bluuebunny/crossref_metadata_2025 huggingface dataset:
PS1428 GCSF ALONE STEM CELL MOBILIZATION IN MULTIPLE MYELOMA PATIENTS CANDIDATES TO HIGH DOSE CHEMOTHERAPY: A MONOCENTRIC RETROSPECTIVE EXPERIENCE
Authors: Bramanti S. , Magri F. , Giordano L. , Sarina B. , Morabito L. , Mariotti J. , De Philippis C. , Girardi D. , Timofeeva I. , Capizzuto R. , Mazza R. , Carlo‐Stella C. , Santoro A. , Castagna L.
Published: June 2019

Background:

Despite the introduction of several effective multidrug combination in the treatment landscape of multiple myeloma (MM), high dose chemotherapy (HDC) is still an important phase in the treatment of MM. On the other hand, chemotherapy used to mobilize stem cell (SC) do not contribute in disease control or long term survival

Aims:

To analyze the efficacy of granulocyte colony stimulating factor (GCSF) alone to mobilize SC, in a consecutive series of multiple myeloma patients candidate to HDC.

Methods:

From January 2016 to January 2019, 61 consecutive MM patients underwent GCSF alone stem cell mobilization in our institution. Every patients received GCSF at the dose of 10 mcg/kg/day for 5 days. Peripheral blood circulating CD34+/mcl were checked from day +4. Plerixafor was administered on demand when CD34+ cells were less than 20/mcl at day +4 or +5, or when CD34 harvested was less than 2  × 10^6/kg after the first or second apheresis. The stem cell harvest were performed processing 2.5 − 3 times total blood volume. After collection, the patients received single or double course of melphalan 200 mg/m2 or 1 course of melphalan 140 mg/m2 according to local guideline. The minimal CD34+ number to perform a single HDC was 2x106/kg.

Results:

Patient characteristics are listed in Table 1. All patients but 2 (3%) achieved the target to perform the planned HCD. Median total CD34+ × 106/kg harvested was 8.6. The proportion of patients able to achieve the goal with one apheresis was 50%. Only 1 patient underwent a third apheresis. Nine patients (14%) received plerixafor, 7 on day +4 and 2 on day +5. Median blood CD34+/mcl on day+4 and +5 was 33.5 (15–98), and 63 (10–171), respectively. Median total blood leucocyte counts (10^3/mm^3) on day 4+ and on day +5 was 41310 and 49250, respectively. Median CD34+ × 106/kg in the first and second apheresis was 6.4 (0,8–16) and 4.7 (1.5–8), respectively. Median total leucocyte count (106) in the graft on first and second apheresis was respectively 71280 and 49250. After HDC, all patients but one experienced engraftment.

Summary/Conclusion:

GCSF alone stem cell mobilization is an effective and safe approach after induction in MM patients candidate to HDC. The main advantages are the possibility to predict peak CD34+ level (4–5 days), to schedule apheresis in an outpatient program and to avoid unnecessary toxicity with chemotherapy.

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PS1429 LIVING ALONE WITH MULTIPLE MYELOMA: THE NEXT‐GENERATION CHALLENGE
Authors: Ríos‐Tamayo R. , Rodríguez D. Sánchez , Collado P. Garrido , Chan Y.L. Chang , Perez J. Sainz , Sierra P.A. González , Aguilar A. Romero , Ruiz A. García , Salas G. , Ballester J. Muñoz , Pérez M.J. Sánchez
Published: June 2019

Background:

According with the Spanish National Institute of Statistics (2017), 25.4% of Spanish households are formed by a single person and this trend is increasing in recent years. The outcome of patients with newly diagnosed multiple myeloma (NDMM) who live alone is not well known.

Aims:

To assess the impact in terms of overall survival (OS) and early mortality (EM) of NDMM patients who live alone, either voluntarily or not.

Methods:

All consecutive patients with the variable of interest available on clinical records and included in the population‐based Granada Myeloma Registry (Ríos‐Tamayo et al, 2015) until the end of 2018 are reported. Comparisons for categorical variables among different groups were made with the x2‐test. Comparisons of means of quantitative continuous variables between two groups were made with the t‐test. OS curves were estimated using the Kaplan‐Meier method, and comparisons among groups were carried out with the log‐rank test.

Results:

200 patients were evaluated, 117 men (58.5%) and 83 women. 35 patients (17.5%) lived alone at diagnosis, 19 men and 16 women. There was a trend to better OS for patients with some caregiver available with respect to patients who live alone (p = 0.074) (Figure 1). Median age for patients living alone was 68.74 vs 62.1 years (p = 0.006). Weight loss was documented in 18/35 (51.4%) vs 53/163 (32.5%) (p = 0.077). No statistical differences were shown between groups for other variables (body mass index, number of comorbidities, sex, ECOG, ISS, Light‐chain only MM and High‐Risk FISH). There were not statistically significant differences in EM at 6 months (6.8% vs 11.8%; p = 0.3).

Summary/Conclusion:

Patients with NDMM who live alone represent approximately 17.5% and have to face a huge challenge, showing a trend to poorer OS in comparison with patients who have a caregiver. This poor outcome may be due in part to a more advanced age. However, we cannot rule out other factors such as a poor adherence to the treatment.

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PS1476 APPLICATION OF WHOLE EXOME SEQUENCING FOR PATIENTS WITH INHERITED PLATELET DISORDERS
Authors: Stevens‐Kroef M. , de Munnik S. , van Heerde W. , Brons P. , Saes J. , Schols S. , Simons A.
Published: June 2019

Background:

Inherited platelet disorders (IPDs) are disorders consisting of thrombocytopenia, thromobocytopathy or a combination of these. Diagnosis is often hampered by the lack of specificity and correct validation of current hematological assays. In addition, these disorders exhibit a genetic heterogeneity with over 50 genes involved.

Aims:

This study evaluates an upfront diagnostic strategy using whole‐exome sequencing (WES) with a targeted analysis of a panel of 145 genes involved in thrombosis and hemostasis in patients suspected for an IPD.

Methods:

Sixty‐Six patients suspicious for an IPD were subjected to WES, followed by targeted analysis of 145 genes (besides platelet genes also genes involved in coagulation and venous thrombosis embolism are analyzed). Variants were classified according to the five‐tier (class 1 to class 5) scheme.

Results:

Fourteen patients (21%) harbored (likely) pathogenic variants that explained the clinical spectrum in these patients. Genes affected in these patients were GP9, MYH9 (2 cases), NBEAL2, P2RY12, RUNX1 (3 cases), SLFN14 and VWF (2 cases), all these genes are involved in thrombocytopenia or thromobocytopathy. In the disorders with an autosomal recessive mode of inheritance either the mutation was homozygous (GP9 and P2RY12), or compound heterozygous (NBEAL2). Additionally, 2 patients with a mutation in the THPO gene and 1 patient with a mutation in SEPRINC1 were observed, both genes are known to be involved in venous thrombosis.

In 4 (6%) other patients only one heterozygous (likely) pathogenic variant of an autosomal recessive disease gene was observed. In 12 patients (18%) a variant of unknown significance (VUS/class 3) was observed. Further segregation studies within the family and functional studies are required to fully solve these cases.

Summary/Conclusion:

We found that WES is a powerful tool in genetically diagnosing patients with IPD.
PS1566 HEMATOPOIETIC STEM CELL GRAFTS AS A SOURCE FOR RECONSTITUTING INNATE LYMPHOID CELLS FOLLOWING STEM CELL TRANSPLANTATION
Authors: Van Hoeven V. , Kroeze A. , Haverkate N. , Omar S. , Jachimowski L. , van Lier Y. , Franken S. , Zeerleder S. , Blom B. , Voermans C. , Hazenberg M.
Published: June 2019

Background:

Graft‐versus‐host disease (GvHD) is a common and life threatening complication of allogeneic stem cell transplantations (ASCT), and is thought to be initiated by chemotherapy‐induced tissue damage. Innate lymphoid cells are involved in tissue remodeling and repair and may therefore have a protective role in the development of GvHD. Indeed, in a previous study we observed that relatively high frequencies of activated ILC3 s before and/or after ASCT were associated with a lower risk to develop GvHD. While rapid reconstitution of ILCs thus seems favorable, ILCs in fact recover slowly and do not reach normal levels within 6 months post‐ASCT.

Aims:

By investigating the composition of stem cell grafts and the ILC‐development potential of graft‐derived multipotent hematopoietic progenitor cells (HPCs), we here aim to gain more insight into how ILCs reconstitute from stem cell grafts.

Methods:

Peripheral blood‐mobilized stem cell grafts of healthy adult donors were thawed and ILCs were phenotyped by flow cytometry. Lineage− CD34+ CD45RA+ HPCs were FACS‐sorted and cultured for a maximum of 4 weeks on JAG1‐expressing OP9 stromal cells in the presence of IL‐2, IL‐7, stem cell factor and Flt3‐ligand. This method was previously shown to support ILC development.

Results:

We detected mature ILC1 s, ILC2 s and ILC3 s in all grafts, and the median frequency of total CD127+ ILCs was 0.26% of the lymphocytes. The distribution of the ILC subsets differed substantially between stem cell grafts. HPCs isolated from human fetal liver successfully developed into ILCs within 4 weeks culture, however, HPCs derived from adult stem cell grafts did not have the capacity to develop into ILCs. We are currently investigating whether the age and the source of the isolated HPCs matters by testing the ILC developmental potential of cord‐blood and bone‐marrow derived HPCs. At the same time we are extending our graft and post‐ASCT analyses to be able to correlate our in vitro findings to in vivo ILC reconstitution.

Summary/Conclusion:

While mature ILCs present in stem cell grafts may be a good source for reconstituting ILCs, the ILC‐developmental potency of (adult) graft‐derived HPCs seems to be poor, possibly reflecting a decline in the potency of stem cells to develop into ILCs with increasing age. These results offer an explanation for the slow reconstitution of ILCs after ASCT.

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S1644 ASSOCIATION OF SYSTEMIC CYTOKINE LEVELS WITH RISK OF VENOUS THROMBOEMBOLISM IN PATIENTS WITH GLIOMA
Authors: Mir Seyed Nazari P. , Moik F. , Marosi C. , Riedl J. , Berghoff A.‐S. , Preusser M. , Hainfellner J.A. , Pabinger I. , Zlabinger G. , Ay C.
Published: June 2019

Background:

Venous thromboembolism occurs frequently in patients with primary brain tumors.

Aims:

Given the strong interplay between inflammation and haemostasis, the aim of the current study was to investigate the association of serum cytokine levels and risk of VTE development in patients with glioma.

Methods:

Within the framework of the Vienna Cancer and Thrombosis Study (CATS), a prospective and observational cohort study of patients with active cancer, we conducted an exploratory analysis. Patients were recruited at the time of cancer diagnosis or progression of disease after remission and followed for two years. Primary endpoint was symptomatic and objectively confirmed VTE. At study entry, a single blood draw was performed. Several cytokines (e.g. Interleukin (IL)‐1b, IL‐4, IL‐6, IL‐8, IL‐10, IL11, CCL3, TNF‐a, VEGF‐a) were measured in serum samples with the xMAP technology developed by Luminex.

Results:

In this study, 128 glioma patients were analyzed. Of those, 98/128 (76.6%) were diagnosed with glioblastoma (WHO grade IV), 24/128 (18.8%) with anaplastic glioma (WHO grade III) and 6/128 (4.7%) with diffuse glioma (WHO grade II). In total, 22/128 (17.2%) glioma had an IDH1 mutation. During follow‐up, 14/128 (10.9%) patients developed VTE. In univariable Cox‐regression analysis, CCL3 levels were significantly associated with risk of developing VTE (hazard ratio [HR] per 10 units increase: 0.629 [95% CI: 0.407–0.0.972], p = 0.037), while there was no significant association between the risk of VTE and serum levels of IL‐1b, IL‐4, IL‐6, IL‐8, IL‐10, IL‐11, TNF‐aand VEGF‐a, respectively. In multivariable analysis, adjusting for potential confounders (sex, age, glioblastoma), the association of CCL3 with the risk of VTE remained statistically significant (adjusted HR: 0.628 [0.397–0.992], p = 0.046). Cumulative incidence of VTE in reverse Kaplan‐Meier estimates was 22.8% in patients with low CCL3 serum levels (≤ 25thpercentile = 1.95 pg/ml) and 9.1% in patients with higher CCL3 serum levels (> 25thpercentile) (log‐rank, p = 0.017). (Figure 1)

Summary/Conclusion:

One out of 10 patients with glioma developed VTE in our study and low serum levels of CCL3 were associated with an increased risk of VTE. In conclusion, CCL3 might be useful as a potential biomarker for prediction of risk of VTE in patients with glioma.

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PB1659 WHOLE EXOME SEQUENCING IN ADULT PATIENT WITH PHILADELPHIA / BCR‐ABL1 POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: Lee P. Chin , Zubaidah Z. , Ranjeev H. , Fei K. Tsung , Ching N. Ching
Published: June 2019

Background:

BCR‐ABL1 gene fusion is detected at approximately 20% of adult acute lymphoblastic leukemia (ALL). Patients with Philadephia (Ph) / BCR‐ABL1 positive are a high risk group that associated with poor prognosis and short duration remission. Patients showed markedly improved with introduction of tyrosine kinase inhibitor combined with chemotherapy regimen but a small fraction of these patients remain refractory and poor response to treatment.

Aims:

The aim of this study was to determine the somatic mutations profile using whole exome sequencing of patient with Ph‐positive ALL.

Methods:

DNA from matched tumour‐normal samples for four patients with Ph‐positive ALL was extracted from peripheral blood or bone marrow leukemia cells by QIAamp DNA Mini kit. The exome library was enriched using the Nextera Rapid Capture Expended Enrichement kit (Illumina, San Diego, CA) according to the manufacturer's protocol and were subsequently sequenced on Illumina HiSeq 2500 system. Somatic mutations were separated from germline variants using Genome Analaysis Toolkits (GATK) best practices filtering strategy.

Results:

We identified a total of 14,804 intragenic somatic mutations (range from 2,948 to 4,165 in each). Of these 760 variants were passed through the variant caller. Among them 462 were single nucleotide variants (SNVs) and 298 were insertion/deletions (InDels). Total of 48 common variants were observed but failed Mutect caller. Among SNVs, 110 variants were nonsynonymous, 46 synonymous, 6 stopgain, 3 unknown and majority 297 (64.3%) null variants. A total of 53 nonsynonymous SNVs and 14 InDeLs (8 were frameshift deletion, 5 frameshift insertion and one stopgain) were identified as possible pathogeneic variants. The identified mutation genes in this study mostly also found in other malignancies disease and two alteration genes MCM7 and STAT5 were found in disease progression of CML.

Summary/Conclusion:

We have sequenced the whole coding sequence of four Ph / BCR‐ABL1 positive ALLs and corresponding normal samples that allows us to overview of candidate gene in the coding regions that driving Ph‐positive ALL development and as well as enhanced our understanding of the candidate genes in diagnosis testing and prognostic prediction of adult ALLs patient.
PB1669 RISK FACTORS FOR THROMBOEMBOLISM IN ADULT PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: Boban A. , Mikulić M. , Serventi‐Seiwerth R. , Ostojić A. , Vrhovac R. , Duraković N. , Perić Z. , Bašić‐Kinda S. , Sertić D. , Rončević P. , Dujmović D. , Radman I. , Pulanić D. , Batinić J. , Zupančić‐Šalek S. , Aurer I.
Published: June 2019

Background:

Thromboembolism frequently complicates treatment of acute lymphoblastic leukemia (ALL).

Aims:

A single‐center retrospective study was conducted with the objective of assessing the risk factors for thromboembolism in adult patients with ALL.

Methods:

The study included 87 consecutive patients (aged 19–70 years; 57 males) treated for ALL; B‐cell (n = 40), T‐cell (n = 26), Ph+ (n = 13), byphenotypic (n = 3) and unclassified (n = 5) during the 10‐year period. All patients but one received intensive treatment, including L‐asparginase in 57 (65%) patients, while 23 (26%) underwent allogenic stem cell transplantation. Vast majority of patients (n = 80, 92%) had central venous catheters at least once during the treatment period, including peripherally inserted central catheter (PICC) placed in 18 (21%) patients.

Results:

Fourteen patients (16%) developed thrombosis during the study period. Deep venous thrombosis was described in 9(65%), pulmonary embolism in 2(14%), and cerebral sinus thrombosis in 3(21%) patients. One death was attributable to thromboembolism. The risk of thromboembolism was associated with the induction treatment, protocols including L‐asparginase, the use of central venous catheters, namely PICC, and non‐0 blood groups.

Summary/Conclusion:

Our results demonstrate high incidence of thromboembolic events in patients with ALL. The highest risk is attributed with the use of L‐asparginase, despite vigorous control of coagulation parameters and antithrombin substitution. Finally, our results strongly suggest against simultaneous use of L‐asparginase and PICC.
PB1709 TET 2 POLYMORPHISM AND MIRNA 22 EXPRESSION AMONG EGYPTIAN PATIENTS WITH ACUTE MYELOID LEUKEMIA
Authors: Dammag E. , Hamed N. , El Halawany N. , Kassem H. , Ayad M.
Published: June 2019

Background:

Acute myelogenous leukemia (AML) is a heterogeneous group of disease characterized by uncontrolled proliferation of myeloid progenitor cells. It is clear that TET2 polymorphisms are common among Egyptian AML patients and larger scale studies are needed to iinvestigate the role of this in both modulating treatment and prognostic impact of the disease. TET2 mutations are established poor prognostic molecular risk factors yet TET2 polymorphism status are not thoroughly studied. Role of miRNA22 and its impact on TET2 expression needs to be further studied to improve risk stratification of AML.

Aims:

The aim of this study is to evaluate the incidence of the TET2 single nucleotide polymorphism (SNP) (rs2454206, rs34402524, rs61744960) and its correlation to miRNA22 gene expression in Egyptian Adult Acute Myeloid Leukemia patients.

Methods:

Cases were selected from Alexandria Main University Hospital Internal Medicine Department (Hematology Unit) from March 2017‐December 2017; 52 patients diagnosed as AML and 30 healthy subjects matched for age and sex to determine SNPs genotype frequency among patients. DNA extraction by Invitrogen purelink genomic DNA minikit (Cat No. k1820‐01, Lot No 1510617) and real time PCR for TET2 SNP polymorphism using Taqman primers and probes of TET2 polymorphism (rs2454206, rs34402524, rs61744960) using an ABI Prism GeneAmp 7500 using peripheral or bone marrow blood. Micro RNA 22 Taqman quantitative Assay using real time PCR (Thermal Fisher Biosystems Taqman miRNA22 Cat. no. 4427975) and control miRNA was U6. Micro RNA extraction was done using Qiagen extraction kits (Cat No./ID: 217004). Written Informed consent was taken from every patient and approval of the Ethical committee (IRB No. 00008699, FWA No.00015712) was provided.

Results:

35 AML patients (14 females, 21 males) had mean age of 43.42 ± 14.0yrs are the subject of the study. SNP RS 34402524 ranged from heterozygous (23/52 46%) to homozygous (27/52 54%) in AML group but was mainly homozygous (24/30 80%) among the control group (p>0.05). As for RS 6843141, most AML patients had wild pattern (31/52 62%) and control group were homozygous (20/30 60%) (p < 0.0001). RS 2454206, and RS 61744960 showed no statistical significance between cases and controls (p > 0.05). miRNA22 were under‐expressed among AML most patients. This was of statistical significance compared to controls p < 0.0001. As for miRNA 22 and TET2 polymorphism, there was no statistical significance between the status of SNPs and miRNA22 expression p > 0.05.

Summary/Conclusion:

miRNA22 is markedly underexpressed in AML patients and may participate in hypermethylation and leukomogenesis. Confirmation of this finding could open a new therapeutic approach in AML and even in bone marrow transplant candidates.

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PB1735 POSTDIAGNOSIS SMOKING WITH RISK OF ALL‐CAUSE AND CANCER MORTALITY AMONG LEUKEMIA SURVIVORS: A PROSPECTIVE COHORT STUDY
Authors: Tao H.
Published: June 2019

Background:

Smoking is associated with higher leukemia risk, but smoking and risk of all‐cause and cancer mortality among leukemia survivors is unclear.

Aims:

To evaluate more thoroughly the risk of all‐cause and cancer mortality between cigarette smoking and leukemia

Methods:

We identified 316 subjects who were diagnosed with leukemia from National Health Interview Survey participants≥18 years of age from 13 cross‐sectional waves conducted during 1997 to 2009 (linked to mortality data in 2015) at baseline. Cox proportional hazards regression models were used to calculate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the risk of all‐cause and cancer mortality caused by smoking exposure.

Results:

After a median follow‐up of 13 years, 141 (50%) were alive and 141 (50%) died due to all‐cause mortality during the follow‐up. Of all the patients who died, 70 (50%) died due to cancer and 20 (14%) died due to cardiovascular disease (CVD). Compared to never smokers, former smoking could increase the risk of cancer mortality (HR, 1.95; 95%CI, 1.04‐3.68), especially for those who quit smoking recently (HR, 2.59; 95%CI, 1.17‐5.74). For cancer mortality, dose relationship was obvious among former smokers who had quit more recently than for those who had quit earlier with a “U” shaped curve (Ptrend < 0.05). Current smokers who smoke less than 10 cigarettes per day had higher risk of cancer mortality (HR, 3.72; 95%CI, 1.01‐13.73) than never smoking when patients with a history of CVD were excluded.

Summary/Conclusion:

This study adds to the existing evidence that cigarette smoking is associated with higher cancer mortality among leukemia patients, especially for former smokers.

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PB1736 IMPACT OF BCR FUSION TRANSCRIPTS ON OUTCOMES IN ACUTE PROMYELOCYTIC LEUKEMIA (APL)
Authors: Pydi V.R. , Chowdary B.S. , Yedla R.P. , Gundeti S.
Published: June 2019

Background:

Acute promyelocytic leukemia (APL) results from fusion of PML RARα gene and accounts for 10% of AML. The breakpoints on chromosome 17 are consistently located in the second intron of the RARα gene, but on chromosome 15, there are different breakpoint cluster regions, namely bcr1, bcr2, and bcr3 located in intron 6, exon 6, and intron 3, respectively. About 70% of patients with APL have bcr‐1 or long (L)‐type transcript, 20% of patients with APL have bcr‐3 or short (S)‐type transcript, and 10% of patients have bcr‐2 or variant (V)‐type transcript

Aims:

The primary objective of this analysis was to study patient characteristics and outcomes in relation to bcr fusion transcripts of APL

Methods:

Data of all patients diagnosed as APL by PCR for PML RARα with known bcr transcripts were retrospectively analysed. Deaths within 72 hours of admission were excluded from the study. Statistical analysis was done using SPSS software, version 25. Overall survival was plotted using the Kaplan‐Meier method

Results:

A total of 54 patients were analysed. bcr 1, bcr 3, bcr 2 and bcr 2’3 transcripts were seen in 29(53.7%), 20(37%), 3(5.6%) and 2(3.7%) respectively. Ten out of 11 paediatric patients (91%) had bcr1 transcript at presentation. The baseline characteristics and chemotherapy regimens used are tabulated in Table 1. Differentiation syndrome during induction chemotherapy was seen in 6 (21%) and 3 (15%) patients in bcr1 and bcr 3 transcripts respectively. Five patients with bcr3 transcript, 2 patients with bcr1 transcript and one patient each in bcr2 and bcr2’3 transcripts succumbed during induction therapy. Sepsis (45%), followed by DIC (45%) were the most common causes of mortality. At a median follow up of 19 months, the overall survival rate was 93.1% and 74.3 % in bcr1 and bcr3 transcript groups respectively (p = 0.09).

Summary/Conclusion:

Most of the paediatric patients had bcr1 transcript at presentation. High risk at presentation was significantly higher in bcr3 group. Sepsis and DIC were the most common causes of induction mortality. Patients with bcr3 transcript had nonsignificant inferior survival compared to bcr1

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PB1759 DNMT3A MUTATION IS NOT RELATED WITH UNFAVORABLE CLINICAL OUTCOME IN ACUTE MYELOID LEUKEMIA PATIENTS
Authors: Lee Y.K. , Lee J. , Jeon K. , Kim M. , Han B. , Kim H.J.
Published: June 2019

Background:

Mutation in DNMT3A (DNA methyltransferase 3A) has been identified as a key factor in the development of hematological malignancy. While some previous reports have suggested that DNMT3A mutation is related with negative outcome in acute myeloid leukemia (AML) patients, the clinical implication and prognostic significance of DNMT3A mutation in AML is still debated.

Aims:

We intended to investigate the incidence of DNMT3A gene mutation and its association with clinical and laboratory findings and prognosis in Korean AML patients.

Methods:

From 2012 to 2018, we enrolled forty‐nine patients diagnosed with AML without recurrent genetic abnormalities. We performed Sanger sequencing to analyze DNMT3A mutation using residual bone marrow samples. We also collected other laboratory data and clinical information via electronic medical records.

Results:

We found DNMT3A mutations in 6 out of 49 AML patients (12.2%). Five patients had the R882H mutation, and one patient the R882C mutation. There was no significant difference in age, complete blood cell count (CBC) parameters, or bone marrow (BM) blast % between the groups with and without DNMT3A mutations. The portion of patients older than 60 years was smaller in DNMT3A mutation positive group (33.3% vs. 60.5%, p = 0.381). DNMT3A mutation group showed higher rate of complete remission (CR) (50% vs. 27.9%, p = 0.353), shorter period to CR (1.1 (CI 1.1 – 1.2) months vs. 1.2 (CI 1.0 – 2.8) months, p = 0.613), and lower relapse rate after CR (0% vs. 41.7%, p = 0.505) than DNMT3A mutation negative group although the difference was not statistically significant. In the survival analysis, the median overall survivals (OS) were 29.0 (CI 5.5 – 52.4) months for DNMT3A mutation positive group and 10.8 (CI 0.5 – 21.0) months for DNMT3A mutation negative group. The median progression free survivals (PFS) were 29.0 months (CI 5.5 – 52.5 months) for DNMT3A mutation positive group and 8.0 months (CI 0.0 – 16.3 months) for DNMT3A mutation negative group. However, the effect of DNMT3A mutation on OS and PFS was not statistically significant (p = 0.814 and p = 0.528, respectively). In a multivariate analysis, the only independent predictive factors for survival were age (HR: 1.027, p = 0.001) and BM blast % (HR: 1.017, p = 0.016). DNMT3A mutation, sex, and CBC parameters were not independent predictors of survival.

Figure 1. Kaplan‐Meier overall survival analysis (A) and progression‐free survival analysis (B) comparing between the groups with and without DNMT3A mutation.

Summary/Conclusion:

The incidence of DNMT3A mutation was 12.2% in Korean AML patients. DNMT3A mutation tended to be related with favorable outcome although statistically insignificant. This statistical insignificance might be due to the small sample size. Considering all, our results at least provide support for the view that DNMT3A mutations is not an unfavorable prognostic factor in AML patients.

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PB1771 EFFECTS OF AJWA ON DISEASE COMPLICATIONS AND CARDIAC AMONG HEMATOLOGICAL MALIGNANCY AND AJWA NANOFORMULATIONS ON THE ANTI‐CANCER AND SAFETY
Authors: Al Jaouni S. , Hussein A. , Ezzat D. , Almuhayawi M. , Raddadi R. , Mousa S.
Published: June 2019

Background:

Phoenix dactylifera, (Ajwa) has been known for a long time for its nutritive and medicinal properties.

Aims:

To evaluate the benefit of Ajwa in minimizing disease complications and cardiac on Pediatric Hematological malignancy at King Abdulaziz University Hospital, Jeddah, Saudi Arabia and to preclinically evaluate Nanoformulated Ajwa Bioactive compounds (N‐Ajwa) on Anti‐cancer efficacy and prevention of cardiac toxicity‐mediated by Doxorubicin (DOX).

Methods:

Our investigation include clinical and preclinical studies. The clinical study is a controlled trial of pediatric cancer patients between 2008 and 2018. A total of 200 patients were screened. Out of the 200 patients, 56 patients were included, 10 patients were AML (17.8%). Out of those 56, 26 (46.43%) agreed to take Ajwa and 30 served as control (53.57%). Both groups were assessed based on the following parameters: infection rates, frequency of hospital admissions for fever neutropenia, safety and mortality rate. The preclinical study examined the impact of N‐Ajwa on the anti‐cancer efficacy and cardiac safety of DOX in human breast cancer in female nude mice model.

Results:

Out of the 56 patients included, twenty six patients opted to be on Ajwa and the rest served as control. The supplementation of Ajwa significantly reduced hospital admissions and infections (P = 0.009 and P < 0.001 respectively). Ajwa group had a better survival rate in comparison to those in the non‐Ajwa group (stratified log‐rank P = 0.005), where the main cause of death of patients on the non‐Ajwa group was disease progression associated with infections (77%), cardiac problems were documented in 3 AML patients(30%). Those who were compliant on Ajwa showed recovery of cardiac problems. Ajwa showed some sort of cardiac protection in cardiac patients. N‐Ajwa bioactive ingredients protected against cardiac toxicity without any impact on anti‐cancer effects of DOX.

Summary/Conclusion:

This controlled study showed the regular intake of Ajwa is safe and significantly decreases disease complications including cardiac and infection and improved survival. Additionally, Ajwa have an effective role in cardiac protection against Doxorubicin.
PB1845 THE EFFICACY OF TRANEXAMIC ACID IN MINOR SURGERY WITH BLEEDING DISORDERS PATIENTS: 17 YEARS EXPERIENCE AT UNIVERSITY HOSPITAL
Authors: Al Jaouni S. , Farsi D. , Al Muhayawi S.
Published: June 2019

Background:

Tranexamic acid (TXA) is an antifibrinolytic agent commonly used to reduce blood loss in different medical disorders.

Aims:

To assess the efficacy and outcome to use TXA in dental work with patient with bleeding disorders at our institute over 17 years period.

Methods:

This is a retrospective study to assess the efficacy of the TXA in all dental works for patients with bleeding disorders treated at King Abdulaziz University Hospital (KAUH) at King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia, between 2000‐2017, also to assess the requirements of transfusion after the procedures.

Results:

One hundred twenty one patients with bleeding disorders underwent dental and minor surgery over 17 years with patient age range 3‐46 years. Tropical oral TXA in majority of the cases only 5% used intravenous TXA in hospitalized patients. Less than 5% required transfusion after the procedures.

Summary/Conclusion:

Strong evidence supports the use of TXA in minor surgery with bleeding disorders in our institute over 17 years. Markedly decrease and minimize the need of transfusion after use TXA in dental works.
PB1856 HEPATITIS ASSOCIATED APLASTIC ANEMIA: ETIOLOGY, CLINICAL CHARACTERISTICS AND OUTCOME
Authors: Tüfekçi Ö. , Hekimci Özdemir H. , Malbora B. , Özbek N.Y. , Yaralı N. , Erdem A. , Evim M. , Baytan B. , Karapınar T. , Oymak Y. , Yılmaz S. , Yılmaz Karapınar D.
Published: June 2019

Background:

Hepatitis associated aplastic anemia (HAA); is a form of acquired aplastic anemia in which bone marrow failure develops after an acute attack of hepatitis. Aplastic anemia can also be seen after liver transplantation due to acute fulminant hepatitis.

Aims:

In this study, we aimed to define clinical and labarotory characteristics, possible causes, treatment strategies and and clinical outcome in patients with HAA.

Methods:

Seventeen children from six centers throughout Turkey were enrolled in the study. Clinical data were retrieved from the medical records.

Results:

The median age at time of diagnosis of acute hepatisis was 8.9 years (min: 5‐max:17).

Search for etiology revealed highly positive CMV‐DNA in one patient and HCV‐RNA in one patient. One other patient was found to be positive for EBV, CMV and parvovirus DNA. Besides, one patient had the diagnosis of autoimmune hepatitis. The median time from diagnosis of hepatitis to diagnosis of aplastic anemia was 30 days (min:0‐max:322). Pancytopenia was simultaneously present in 5 out of 17 (29%) patients. Liver transplantation due to acute fulminant hepatitis was performed in 5 patients (29%). Aplastic anemia developed before liver transplantation in two patients and after liver transplantation in three patients. In terms of treatment for aplastic anemia; 8 patients (47%) received immunsuppressive treatment (IST) with anti‐thymocyte globulin and cyclosporine. HLA identical hematopetic stem cell transplantation (HSCT) was performed in 5 patients (29%). Two patients who received IST later underwent HSCT. The median time from diagnosis of AA to IST and HSCT were 45 days (min:1‐max:218) and 104 days (min:86‐max:1282), respectively. At the end; 9 out of 17 patients (52%) were alive, in remission and transfusion free. Those who were alive either received HSCT and/or IST, except one patient who received no treatment. Eight patients (48%) died mainly due to infectious causes.

Summary/Conclusion:

Although there have been limited number of patients in the present study, it was noteworthy that approximately one‐third of patients presented with pancytopenia at the time of diagnosis of hepatitis. Further research is needed to investigate the effect of some etiological agents on the clinical outcome. The loss of patients who did not undergo IST and HSCT revealed once again the importance of initiating IST at the appropriate time together with donor search for HSCT in this group of patients.
PB1869 PERSISTENT COMPLEMENT ACTIVATION IS PROVOKED BY IGG‐AGGREGATES IN A SUB‐POPULATION OF CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS
Authors: Michelis R. , Tadmor T. , Barhoum M. , Shehadeh M. , Shvidel L. , Aviv A. , Stemer G. , Dally N. , Rahimi‐Levene N. , Yuklea M. , Braester A.
Published: June 2019

Background:

Therapeutic monoclonal antibodies used in Chronic lymphocytic leukemia (CLL) act through complement‐mediated cytotoxicity and other mechanisms, and thus depend on the complement (C) availability and activity. Recently we showed abnormal Western analysis pattern of the C5 component in some CLL patients, that was associated with high basal levels of C activation markers, and decreased activity of the classical pathway (CP). We hypothesized that the CP may be constantly activated, and thus exhausted, in a sub‐group of CLL patients, identified by the abnormal appearance of C5.

Aims:

The aim was to study the circulating abnormal C5 and its association with the observed decrease in CP activity, and to search for potential CP‐activating factors in CLL plasma.

Methods:

Blood samples were collected from 40 naïve CLL patients and 15 normal controls (NC). Activities of the CP and of the CP C5‐convertase were studied. C5, C5a and C5b were studied by Western blot analysis. The presence of high molecular weight (HMW) protein complexes, such as IgM or hexameric‐IgG, as potential CP activators was assessed by sera fractionation (gel‐filtration chromatography) followed by C activation with the obtained HMW, and low molecular weight (LMW) fractions. The levels of IgM were measured. Data from patients with abnormal C5 was compared to normal NC subjects and to patients with normal C5.

Results:

In patients with abnormal C5, activities of the CP and of the CP C5‐convertase were decreased, compared to NC subjects and to patients with normal C5. The abnormal C5 was identified as a complex of immunoglobulin with C5a (Ig‐C5a). In agreement, the high levels of C activation markers showed negative and significant correlation with activity of the CP, but not with the alternative pathway. The data on C activation by the HMW fraction indicated the presence of IgG‐aggregates, and not IgM, as the C activating factor in sera.

Summary/Conclusion:

In some CLL patients, factors such as IgG‐aggregates that are present in sera constantly trigger the activation of the CP. This constant activation results in the release of activation products, such as C5a, that form the complex Ig‐C5a. Another result is the exhaustion of the CP and the inability to exert CP activity that is comparable to normal subjects. The data provides a potential prognostic tool that may personalize therapy by identifying a sub‐group of CLL patients who display Ig‐C5a and impaired CP activity, and are likely to be less responsive to immunotherapy due to compromised CP activity.
PB1899 CONCEPTUAL MODEL OF CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: Eek D. , Blowfield M. , Krogh C. , Chung H. , Eyre T.A.
Published: June 2019

Background:

A comprehensive conceptual model (CM) of chronic lymphocytic leukemia (CLL) is required to help researchers understand patients’ unmet needs and direct future advancements in the field, particularly in developing patient‐centered endpoints to evaluate the benefits of new therapies within clinical trials.

Aims:

The current study aimed to create a CM of disease‐ and treatment‐related signs, symptoms and impacts in patients with first‐line (1L) or relapsed/refractory (R/R) CLL.

Methods:

The CM was based on literature searches, review of CLL patient blogs/forums, interviews with expert hematologists, and semi‐structured concept elicitation interviews with 40 patients with CLL (20 1L, 20 R/R; with fatigue, weight loss, fever, and/or night sweats in previous week). To identify salient concepts, the number of patients mentioning each concept and the concept's mean disturbance rating (from 0 [not at all] to 10 [very]) were mapped.

Results:

Literature searches identified 32 prevalent concepts, with the most common being fatigue/tiredness. Patient blogs/forums revealed further symptoms (muscle/joint aches, headaches, weakness) and impacts (stress, fear of death, uncertainty). Clinicians reported recurrent infections and enlarged lymph nodes as key signs of CLL and noted that fatigue is related to both symptoms (e.g. tiredness) and impacts (e.g. needing to rest and limit daily activities). In patient interviews, 50 concepts were revealed, with 42 present in both 1L and R/R; fatigue was the most prominent and impactful. Fatigue‐related sub‐concepts were identified, covering symptoms (tiredness/need for sleep, lack of energy, weakness, cognitive fatigue) and impacts (decreased ability to maintain social/familial/professional role, decreased physical functioning, frustration). Three versions of the CM were created: an overall model with all identified concepts, and two models highlighting the most salient concepts in 1L and R/R (Figure 1). Muscle/joint aches, night sweats, bruising, fatigue‐related symptoms, fever and recurrent infections/illness were salient symptoms in both 1L and R/R. Salient impacts in both 1L and R/R were fatigue‐related impacts, insomnia, decreased cognitive/emotional functioning, anxiety/worry, stress, depression, financial difficulty, and fear of death. Dyspnea and cough were salient in 1L only, and enlarged lymph nodes, headaches, pain/discomfort, weight loss, nausea/vomiting, and infusion reactions were salient in R/R only.

Summary/Conclusion:

The three versions of the CM can help to inform patient‐centered endpoints to evaluate new treatments for 1L and/or R/R CLL.

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PB1915 CD14 AS A POTENTIAL PROGNOSTIC FACTOR AND BCL‐2 AS A THERAPEUTIC TARGET IN EGYPTIAN B‐CELL CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS
Authors: Elkhawanky M. , Morsy M.
Published: June 2019

Please indicate where the abstract has been published before: Journal of Applied Hematology.

Background:

B‐cell chronic lymphocytic leukemia (B‐CLL) is a unique lymphoproliferative disorder that scarcely occurs under the age of 40. B‐CLL represents a neoplastic disorder caused primarily by defective programmed cell death and accompanied by a myriad of cellular and humoral immune defects.

Aims:

This study aimed to assess Bcl‐2 and CD14 expression in B‐CLL patients and their study as probable prognostic and therapy targeting factors.

Methods:

In this study, we assessed Bcl‐2 and cluster of differentiation (CD14) expression in a group of Egyptian patients with B‐CLL. Forty B‐CLL patients and 20 apparently healthy individuals served as the control group were included in this study.

Results:

Aberrant expression of Bcl‐2 protein appeared in all B‐CLL patients (100%). Bcl‐2 expression showed a highly positive correlation with total lymphocyte count and lymphocyte count (P = .000 for both) and a positive correlation with lactate dehydrogenase (P = 0.044). The expression of myelomonocytic antigen “CD14” above the cutoff value 5 × 109/L was reported in 70% (28/40) of B‐CLL patients, 55.6% (10/18) of the intermediate‐risk group, and 81.8% (18/22) of high‐risk group.

Summary/Conclusion:

There was a significant increase in Bcl‐2 protein and CD14 in B‐CLL patients. Bcl‐2 was highly increased in all patients and CD14 more observed in the high‐risk group than that of the intermediate risk group.
PB1972 RIBOCICLIB INDUCES MACROCYTOSIS IN THERAPEUTIC DOSES: CHARACTERIZATION OF OUTCOME
Authors: Alves S. , Alves S.
Published: June 2019

Background:

Ribociclib is a small molecule that selectively inhibits cyclin‐dependent kinases 4 and 6, blocking the phosphorylation of retinoblastoma protein and inducing of G1 phase arrest hence having an important role in the regulation and prevention of cell‐cycle progression. The project OncoDynamics aims to explore possible correlations between therapeutic doses of ribociclib for treatment of breast cancer and other therapies with several analytic biomarkers and clinical data. Adverse events of CDK 4/6 inhibitors are mostly hematologic being neutropenia the most frequent followed by anemia and thrombocytopenia as it is the case of palbociclib which has been recently described as associated with macrocytic, dysplastic anemia.

Aims:

This study aims to characterize the outcome of macrocytosis evident in our patients treated with ribociclib in therapeutic doses for treatment of breast cancer.

Methods:

This study is integrated in the OncoDynamics project and is a prospective, unicentric cohort study with patients treated for metastatic breast cancer with ribociclib plus letrozole, each patient registered as digital case report form and evaluated data of mean corpuscular volume (MCV), hemoglobin (Hg) and red cell distribution width (RCDW) for descriptive analyses.

Results:

Of the 7 patients with breast cancer treated with ribociclib (14,8%) with a follow up period ranging from 3 to 18 months, 4 patients (57,1%) had a sustained rise of the mean corpuscular volume (MCV > 97 fL), Hg ranging from 8,8 to 13,5 g/dL and RCDW from 12,7 to 20,9 CV%.

Summary/Conclusion:

We found this macrocytosis to be related to the treatment with ribociclib in therapeutic doses and in literature the correlation between CDK 4/6 inhibitors and macrocytosis has been described in relation to palbociclib. Clinical evolution of these patients is under evaluation. We aim to extend this study and to explore the inherent mechanism of action of ribociclib regarding anemia and macrocytosis.
PB1973 CONTRIBUTION OF NGS IN THE DIAGNOSIS OF HEREDITARY SPHEROCYTOSIS: CASE REPORT
Authors: Verstraete G. , Graux C. , Collinge E. , Depaus J. , Vellemans H. , Bianchi P. , Gulbis B.
Published: June 2019

Background:

Hereditary spherocytosis (HS) is the most frequent cause of non‐immune haemolytic anaemia (HA) among individuals of Northern European ancestry; its estimated prevalence is 1:2000. HS results from various molecular defects leading to decreased production or abnormality of one or more red blood cell (RBC) membrane proteins i.e., ankyrin, protein 4.2, band 3 and spectrin. The majority of HS cases (75%) are inherited in an autosomal dominant manner. Especially because of the spherical shape, RBCs are trapped in the spleen and have a shortened life span. Among other factors, according to the importance of the deficiency or protein abnormality it conducts to a clinical expression that may range from asymptomatic to severe chronic HA. Most often a phenotypic diagnosis can be made but next‐generation gene sequencing (NGS) has a place in difficult cases i.e. unsolved cases of HA, transfusion prior to diagnosis and discrepancy between clinical phenotype and diagnosis.

Aims:

We report here the case of a 18‐year‐old patient with a suspected HS, prominent splenomegaly and unknown personal or family history.

Methods:

Case report:

The patient complained of fatigue for several months and grade 2 dyspnea. In the past, he repeatedly presented with biliary colic pain. He apparently had no personal or family medical history. Two years ago, he nevertheless had jaundice secondary to haemolytic anaemia. The evolution was spontaneously favourable and no further investigation was undertaken. He has a twin brother and a 20‐year‐old sister, both in good health. The clinical examination found a prominent splenomegaly. Haemoglobinopathy and most frequent RBC enzyme deficiencies were excluded. Given the high clinical suspicion of HS, his parents and siblings (although asymptomatic) were screened for HS.

Results:

The main biological data are reported in the Table 1.

Molecular genetic analyses were performed: NGS targeted sequencing panel, containing panel 40 genes associated to haemolytic anemia, and confirmation by Sanger identified a nonsense mutation on the cytoplasmic domain of Band3. The mutation is novel and drastic; it causes a stop codon at 75 residues. The mutation is transmitted by the mother. NGS targeted sequencing analysis did not demonstrate any other abnormalities that could explain the phenotypic variability observed in the propositus and his mother.

Given the profound anaemia associated to the voluminous spleen (main diameter of 25 cm by CT‐scan evaluation) and given the presence of symptomatic gallstones, the patient underwent a splenectomy and a cholecystectomy. After the procedure, he recovered from fatigue and the haemoglobin level returned to normal with no signs of residual haemolysis.

Summary/Conclusion:

This case reports a HS related to a new nonsense mutation in SLC4A1. The transmission is autosomal dominant but the penetrance is heterogeneous within the same family.

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PB1974 PYRUVATE KINASE DEFICIENCY IN FOUR CHILDREN WITH TWO UNPUBLISHED MUTATIONS
Authors: Unal E. , Gok V. , Roy N.B.A. , Hipkiss R. , Howard K. , Ozcan A. , Yilmaz E. , Karakukcu M. , Henderson S. , Patıroglu T.
Published: June 2019

Background:

Pyruvate kinase is a key enzyme of anaerobic glycolysis which helps keeping the energy level of red blood cells and their viability in circulation. The genetic heterogeneity of pyruvate kinase deficiency (PKD) is high and, to this day, over 250 different mutations have been identified.

Aims:

We aimed to emphasize the importance of genetic testing in patients with unexplained non‐immune hemolytic anemia.

Methods:

Four patients who had been followed because of non‐spherocytic hemolytic anemia and in whom no causative enzyme deficiencies were identified were referred for targeted next‐generation sequencing using the Oxford Red Cell Panel, a 50‐gene panel for inherited anemias.

Results:

We studied four patients (2 females, and 2 males) with evidence of chronic hemolytic anemia aged between 4 years and 24 years. Three of the four patients had jaundice, pallor and hepatosplenomegaly, while one patient had growth retardation and hypotonicity. One patient had gallstones and also undergone splenectomy at the age of two. While homozygous mutation was detected in three of four patients, only one patient had a compound heterozygous mutations (c.602G > A, c.1675C > G). The five identified mutations are single nucleotide gene changes. Two of the five mutations (c.602G > A, and c.172C > T) are previously unpublished.

Summary/Conclusion:

The clinical presentation of PKD ranges from frequent transfusion in neonates to mild jaundice in adulthood. Total pyruvate kinase in liver and red cell (PKLR) gene sequencing is necessary for the characterization of all patients with PKD and for genetic counselling. We also report two previously unpublished mutations in PKLR.