Y12 SNPs were determined in the study population and the genetic differences between ethnic groups in P2Y12 were elucidated. In addition, the frequency of the genotypes were calculated among the different ethnic groups.

Results:

In this study, five benign single nucleotide polymorphisms (SNPs) were genotyped and identified; 18C>T, 36G>T, 162G>T, 546C>T and 989A>G. The overall frequencies of each SNP in the study population (n = 254) was 21.9, 10, 0.4, 0.6 and 0.4%, respectively. The frequency of H2 haplotype was among Swedish 23.6% (n = 55), Congolese 12.0% (n = 54) and Palestinian 4.1% (n = 145). There were significant differences in frequency of H2 haplotype and 18C>T among the ethnic groups (P < 0.001). In regard to the pathological SNPs (767G>A [p. Arg256Gln] and (793C>T [Arg265Trp]) all of the study participants were negative.

Summary/Conclusion:

There are significant differences in the frequencies of the genetic variants of the P2Y12 exon‐3 between the studied ethnic groups. Application of these findings may explain the variable platelet response in healthy individuals and in patient under thienopyridine compounds. Further studies should be performed to study the effect of the genetic variations effect on ADP or TRAP‐ induced platelet aggregation.
PS1585 ELDERLY WITH ANTIPHOSPHOLIPID SYNDROME PRESENT WITH DISTINCT CLINICAL PROFILE: A RETROSPECTIVE SINGLE CENTER STUDY
Authors: Bountola S. , Perifanis V. , Kazantzi A. , Keramidioti C. , Hassapopoulou‐Matami E. , Hatzitolios A. , Girtovitis F.
Published: June 2019

Background:

Antiphospholipid syndrome (APS) is an acquired autoimmune disorder. It is characterized by venous and/or arterial thrombosis and/or pregnancy related morbidity in the presence of persistent antiphospholipid antibodies (aPL). It can occur as primary or as secondary APS in association with an autoimmune disorder (usually SLE). APS mainly affects women who are of child‐bearing age and less often elderly patients.

Aims:

We aimed to describe the clinical and immunological features of APS in patients diagnosed after the age of 55.

Methods:

The PSA (Phospholipid Syndrome Aged) study is a retrospective study of patients with suspected APS, who were referred to the Thrombosis and Haemostasis Clinic during the last decade (2009–2018). Clinical and serological data of patients with late onset APS (occurred after the age of 55) were analyzed and compared with patients presenting with early onset APS. The aPL (anticardiolipin (ACA) and anti‐b2GP‐I antibodies, IgG and IgM) were measured by ELISA (Euroimmun, Germany).

Results:

We evaluated 149 patients diagnosed with APS (56,4% males, median age 43,74 ± 13,4 years). Patients with late onset APS were 32 (21,5%) and consisted Group A. The other 117 patients were Group B. Median follow‐up was 62,5 months (13–147). The most common clinical manifestation was stroke (20,5%), followed by deep vein thrombosis of the lower extremities (15,4%) and pulmonary embolism (12,7%). Clinical characteristics of patients are shown in table 1. x2 test was used to assess statistical significance.

All triple positive patients were in group B (10 women and one man). All patients were treated with antithrombotic treatment including antiplatelet agents (26,5%) and/or oral anticoagulants (69%). 14% of the patients received only LMWH (younger women). Male gender, LA positivity and a higher frequency of secondary APS were statistically significant in the older group.

Summary/Conclusion:

Elderly APS patients should not be disregarded because they represent 21,4% of an APS population. Patients aged >55 who are diagnosed with APS share a distinct disease profile. Clinicians must be aware of this situation in order to identify specific causes, to evaluate the risk of recurrence and to establish a therapeutic approach.

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PB1649 EXOSOMES‐MEDIATED DELIVERY OF RNA OLIGOS DIRECTED TO CHE‐1/AATF IMPAIRS BCP‐ALL VITALITY
Authors: Caforio M. , Sorino C. , Bertaina V. , Pitisci A. , Battafarano G. , Del Fattore A. , Fanciulli M. , Folgiero V. , Locatelli F.
Published: June 2019

Background:

Precursor B cell acute lymphoblastic leukemia (BCP‐ALL) is the most common childhood malignancy and represents the leading cause of cancer‐related death in children and young adults. BCP‐ALL arises from a monoclonal or oligoclonal expansion of malignant B cell precursors in the bone marrow and despite the overall progress in treatment relapse occurs across the whole spectrum of all subtypes with an overall survival of 30%. We recently found that Che‐1/AATF, an important RNA polymerase II binding protein involved in the regulation of gene transcription with anti‐apoptotic activity in different tumour contests, exerts a pivotal role in BCP‐ALL. Che‐1 is highly expressed in a cohort of BCP‐ALL patients at the onset of disease and at time of relapse, irrespective of genetic heterogeneity, but were barely detectable when patients obtained leukemia remission. Notably, Che‐1 depletion strongly affected growth of BCP‐ALL cells and sensitized to Adriamycin.

Aims:

With the aim to therapeutically inhibit Che‐1 expression, overcoming the difficulty of the nuclear localization, and to find a technical approach available in in vivo models we focused on exosome‐mediated delivery of RNA oligos.

Methods:

To test this hypothesis, peripheral blood obtained from healthy donors was used for monocytes isolation and differentiation to immature dendritic cells. Supernatants were harvested and submitted to exosomes extraction procedure. Vesicles were electroporated with FITC‐conjugated oligos to set up experimental conditions. We observed high oligos loading and a 100% efficiency of oligo delivery in BCP‐ALL cell lines and in primary blast cells upon cellular co‐culture. In the same experimental conditions, we tested the efficacy of a panel of FITC‐conjugate oligo targeting Che‐1.

Results:

The exosome‐mediated delivery of combination of two oligos resulted in downregulation of Che‐1 expression in BCP‐ALL cell lines. The obtained result produced also an increase in PARP cleavage and an higher amount of cells in subG0‐1 phase.

Summary/Conclusion:

Since part of this procedure is an already approved GMP‐grade procedure, we will test the cooperation between exosome‐mediated Che‐1 downregulation and the current therapeutic treatments with the aim to develop a new applicable clinical approach, particularly in BCP‐ALL relapsed patients.
PB1731 ELEVATED FETAL HEMOGLOBIN (HBF) IN ELDERLY AML PATIENTS RECEIVING HYPOMETHYLATING AGENTS: ENHANCEMENT OF HBF INDUCTION BY RETINOIC ACID?
Authors: Stomper J. , Bissé E. , Lübbert M.
Published: June 2019

Background:

We recently reported elevation of fetal hemoglobin (HbF) as a potential predictor of outcome in elderly AML/MDS patients treated with DNA‐hypomethylating agents (HMA). HbF elevation prior to decitabine (DAC) treatment (Lübbert et al., Br. J. Haematol. 2017; 176:609‐617) as well as HbF induction following 2 courses of DAC treatment (Stomper et al., Haematologica 2019; 104:59‐69) were associated with superior outcome of AML/MDS patients. Interestingly, HbF elevation was shown to be associated with cytogenetic remissions and to be reversed at relapse, suggesting that HbF is preferentially induced in non‐clonal erythroid cells during HMA therapy.

Preclinical work suggests that epigenetically active agents such histone deacetylase inhibitors (HDACi) can be combined with retinoic acid to induce HbF.

Aims:

We now investigated the effect of the add‐on drugs all‐trans retinoic acid (ATRA) and valproic acid (VPA, an HDACi) on HbF induction during DAC treatment in AML patients.

Methods:

The DECIDER trial addresses the effects of the add‐on of ATRA or VPA to DAC (Grishina et al., BMC Cancer 2015; 15:430). We serially studied HbF levels in 16 AML patients ≥60 years old that received >2 cycles of treatment within the DECIDER trial. Four patients received only DAC, 5 patients DAC+VPA, 5 patients DAC+ATRA, and 2 patients DAC+VPA+ATRA. HbF levels were measured in peripheral blood erythrocytes by HPLC before treatment and sequentially, i.e. after the end of each treatment course. HbF >1.0% was considered induced.

Results:

In this albeit small cohort, continued treatment appeared to result in variations in maximally attained levels of HbF depending on the type of drug add‐on. As to VPA, the median peak HbF level attained was 1.5% (range, 0.4 ‐ 5.0%) in 9 patients not having received VPA compared to 1.0% (range, 0.2 ‐ 4.8%) in 7 patients having received VPA. The median peak HbF level in the absence of ATRA (9 patients) was 0.8% (range, 0.2 ‐ 2.8%) compared to 2.1% (range, 0.3 ‐ 5.0 %) in 7 patients having received ATRA.

Summary/Conclusion:

Given that the add‐on of ATRA (but not VPA) to DAC resulted in superior outcome (Lübbert et al., ASH 2016), these preliminary results suggesting a higher induction of HbF in the presence of ATRA warrant prospective, serial HbF determinations in a planned randomized validation trial. Also, RNA‐sequencing studies in AML cell lines treated with DAC ‐/+ ATRA are addressing de‐repression of the gamma‐globin locus in vitro.
PB1848 CAN VON WILLEBRAND ANTIGEN LEVEL AT THE INITIAL PRESENTATION BE ABLE TO PREDICT THE INHIBITOR DEVELOPMENT IN PATIENTS WITH SEVERE HEMOPHILIA A?
Authors: Aytac S. , Gumruk F. , çetin M.
Published: June 2019

Background:

There is a large heterogeneity in bleeding events and arthropaty among patients with severe Hemophilia A which is multifactorial. Mostly FVIII gene mutations seems to influence phenotype however underlying prothrombotic risk factors and FVIII half life may both have an affect on the heterogeneity.VWF is the specific carrier of factor VIII in plasma and protecs it from proteolytic degradation,prolonging its half life in circulation and efficiently localizing it at the site of vasculary injuiry.

Aims:

Here, we want to evaluate von Willebrand antigen levels of the children with severe Hemophilia A at the initial diagnose and want to figure out whether low initial von Willebrand antigen (VWF:Ag) levels may asssociated with a frequent bleeding phenotype or not, retrospectively.

Methods:

We retrospectively evaluate charts of 40 children with severe hemophilia A who was diagnosed in between 1997 and 2017 at the Hacettepe University, Department of Pediatric Hematology. All of these patients were receiving prophylaxis and among those 40 patients only 6 had a history of inhibitor in which 2 of them still persist.

Results:

Mean VWF:Ag levels were found to be 114 ± 40 (32‐200)IU/dL. Ten out of 40 children VWF:Ag levels was found to be under 100IU/dL and from those 5 out of ten were found to be under 80IU/dL. Interestingly none of them were have the blood group ’O’. Initial bleeding age were found to be lower (median 6 months)in patients with low VWF:Ag (<100IU/dL) than that of the patients with high VWF:Ag (≥100IU/dL)(median 18 months)(p = 0.05).2/10 had a history of inhibitor (1 low titer 1 high titer) development and 7/10 had a target joint which requires radiosyneviectomy during the follow up period.On the other hand 4 out of 30 patients with VWF:Ag>100IU/dL had a history of inhibitor development (4 high titre inhibitor: 2 was still found to be positive) and 5/30 had a target joint.

Summary/Conclusion:

Despite we do not have the half lifes of FVIII, a significant shorter half life in patients with a low VWF:Ag level was previosly reported. Although there is no follow up of VWF:Ag levels in this small group of patients with a frequent bleeders initial VWF:Ag levels may give some clues about the clinical outcome.
PB1849 WHEN DO WE HAVE TO SUSPECT AND DIAGNOSE VON WILLEBRAND DISEASE?
Authors: Hyun S.Y. , Lee K.S.
Published: June 2019

Background:

Although von Willebrand disease (vWD) is the most common hereditary coagulation disorder, most of patients do not pay attention to their daily lives. While it is easy to treat already diagnosed vWD patients, it is also a characteristic of the disease that it is not easy to suspect and diagnose. The patient does not tell the doctor easy bruise as a major symptom because he (or she) does not know that this may have been caused by coagulation disease. It is very important to ask the patient whether he suffers from ’easy bruise or intractable nosebleed?’, ’ever suffered from poor stop‐bleeding on the injection site?’ or ’a family history of bleeding disorders?’ to determine the pressure time (10 minutes or more) to stop the injection site bleeding in cases of invasive procedure such as vaccination, blood collection or injection even when the patient is diagnosed and treated with other diseases. Menorrhagia or hypermenorrhea, delivery history and family history of coagulation disorder is hard to get medical history without specially asking. The reason why we are difficult to suspect and diagnose vWD: Many think easy bruise is not a disease. No one considered a repeat intractable nosebleed after stop as a result of basically coagulation defect. It seems to accept menorrhagia or hypermenorrhea as a mother's similarity and to solve only by gynecological treatment. Most doctors fail to treat iron deficient anemia because they do not pay attention for etiology. Do not recognize repeat test may be necessary because exercise and stress will make false positive result of vWF.

Aims:

Objective of this study was to examine the icidence and clinical features of VWD among the patients with easy bruising in the setting of primary care clinic.

Methods:

The screening test and the primary specific test for vWD (FVIIIc, vWF:RiCoF and vWF:Ag) and iron deficiency anemia (IDA) were done in 182 patients with bleeding symptoms (menorrhagia, easy bruising, etc.) among the patients who visited one private physician's clinic (Han's Clinic) for 4.5 years.

Results:

Twenty‐one patients were confirmed as vWD (vWF:RCo or vWF:Ag value was less than 30 or vWF:RCo/vWF:Ag < 0.6) and 23 had vWF values less than 50. All except two were female. Median age was 34.7 (13‐71) years. Six of 21 patients had a family history. Most of them had iron‐deficiency anemia of moderate to severe. The main symptom was easy bruise in 16, anemia in 10, menorrhagia in 7, hypermenorrhea in 5, easy epistaxis in 2 and dizziness in 1. Iron deficiency anemia was confirmed in 8 of 21 patients. Four patients received prophylactic therapy with Minirin® effectively and 1 had treated with Immunate® for tooth extraction and 50 days’ menstruation. The menstrual period lasting for one month was reduced to normal with DDAVP inhalation and vWF infusion could stop bleeding soon after tooth extraction.

Summary/Conclusion:

Because accidents or emergency surgery can happen in life time to anyone, early suspicion and diagnosis will save life and reduce sequelae.
PB1859 PROSPECTIVE COHORT STUDY OF KOREAN PATIENTS WITH BONE MARROW DISORDERS WITHOUT LARGE PNH CLONE TO DEFINE FACTORS ASSOCIATED WITH PNH CLONE EXPANSION
Authors: Koh Y. , Yoon S.‐S. , Lee J.W. , Jang J.H. , Lee J.‐H. , Kim J.S. , Choi S.E. , Kim S.‐H.
Published: June 2019

Background:

Factors associated with PNH clone evolution is not well described in the Asian population.

Aims:

In this prospective cohort study, we recruited Korean patients with bone marrow disorder to define factors associated with an increase in PNH clone size.

Methods:

We included patients with aplastic anemia (AA) or myelodysplastic syndrome (MDS) if PNH clone is not absent at the time of screening. We also included patients who have small PNH clones (<10%) regardless of bone marrow pathology except for hematologic malignancies. Patients should be free of complement inhibitor treatment for at least 8 weeks before study enrollment. PNH clone size testing was performed using high‐resolution flow cytometry and FLARE.

Results:

We enrolled 227 patients (Male:Female 121:106, mean age 53 years) from 6 centers in Korea. PNH clone was ≥ 1% in 28 patients, 0Table1 Characteristics of 5 patients who experienced more than 10% of PNH clone expansion

Summary/Conclusion:

We constructed a prospective cohort of Korean patients with AA, MDS or small PNH clones. PNH clone distribution had a distinctive pattern according to underlying bone marrow pathology. We expect to construct a precise model for PNH clone expansion using this cohort.

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PB1957 EVALUATION OF HEMATOLOGICAL AND NONHEMATOLOGICAL COMPLICATIONS OF IMATINIB MESILATE (IM) IN PATIENTS WITH PHILADELPHIA POSITIVE CHRONIC MYELOGENOUS LEUKEMIA (PH+ CML)
Authors: Ter‐Grigoryan A. , Melkikyan N. , Danelyan S.
Published: June 2019

Background:

Chronic myelogenous leukemia (CML) is caused by the BCR‐ABL tyrosine kinase, the product of Philadelphia chromosome. Imatinib mesylate (IM) is a selective inhibitor of this kinase.

Aims:

The objective of this study was to determine the hematological and non‐hematological complications of IM in patient with CML in Armenian population.

Methods:

The object of the study were patients of the Hematology Center of the Ministry of Health of the Republic of Armenia, registered from 2000 to 2017. During this period 377 patients with a diagnosis of Ph+ CML were observed. Total of 326 (86%) patients treated with IM were involved in research (45.4% male and 54.6% female, who were at the age of 7‐81 years). The 282 patients (86.5%) were in chronic phase, 44 patients (13.5%) ‐ in phase of acceleration and blast crisis. The doses of IM were 400 mg daily for the chronic phase and 600‐800 mg daily for the accelerated and blast phase of disease. The patients were thoroughly monitored for both hematological and non‐hematological complications, in some cases temporary dose adjustment was necessary.

Results:

213 patients experienced various side effects which, in decreasing order of frequency were: peripheral edema, bone pains, joint pains, allergic reactions, muscle cramps, nausea, vomiting, hepatic enzyme elevation, gastric pain and headaches as non‐hematologic complications (table 1) and leucopenia, thrombocytopenia and anemia as hematological complications (table 2).Three patients developed grade IV complications in form of toxic hepatitis, anasarca and allergic reaction, which required treatment discontinuation.

Cytopenias developed in cases of 48 patients, and CHR/complete hematological response/ within the first 4 months from the start of therapy was observed in 65.3% of their cases. At the same time, in the group of patients who did not have these complications, CHR was achieved in 84% of cases (p = 0.0207).

It is noteworthy that in case of patients with cytopenias, CCR/complete cytogenetic response/ was achieved in 15.3% of cases, whereas in case of patients without these complications‐ in 32.4% of cases (p = 0.0754). Thus, hematological complications in the form of cytopenias, which require a temporary cessation of treatment, reduce the likelihood of CHR and CCR.

Such statistics show that hematological complications, quite possibly, were originally due to patients belonging to a higher prognostic group. And the group of patients, who in the first 4 months did not reach the CHR, requires a broader cytogenetic examination according to the karyotype and, if necessary, sequencing.

Summary/Conclusion:

Imatinib mesylate is a well‐tolerated drug with some adverse events that rarely require treatment discontinuation.

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