bluuebunny/crossref_metadata_2025 huggingface dataset:
PS1480 INTERLEUKIN‐37 REDUCES INFLAMMATION AND IMPAIRS PHAGOCYTOSIS OF PLATELETS IN IMMUNE THROMBOCYTOPENIA
Authors: Zhao Y. , Li G. , Liu X. , Peng J. , Hou M.
Published: June 2019

Background:

Immune thrombocytopenia (ITP) is an autoimmune and inflammatory disease characterized by low platelet count with heterogeneous bleeding manifestations. Severe bleeding in ITP is not completely related with low platelet count. Thus, there is a great need for reliable indicators of the susceptibility of bleeding in ITP patients. Interleukin‐37 (IL‐37) is an anti‐inflammatory cytokine that participates in the process of several inflammatory and autoimmune diseases. However, the role of IL‐37 in the pathogenesis of ITP is unknown.

Aims:

Our study aimed to evaluate the regulatory role of IL‐37 in the process of ITP and its association with disease severity.

Methods:

Plasma IL‐37 was detected by enzyme‐linked immunosorbent assay (ELISA). We cultured the monocytes/macrophages from ITP patients to investigate the regulatory role of IL‐37 on monocytes/macrophages. Fcγ receptors (FcγRs) of macrophages were analyzed using flow cytometry and q‐PCR. Signaling pathways were determined by western blotting. Phagocytic capacity of macrophages was measured by the engulfment of opsonized platelets.

Results:

Plasma and mRNA levels of the anti‐inflammatory cytokine IL‐37 were elevated in ITP patients with platelet counts below 30 × 109 /L compared to healthy controls and to ITP patients with platelet counts above 30 × 109 /L. Furthermore, plasma IL‐37 levels correlated with the platelet number and IBLS bleeding scores of ITP patients. Specifically, ITP patients with skin and oral bleeding symptoms had higher plasma IL‐37 levels than patients without these bleeding symptoms. Patients with more severe skin and oral bleeding exhibited higher plasma IL‐37 levels, indicating that IL‐37 could be a candidate in evaluating disease severity of ITP. IL‐37 initiated an anti‐inflammatory effect on monocytes/macrophages from ITP patients by down‐regulating the phosphorylation of MAPK, AKT, and NF‐κB signaling pathways, which are pivotal in mediating inflammation. Moreover, IL‐37 restored the balance of activating and inhibitory FcγRs (Figure 1) and decreased antibody‐mediated platelet phagocytosis by monocytes/macrophages, suggesting that IL‐37 might be a potential therapeutic agent in ITP.

Summary/Conclusion:

Our study demonstrated that ITP patients exhibited higher IL‐37 expression, especially patients with severe hemorrhage or low platelet count. IL‐37 decreased antibody‐mediated platelet phagocytosis, restored the balance of activating and inhibitory FcγRs, and inhibited inflammatory activity via MAPK, AKT, and NF‐κB signaling pathways among monocytes/macrophages. Therefore, IL‐37 might be a candidate in evaluating the severity of ITP and a promising therapeutic agent for the management of ITP.

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PS1487 EFFECT OF PLASMA EXCHANGE ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF CAPLACIZUMAB
Authors: Sargentini L. , Hansson E. , Bergstrand M. , Callewaert F. , Sousa R.
Published: June 2019

Background:

During clinical trials in patients with acquired thrombotic thrombocytopenic purpura, caplacizumab was administered as a 10 mg intravenous (iv) bolus prior to plasma exchange (PE), followed by 10 mg daily subcutaneous (sc) doses during the daily PE period and at least 30 days thereafter.

Aims:

The potential effect of different time intervals between the first iv bolus and the subsequent PE, and the effect of different PE schedules, have been investigated.

Methods:

An integrated pharmacokinetic (PK)/pharmacodynamic (PD) model was developed to describe the interaction between caplacizumab and vWF using non‐linear mixed effects modeling and used to simulate the resulting PK and PD for different predetermined scenarios:

1) PE start 3, 5, 11, 23 h post‐caplacizumab 10 mg iv bolus

2) PE schedule: daily and twice per day (bid) at the first day or during 7 days

Results:

Data from clinical trials indicate complete neutralization of vWF activity for caplacizumab peak plasma concentrations ≥500ng/mL. Simulations suggest that median caplacizumab peak plasma levels would remain above this threshold if the PE starts up to 5 h post‐caplacizumab iv bolus. For longer delays median caplacizumab peak plasma levels can fall below 500ng/mL, and an additional 10 mg sc dose prior to PE can maintain an effective drug exposure.

Simulations of the effect of a bid PE for 7 days, suggest that the sc dosing schedule of caplacizumab during the PE period could be adjusted with bid 10 mg caplacizumab sc dosing after each PE treatment during the time of bid PE treatment.

Summary/Conclusion:

Effective drug levels are expected if PE is started up to 5 h following the first iv dose of caplacizumab. For longer delays, an additional 10 mg sc dose prior to PE can be envisaged.

In case of bid PE for 7 days, the sc administration schedule of caplacizumab could be adjusted with bid caplacizumab after each PE treatment.
PS1491 PLATELET KINETICS IN PATIENTS WITH CHRONIC IMMUNE THROMBOCYTOPENIA TREATED WITH THROMBOPOIETIN RECEPTOR AGONISTS
Authors: Pravdic Z. , Mitrovic M. , Todorovic‐Tirnanic M. , Virijevic M. , Sabljic N. , Suvajdzic‐Vukovic N.
Published: June 2019

Background:

Chronic immune thrombocytopenia (ITP) is characterised by antibody‐mediated platelet destruction, shortened platelet survival (PS) and impaired platelets production. Platelet kinetic study (PKS) assesses in vivo the mean PS, platelet production and the platelet sequestration site. Thrombopoietin receptor agonists (TPO‐RA) increase platelets counts (PC) in majority of chronic ITP patients. Moreover, some patients could retain stabile response after TPO‐RA discontinuation, which is attributed to the immunomodulatory effects of the drugs. Addressing this issue only a few studies have been done assessing the effect of TPO‐RA on PKS parameters.

Aims:

To evaluate the effects of TPO‐RA on PKS parameters.

Methods:

Ten patients with chronic ITP, median age 55.3 years (range 12–72), gender (f: n = 7, m: n = 3), splenectomised 6/10, were treated with TPO‐RA (eltrombopag, n = 7, romiplostim, n = 3). Response was assessed according to the criteria of the International Working Group (IWG) on ITP. Autologous 111Induim‐oxinate‐labeled PKS were performed in all patients before and 5 months after TPO‐RA therapy initiation.

Results:

A good treatment response was achieved in 8/10 of patients (eltrombopag, n = 6, romiplostim, n = 2). Two refractory patients were treated with TPO‐RA and low dose prednisolone. Baseline median parameters were as follows: PC 6.5x109/L (range 1–17), PS 0.5 days (range 0.1–1.6, normal: 7–10), platelet production ratio 0.65 (range 0.01–3.2, normal 1 ± 0.2), platelet turnover 30875 Plt/μL/day (range 1731–103500). The post−treatment PKS showed significantly higher median PC of 62.5x109/L (range 5–501) (p = 0.013) and median platelet production ratio of 1.8 (range 0.5–37.9) (p = 0.05). However, median PS of 0.7 days (range 0.1–2.9) (p = 0.09), as well as platelet turnover of 58471.5 Plt/μL/day (range 2800–462236) (p = 0.086) and platelet destruction site remained unaltered. It is of note that two refractory patients (N08 and N010 in table) increased their platelet production (platelet production ratio and platelet turnover), while their PS remained reduced. It is of note that there was no clear correlation between PC and PS. Nevertheless, PC correlated only with platelet turnover prior (p = 0.006) and after TPO‐RA therapy (p = 0.029).

Summary/Conclusion:

Our prospective study in which PKS was performed initially and during TPO‐RA therapy suggests that TPO‐RA could increase PC by augmented production. Further studies on larger cohorts are needed to confirm this idea.

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PS1494 REDUCED ANTIOXIDANT CAPACITY INDUCED PYROPTOSIS IN PLATELETS IN IMMUNE THROMBOCYTOPENIA PATIENTS
Authors: Wang S. , Liu Y. , Hou M. , Peng J.
Published: June 2019

Background:

The pathophysiology of primary immune thrombocytopenia (ITP) is not fully understood. Antioxidant capacitie (AOC) is reduced in ITP platelets. Mitochondrial reactive oxygen species (ROS) generation can lead to NLRP3 inflammasome activation and pyroptosis. However, the process has not been studied in ITP platelets.

Aims:

To assess whether the reduced AOC of platelets in ITP can affect the NLRP3 inflammasome signaling pathways and to further explore the pathophysiology of ITP.

Methods:

We measured mitochondrial membrane potential (MMP) of platelets from patients and healthy donors using JC‐1 by flow cytometry. Next, we investigated AOC of platelets by supplementation of 300 μM H2O2following loading with 50 μM 2’,7’‐dichlorodihydrofluorescein diacetate. ROS level as well as expression of NLRP3, ASC, pro‐caspase‐1 and p20 in platelets after stimulation with H2O2was detected. Besides, co‐localization of NLRP3 and ASC in platelets after stimulation was assessed by immunofluorescence. Blocking experiments were performed using antioxidant N‐Acetyl‐L‐cysteine, NLRP3 inhibitorMCC950 (CP‐456773) and caspase‐1 inhibitorZ‐VAD‐FMK. Furthermore, we studied the pyroptosis of platelets in passive ITP mouse model using NLRP3‐/‐ mice, Caspase‐1‐/‐ mice and wild type mice.

Results:

The platelets from ITP patients showed significantly reduced antioxidant capacity compared to healthy donors. A significant lower MMP and higher ROS level were detected in ITP platelets. Expression of NLRP3, ASC, pro‐caspase‐1 and p20 was obviously increased and co‐localization of NLRP3 and ASC was more evident in ITP platelets. An increased level of IL‐1β and IL‐18 were observed in culture supernatant. The application of antioxidant N‐Acetyl‐L‐cysteine (NAC), NLRP3 inhibitor MCC950(CP‐456773) and caspase‐1 inhibitor Z‐VAD‐FMK to H2O2‐stimulated ITP platelets significantly inhibit pyroptosis. The indicators of pyroptosis were down‐regulated in NLRP3‐/‐ and Caspase‐1‐/‐ mice.

Summary/Conclusion:

The reduced AOC of platelets in ITP results in accumulation of intracellular ROS, which contributes to the activation of NLRP3 inflammasome signaling pathways and leads to pyroptosis, which accelerates thrombocytopenia in ITP.

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PS1507 INCREASED VOC FREQUENCY ASSOCIATED WITH REDUCED HRQOL AMONG PATIENTS WITH SCD
Authors: Besser M. , Bailey M. , Brown S. , Thompson M.
Published: June 2019

Background:

Sickle cell disease (SCD) is a global health concern. Each year as many as 200,000 infants are born with this disease worldwide. Despite improvements in outcomes over the last few decades, patient life expectancy remains 10 to 30 years shorter than that of the healthy population. A major cause of morbidity among patients with SCD is the occurrence of intense, recurrent, acute, severely painful episodes, known as vaso‐occlusive crisis (VOCs). As patients age and SCD progresses, an increased frequency of VOCs and other disease‐related complications is correlated with an increased risk of morbidity and mortality.

Aims:

The aim of the current analysis was to determine whether VOC frequency is associated with a decrease in the health‐related quality of life (HRQoL) and associated utility of patients with SCD.

Methods:

LEGACY was a prospective, multicenter, observational study that documented the outcomes of 181 adult patients with SCD living in the United States. Patients were assessed at baseline and every six months for 3 years, on several health outcomes, including the number of VOCs experienced and patient health as assessed by the Short Form‐36 (SF‐36) Health Survey. For the cohort of patients aged 18 years and older, the total number of VOCs experienced over the previous 12 months was determined for each administration of the SF‐36. Patients were categorized into three groups:

‐ 0 VOCs in the previous 12 months

‐ 1 to 2 VOCs in the previous 12 months

‐ 3 or more (3+) VOCs in the previous 12 months

The SF‐36 scores for individual questionnaires were then mapped to the EuroQoL five‐dimension (EQ‐5D) questionnaire, which is a standardized instrument that can be used to derive a single utility value. The mapping was done using the random effects GLS mapping algorithm published by Rowan and colleagues (2009). Mean EQ‐5D scores were compared between groups using the Student's T‐test. Differences between the groups on the SF‐36 component scores and SF‐36 domains were also assessed.

Results:

Patients with 3+ VOC events in the previous 12 months had mapped mean EQ‐5D scores that tended to be lower (15%) than those of patients who had no VOC events (see Figure 1). Patients who had 3+ VOC events also showed decreases in both SF‐36 Physical Component Scores and Mental Component Scores compared to patients with no VOC events.

Summary/Conclusion:

To our knowledge, this is the first analysis to examine the relationship between VOC frequency and HRQoL in patients with SCD. The results of this analysis indicate that patients who have a higher number of VOC events experience a worse HRQoL compared to patients with no events. Additional research is required to understand the drivers of this difference in HRQoL.

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PS1513 ESTIMATING LIFE‐YEAR LOSS OF PRIMARY MYELOFIBROSIS IN EUROPE
Authors: Li Z. , Tang D. , Tang J. , Cavalli L. , Oliva E.
Published: June 2019

Background:

Primary myelofibrosis (PMF) is a myeloid neoplasm impacting patient survival and quality of life. Although JAK2 inhibitors were recently approved for the treatment of patients with PMF, there is still a lack of strong evidence supporting a survival benefit in this patient population.1 Existing published survival data focus on describing duration of survival, however as there is no general population comparator for this outcome, interpretations are often subjective.

Aims:

This study aimed to quantify the real‐world mortality caused by PMF in comparison with the general population in Germany, France, Italy, Spain, and the UK (EU5).

Methods:

A simulation model was developed in Microsoft Excel, using parameters sourced from a large‐scale European‐based real‐world retrospective MF study by the International Working Group for Myeloproliferative Neoplasm Research and Treatment.2 Baseline demographics predictive of survival, including age, sex, and International Prognostic Scoring System (IPSS) risk level, were simulated using the patient characteristics statistics published by Cervantes et al. in 2012.2 The survival of patients with PMF was simulated using the exponential survival function. To examine the rate of mortality, the exponential distribution parameter (modeled as a function of age, sex, and IPSS risk level) was estimated using published median survival times and derived hazard ratios. Patient characteristics and survival statistics from the simulation sample were verified with the published data.2 Real‐world life‐year loss was calculated as the difference between simulated survival time and the population‐level life expectancy specific to the patient's age, sex, and country.

Results:

A total of 5,000 patients were simulated (Table), with 1,000 from each EU5 country. The simulated sample generated similar patient characteristics statistics and median survival years as found by Cervantes et al.2 The additional mean life‐year loss of PMF was estimated at 9.6 years (median 10.7 years; 5 and 95 percentile [−18.7, 33.4]), with a 45% relative survival loss, compared with the general population. Overall, 81% of patients with PMF were estimated to experience life‐year loss. More pronounced life‐year loss was found to be associated with being male (mean 11.3 years; 57% relative survival loss; 86% with life‐year loss), age <65 years (mean 14.3 years; 48% relative survival loss; 84% with life‐year loss), and IPSS Intermediate‐2 to High risk classification (mean 15.4 years; 73% relative survival loss; 95% with life‐year loss). The results were consistent among the EU5 countries modeled.

Summary/Conclusion:

PMF patients experience significant real‐world life‐year loss when compared with the general population in Europe.

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PS1549 SELF‐REPORTED PHYSICAL ACTIVITY IS PREDICTIVE OF SURVIVAL IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HCT)
Authors: Jayani R. , Pidala J. , Jim H. , Zhou J. , Mo Q. , Mishra A.
Published: June 2019

Background:

Increased physical activity is associated with improved survival in patients undergoing cancer treatment. However, the association of self‐reported physical activity and activity intensity with HCT outcomes is less clear.

Aims:

The goal of this study is to evaluate the relationship of self‐reported physical activity and HCT outcomes.

Methods:

Data was collected from the Moffitt Cancer Center Health Research Informatics and transplant databases. Between 01/01/2011 and 7/5/2018, 587 patients received an allogeneic HSCT and completed IPAQ short form. IPAQ scoring algorithm was used to ascertain metabolic equivalent of task‐minutes (MET‐minutes) per day. Based on MET‐minutes/day aggregate score, patients were subsequently divided into three activity categories: low (n = 337), moderate (n = 52), and vigorous (n = 198).

Results:

Median follow‐up was 41.7 months (range 11.4–267months). Patients with lower physical activity were older (Age = 59.67 [20.3–75.4] and had more comorbidities (HCT‐CI = 3 [0–9]), in comparison to patients with moderate and vigorous activity. Males reported vigorous activity more commonly (66.7%) in comparison to females (33.3%) whereas low activity level was similar for each gender (females 51.3%, males 48.7%). There was no significant difference in Karnofsky performance status (KPS), Armand disease risk, conditioning intensity, number of prior chemotherapy regimens, and cardiopulmonary function amongst the three categories (Table 1). Patients with vigorous physical activity had lower risk of NRM in comparison to low and moderate activity (Figure 1). In multivariate modeling, after accounting for KPS, graft‐versus host disease, and FEV1, physical activity level was an independent predictor of non‐relapse mortality with lower activity levels associated with increased risk of NRM (HR: low 1.7 (95% CI: 1.07–2.93); moderate 2.11 (95% CI: 1.03–4.31); overall P = 0.049). However, no association was seen between activity level and overall survival or relapse free survival (P = NS).

Summary/Conclusion:

Self‐reported vigorous activity prior to HCT is an independent predictor of NRM after HCT. This easy to employ tool can be of utility in the clinic to risk stratify HCT candidates. Further studies are warranted to evaluate impact of self‐reported physical activity on HCT outcomes.

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PS1588 FIBRINOLYSIS IN PATIENTS WITH CHEMOTHERAPY INDUCED THROMBOCYTOPENIA AND THE EFFECT OF PLATELET TRANSFUSION
Authors: Heubel‐Moenen F. , Henskens Y. , Verhezen P. , Wetzels R. , Schouten H. , Beckers E.
Published: June 2019

Background:

Bleeding events in chemotherapy induced thrombocytopenic (CIT) patients with similar platelet counts might be influenced by changes in clot lysis potential.

Aims:

In this observational study we investigated thromboelastographic lysis parameters, alterations in clot strength and susceptibility to clot lysis in CIT patients and identified factors associated with fibrinolytic profiles. Furthermore, the effects of platelet transfusions were evaluated.

Methods:

Independent determinants of tPA‐ROTEM lysis parameters were identified with multivariable linear regression. Clot formation, strength and lysis parameters were compared with results of healthy individuals. Characteristics of CIT patients with and without hyperfibrinolytic profiles were compared. tPA‐ROTEM results before, 1 hour and 24 hours after platelet transfusion were compared.

Results:

A total of 72 consecutive CIT patients were included. tPA‐ROTEM lysis parameters correlated with changes in fibrinolytic proteins. Compared to healthy individuals, clot formation time was longer, maximum clot firmness was weaker and lysis times were shorter. CIT patients had low PAI‐1 and TAFI levels and forty percent exhibited hyperfibrinolytic profiles. Platelet transfusions resulted in less hyperfibrinolytic profiles in many, but not all CIT patients. Patients without hyperfibrinolytic profiles had higher fibrinogen, FVIII and a2‐AP levels.

Summary/Conclusion:

tPA‐ROTEM can be used as a fast and reliable assay to detect hyperfibrinolytic profiles in CIT patients. CIT patients have weaker clots which are more susceptible to clot lysis compared to healthy individuals. Besides platelets, other factors are likely to influence clot susceptibility to fibrinolysis in CIT patients. The impact of a hyperfibrinolytic tPA‐ROTEM profile on bleeding remains to be investigated.
PS1589 RETROSPECTIVE ANALYSIS OF HEMOGLOBIN LEVEL IN 500 TRANSFUSION EVENTS AS A STUDY MODEL FOR THE EVALUATION OF TRANSFUSION APPROPRIATENESS
Authors: Crocchiolo R. , Cuppari I. , Boiani E. , Cesana C. , Cornacchini G. , Ferrera A. , Lando G. , Mazza A.M. , Pugliano M.T. , Sica L. , Volpato E. , Rossini S.
Published: June 2019

Background:

The hemoglobin (Hb) value adopted in the real life setting for the clinical decision of packed red blood cell (RBC) transfusion (transfusion trigger) is sometimes difficult to accurately retrieve and could be different to what is indicated in the blood request. The identification of the transfusion trigger is critical for the analysis of the distinct physicians’ attitudes across the different units within the same hospital and for the dissection of transfusion appropriateness.

Aims:

The aims of the present analysis is to compare the transfusion trigger across the multiple medical and surgical units at our Center and to describe the Hb values before and after the transfusion events. Further, considerations about the feasibility and the potential applications of this analytical approach are discussed.

Methods:

Data extraction procedure focused on the first semester 2018, dealing with transfusion episodes of 1–2 packed RBCs administered to patients hospitalised at ASST GOM Niguarda, Milan, Italy. Each single episode was registered, regardless of the number of the total packed RBCs transfused, as well as the Unit where the patient was admitted and the Hb values at admission, before and after the transfusion, together with the respective date and time. Comparisons analyses were made using the classical statistical tests. The Hb value before the transfusion is considered as the trigger for transfusion decision by the physician(s) in charge of the patients.

Results:

On a total of n = 501 episodes, n = 497 were evaluable for completeness of data. The corresponding number of packed RBCs represents the 2% of all the packed RBCs transfused at our Hospital in one year (n = 22170 in 2018). Median Hb was 10.70 (range: 6.30–16.70), 8.60 (range:3.00–15.10) and 10.30 (range: 5.00–16.30) at admission, before and after transfusion, respectively. Analyzing separately by unit, we observed that the transfusion trigger was higher in Cardiac Surgery, Vascular Surgery and Intensive Care Units, with median values of 9.50, 8.75 and 8.70 respectively. Conversely, transfusion trigger was comparable among the other surgical units (including Orthopedics) and the medical ones: Hb median values were 8.20, 8.20 and 8.30 respectively. Cardiology showed a slightly higher trigger: 8.65 when compared with the other non‐surgical units.

Summary/Conclusion:

The present analysis, accounting for « only » the 2% of the total transfusion burden at our Hospital in 2018, allows for a satisfactory definition of the transfusion trigger across the multiple medical and surgical units as well as the confirmation of the expected post‐transfusion Hb values. Our analysis model supports the feasibility of such an approach as a potential audit instrument and intervention policies in the area.
PS1592 EFFECT OF ANAEMIA ON MUSCLE OXYGEN SATURATION DURING EXERCISE
Authors: Crispin P.
Published: June 2019

Background:

Transfusion of red cells in chronic hypoproliferative anemia aims to improve function in the recipients. Few studies examine functional measures as a trigger for transfusion, in part due to limited tools to functionally assess anemia.

Aims:

To evaluate the effect of anemia on muscle oxygen saturation (SmO2) during exercise.

Methods:

Haematology patients with and without anaemia and normal controls were invited to participate. Each undertook a six minute walk test (6MWT) with continuous gastrocnemius SmO2 monitoring. Patients with a significant change in haemoglobin (such as due to transfusion) were invited to repeat the investigation, up to three subsequent times. Changes in SmO2 were examined in the pooled results of controls, key parameters identified and then extracted from individual participants. The correlation of each parameter with 6WWT distance, as a measure of functional capacity, was evaluated by linear and multifactorial regression. Participants with repeated 6MWT before and after hemoglobin changes were compared with paired T tests.

Results:

There were 73 participants, including 28 with known or presumed normal haemoglobin levels, undertaking 93 walking tests. Examination of control participant curves identified the SmO2 parameters at baseline, nadir and plateau levels, with the fall in SmO2 defined as the difference between baseline and nadir SmO2. In univariate analysis the distance walked correlated with haemoglobin (r = 0.47, p < 0.001), baseline SmO2, (r = 0.34, p = 0.001), nadir SmO2 (r = 0.26, p = 0.013) and the plateau SmO2(r = 0.4, p = 0.001) however these were not independent cofactors in multivariate analysis. The fall in SmO2 did not correlate with the distance walked. There were 17 paired sets of walks with changed hemoglobin levels. An improved 6MWT distance was observed with increased hemoglobin concentration (p < 0.01), but there was no significant improvement in SmO2 values in individuals with higher haemoglobin concentrations.

Summary/Conclusion:

Anemia is associated with reduced function as measured by 6MWT distance and reduced SmO2 before and during exercise. The absolute fall in SmO2 during submaximal exercise was not increased by anemia. This may be due to decreased rate of oxygen demand with shorter walk distances seen in anemia. Although SmO2 values are associated with the functional impairment of anemia, they are not superior to currently used triggers.
PB1668 EARLY T‐CELL PRECURSOR (ETP) ACUTE LYMPHOBLASTIC LEUKEMIA (ETP‐ALL) IN ADOLESCENTS AND ADULTS: A HIGH‐RISK SUBTYPE
Authors: Chong S. , Hon S. , Law K.
Published: June 2019

Background:

Early T‐cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL/LBL) is recognized as high‐risk T‐ALL/LBL subgroup. The optimal therapeutic approached to adult patients with ETP‐ALL/LBL not well characterized.

Aims:

In this study, we compared the outcomes of adults with ETP‐ALL receiving treatment with frontline regimes to those with other T‐ALL immunophenotypic subtypes.

Methods:

This is a 10 years retrospective analytical study of adult patient diagnosed with T‐ALL. Patients with newly‐diagnosed T‐ALL/LBL receiving frontline chemotherapy between the years of 2008‐2018 at Ampang Hospital, Malaysia were identified and immunophenotypically categorized into TI(pro‐T), T‐II(pre‐T), T‐III (cortical‐T) and T‐IV(mature‐T) as per European Group for the Immunological Characterization of Leukaemia (EGIL) classification using CD1a and cytoplasmic/surface CD3. Overall survival (OS) was analysed using Kaplan‐Meier survival function and different groups were compared using log‐rank test. Event‐free survival (EFS) was calculated from the time of CR until relapse or death.

Results:

A total of 77 patients with T‐ALL were identified with adequate immunophenotype data. Of the 77 patients, only 60 could be subtyped into Pro‐T (6.7%), Pre‐T (21.7%), Cortical‐T (6.7%), Mature T (23.3%) and ETP (41.7%) subtypes, largely due to discordant expression of differentiation markers that do not conform to this immunophenotypic classification scheme. The ETP‐ALL group had a median age of 29 years, compared to non‐ETP which was 25 years. Among these subtype T‐ALL, 71.7% (n = 43) were age of 35 and above, and 28.3% (n = 17) were below age of 35. There was male predominance (76.7%). Patients were mainly Malay (58.3%), followed by Chinese (21.7%) and Indian (16.7%), with the remaining 3.3% of other racial origins. There was no significant association between total white count (TWC) at presentation and ALL subtypes (ETP vs non‐ETP) using cut‐off of 100 TWC (χ2 = 1.34, df = 1, p = 0.248). This cohort presented median overall survival (OS) of 13 month (95%CI: 9.4; 18.0) and median event free survival (EFS) of 10 month (95%CI: 6.6; 16.4). The majority of patients underwent induction chemotherapy with curative intent (95%, n = 60)whereas 5%(n = 3) were upfront palliative intent. The induction chemotherapy were mainly GMALL or HyperCVAD (93%, n = 57) where less than 10% were BLOCK and BFM (5.3% and 1.8%, n = 6). Median OS and EFS were further evaluated and we found no significant difference among patients of different subtypes, TWC (cut‐off = 100). However, among these factors, TWC appeared to be a potential predictor for OS due to marginal p‐value to 0.05.

Summary/Conclusion:

ETP‐ALL/LBL represents a high‐risk disease subtype of adult ALL. Novel treatment strategies are needed to improve treatment outcomes of this T‐ALL/LBL subset.
PB1677 SIXTEEN YEAR'S EXPERIENCE OF THE EORTC 58951 PROTOCOL FOR THE TREATMENT OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IN THE SOUTH OF TUNISIA
Authors: Frikha I. , Turki I. , Medhaffer M. , Louati N. , Chaari M. , Hdijji S. , Charfi M. , Kassar O. , Kallel F. , Ghorbel M. , Mnif H. , Elloumi M.
Published: June 2019

Background:

Childhood acute lymphoblastic leukemia (ALL) is an hematologic malignancies with high rate of cure. We report the experience of the clinical hematology department of Sfax‐Tunisia for the treatment of childhood ALL with the EORTC 58951 protocol.

Aims:

We report in this study the experience of the clinical hematology department of Sfax‐Tunisia for the treatment of childhood ALL with the EORTC 58951 protocol.

Methods:

From January 2000 to December 2015, we retrospectively studied the outcome of all childhood ALL treated with the EORTC 58951 pediatric protocol. For those patients we studied the leukemia characteristics (sex ratio, white blood cell counts WBC, blast's phenotype, cytogenetic abnormalities) and response to treatment: response to prophase, remission rate, risk group stratification, treatment related mortality (TRM) (induction and post induction death) and survival (overall survival OS, event free survival EFS and disease free survival DFS).

Results: From January 2000 to December 2015, 193 children were treated with the EORTC 58951 protocol. Median age was 6 years (range: 13 months to 15 years). Sex ratio M/F was 1.47. WBC counts less than 10 G/l, from 10 to 100 G/L and more than 100 G/L were observed respectively in 42, 42 and 16% of cases. The blast's phenotype was B in 71% and T in 29%. Cytogenetic abnormalities were noted in 38% of cases. A good response to prophase was noted in 83% and complete remission in 96% of cases. The EORTC risk group stratification was Low Risk (LR) in 6%, Average Risk1 (AR1) in 46%, Average Risk2 (AR2) in 23.5% and Very High Risk (VHR) in 24.5%. TRM was 10.5%: induction rate death was 6% and post‐induction rate death was 4.5%. Nine patients from VHR group with familial donor underwent allograft. The relapse rate was 28% of all patients in remission; 8% for LR group, 32% for AR1 group, 18% for AR2 group and 44% for VHR group. At 5 years of follow up, OS and EFS were 66 and 60 respectively and DFS was 70%.

Summary/Conclusion:

At diagnosis, childhood ALL in our study had poor characteristics particularly higher rate of T phenotype of blasts, higher rate of leukocytosis more than 100 G/L, higher rate of VHR therapeutic group and higher rate of cortico‐resistant regarding occidental series. Despite the acceptable results concerning remission rate but survival rates remain lower than those observed in the literature, this is explained mainly by the high rate of relapse (28% vs ∼15%). It can be improved our results by detecting high risk patient with MRD study especially for AR1 risk group and doing allograft for VHR patients.
PB1681 OUTCOME OF PATIENTS WITH PHILADELPHIA CHROMOSOME POSITIVE ALL IN SOUTHERN TUNISIA: ABOUT 13 CASES
Authors: Fakhfakh Y. , Frikha I. , Sannenna H. , Mnif S. , Chaari M. , Hdiji S. , Mdhaffar M. , Kassar O. , Ghorbel M. , Charfi M. , Saad A. , Benothmen T. , Elleuch H. , Elloumi M.
Published: June 2019

Background:

Since the era of therapy targeted by tyrosine kinase inhibitors (TKIs), the prognosis of acute lymphoblastic leukemia (ALL) in adult Philadelphia chromosome positive (Ph +) has been significantly improved.

Aims:

We evaluate in this study the outcome of adult Ph + ALL treated with TKI associated with chemotherapy.

Methods:

Our study is retrospective, including cases of de novo Ph + adult ALL diagnosed in the Hematology Department of Hedi Chaker Hospital of Sfax from January 2009 to March 2018. Cytogenetic analysis and research Bcr‐Abl transcript was performed for all patients. They were treated according to the GRAAPH 2005 protocol. TKI, Imatinib, was used at a dose of 600 to 800 mg/day. Bone marrow allograft has been indicated in patients younger than 50 years, in complete remission and with an HLA compliant intra‐familial donor. The current study reports the clinical features and treatment outcome of patients with Ph + ALL.

Results:

There were 13 patients diagnosed with Ph + ALL among 51 with ALL (25%). The median age at diagnosis was 44 years (range 20‐54 years) and the sex ratio was 0.62. The presence of t (9.22) was found in 8 cases, for all patients with a conclusive karyotype, 5 of them had additional abnormalities. Twelve had a positive Bcr‐Abl transcript. One patient had a positive Bcr‐Abl transcript but the cytogenetic study was not concluded. Complete remission (CR) was noted in 92% of cases. Eight patients (age <50 years) were on allograft indications, seven of them had a compatible HLA donor. Of these, five patients had an allograft: four patients are alive in major molecular response after a mean follow‐up of 5 years (1‐7 years). One patient died in post‐transplant by acute GVH. For the 8 patients who did not have an allograft, 4 unfortunately died, the 4 others are alive in major molecular response after a mean follow‐up of 4 years (1‐7 years).

Summary/Conclusion:

Before the TKI era, adult Ph + ALL had a poor prognosis with unsatisfactory CR and survivals not exceeding 40%. Allogenic stem cell transplantation remains the only curative option for patients with suitable matched donors. Since the introduction of TKIs in chemotherapy regimens, the prognosis has been much improved, leading to a CR rate exceeding 80% in the literature, and an event‐free 5‐year survival rate exceeding 70%t, this was also found in our series.
PB1695 ACCURATE DETECTION OF PATHOGENIC FUSION TRANSCRIPTS IN HEMATOLOGICAL MALIGNANCIES USING RNA‐SEQ AND STAR‐FUSION
Authors: Lee J.H. , Lim H.J. , Kee S.J. , Kim S.H. , Shin J.H. , Yang D.H. , Kim H.J. , Shin M.G.
Published: June 2019

Background:

As driver gene fusions that cause hematological malignancy continues to be discovered, appropriate detection methods are needed to diagnose it. Although the conventional multiplex RT‐PCR method showed high sensitivity and specificity, there was a limitation in detecting various newly discovered fusion transcripts. Recently, the next‐generation sequencing (NGS) method introduced into clinical laboratories has been successfully applied to DNA sequencing, while RNA sequencing (RNA‐Seq) have not yet been widely used. This is because of the concerns about sensitivity and specificity, although RNA‐Seq based test have the advantage of being able to detect various novel fusion transcripts.

Aims:

The aim of this study was to develop an optimized fusion transcript detection method that can accurately detect clinically important pathogenic gene fusions and minimize false positive results by analyzing RNA‐Seq results in various hematological malignancies.

Methods:

RNA‐Seq was performed in 11 patients with hematologic malignancies (4 AML, 2 APL, 2 ALL, and 3 CML) diagnosed at Chonnam National University Hwasun Hospital, using RNA samples extracted from bone marrow aspirates at the diagnosis. Library were prepared with 1 ug of total RNA for each sample by TruSeq mRNA Sample Prep kit (Illumina, San Diego, USA). Indexed libraries were sequenced using HiSeq2500 platform (Illumina). The data obtained from the sequencing was analyzed using STAR‐Fusion (v1.2.0) and the final pathogenic fusion transcripts were selected by applying the filtering algorithm developed in this study.

Results:

A total of 12594 fusion transcripts were detected from RNA‐Seq results in 11 subjects, which was 1144.9 per patient. An average of 1.8 final pathogenic fusion transcripts were detected per sample using the optimized filtering algorithm from step 1 to step 4 (fig. 1). The results were consistent with those of conventional multiplex RT‐PCR. The analytical performances of the RNA‐Seq assay for pathogenic fusion detection were a sensitivity of 100% and a specificity of 99.98%. Though the clinical significance was not clear, the presence of five novel fusion transcripts has been demonstrated by direct sequencing.

Summary/Conclusion:

By applying the filtering algorithm developed in this study, it was possible to find all the pathogenic fusion transcripts with the sensitivity and specificity comparable to the conventional multiplex RT‐PCR method. Using RNA‐Seq, it is possible to identify the exact nucleotide sequence of the fusion transcript and to predict the amino acid sequence of the fusion protein. Therefore RNA‐Seq can be used to establish accurate targets for diagnosis, treatment, and prognosis, and this will open new horizons for future diagnosis and treatment of hematologic malignancies.

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PB1712 PROGNOSTIC IMPACT OF ABERRANT EXPRESSION IN ACUTE MYELOID LEUKEMIA
Authors: Turki I. , Louati N. , Rekik T. , Kassar O. , Mnif H. , Elloumi M.
Published: June 2019

Background:

Immunophenotyping allows identification of aberrant antigen expression in acute myeloid leukemia (AML). These antigens are related with particular and genetic abnormalities and recognized as factors of poor prognosis in AML.

Aims:

To assess prognostic impact of aberrant expression in treated AML.

Methods:

Our study is retrospective (January 2017‐June 2018) concerning 97 cases of AML (AML 3 and mixed phenotype acute leukemia were excluded) of the adult from 18 to 60 years old diagnosed and treated at one institution. The immunophenotyping was performed by flow cytometry (BD Facs Canto II®) after incubation with monoclonal antibodies labeled with different flurochromes. Aberrant expression correspond to the expression of antigens of the lymphoid line B or T in AML. We studied the impact of aberrant expression on complete remission (CR) and relapse in a delay of 1 year. We excluded the cases with missing data.

Results:

We had collected 33 cases of treated AML. Aberrant lymphoid antigen were seen in 18 cases (54.54%). It is about CD 56 in 6 cases (33%), CD7 in 6 cases (33%), CD4 in one case (5.5%) and CD19 in 2 cases (11%). Association between lymphoid B and T antigens or T and NK antigens was seen in 3 cases (CD19 + CD7, n= 1; CD7 + CD56, n=2). We didn’t find any correlation between expression of lymphoid antigen and lower CR rates (93% vs 54%; r= 0.17, p = 0.42). Analysed individually, no lymphoid antigen was associated with more induction failure. Relapse seems to be associated with aberrancy expression without statistically significant association (p = 0.29); CD7 was the most aberrant antigen expressed in cases of relapses (75%).

Summary/Conclusion:

The expression of aberrant antigens in AML is correlated with poor prognosis in literature. This result was not statistically prouved in our study and that's can be explained by the reduced size of our sample. Otherwise, our study shows the pejorative impact of the expression of CD7 on cases of relapses. Expression of CD56 (33% of our cases), similar to literature (10‐30% of cases), was not associated with higer relapse's rate in the limit of our sample (12.5% of AML CD56 + ).

Despite the limited number of cases, this study allow us to better understand the impact of aberrant antigens expression in prognosis of AML. A study on a larger series is underway.
PB1719 TRENDS IN EFFICACY PARAMETERS STUDIED IN CLINICAL TRIALS FOR ACUTE MYELOID LEUKAEMIA
Authors: Said D. , Borg J.J. , Attard Pizzuto M. , Serracino‐Inglott A.
Published: June 2019

Background:

Acute myeloid leukaemia (AML) accounts for one third of adult leukaemias in developing countries and is associated with poor prognosis in Europe. Biomarker‐based endpoints have been validated as surrogate measures to predict overall survival (OS) in AML, potentially leading to shorter clinical trial (CT) durations and faster patient access to innovative treatments.

Aims:

To analyse the evolvement of efficacy endpoints over time for CTs in AML conducted in the European Union (EU).

Methods:

Interventional Phase II to Phase IV AML CTs registered in the EU Clinical Trials Register over an 11‐year period (2007‐2017) were identified. Therapeutic CTs reporting efficacy data in the English language for investigational medicinal products (IMPs) of chemical, biological and biotechnological origin were included in the study. A protocol design or age filter was not applied to avoid limiting the scope of outcomes identified. Primary and secondary efficacy endpoints were extracted from the selected CTs and categorised according to type of measurement. Descriptive and inferential statistics were operated in a data mining process to detect trends in outcomes studied by pharmaceutical developers.

Results:

The final data set comprised 161 CTs representing 46,914 patients, with the majority of trials (67%, n=108) recruiting only patients from the adult (18‐64 years) and elderly (>=65 years) populations. Twenty‐nine unique efficacy measures were identified and stratified into the endpoint clusters of survival (n=4), time‐to‐event (n=5), response rates and biomarkers (n=13) and other (n=7) parameters. Sixty‐eight per cent (n=110) of the trials reported 4‐10 outcomes, with a mean of 5 per CT. The principal outcomes examined included OS (CTs: 78%, n=126), complete response rate (CR) (CTs: 52%, n=84) and event‐free survival (EFS) (CTs: 44%, n=71). The endpoints EFS, OS and complete response rate with incomplete blood recovery (CRi) registered the highest frequency change of selection pre‐ and post‐2012 (EFS: 30%, p < 0.001; OS: 27%, p < 0.001; CRi: 18%, p = 0.01).

Summary/Conclusion:

The increase in uptake of EFS and CRi as efficacy parameters in AML CTs is in line with previous findings correlating these measures to OS. Significant heterogeneity in the selection of efficacy endpoints was observed. This warrants future work on the development of a core, standardised set of efficacy outcomes prioritised by relevant stakeholders for AML CTs.
PB1732 ASSOCIATION OF FLUDARABIN, CYTARABINE AND GEMTUZUMAB FOR FIRST‐LINE REFRACTORY AML IN CHILDREN: A SINGLE‐CENTER EXPERIENCE
Authors: Penel‐Page M. , Plesa A. , Girard S. , Marceau‐Renaut A. , Renard C. , Bertrand Y.
Published: June 2019

Background:

Acute myeloblastic leukemia (AML) is a rare disease in children, with only 50 to 60% of event‐free survival. Ten percents of patients do not respond to first‐line chemotherapy, and there is no recommendation about their second‐line treatment. Gemtuzumab ozogamicin (GO) is a monoclonal antibody targeted against CD33, linked to calicheamicin.

Aims:

We report the efficacy and tolerance of a salvage regimen with fludarabin, cytarabine and GO (FLA‐GO) in our comprehensive cancer center, for patients refractory to first‐line treatment.

Methods:

Eight patients (median age 14.5 years) received this protocol between 2013 and 2018. They received Gemtuzumab 3 mg/m2 on day 1, 4, 7, associated with cytarabine 2000 mg/m2 and fludarabin 30 mg/m2 d1‐d5.

Results:

Six out of the 8 treated patients achieved complete remission with blast count ≤10‐2. Five of them received a second course. We observed 11 febrile neutropenia, including 6 septicemias without complication. There was no fungal infection, nor toxic death. Two patients received G‐CSF. One had partial platelet recovery (CRp), one prolonged pancytopenia. The 8 patients received hematopoietic stem cell transplant (HSCT). We observed 5 mild to severe sinusoidal obstruction syndrome during HSCT procedure, especially in patients who did not receive prophylaxis with defibrotide. At the date of last contact, 6 patients are in continuous complete remission, with a median follow‐up of 41 months (12‐51). Two patients presented post‐HSCT relapse and died.

Summary/Conclusion:

FLA‐GO is a good salvage regimen for refractory AML in children, with acceptable toxicity. HSCT is mandatory to achieve sustained CR in these patients.
PB1765 CHARACTERISTICS OF ERYTHROLEUKEMIA ABOUT 10 CASES WITH REVIEW OF THE LITERATURE
Authors: Talbi T.F. , abbadi M.R. , ghassoul Y. , djilali M. , belateche K. , bouteldja L. , menouer S. , ardjoun F.Z. , belakhel S. , djouadi K.
Published: June 2019

Background:

Acute erythroblastic leukemia (AML‐M6) is a rare entity, accounting for 3‐4% of all LAs. There are two types: erythroleukemia and pure erythroid leukemia. It is most often manifested by signs of cytopenia and infiltration of extrahematopoietic tissues, and is more common in adults than in children with a poor prognosis.

Aims:

The objective of this study is to describe the clinical, biological and evolutionary aspects of erytholeukemia in a monocentric retrospective study.

Methods:

the diagnosis is based on a cytological examination of the blood smear (FS) and medullary (PMO) as well as the immunophenotypic examination. We calculated overall survival by Kaplan Meier method

Results:

n = 181 (evaluable), n = 10 patients with AML6 according to the FAB classification (5%). • The cytological study of FS and PMO + CMF results led to the diagnosis of erythroleukemia in 08 of our patients and pure erythroid leukemia in 2 patients. Mean age = 47 ± 21.77 years [0‐64]. Sex ratio = 1.5 (6H / 4F). Duration: 40 ± 35 days [01‐90]. Symptoms of bone marrow failure: PCM (100%), hemorrhagic syndrome: 3 cases (30%), infection: 04 cases (40%), splenomegaly: 04 cases (30%), mean WB = 84,300 ± 11.260 giga / l [125.000‐83.400], peripheral blast level (avg = 26 ± 23% [1‐65]), medullary blasts = average 49.5 ± 19% (08‐93) • mean hemoglobin level = 8.06 ± 1.09 g / dl [5‐10], platelets: 21‐151giga / l (avg: 65,900 ± 47,450 / mm3) n = 03 patients had severe thrombocytopenia at 13‐21‐39 giga / respectively (30%), pancytopenia found in n = 05 cases (50%), LDH level (mean) = 905 ± 896 IU / L [12‐2,900], n = 02 patients had 1 metabolic complication at diagnosis (hyperkalemia, hyponatremia). n = 8 patients received induction CT (3 + 7), n = 01 patient received only 2 aracytin‐associated antracycline injections. Newborn LAM, the newborn clinically presents: cutaneous and mucosal paleness and hepatosplenomegaly, on the biological plane: GB: 125giga / l, (EB = 64%, blast = 3%), HB = 10 g / dl, PLQ = 13gigal / l, PMO: infiltration by 68% of dystrophic EB, 08% of MB, the newborn t under aseptic vacuum The specific treatment has not yet been started. The complete remission is obtained (n = 04 cases (40%)) and n = 03 failures (30%), n = 01patient came out against medical advice; one induction death is listed (acute cardiac toxicity) • Overall survival = 27% (fig1)

Summary/Conclusion:

our data are similar to those of the literature: rare pathologic LAM6 (3‐5 / series, 05% in ours), exceptional in children. The signs of bone marrow failure are almost constant, 1 pancytopenia in 50%. Splenomegaly is found in 1/3 of the cases. The prognosis is reserved (overall survival = 25% at 05 years) from wherethe value of rapid diagnosis and adequate management

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