bluuebunny/crossref_metadata_2025 huggingface dataset:
PF732 AN INDEPENDENT OBSERVATIONAL STUDY OF REAL LIFE COSTS OF CARE TO MYELOMA PATIENTS IN THE ERA OF NOVEL THERAPIES
Authors: Thompson J.
Published: June 2019

Background:

Novel haematological therapies offer advantages in management of malignant and non‐malignant conditions, but treatment access is limited by cost, typically referenced as medication cost alone. The addition of real world costs of care provides a more complete cost‐benefit analysis, and limited published data and common perception have suggested additional costs are greater for novel agents.

Aims:

We analysed and compared total dollar value costs of care excluding the cost of the novel agent for myeloma patients treated first‐line with bortezomib and non‐novel agent based regimens in an inclusive (encompassing all patients within a local health network), real‐world cohort.

Methods:

We interrogated electronic and case note databases to record hospital admissions, outpatient visits, investigations, and non‐primary‐therapy medications and costed these using standard values using single payer government benchmarks. The primary end point was the real world cost of treatment per patient for the first year of treatment.

Results:

After using generalised linear models to adjust for patient age, gender, International Staging System (ISS) stage, trial status and transplant status, the mean yearly cost of care for patients receiving bortezomib‐based regimens was AU$24,162 (CI $20,207–28,118), which was 2.6% lower (CI −22.1–21.7, p = 0.814) than that for those receiving regimens not containing a novel agent ($26,300, CI $23,121–29,479) excluding the novel agent. Compared to patients at Stage 1 at baseline ($, CI$‐), costs of care were 62.2% higher (CI 50.1–81.8, p < .0001) for patients at Stage 3 at baseline ($, CI$‐). Costs were 36.0% lower (CI 18.2–49.9, p < .0001) for trial patients ($21,381, CI $17,404–25,358) compared to non‐trial patients ($25,130, CI $20,120–30,139). Yearly costs of care are estimated to be on average 51.5% higher (CI 22.0–88.1, p < .0001) for transplant patients ($27,288, CI $23,351–31,226) compared to non‐transplant patients ($17,088, CI $10,980–23,196).

Summary/Conclusion:

Contrary to common perceptions and previously published data, bortezomib‐based regimens do not confer higher costs of care in the real world than conventional regimens. Subgroup analysis indicates significant cost differences based on ISS stage, trial involvement, transplant status and age.
PF743 PENICILLIN PROPHYLAXIS AND PNEUMOCOCCAL VACCINE USE IN ADULT SICKLE CELL PATIENTS: A RETROSPECTIVE ANALYSIS OF CLINICAL PRACTICE AND OUTCOMES IN OXFORD, UK
Authors: Ejaz A. , Hayes S. , Akanni M. , Roy N.
Published: June 2019

Background:

Pneumococcal disease prophylaxis with antibiotics and vaccination has a clear mortality benefit in children with sickle cell disease (SCD), with the greatest benefit in children under 5 years [1]. The benefit in adults, who also have functional hyposplenia, is less clear with no trial evidence to support or refute prophylaxis in this group. Current guidelines [2] recommend that adults with SCD have pneumococcal vaccination every 5 years and take antibiotic prophylaxis only if they are compliant, so reducing the theoretical risks of antimicrobial resistance in those who are partially compliant.

Aims:

Our aim was to establish the current uptake of pneumococcal vaccination and antibiotic prophylaxis in our adult patients with SCD. We wished to ascertain whether a difference exists in episodes of infection for patients who are fully compliant with pneumococcal prophylaxis and those who are not. MiniTab 18 was used for data analysis.

Methods:

Adult patients with SCD known to the Oxford Red Cell tertiary centre were identified from annual review assessments and a descriptive analysis was undertaken on patient demographics, co‐morbidities, prophylaxis compliance and pneumococcal vaccination status, and episodes of infection occurring from 2015‐2019.

Results:

133 patients with SCD were identified. 53% were female and the median age was 34 years (range 16–75 years) (see Table 1). 67% of patients were prescribed antimicrobial pneumococcal prophylaxis. Of these, 21% were known to be non‐compliant. 100% of patients were asked to attend their GP for vaccination but only 58% of patients had documentation of pneumococcal vaccination. From 2015 to 2019 there were 41 episodes of infection recorded in 31 patients but only 12 had positive cultures. There was no significant difference in infection rate between patients on prophylaxis and compliant (17/31) and remaining patients (14/31) (p = 0.61). There was one episode of confirmed pneumococcal disease and this was in a patient non‐compliant with prophylaxis and not up‐to‐date with vaccination.

Summary/Conclusion:

While the majority of our patients were prescribed antibiotic prophylaxis, due to non‐compliance, only half of our cohort were taking antibiotics reliably. There were few culture positive cases of infection, indicating that adults with SCD are at lower risk of infection compared with children, consistent with the literature [3]. In our cohort, over the 3 year period, there was only 1 documented case of pneumococcal disease. The low incidence of infection may have been due to our cohort being of younger age, with few comorbidities and a relatively high proportion of lower risk genotype. This work highlights the need for prospective, randomised evidence in SCD patients to establish whether a benefit exists for pneumococcal prophylaxis in adulthood.

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PF753 IMPACT OF ANTI‐THYMOCYTE GLOBULIN DOSES IN UNRELATED HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR PATIENTS WITH MYELOID NEOPLASM
Authors: Nam J.Y. , Bae S.H. , Kim M.K. , Hyun M.S. , Moon J.H. , Sohn S.K.
Published: June 2019

Background:

Anti‐thymocyte globulin (ATG) is widely used for the prophylaxis of graft‐versus‐host disease (GVHD) in hematopoietic stem cell transplantation (HSCT). However, there is still controversy regarding the optimal dose of ATG.

Aims:

We analyzed the impact of ATG doses in unrelated HSCT for patients with myeloid neoplasm.

Methods:

This was a retrospective multi‐center study that assessed the impact of ATG doses on clinical outcomes in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing an unrelated HSCT. The patients who received peripheral blood stem cells (PBSC) transplantation after conditioning regimens containing i.v. busulfan (BU), fludarabine and rabbit ATG between 2010 and 2017 were included in this study.

Results:

A total of 96 patents, median age 45 years, with AML (n = 74) or MDS (n = 22) were included in our analyses. 66 patients (69%) received a myeloablative regimen (i.v. BU>6.4 mg/kg). High‐ATG (ATG 9 mg/kg), intermediate‐ATG (ATG 4.5–5 mg/kg) and low‐ATG (ATG 3 mg/kg) were given in 11, 49 and 36 patients, respectively. After a median follow‐up of 23 months, the cumulative incidence of extensive chronic GVHD was 9.1% in the high‐ATG group, 13.8% in the intermediate‐ATG group and 29.7% in the low‐ATG group (p = 0.31). The rate of 2‐year relapse‐free survival was significantly higher in the intermediate‐ATG group than other groups (30% in the high‐ATG group vs. 73.2% in the intermediate‐ATG group vs. 53.8% in the low‐ATG group, p = 0.048). The rate of 2‐year overall survival was similar (45.5%, 68.5% and 44.8%, respectively; p = 0.09). The rate of chronic GVHD–free and relapse‐free survival at 2 years was significantly higher in the intermediate‐ATG group (18.2% in the high‐ATG group vs. 53.8% in the intermediate‐ATG group vs. 18.8% in the low‐ATG group, p = 0.0086).

Summary/Conclusion:

Our study shows that the incidence of extensive chronic GVHD was similar regardless of the doses of ATG after transplantation of PBSC from unrelated donor for patients with AML or MDS. However, the rate of relapse‐free survival and the rate of a composite end point chronic GVHD–free and relapse‐free survival were significantly higher in the intermediate dose (4.5–5 mg/kg) of ATG group.
PF765 RESULTS OF AUTOLOGOUS STEM CELL TRANSPLANT (ASCT) IN PATIENTS ABOVE THE AGE OF 70 ARE COMPARABLE TO THE RESULTS IN YOUNGER PATIENTS
Authors: Mamat K. , Murray J. , Bloor A. , Cavet J. , Dennis M. , Castleton A. , Wiseman D. , Somervaille T. , Kulkarni S.
Published: June 2019

Background:

High dose chemotherapy and autologous stem cell transplant is an important therapeutic procedure for select solid tumours and haematological malignancies providing chance of durable remission following induction therapy and in some patient potential cure. Increasing numbers of patients above the age of 70 are offered high dose chemotherapy and Auto‐PBSCT. This retrospective analysis compares the outcomes, morbidity and mortality of Auto‐PBSCT in patients above the age of 70 to those in the age group of 65‐69.

Aims:

To evaluate the results of ASCT in patients with lymphoma or myeloma who were above the age of 70 yrs to the reults in matched group in the age group of 65 to 70 yr. with the aim to compare engraftment data, morbidity, mortality and overall survival.

Methods:

Retrospective evaluation using case notes, electonic patient records and haematology database.

Results:

We analysed 54 patients, ages 70 and over, and 56 patients, ages between 65 and 69 years, who received AutoPSCT from 1990 to 2018 in Haematology and Transplant Unit, The Christie NHS Foundation Trust, Manchester, UK. Median age was 71yr(70–75) and 67yr(65–69). Male to female ratio are 38:16 (>70yr) and 41:15 (65–69). The two indications for transplants are Myeloma and lymphoma. The proportions are similar for both age groups, Myeloma:Lymphoma 37(68.5%):17(31.5%) in >70yrs and 40(71.4%):16(28.6%) in 65–69yr The numbers of patients undergoing second Auto‐PBSCT are 9(17%) in >70yr and 11(20%) in 65–69yrs. The follow up period was 2 years (43d‐14.1years) in >70yrs and 4 years (41d‐16.3years) in the 65–69yrs. Median time to neutrophil engraftment (ANC>0.5) was 12 days(9–19days) and 12 days(9–21days). Median platelet recovery (>25) was 21days(10–195days) and 29 days (10–694 days). Median hospitalisation was 27 days (14–91days) and 21days (14–60days). In terms of morbidity during transplant, patients needing intensive or high dependency care was 8 (15%) in >70yr and 5(9%) in 65–69yrs). Patients requiring readmission post discharge was 14(26%) in >70yrs and 9 (16%) in younger age group.

here was no difference in treatment related mortality and less than 3% in both groups.

Summary/Conclusion:

It is feasible to offer ASCT to patients above the age of 70 yr. Patient selection is crucial and should be based not only on the objective organ function evaluation but also the subjective assessment of transplant physician about appropriateness to undergo the ASCT therapy. The decision should be based on the individualised risk benefit ratio, risk of morbidity and expected survival benefit.

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PF777 IMMUNOLOGICAL RECONSTITUTION AS A BASIS FOR THE EARLY INITIATION OF PNEUMOCOCCAL VACCINATION AFTER AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION
Authors: Stoma I. , Iskrov I. , Smolnikova V. , Lendina I. , Milanovich N. , Uss A.
Published: June 2019

Background:

In the context of significant advances in the treatment of hematological diseases using the method of autologous hematopoietic stem cell transplantation (auto‐HSCT), the number of patients requiring early vaccination against pneumococcal infection increases worldwide. Current guidelines indicate the early initiation of pneumococcal vaccination starting from 3 months after HSCT. Still, the topical issue is the determination of the earliest optimal dates for the start of vaccination after transplantation, taking into account the dynamics of immunological recovery.

Aims:

The aim of this study was to determine the optimal timeline for the onset of vaccination with conjugated pneumococcal vaccine in patients with multiple myeloma after auto‐HSCT.

Methods:

The immune response to the conjugated pneumococcal vaccine is based on the T‐dependent (CD4+) activation of B‐cells, what was taken into account when estimating the timing of immune reconstitution after auto‐HSCT in candidates for vaccination.

An immunological study using flow cytometry was performed in 37 adult patients with multiple myeloma prior to the auto‐HSCT procedure, as well as on days +30, +60, +90, +180 after transplantation.

Results:

After auto‐HSCT, the level of naive B‐cells returns to its original value by the 60th day from transplantation (Kruskal‐Wallis test 41.97; P < 0.001), shown on Fig. 1. At the same time, the level of CD4 + cells did not fall below 200 cells/μl starting from day +30, what indicates the effectiveness of early vaccination with T‐dependent vaccines in this category of patients with immunosuppression. Dendritic cells (DC1 and DC2) are restored in parallel by the 30th day from auto‐HSCT (Kruskal‐Wallis test 25.78; P <0.001 for DC‐1 cells and Kruskal‐Wallis test 11,17; P <0.025, respectively), what confirms the basis for the early vaccination with conjugated pneumococcal vaccines in this category of patients.

Summary/Conclusion:

The obtained data allows planning the introduction of the first dose of the conjugated pneumococcal vaccine 60 days after autologous HSCT, with the perspective of introducing an individualized vaccination calendar based on immunological parameters. It is also necessary to further implement immunization programs for immunocompromised patients, especially in hematology and cancer setting with the participation of a multidisciplinary team of specialists.

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PF792 IDENTIFICATION OF REFERENCE GENES IN HUMAN TUMORS FOR TUMOR EDUCATED PLATELETS (TEPS) STUDY BASED ON RNA‐SEQ DATA
Authors: LUO L. , Luo H.
Published: June 2019

Background:

The previous studies have shown that Tumor Educated Platelets (TEPs) RNA may complement currently used biosources and biomolecules employed for liquid biopsy diagnosis. RT‐PCR is a regular method to measure gene expression levels to stage the patients and evaluate their prognosis. As there are little research on reference mRNA in platelets, especially in cancer.

Aims:

Our study is to find the proper internal controls for RT‐PCR in platelet study.

Methods:

Firstly, based on dataset GSE68086, we found 285 genes with relatively equal expression in 4 kinds of high incidence cancer (non‐small cell lung cancer (NSCLC), colorectal cancer (CC), breast cancer (BC) and liver cancer (LC)) and healthy control (HC). 95 genes left after screening with the criteria of mean>1 and coefficient of variation (cv) <1. Secondly, we gained 73 common reference genes from previous reported studies. Thirdly, we obtained 7 candidate reference genes (ACTB, B2 M, GAPDH, GNAS, OAZ1, PTMA and YWHAZ) after intersected the 95 genes and 73 genes. At last, we extracted total RNA from 1.5 ml blood in 30 unselected persons, including 6 NSCLC, 6 CC, 6 LC, 6 BC, and 6 HC, and performed RT‐PCR with equal quantity of RNA to measure the expression levels of the candidate reference genes.

Results:

All of 7 candidate reference genes performed well in 5 tested groups with a cv<0.1. Both B2 M and GAPDH were the most stably expressed with a cv<0.05, but the expression of B2 M was much higher than GAPDH in platelets.

Summary/Conclusion:

We have found 7 platelets mRNA with relatively same expression levels among several solid tumors and healthy people, which can be used as reference genes for mRNA measuring of platelets. Among them, B2 M may be the best reference control gene.

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PF814 KNOWLEDGE, ATTITUDES AND PRACTICES ON BLOOD TRANSFUSION OF MEDICAL RESIDENTS IN A TERTIARY HOSPITAL: A QUESTIONNAIRE‐BASED STUDY
Authors: Miranda R.S. , Dumagay T.
Published: June 2019

Background:

Blood transfusion remains to be one of the most common procedures performed in hospitals. It is an extremely efficient and perhaps life‐saving procedure which is very much an essential part in the management of hematologic and non‐hematologic cases. The knowledge of doctors on blood transfusion has a substantial influence on the rational utilization of blood products.

Aims:

We aim to assess the knowledge, attitudes and practices on transfusion of internal medicine (IM) residents at the Philippine General Hospital, using the BEST‐TEST, a validated questionnaire on transfusion medicine (TM).

Methods:

This is a descriptive cross‐sectional study design, which included all 63 internal medicine residents undergoing training at the Philippine General Hospital for the year 2016. General data on demographics were collected, after which the participants were asked to answer the BEST‐TEST validated questionnaire on transfusion medicine

Results:

A total of 63 internal medicine residents with a mean age 27.9 ± 1.6 ranging from 25 to 33 years old and majority (61.9%) were between 28 to 30 years old were included in this study. Gender distribution is almost even (50.8% males). In terms of number of hours of training on transfusion medicine in medical school, a third had 4+ hours and a little more than half (50.8%) had 3+ hours. Majority (58.7%) of the internal medicine residents appraised their knowledge of transfusion medicine as intermediate, and almost all (98.4%) rated it as beginner to intermediate. BEST‐TEST mean scores were 39.1%, 40.0%, and 41.0% for the first, second, and third year residents, respectively. There is no significant correlation between test scores of the residents and number of hours of training in transfusion medicine in medical school (p = 0.694) and in residency (p = 0.927). On the other hand, there is a significant correlation between the quality (perceived helpfulness) of residency training on transfusion medicine and test scores with the scores increasing as the year level increases.

Summary/Conclusion:

Indeed, the results of this study has shown inadeqacy in the knowledge on transfusion medicine among internal medicine residents. Therefore, further training on transfusion medicine, maybe in the form of lecture series and seminars, may help strengthen the knowledge of the residents.
S849 TNF‐α BLOCKADE CORRECTS THE MONOCYTE/MACROPHAGE IMBALANCE IN PRIMARY IMMUNE THROMBOCYTOPENIA (ITP)
Authors: Zhao Y. , Liu X. , Li G. , Peng J. , Hou M.
Published: June 2019

Background:

Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder. Deviation of monocyte/macrophage subsets plays an important role in the pathogenesis of ITP. TNF‐α blockade is widely used in many autoimmune diseases with satisfactory effects. However, the effect of TNF‐α blockade on monocyte/macrophage system in ITP remains unknown.

Aims:

Our study aimed to investigate whether TNF‐α could restore the disturbed balance of monocyte/macrophage subsets and be a potential therapeutic strategy for ITP.

Methods:

Plasma TNF‐α was detected by ELISA. The monocyte/macrophage subsets were analyzed using flow cytometry and immune fluorescence. Macrophage polarization was analyzed using western blot, q‐PCR, and flow cytometry. Phagocytic capacity of macrophages was measured by the engulfment of opsonized platelets. T‐cell priming ability of macrophages was determined through co‐culturing with CD4+ T cells and CD8+ T cells. We established a passive model of murine ITP. Platelet count was measured every other day. The retention of platelets in liver and spleen was assessed by the fluorescence intensity detected using the in vivo imaging system.

Results:

ITP patients manifested with an increased TNF‐α expression which was inversely correlated with platelet count. Moreover, the numbers of TNF‐α‐expressing macrophages in spleen and CD16+ monocytes were more than that of healthy controls. TNF‐α blockade inhibited M1 macrophage polarization by suppressing the NF‐κB signaling pathway, and dampened the phagocytic capacity and T‐cell priming ability of macrophages. Moreover, anti‐TNF‐α therapy reduced the number of non‐classical monocytes and M1 macrophages, ameliorated the retention of platelets in spleen and liver, and significantly increased the platelet count of ITP mice.

Summary/Conclusion:

Our study demonstrated that TNF‐α blockade could decrease the number and functions of pro‐inflammatory subsets of monocytes/macrophages by inhibiting NF‐κB signaling pathway, leading to remarkable attenuation of antibody‐mediated platelet destruction both in vitro and in vivo, thus might be a promising therapeutic strategy for the management of ITP.

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S870 SINTILIMAB FOR RELAPSED/REFRACTORY (R/R) EXTRANODAL NK/T CELL LYMPHOMA (ENKTL): A MULTICENTER, SINGLE‐ARM, PHASE 2 TRIAL (ORIENT‐4)
Authors: Tao R. , Fan L. , Song Y. , Hu Y. , Zhang W. , Wang Y. , Xu L. , Zhou H. , Li J.
Published: June 2019

Background:

ENKTL account for more than 20% of the peripheral T‐cell lymphoma in Asia. Patients with r/r ENKTL have a poor prognosis after failing an L‐asparaginase based regimen, and the median overall survival is less than 6 months. The overexpression of PD‐L1 induced by EBV infection is a potential mechanism for ENKTL to avert immune surveillance, and recent studies of PD‐1 antibodies in pts with r/r ENKTL have demonstrated potential efficacy. Sintilimab, a fully human anti‐PD‐1 monoclonal antibody, has a safety profile consistent with other approved PD‐1 antibodies and was approved for r/r classical Hodgkin lymphoma in China in 2018.

Aims:

This multicenter, single‐arm, phase 2 study aims to validate the efficacy and safety of sintilimab monotherapy in patients with r/r ENKTL in China.

Methods:

Patients with pathologically confirmed r/r ENKTL were enrolled. Sintilimab was given 200 mg IV Q3W, until PD, death, unacceptable toxicity, or withdrawal from the study. Treatment beyond PD is allowed. Tumor response evaluation was performed by both PET‐CT and CT/MRI with contrast. The primary endpoint was objective response rate based on LUGANO 2014 criteria. Data cut‐off date for this analysis was Feb 2, 2019.

Results:

From Aug 31, 2017 to Feb 7, 2018, a total of 28 patients were enrolled: 60.7% male and the median age was 37 (range: 19∼65) yr. Sixty‐eight percent of patients were stage IV and 89.3% were ECOG PS ≥ 1. All patients had failed an L‐asparaginase based regimen, the median lines of previous therapy were 3 (range: 1∼13), 78.6% patients received prior radiotherapy and 7.1% had failed HSCT. Median duration of therapy was 14.04 (range: 1.4∼17.3) months and 19 patients are still receiving sintilimab. Sixty‐eight percent (19/28, 95%CI: 47.6%∼84.1%) of patients achieved response (CR+PR), including 4 pts who experienced PD prior to having a response. DCR was 85.7%, including 5 pts who experienced PD before SD or response. The 1‐year OS rate was 82.1% and the median OS has not been reached. Most TRAEs were G1∼2 (67.9%) and no patients discontinued treatment due to AEs. The most common TRAE was decreased lymphocyte count (46.4%) and 84.6% were grade 1∼2. SAEs occurred in 21.4% of patients and none were related to sintilimab. No patients died from AEs.

Summary/Conclusion:

Sintilimab is effective and well tolerated in r/r ENKTL and could be a promising treatment option for these patients. Early disease progression observed by PET scan in this study could be pseudo‐progression as it did not correlate with poor outcome, which warrants further investigation. NCT03228836
S890 NEW WHOLE GENOME ASSOCIATION SCANNING APPROACH FOR THE DISCOVERY OF HLA CLASS I‐RESTRICTED MINOR HISTOCOMPATIBILITY ANTIGENS
Authors: Fuchs K. , Adriaans A. , Honders W. , van der Lee D. , van der Meijden E. , Pont M. , Monajemi R. , Kielbasa S. , ’t Hoen P. , van Bergen C. , Falkenburg F. , Griffioen M.
Published: June 2019

Background:

Patients that undergo allogeneic stem cell transplantation (SCT) as treatment for hematological diseases face the risk of relapse as well as Graft‐versus‐Host Disease (GvHD). GvHD as well as the favorable Graft‐versus‐Leukemia effect are mediated by donor T cells. These T cells recognize minor histocompatibility antigens: polymorphic peptides, which are presented on the cell surface by HLA molecules and are caused by genetic differences in single nucleotide polymorphisms (SNPs) between patient and donor. Knowledge about mismatched minor histocompatibility antigens may enable a more directed donor search as well as better prediction and measurement of the Graft‐versus‐Leukemia effect and GvHD for personalized treatment after transplantation, thereby contributing to a better outcome for patients treated with allogeneic SCT.

Aims:

Identification of minor histocompatibility antigens has been a laborious process in the past. Therefore, whole genome association scanning was developed in our laboratory. However, this method was restricted to two HLAs and screening of one million SNPs. The aim of this study is to develop and use an optimized method to identify the dominant repertoire of minor histocompatibility antigens in common HLA class I alleles.

Methods:

Donor T‐cells isolated from patients after allogeneic SCT are tested for recognition of a new panel of 191 selected B‐cell lines, which are sequenced in the 1000 Genome Project. This panel enables the inclusion of seven common HLAs and increases SNP coverage to 12 million (MAF > 0.01). SNPs that strongly associate with T‐cell recognition are subsequently validated to encode minor histocompatibility antigens.

Results:

A total of 19 novel minor histocompatibility antigens have been identified that are presented in seven common HLA class I alleles, showing the potential of this optimized approach. Besides conventional antigens, cryptic peptides were found as well as peptides restricted to HLAs that were not primarily targeted.

Summary/Conclusion:

This improved approach for whole genome association scanning has been successfully applied in rapidly discovering new minor histocompatibility antigens. The new method surpasses previous methods in its rapidness and coverage of HLAs and SNPs across the human genome, which additionally allows for identification of cryptic peptides. With the increasing number of patients that are analyzed in this study, T‐cells recognizing known minor histocompatibility antigens are more often isolated, indicating that the repertoire of minor histocompatibility antigens is limited. Our optimized method is expected to discover the majority of unknown antigens in this repertoire, thereby contributing essential knowledge for new strategies to improve clinical outcome after allogeneic SCT.
S906 PRECLINICAL EVALUATION OF THE PRESERVATION OF RED BLOOD CELL CONCENTRATES IN HYPOXIA BY HYPOXIC STORAGE TECHNOLOGY FOR TRANSFUSION IN SICKLE CELL DISEASE.
Authors: Bencheikh L. , Nguyen K.‐A. , Chadebech P. , Kiger L. , Bodivit G. , Jouard A. , Pakdaman S. , Adypagavane S. , Audureau E. , Tebbakha K. , Hebert N. , Pirenne F. , Sowemimo‐Coker S. , Dunham A. , Bartolucci P.
Published: June 2019

Background:

Sickle cell disease (SCD) is the most common genetic disease, due to a mutation of the sixth amino acid of gene coding for the Hemoglobin (Hb) beta chain. The mutated Hb, called HbS, is able to polymerize which entails red blood cell (RBC) sickling, leading to chronic hemolysis and painful vaso‐occlusive crisis. Transfusion exchange is one of the therapeutic strategies used for this pathology since it allows the replacement of sickle RBCs. The quality of the transfused RBCs is essential, both to improve the transfusion yield but also to limit the pathological interactions between RBCs and endothelial cells, damaged by hemolysis. RBC concentrates can be stored up to 42 days at 4°c, however, during their hypothermic storage, the quality of RBCs decreases, mainly because of oxidative damage. Hypoxic storage technology helps to keep RBC in hypoxia, improving the concentration of ATP, 2‐3DPG, hemolysis and deformability of RBCs.

Aims:

The purpose of our study was to compare the quality of conventionally conserved RBCs with those conserved with hypoxic storage technology.

Methods:

We assessed several parameters including sickle RBC flow adhesion to HUVEC (human umbilical vein endothelial cells), previously exposed to hemolysate, to mimic endothelial damage present in patients. We also evaluated hypoxic RBC senescence parameters by flow cytometry. In that purpose, we measured intracellular calcium and reactive oxygen species (ROS) concentration as well as phosphatidylserine exposure by annexin V staining in hypoxic RBCs and control RBCs, after incubation 24 h in plasma from healthy donors and SCD patients. RBC adherence on thrombospondin (TSP) under flow was also quantified, since RBC adhesion to TSP was shown to increase during storage and since TSP concentration is elevated in sickle cell disease patients during acute chest syndrome (ACS) or at risk of ACS. In addition, we assessed hemolysis in the bags by measuring free hemoglobin concentration in the supernatant by spectroscopy.

Results:

We found a reduction in the concentration of free Hb (produced by RBC lysis) in hypoxic storage bag, a decrease in RBC senescence (ROS and calcium intracellular concentrations) in hypoxic RBCs and a reduced adherence to thrombospondin when hypoxic RBCs are incubated during 24 h in plasma from healthy donors or SCD patients. There was no difference of RBC adhesion to endothelial cells.

Summary/Conclusion:

These results suggest that hypoxic storage technology meets the safety criteria for transfusion in SCD patients and may provide significant clinical benefits.
PS941 ANTI‐CD19 CAR‐T THERAPY BRIDGING TO ALLO‐HSCT IMPROVES LONG‐TERM OUTCOME OF B‐ALL PATIENTS WITH HIGH LEUKEMIA BURDEN OR POOR PROGNOSTIC MARKERS
Authors: Mei H. , Hu Y. , Jiang H. , Zhou F. , Guo T. , Wu Y. , Liu L. , Ai L. , Shi W. , Li C. , Tang L. , Xiong W. , Xia L. , Jin R.
Published: June 2019

Background:

Anti‐CD19 chimeric antigen receptor T cell (CAR‐T) therapy was an effective treatment method for relapsed and/or refractory B‐cell acute lymphoblastic leukemia (r/r B‐ALL) patients, but its ability to maintain long‐term leukemia‐free survival was limited. New strategies that can help CAR‐T therapy achieve lasting effect are urgently warranted.

Aims:

Our study aimed to answer the question that whether subsequent allo‐HSCT could improve the long‐term prognosis of the minimal residual disease‐negative (MRD‐) CR patients after CAR‐T therapy.

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Methods:

In the first stage, patients received split doses of CAR‐T cells after lymphodepleting chemotherapy, consisting of fludarabine and cyclophosphamide. In the second stage, MRD‐ CR patients who had no history of allo‐HSCT and had no contraindications or other restrictions would, on their own accord, receive allo‐HSCT from 1 to 3 months after CAR‐T therapy.

Results:

58 r/r B‐ALL patients were treated with anti‐CD19 CAR‐T cells, and 51 (87.9%) achieved complete remission (CR) (47 MRD‐ CR). The 6‐month and 12‐month overall survival (OS) rates were 68.9% and 61.1% respectively. During the follow‐up (median, 7.7 months), 21 of the 47 MRD‐ CR patients received consolidative allo‐HSCT and 17 remained leukemia‐free, while the other 26 patients received CAR‐T therapy alone and only 10 remained in CR. (Fig. 1A) There was no difference in OS between the MRD‐ CR patients who received allo‐HSCT and those who didn’t, but event‐free survival (EFS) and relapse‐free survival (RFS) were significantly prolonged by allo‐HSCT in the subgroups with either high pre‐infusion bone marrow MRD (≥ 5%) or poor prognostic markers (P < 0.05). (Fig.1B∼E) However, no difference was found in OS, EFS and RFS in subgroup with MRD < 5% and without poor prognostic markers.

Summary/Conclusion:

These data demonstrate that CAR‐T therapy bridging to allo‐HSCT is a safe and effective therapeutic strategy for r/r B‐ALL patients, and can achieve better efficacy in terms of maintaining long‐term EFS and RFS. Patients with high pre‐infusion MRD or with poor prognostic markers can benefit from the early consolidative allo‐HSCT after CAR‐T therapy. Trials were registered at www.clinicaltrials.gov as # NCT02965092 and #

NCT03366350.
PS1006 INHIBITORS OF HOXA9 LEUKEMOGENIC TRANSCRIPTION FACTOR ARE EFFICIENT ON HUMAN AML CELL MODELS BUT NOT ON NORMAL HUMAN BONE MARROW CD34+ HEMATOPOIETIC CELLS
Authors: Lambert M. , Depauw S. , Jambon S. , Bellart M. , Lutchmee L. , Louis‐Thérèse L. , Nhili R. , David‐Cordonnier M.‐H.
Published: June 2019

Background:

The HOXA9 protein is a transcription factor associated with normal hematopoiesis and which expression on hematopoietic stem cells and progenitor cells decreases in the course of blood cell differentiation. The expression of HOXA9 is however maintained at high level in several subtypes of acute myeloid leukemia (AML) such as mll‐rearranged leukemias, NPM1‐mutated AMLs and AML presenting MYST3‐CREBP, NUP98‐NSD1 or RUNX/EVI1 translocations. The over‐expression of HOXA9 in these AML subtypes is associated with the maintenance of cell proliferation and the blockade of cell differentiation. It is well known that HOXA9 exerts its leukemic potential through DNA interaction and, therefore, we selected direct inhibitors of HOXA9/DNA interaction to block its activity and evaluate them on a murine leukemia cell model (Depauw et al., 2019).

Aims:

In order to go further, we aim at evaluating them on human AML cell models expressing or not HOXA9 and on normal human CD34+ hematopoietic cells to address any potential effect of our inhibitors on normal hematopoiesis.

Methods:

The expression level of HOXA9 was quantified by qRT‐PCR on a series of human AML cell lines. The sensitivity of those cell lines regarding two selected inhibitors was seen addressed using global cell survival analysis using MTS reaction. Methylcellulose clonogenic assays were performed on a series of human AML cell lines and on normal human bone marrow CD34+ hematopoietic cells. Knock‐down of HOXA9 expression was performed as a control using lentiviral delivery of HOXA9‐specific or control shRNAs.

Results:

A strong correlation between HOXA9 expression and the sensitivity to two of our inhibitors was evidenced in a series of 14 human AML cell lines with linear determination coefficients of R of ∼0.75 and ∼0.8.

Clonogenic assays evidenced a decrease in the number and size of the colony forming units of treated related to untreated AML cell models. The relevance of HOXA9 expression in the clonogenicity is addressed by use of lentivirally transduced shHOXA9 in some of the AML cell models. By contrast, no difference were observed on either the number, the size and the differentiation subtypes of the colonies obtained from treated versus untreated normal human CD34+ hematopoietic cells.

Summary/Conclusion:

In conclusion, we selected inhibitors of HOXA9/DNA interaction that alter cell proliferation and clonogenic activity in a series of HOXA9‐positive AML cell models but that do not affect the progenitor cell number from normal bone marrow CD34+ cells.
PS1044 THE PROGNOSTIC SIGNIFICANCE OF BCR‐1 AND BCR‐3 ISOFORM OF PML‐RARA AND FLT3‐ITD IN PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA
Authors: Rasekh E. , Elsayed G. , Madney Y. , Gammal M. El
Published: June 2019

Background:

Acute promyelocytic leukemia (APL) has a characteristic peculiar morphologic, genetic features and more favorable outcome.

Aims:

is to study the differential effect of BCR‐1 and BCR‐3 isoforms of PML‐RARA together with FLT3‐ITD mutational status on outcome of APL patients.

Methods:

All patients referred to the outpatient medical and pediatric oncology clinic, National cancer institute (NCI), Cairo University, Egypt in the period from May 2012 to January 2018. The diagnosis of APL was based on morphologic examination of the bone marrow and peripheral blood smears and was confirmed by the detection of the PML‐RARA transcript by FISH and RT‐PCR.

Results:

the study included 118 patients with newly diagnosed de novo APL (71 (60%) adults and 47 (39.8%) children). Based on the initial TLC, pediatric APL patients have higher (48.9%) risk than adults (30%) (p = 0.044). The CR rate was 91% (77/84), after excluding early induction related deaths (18) and patients who did not receive treatment at NCI (no beds available) (16). All pediatric patients (both BCR‐1 and BCR‐3) and all adult patients with BCR‐3 achieved CR while 22/28 (78.5%) of patients with BCR‐1 achieved CR (p = 0.04). Adult patients with FLT3 mutation (5/8 = 62.5%) received more high‐risk regimen than patients with wild FLT3‐ITD (10/38 = 26.3%)(p = 0.047). FLT3‐ITD mutation was associated with more hemorrhage and DIC (p = 0.038), and lower 2‐year OS (96% v 44.6%)(p = 0.001) in pediatric patients. Also DIC and Hemorrhage are associated with lower 2‐year OS in pediatric patients (91.4% v 48.6%)(p <  0.001). The 1‐year and 2‐year OS for pediatric patients were better than adults (56.2% v 83% and 80.7 % v 49.8% respectively) with a median of 39.4 month versus 12month respectively (p = 0.005). On multivariate analysis, Age was an independent prognostic variable affecting survival, HR 2.6 (95% CI 1.3–5.3, P = 0.007)(adults had hazards ratio of death 2.6 times higher than pediatrics). DIC & FLT3‐ITD were independent prognostic variables affecting survival in the pediatric APL with HR 12.3 (95% CI 1.46–104.61, P = 0.021) and 5.2 (95% CI 1.01–26.95, P = 0.048) respectively.

Summary/Conclusion:

BCR‐1 isoform of PML‐RARA is associated with decreased response to ATRA‐based regimens in adult APL patients. DIC & FLT3‐ITD are adverse prognostic factors in pediatric APL patients. Age is an independent prognostic factor in APL patients (whole group). Despite higher high risk groups in pediatric patients, the outcome is better than adult patients.

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PS1062 PEDIATRIC ACUTE MYELOID LEUKEMIA (AML) IN DEVELOPING COUNTRIES, BARRIERS AGAINST BETTER OUTCOME 10 YEARS’ EXPERIENCE AMONG EGYPTIAN PEDIATRIC ACUTE MYELOID LEUKEMIA
Authors: Madney Y. , Ezzelden N. , Elsharkawy N.
Published: June 2019

Background:

Pediatric AML outcome improved significantly with current survival rates of 70% in developed countries. The outcome of childhood AML in developing countries still lacking.

Aims:

The aim of the study to assess the causes of mortality and survival outcomes among pediatric AML patients in countries with limited resources.

Methods:

Retrospective analysis of 344 pediatric AML (2007 ‐ 2016) treated at National Cancer Institute, Egypt including 3 phases protocols with different aims and hypothesis.

Results:

From 2007–2010, Less intensified induction chemotherapy without antimicrobial prophylaxis,103 patients enrolled, Complete remission (CR) post induction 1(55%), Refractory disease (34%) and induction mortality (11%). End of study;Relapse 40 %. Mortality 63 patients (61%):(42%) disease‐related (DRM), (42%) infection related (IRM) and (14%) toxicity related (TRM). 70% had fungal infections. 2 years DFS 27% and OS 30%.

From 2011‐ 2013, Hypothesis was Antimicrobial prophylaxis can help for a better outcome,136 patients enrolled used less intensified induction but with levofloxacin and voriconazole prophylaxis. CR rate induction 1 was 75%, refractory disease (17%) and induction mortality was 8%. End of study: Relapse 16%. Mortality in 86(63%) patients: 57 % IRM mostly multidrug resistance (MDR) gram‐negative bacteremia while DRM 33%. 10% had fungal infections but still poor 3y DFS (34%) and OS (37%).

From 2014–2016, Hypothesis was intensified induction chemotherapy with antimicrobial prophylaxis can be a better solution; 105 patients enrolled, Post induction1, CR 48%, refractory disease 8% and induction mortality 44%. End of study; Relapse rate 6%, Mortality 88(80%) patients: IRM was 72% with MDR gram‐negative bacteremia was the main cause of deaths (62%), DRM 4% and TRM 4% with poor 2y DFS 34% and OS 24%.

Summary/Conclusion:

A significant gap in the outcomes of pediatric AML as compared to those reported developed countries. The balance between treatment intensification and toxicity are needed. Infections are the major barrier against better outcome needs more strict guidelines protocols.
PS1073 PRELIMINARY RESULTS OF ASTX660, A NOVEL NON‐PEPTIDOMIMETIC CIAP1/2 AND XIAP ANTAGONIST, IN RELAPSED/REFRACTORY PERIPHERAL T‐CELL LYMPHOMA AND CUTANEOUS T CELL LYMPHOMA
Authors: Mehta A. , Hollebecque A. , Foss F. , Lister J. , Mita M. , Wagner‐Johnston N. , Dyer M.J. , You B. , Prica A. , Hernandez‐Llizaliturri F. , Ferraldeschi R. , Chan D. , Zhang J. , Samaniego F.
Published: June 2019

Background:

ASTX660 is an oral, novel non‐peptidomimetic, small‐molecule antagonist of cellular/X‐linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP). ASTX660 is currently being evaluated in a first‐in‐human phase 1‐2 study in patients (pts) with advanced solid tumors and lymphoma (ClinicalTrials.gov NCT02503423). In the phase 1 part of the study, the recommended phase 2 dose (RP2D) was identified with a favorable safety profile and initial evidence of clinical activity in a pt with mycoses fungoides (Mita et al, presented at the AACR‐NCI‐EORTC Conference 2017, abs #A091).

Aims:

Herein, we report preliminary efficacy and safety results from the ongoing relapsed/refractory (r/r) peripheral T‐cell lymphoma (PTCL) and cutaneous T‐cell lymphoma (CTCL) Phase 2 cohorts.

Methods:

Pts receive treatment with ASXT660 at the RP2D 180 mg/day on Days 1 to 7, and 15 to 22 in a 28‐day cycle. The primary endpoint is response rate as assessed by the investigator according to either the Lugano criteria (PTCL) or Global Assessment (CTCL). Adverse events (AEs) are assessed per CTCAE V4.03.

Results:

As of 15 January 2019, 16 PTCL pts and 13 CTCL pts have received ASTX660. Pt characteristics: median (range) age: PTCL: 59 (39–81) years and CTCL: 57 (23–75) years; median number of prior therapies: PTCL: 3 (1–7) and CTCL: 3 (1–9). In the PTCL cohort the ORR is 28% (4/14); 2 pts have yet to reach their first assessment. Three responding pts remain on study drug for 7–10 months. Responses have been observed in pts with AITL and PTCL‐NOS. In the CTCL cohort the global response is 25% (3/12); 1 pt has yet to reach their first assessment. Two responding pts remain on study drug for 4–6 months. Responses have been seen in pts with large cell transformation, sezary syndrome and visceral metastases. Among all pts, the most common related AEs of any grade (≥ 15%) were lipase elevation (38%), amylase elevation (34%), ALT elevation (28%), elevation (24%) and rash (24%). Related AEs ≥ Grade 3 occurring in ≥3 pts were rash (n = 5) and lipase elevation (n = 4). Accrual continues; updated efficacy and safety results will be presented at the meeting.

Summary/Conclusion:

In the ongoing Phase 2 cohorts ASTX660 has shown activity against PTCL and CTCL with manageable safety profile. These early data support continued development of ASXT660 for the treatment of r/r PTCL and CTCL. Correlative studies are aimed at identifying predictors of response.
PS1091 TREATMENT OF ACTIVATED B‐CELL LYMPHOMA WITH RITUXIMAB,DOXORUBICIN,ETOPOSIDE,PREDNISOLONE/IFOSFAMIDE+CISPLATIN PLUS LENALIDOMIDE (R‐ACEP/ICL), CONFERS LONG PROGRESSION FREE AND OVERALL SURVIVAL RATES
Authors: Salamoon M. , Balti M.
Published: June 2019

Background:

gene profiling (GEP) revealed the main two types of DLBCL [the germinal center B‐cell (GCB) and the non‐germinal center or Activated B‐cell lymphoma(ABC)]. Immuno‐histochemistry plays an important role in differentiating between the two types using several algorithms, however, Hans algorithm and the improved Hans are considered the more reliable. Patients with GCB are still doing well in the era of type I and II anti‐CD20, however, ACB patients are experiencing bad prognosis with shorter progression free and overall survival rates, therefore, we have developed a high‐dense high intense protocol to treat those population with ABC.

Aims:

the study aims at evaluating a new dose intense chemotherapy in patients with ABC lymphoma with end points including progression free and overall survival

Methods:

this is a multicenter study Al Bairouni university cancer center in Damascus, Syria between 2013 and 2015 where we recruited 122 patients having ABC DLBCL confirmed by immuno‐histochemistry using the improved Hans algorithm. Patients received a dose dense protocol as follows: (Rituximab 375 mg/m2 with Doxorubicin 75 mg/m2, Cyclophosphamide 1200 mg/m2, Etopdside 300 mg/m2 and Prednisolone 1 mg/kg for 5 days) repeated every 21 days for 6 cycles with 5 days G‐csf support. Then partial and complete responders were given (Ifosfamide 4 gr/m2 day 1–3 + Cisplatine 40 mg/m2 day 1–3) for 4 cycles repeated every 15 days with 4 days G‐csf support. Lenalidomide 10 mg/d was given upfront lasting for 1 year. End‐points were progression free survival and overall survival at 5 years.

Results:

overall response rate (ORR) was documented in 118 patients (96.7%) (92 complete responders and 26 partial responders). 10 patients progressed at different stages of follow up with a progression free survival (PFS) of 88.6% (95% CI 83–94). However, 113 patients were found to still alive at 5 years with an overall survival (OS) rate of 92.6 (95% CI 86–97). In spite of G‐csf support, neutropenia of different grades was documented in 23 patients (18.8%). Acute and transient renal failure was observed and managed in 15 patients (12.2%) mainly in the first 6 cycles. Other side effects were manageable.

Summary/Conclusion:

ABC forms a special entity of DLBCL carrying a bad prognosis compared with GCB subtype. Progress was made using the R‐CHOP, however, results were still poor until the addition of Ibrutinib, Lenalidomide or Bortezomib to R‐CHOP in different trials which improved OS to exceed 90%. In this study, we present a dose intense protocol conferring a good PFS and OS rates with acceptable toxicity profile. However, a big randomized trials including both ABC and GCB patients in order to identify factors having bad impact on progression.
PS1100 CONGENITAL FACTOR V DEFICIENCY FROM COMPOUND HETEROZYGOUS MUTATIONS WITH A NOVEL MUTATION C.2426DEL (P.PRO809HISFS∗2) IN THE F5 GENE
Authors: Park C.‐H. , Park M.‐S. , Lee K.‐O. , Kim S.‐H. , Park Y.S. , Kim H.‐J.
Published: June 2019

Background:

Congenital factor V deficiency (FVD) is a rare bleeding disorder characterized by low or undetectable plasma FV levels leading to mild to severe bleeding symptoms. Currently, more than 100 mutations have been reported in F5. The majority of F5 mutations are missense mutations (61.5%), and small deletion and splicing mutations account for 18.5% and 11.9%, respectively.

Aims:

We herein report a patient with FVD from compound heterozygous mutations including a novel deleterious mutation.

Methods:

The patient was a 52‐year‐old man with prolonged PT and aPTT corrected by mixing test on preoperative screening. His past medical or family history was not remarkable. Factor assays revealed a markedly reduced FV activity at 7%. Other factors were not decreased. DNA sequencing analysis to detect F5 gene mutations was performed after obtaining written informed consent.

Results:

Two different heterozygous mutations in F5 were detected: a missense variant (c.286G>C [p.Asp96His]) and a frameshift variant from small deletion (c.2426del [p.Pro809Hisfs∗2]). The Asp96His was previously described missense mutation and Pro809Hisfs∗2 was a novel deleterious mutation.

Summary/Conclusion:

We herein report an asymptomatic patient with FVD from compound heterozygous mutations of F5 including a novel frameshift mutation. As was the case in our patient, genotype‐phenotype correlations are poor in FVD, and molecular genetic test is necessary to confirm the diagnosis.