bluuebunny/crossref_metadata_2025 huggingface dataset:
S891 SUCCESSFUL TREATMENT OF INTESTINAL GRAFT‐VERSUS‐HOST DISEASE WITH FECAL MICROBIOTA TRANSPLANTATION
Authors: Van Lier Y. , Davids M. , Haverkate N. , de Groot P. , Donker M. , Heubel‐Moenen F. , Nur E. , Zeerleder S. , Nieuwdorp M. , Blom B. , Hazenberg M.
Published: June 2019

Background:

Disruption of the intestinal microbiome has a negative influence on the outcome of allogeneic hematopoietic stem cell transplantation (HSCT). Decreased gut flora diversity with loss of commensals and pathobiont domination, is associated with an increased risk to develop graft‐versus‐host disease (GvHD). Fecal microbiota transplantation (FMT) has successfully been used to treat Clostridium difficile enteritis but the safety and efficacy of FMT in immunocompromised GvHD patients remains to be elucidated.

Aims:

1. To assess the safety and effectiveness of FMT as treatment for GvHD patients in a prospective, single‐arm pilot study

2. To analyze the microbiome dynamics of GvHD patients receiving an FMT

Methods:

Fifteen patients with steroid‐refractory or steroid‐dependent intestinal GvHD received a single FMT from an unrelated, healthy donor via nasoduodenal infusion. Follow‐up included collection of blood and fecal samples prior to FMT and at 1, 4, 12 and 24 weeks after FMT as well as clinical follow‐up up to 6months.

Results:

FMT was well tolerated by all patients, there were no serious adverse events observed that could be attributed to FMT. Response evaluation at 4 weeks after FMT identified 11 participants with a complete response (CR), defined as resolution of all GvHD, without other interventions to alleviate symptoms. In 6 CR patients, the normalization of stool frequency and consistency was sustained throughout the whole period of follow‐up, with successful taper of immunosuppressants. Five other responders initially showed improvement of GvHD after FMT but relapsed upon prednisolone taper (CR/sf; complete responders with secondary failure). A durable response to FMT was associated with a better prognosis (Figure 1). Analysis of peripheral blood immune cell subsets did not reveal significant differences. Alpha diversity of fecal samples, analyzed by 16S ribosomal RNA sequencing, was low in patients pre‐FMT but improved upon response to treatment in CR and CR/sf patients. One week after FMT, the fecal microbial composition of CR patients resembled that of the donor the most, suggesting a better engraftment of fecal donor species in patients with persistent responses.

Summary/Conclusion:

This pilot study shows the potential of donor FMT to safely restore microbial diversity and improve symptoms of steroid‐refractory or steroid‐dependent GvHD patients. These encouraging data promote further investigation of this therapy in larger cohorts.

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PS959 MVP COMBINED WITH FC AS LYMPHOCYTE‐DEPLETING CHEMOTHERAPY BEFORE CAR‐T TREATMENT CAN REDUCE THE INCIDENCE OF SEVERE CYTOKINE RELEASE SYNDROME FOR R/R ALL PATIENTS WITH HIGH TUMOUR BURDEN
Authors: Tang X. , Liu Q. , Li Z. , Dai H. , Yin J. , Tian X. , Xue S. , Xu Y. , Zhu X. , Wu D.
Published: June 2019

Background:

CAR‐T immunotherapy have shown remarkable promising results for relapsed/ refractory (R/R) acute lymphoblastic leukemia(ALL). However, the most common toxicity associated with CD19 CAR‐T treatment is Cytokine Release Syndrome(CRS) which can be a life threatening complication especially for high tumour burden ALL patients. How to reduce the incidence of severe CRS can be a great challenge for advanced high tumour patients.

Aims:

In order to evaluate the efficacy and safety of MVP+FC as lymphocyte‐depleting chemotherapy to reduce tumour burden before CAR‐T therapy.

Methods:

If patients’ blasts in bone marrow was more than 28%, the chemotherapy MVP(Mitoxantrone 10 mg/w once(d1)+ Vindesine 4 mg/w once(d1) + Dexamethasone 10 mg/d × 7d(d1‐d7) followed by FC(Fludarabine 30 mg/m2 × 3d (d8‐ d10)+ cyclophosphamide 300 mg/m2 × 3d(d8‐d10)) were performed. CD19 CAR‐T, CD22CAR‐T and CD19CD22 tandem CAR‐T were infused with dose escalation schedule: 10%>‐ 40%>‐ 60% (d13, d14, d15). Total dose of CAR‐T for infusion was 5–10 × 106/kg.

Results:

16 patients were enrolled in this study with median age of 24 (6–56) years old. 11 patients were relapse post multiple chemotherapies. Another 5 patients were relapse post allo‐HSCT including T315I and TP53 mutation patients. The median blasts in BM before and after MVP treatment were 56% (28–89%) and 34%(0–85%). Furthermore, the median blasts in BM after MVP+FC treatment were 6%(0–60.5%). Overall response of CAR‐T were 93.75% with hematological remission 93.75% and molecular remission 63.75%. Only 4 patients experienced 3 grade CRS and other patients just had 1–2 grade of CRS. Only one presented sepsis. No one experienced neurotoxicity. Treatment related mortality was 0. With the median follow up of 9(1–26)months, 6 and 12 months leukemia free survival were 56.9% and 40.6% respectively.

Summary/Conclusion:

MVP combined with FC was an effective and safety conditionning regimen before CAR‐T treatment with low incidence of severe CRS especially for high tumour burden ALL patients.
PS996 TCF4 IS IMPORTANT FOR MUTANT RUNX1‐MEDIATED CELL IMMORTALIZATION AND PREDICTS OUTCOME IN ACUTE MYELOID LEUKEMIA
Authors: In ’T Hout F. , Gerritsen M. , Bullinger L. , van der Reijden B. , Huls G. , Vellenga E. , Jansen J.
Published: June 2019

Background:

Aberrations of the RUNX1 transcription factor, either mutations (RUNX1
mut) or translocations t(8;21) creating a RUNX1‐RUNXT1 fusion gene, are frequently observed in AML. However, the pathomechanisms underlying RUNX1
mut AML and explaining its poor prognosis in contrast to t(8;21) cases are still poorly understood.

Aims:

As recent data suggested deregulation of the transcription factor 4 (TCF4) gene to play a potential role, we studied the importance of TCF4 in the context of RUNX1
mut and t(8;21).

Methods:

Chip‐sequencing data was analyzed to identify binding of RUNX1 on the TCF4 promoter and Luciferarse reporter assays were used to assay impact of RUNX1 on TCF4 promoter activity.

CD34+ UCB cells were transduced with a pRRL construct overexpressing the RUNX1 R201Q mutant (RUNX1mut) or an empty vector (EV). Simultaneously, TCF4‐RNAi (TCF4kd) or a non‐targeting control (NT) was co‐transduced. These double transduced CD34+ UCB cells were cultured on MS5 bone marrow stromal layer and proliferation assays, colony forming unit assays and long‐term culture‐initiating cells assays were performed. TCF4 expression values were derived from a previously reported cohort of 436 AML patients of which 330 had a known RUNX1 status. Survival curves were calculated by the Kaplan‐Meier method and compared using the logrank test. Multivariate survival analysis was carried out using the Cox proportional hazards model, and covariates included were RUNX1 mutation and white blood cell count (WBC > 100 ∗109/L) with and without TCF4 expression (lowest 75% vs highest 25%).

Results:

While TCF4 is found upregulated in RUNX1
mut in contrast to t(8;21) AML, Chip‐seq and transactivation assays revealed that RUNX1 binds and regulates the TCF4 promoter activity. RUNX1 wild type (RUNX1wt) and the RUNX1‐RUNX1T1 fusion protein repressed TCF4 promoter activity, which was lost in RUNX1mut AML. In CD34+ cells RUNX1
mut enhanced colony‐formation and increased long‐term culture initiating cells, whereas RNA interference based TCF4 downregulation in RUNX1
mut cells abolished this effect. Being required for stem cell maintenance activity in RUNX1
mut AML, TCF4 upregulation accounted for the poor prognostic outcome of RUNX1
mut in AML patients, as RUNX1
mut lost its significance in multivariate analysis if TCF4 expression was included.

Summary/Conclusion:

In summary, TCF4 is an important downstream target of RUNX1mut AML contributing to leukemogenesis and poor response to standard AML therapy.
PS1012 PREDICTING A PML‐RARA FUSION GENE IN PATIENTS WITH ACUTE MYELOID LEUKEMIA BY CONVOLUTIONAL NEURAL NETWORKS
Authors: Liu C.‐J. , Liu Y.‐C. , Yuan W. , Yu K.‐H.
Published: June 2019

Background:

Acute myeloid leukemia (AML) is a prevalent hematological malignancy worldwide. The estimated incidence of AML was 2.4 per 100,000 standard population in Taiwan in 2016. Bone marrow studies are essential for the initial workup in most cases. However, these examinations require a thorough evaluation of the histopathology slides by hematopathologists. Acute promyelocytic leukemia (APL) is a subtype of AML. APL has completely different initial treatment and prognosis from the other subtypes of AML. Convolutional neural network (CNN) is the state‐of‐the‐art technology of image recognition and has been shown to successfully predict common gene mutations by using cancer pathology images (Nicolas et al. 2018 Nature Medicine).

Aims:

We planned to use the whole‐slide scanning images of bone marrow aspiration smears to examine the utility of CNN in predicting APL in AML patients.

Methods:

We collected the whole‐slide scanning images of patients with newly diagnosed AML at Taipei Veterans General Hospital between November 2009 and September 2017. The final cohort consisted of 261 AML cases. The patients’ age, sex, bone marrow blast percentage, cytogenetics and molecular studies, such as FLT3‐ITD and NPM1 and outcomes, were collected. The cohort was split into a training set (80%) and a testing set (20%). In addition, two AML cohorts from Far Eastern Memorial Hospital (n = 19) and Kaohsiung Veterans General Hospital (n = 29) were served as external validation cohorts. Inception V3 was used as the baseline model. Stochastic gradient descent was employed to refine the weights in the CNNs using the training set. The finalized model was tested on the held‐out test set. Prediction accuracy and the area under the receiver operating characteristic curves (AUCs) were analyzed to evaluate the performance of the algorithms. All CNN models were trained using Keras version 2.1.5 with Tensorflow 1.7.0, and statistical analysis was performed with R version 3.5.1.

Results:

The median age of the AML patients at diagnosis was 65 (range 17–96) years and 58.9% of them were male. CNN classified APL from the other subtypes of AML with high accuracy (AUC 0.92). In addition, CNN also could predict other chromosomal abnormalities, such as complex karyotypes, and molecular abnormalities, such as NPM1 mutation. Furthermore, CNN successfully predicted patients’ overall survival by using its classification.

Summary/Conclusion:

CNN successfully predicted genetic alterations of AML patients by using the histopathology images of the bone marrow aspiration smears. These results demonstrated the utility of convolutional neural networks in predicting common genetic mutations. Our developed methods are generalizable to other hematological malignancies or other cancers.

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PS1017 MICRO RNA SIGNATURE OF ONCOGENIC MUSASHI RNA BINDING PROTEINS MSI1 AND MSI2
Authors: Duggimpudi S. , Höll J. , Borkhardt A.
Published: June 2019

Background:

MSI1 and MSI2 are two paralogous RNA binding proteins (RBPs) which are frequently dysregulated in multiple cancers ranging from breast cancer, gliomas, medullobalstoma to acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). RBPs along with MicroRNAs are key form of regulatory molecules working post‐transcriptionally. The interplay between miRNAs and Musashi proteins on target 3’UTRs can rapidly modulate their target mRNA expression. Therefore, identification of mRNA and miRNA interactome is essential for defining the roles of these proteins. We previously identified the mRNAs that are bound and regulated by MSI proteins, next we chose to identify the microRNAs that are regulated by MSI1/2

Aims:

The overall objective of the study is to identify the microRNAs that are regulating and regulated by MSI1 and MSI2 to increase our understanding on the function of these oncogenic proteins.

Methods:

AGO2 PAR‐CLIP experiments aid in identifying the miRNAs that bind to the MSI1/2 mRNA sequence. We will also bioinformatically identify the seed sequence regions on mRNAs that are preferentially bound by miRNAs. Next, we silenced the expression of MSI1 and MSI2 and sequenced the resulting small RNAs using Truseq small RNA sequencing on Illumina platform to identify the miRNAs that are differentially expressed. We carried out functional validation of some of the most promising leukemic miRNA candidates of MSI1/2 using microRNA mimics which will help us uncover new biomarkers and potential therapeutic targets.

Results:

We have performed AGO2 PAR‐CLIPs on AML and CML cell lines THP‐1 and K562 along with a control and found several interesting oncogenic microRNAs binding MSI1/2. Additionally, we knocked down the expression of MSI1/2 using siRNA cocktail and isolated the microRNAs. We sequenced these microRNAs and are currently in the process of identifying the differentially regulated miRNAs.

Also, miR‐143 was identified as top microRNA that bind to MSI2, therefore using miR143 mimics, we validated its binding and effect of its binding on MSI2 expression. We noted a decreased expression of MSI2 upon transfection of cells with miR143 mimics compared to controls. Other top microRNA targets like miR128, miR137, miR320 and miR181 as currently being validated.

Summary/Conclusion:

We identified transcriptome wide microRNAs that bind and regulate the expression of MSI1 and MSI2. We are also evaluating the miRNAs that are differentially regulated by MSI1/2. We validated the binding and regulation of miR143 on MSI2 expression. Combining the data from AGO‐CLIPs and TruSeq small RNA sequencing data, we will be able to establish the microRNA interactome of Musashi family of RBPs. Data from this study can help us to design therapeutic RNA‐decoys that can target the expression of oncogenic musashi proteins.
PS1053 IMPACT OF CYTOMEGALOVIRUS REACTIVATION ON RELAPSE RATE AFTER ALLOGENEIC STEM CELL TRANSPLANTATION IN PATIENTS WITH ACUTE MYELOBLASTIC LEUKEMIA
Authors: Abdeljelil N. Ben , Hmida M. Ben , Ouerghi R. , Lakhal A. , Fatmi R. El , Torjemane L. , Belloumi D. , Ladeb S. , Achour W. , Othman T. Ben
Published: June 2019

Background:

Cytomegalovirus (CMV) infection is a major complication after allogeneic stem cell transplantation (ASCT).

Aims:

The aim of the study was to evaluate the impact of CMV reactivation on the relapse rate after ASCT in patients with acute myeloid leukemia (AML).

Methods:

Retrospective study conducted in patients with AML who underwent ASCT from HLA identical sibling donor between January 2011 and December 2018. Conditioning regimen consisted of Busulfex and Cyclophosphamide (Bu/Cy) or Fludarabine and Busulfex (F/Bu). Graft‐versus‐host disease (GVHD) prophylaxis consisted of cyclosporine and a short course of methotrexate. Antiviral prophylaxis for CMV infection was assured by Acyclovir from day +1 to day +180. CMV detection was carried out once‐a‐week from engraftment to day +100 by either pp 65 antigenemia test or real‐time quantitative PCR.

Results:

Ninety‐three patients were enrolled (55 men and 38 women). Median age was 33 years (range, 5 ‐ 49 y). At the time of transplant, 73 patients (78.5%) were in CR1, 16 patients (17.2%) were in CR2 and 4 patients (4.3%) were in response failure. CMV serostatus for donor (D) and recipient (R) was available for 44 cases (47.3%). Serostatus of R+/D+ and R+/D− was observed in 38 patients (86.4%). Stem cell source were BM in 49 cases (52.7%) and PBSC in 44 cases (47.3%). No graft failure was observed. Acute GVHD grade II‐IV occurred in 19 patients (20.4%). Chronic GVHD was observed in 40 patients (45.4%). Twenty‐nine patients (31.2%) developed CMV reactivation. With a median follow‐up of 2 years (range 49 days – 7 years), the overall survival (OS) and the non‐relapse mortality (NRM) were not statistically significant between patients with CMV reactivation and those without CMV reactivation (74% vs 63%, p = 0.3 and 20.7% vs 7.8%, p = 0.08, respectively). Twenty‐four patients (25.8%) relapsed at a median of 6 months (range 2 ‐ 67 months). the rate of relapse among patients with CMV reactivation was significantly lower than in those without CMV reactivation (10.3% vs 32.8%, p = 0.02). In univariate analysis, the CMV reactivation was the only factor associated with a decreased risk of relapse (OR = 0.23, 95% CI: 0.06–0.87, p = 0.02).

Summary/Conclusion:

CMV reactivation was associated with decreased relapse risk after ASCT for patients with AML without a benefit in OS.
PS1056 ACUTE MYELOID LEUKEMIA OR MYELODYSPLASTIC SYNDROME WITH CHROMOSOME 17 ABNORMALITIES AND LONG‐TERM OUTCOMES WITH OR WITHOUT HEMATOPOIETIC STEM CELL TRANSPLANTATION
Authors: Mohyuddin G.R. , Britt A. , Skikne B. , Singh A. , Lin T. , McGuirk J. , McClune B. , Ganguly S. , Abhyankar S. , Shune L. , Dunavin N. , Dias A.
Published: June 2019

Background:

Chromosome 17 (ch17) abnormalities, especially loss of the 17p region and P53 gene mutations (p53mut) result in very low rates of cure for patients with acute myeloid leukemia (AML) treated with conventional chemotherapy or allogenic stem cell transplant (ASCT).

Aims:

We assessed whether such poor outcomes extend to patients with all types of ch17 abnormalities and whether p53mut has further prognostic value.

Methods:

We retrospectively analyzed 98 patients at our institution with AML/myelodysplastic syndrome (MDS) who had ch17 abnormalities noted on cytogenetics. p53mut was analyzed by next generation sequencing (NGS).

Results:

61 patients with AML and 37 patients with MDS were included. Patient characteristics are in Table 1. 95 out of the 98 patients had 17p abnormalities as part of a complex karyotype, whereas 67 out of the 98 patients had a monosomal karyotype.

Complete remission (CR) with first line treatment was similar between induction chemotherapy or hypomethylating agents, 22.9% vs 21.6 % (p = 0.33).

Median overall survival (OS) for all patients was 10 months. Ch17 abnormalities were classified into those resulting in deletion of the p53 loci such as 17p deletion and monosomy 17 (17pdel/mono17) and all other ch17 abnormalities (ch17oth). Amongst patients with 17pdel/mono17with NGS available, 19 of 26 had p53mut, while for ch17oth, 13 of 17 had p53mut (p = 0.72).Patients having both p53mut and abnormal ch17 exhibited poorer OS compared to patients with no p53mut (10 vs 23 months, p = 0.02).

30 patients (19 AML, 11 MDS) underwent ASCT, with a median post‐transplant OS of 11 months. For AML ASCT patients, 18 were in CR (13 with cytogenetic remission) and 1 had refractory disease at transplant, whereas for MDS patients, 3 were in CR (2 with cytogenetic remission) and 8 had stable disease. The post‐ASCT survival between AML/MDS cohorts did not differ (p = 0.6), although cytogenetic CR at time of ASCT trended towards improved OS (17 vs 8 months; p = 0.6). At last follow‐up, only 5 of 30 patients were alive, 4 in CR.

Summary/Conclusion:

AML/MDS patients with all types of ch17 abnormalities have a poor prognosis with or without ASCT, representing a distinct subset of patients amongst that that have complex cytogenetics. TP53 abnormalities detected by NGS are not limited to patients with 17pdel/mono17 and can be seen with other ch17 abnormalities. Drugs targeting the TP53 pathway and improving depth of response prior to ASCT are needed for improved outcomes in these patients.

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PS1059 DEFINING TRANSIENT ABNORMAL MYELOPOIESIS BY GATA1 MUTATION IN INFANTS WITH DOWN SYNDROME
Authors: Elalfy M. , Ragab I. , Abdel‐Khalek H. , Fayek M. , Kamal T. , Abdel‐Fattah N.
Published: June 2019

Background:

Infants with Down syndrome are more prone to transient abnormal myelopoiesis. A small percentage of this condition can be fatal, yet they are more prone to develop acute myeloid leukemia if harboring GATA1 mutation.

Aims:

Aim of the Work was to screen infants with Down syndrome for peripheral GATA1 mutation by sequencing of exon2 and to correlate it with clinical and laboratory parameters.

Methods:

The study included 79 patients with Down syndrome aged 1–90 days from the outpatient Genetics Clinic, Children's Hospital, Ain Shams University. Complete blood count with manual differential leukocytes count and blast cells count was assessed to all patients.By peripheral blast count patients were divided into three groups, Group A with peripheral blast count more than 10%, group B with blast count >0–10% and group C with no detected blasts in peripheral blood. Mutation analysis of exon2 of GATA1 gene was performed by Sanger sequencing to 15 cases based on results of blast cells count.

Results:

The median age of patients was 23.5 days. Prematurity was detected in only 6.3% of patients. Eighteen percent of DS patients (15 of 78) had blasts on blood smears (range 1%>60%). %). Group A included 4 patients, group B 11 patients and Group C 63 patients. The patients in group A were younger in age than patients in group B and C. Those 15 patients were divided into two groups: Mutation positive group: 4 patients, all of them had blast cells count >10% and Mutation negative group: 11 patients. The peripheral blast cells% was significantly higher in the mutation positive than mutation negative group. The only patient presented with splenomegaly was positive for the mutation of exon 2 of GATA‐1 gene.There was higher leucocytic count in patients with positive mutations compared to negative ones.One patient with positive GATA1 mutation developed AMKL and died of disease, he had initial blast count more than 10% in peripheral blood.

Summary/Conclusion:

All patients with positive GATA1 mutations had blasts>10% in their peripheral blood. One of the mutation positive patients developed acute myeloid leukemia. We conclude that blast cells count in peripheral blood combined with peripheral GATA1 mutation analysis can be used for close follow up of patients for early detection of acute megakaryocytic leukemia in infants with Down syndrome.
PS1080 LYMPHOMA ASSOCIATED HEMOPHAGOCYTIC SYNDROME: A SINGLE‐CENTER EXPERIENCE
Authors: Rojas Martínez J.A. , Prats‐Martín C. , Pérez Ortega L. , Morales Camacho R. , Knight Asorey T. , Pérez‐López O. , Caballero‐Velázquez T. , De la Cruz‐Vicente F. , Vargas de los Monteros M.T. , Bernal Ruiz R. , Pérez‐Simón J.A.
Published: June 2019

Background:

Aproximately 1% of the patients with haematological malignancies will develope an hemophagocytic syndrome. Some types of lymphoma are associated with higher risks of developing hemophagocytic syndrome. It is described a high rate of lymphoma associated hemophagocytic syndrome (LAHS) related‐mortality. Only few studies have addressed LAHS.

Aims:

To describe the clinical and epidemiological features and the prognosis of LAHS in a tertiary hospital from January 2008 to December 2018.

Methods:

We performed a ambispective observational study of the cases of hemophagocytic lymphohistiocytosis (HLH) diagnosed by bone marrow aspirate. The diagnosis was made according to the diagnostic criteria of the International Histiocyte Society (IHS‐2004). Lymphoma classification followed the World Health Organization (WHO) 2017 system. Epidemiological and clinical features of the patients diagnosed of LAHS were analysed. Statistics performed with SPSS 17.0.

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Results:

48 patients were diagnosed with HLH in our center in this period. 16 cases (37%) were associated to lymphoma. The median age for patients diagnosed with LAHS was 63 (range: 13–80). The most common histological type was diffuse large B cell lymphoma, which occurred in 7 of 16 patients (44 %). Peripheral T cell lymphoma and Hodgkin lymphoma occurred both in 3 of 16 patients. 7 patients (44%) had other known risk factor for LAHS: viral infection, autoimmune disease and immunosuppression. The clinical and analytical features are summarized in Table 1. The histopathological analysis of the bone marrow did not identify hemophagocytosis in any cases.

Most of the patients diagnosed with LAHS (9 of 14) were treated with the first‐line chemotherapy regimen for lymphoma. 3 patients were treated following the HLH‐2004 protocol. 2 patients died before receiving any treatment. The median overall survival time was 88 days (range: 0 days‐6 years). The three months mortality rate was 50%. 4 patients are still alive with 2, 3, 35 and 71 months after the diagnosis of LAHS (Fig 1).

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Summary/Conclusion:

The most common associated lymphoma was diffuse large B cell lymphoma. 44% of the patients had other known risk factor for LAHS. The bone marrow aspirate is superior to the histopathological examination for the diagnosis of LAHS. The three months mortality rate was 50%. Further researches are needed to gain better understanding about this entity.
PS1085 ORAL CHOP LIKE CHEMOTHERAPY IN ELDERLY PATIENTS WITH HIGH‐GRADE NON HODGKIN B CELL LYMPHOMA
Authors: Guidez S. , Tomowiak C. , Princet I. , Motard C. , Corby A. , Machet A. , Debiais C. , Guilhot J. , Delwail V.
Published: June 2019

Background:

The Doxorubicin based R‐CHOP regimen remains the standard of care for the upfront treatment of DLBCL. The advent of oral idarubicin permitted to develop an all‐oral ambulatory oro‐CIEP regimen.

Aims:

We hypothesized this regimen would improve the treatment of elderly DLBCL.

Methods:

We have performed a phase 1/2 study to determine the MTD[CA1] of idarubicin in the oro‐CIEP regimen. Idarubicin was orally administrated on day 1 with starting dose at 20 mg/m2 and escalated per 10 mg/m2 increment.

Results:

Twenty‐six newly diagnosed patients were enrolled, median age of 71 years (range, 62–80). All first 3 patients developed a DLT at level 3 (40 mg/m2), and 14 patients were then enrolled at RP2D 30 mg/m2 in the phase 2. The most significant hematological toxicities were thrombocytopenia grade 3 or 4 (3.3%) and neutropenia grade 3 or 4 (26%); and extra‐hematological toxicities were infectious disease (5% grade 3 or 4). Second primary malignancies were reported in three patients. No toxic related death was observed. ORR and CR rates were 85% and 77%, respectively. The 5‐year overall survival and event free survival were 65% (95%CI 41;81) and 65% (95%CI 42;81), respectively.

Summary/Conclusion:

This analysis shows that oral idarubicin at the MTD of 30 mg/m2 is safe and active in elderly DLBCL. The results we have observed, particularly overall survival seemed to be superimposable to previous publications with the regular CHOP‐like regimens for this population. Further improvements in the protocol will be introduced with the subcutaneous anti‐CD20 immunotherapy approach. This data needs to be confirmed in the context of a larger study.
PS1104 EPIDEMIOLOGICAL STUDY OF IDIOPATHIC THROMBOCYTOPENIC PURPURA AMONG THE ADULT POPULATION OF THE RUSSIAN FEDERATION
Authors: Melikyan A. , Egorova E. , Pustovaya E. , Kolosheinova T. , Ladygina E. , Volodicheva E. , Kaporskaia T. , Ilyasov R. , Shelekhova T. , Fedorova N. , Zotova I. , Sycheva T. , Kontievskii I. , Shestopalova I. , Kurkina N. , Syrtseva E. , Tarasenko E. , Meresiy O. , Cherkashenko Z. , Chabaeva Y. , Kulikov S.
Published: June 2019

Background:

Primary immune thrombocytopenia (idiopathic thrombocytopenic purpura ‐ ITP) is a rare autoimmune disease, the main clinical manifestations of which are hemorrhagic syndrome of varying severity. The incidence of ITP in the adult population of different countries varies from 1.6 to 12.5/100,000 person‐years. ITP register started in the Russian Federation (RF) In December 2014. This is multicenter, prospective observational cohort study “Epidemiological and clinical characteristics of ITP in adults in Russia”.

Aims:

Assessment of the epidemiological characteristics of ITP in the adult population of the RF.

Methods:

Clinical and laboratory data of the register “Epidemiological and clinical characteristics of ITP in adults in Russia”. Methods of descriptive statistics, frequency, variance analysis and event analysis used in statistical processing.

Results:

The incidence of ITP in the adult population of the Russian Federation averaged 2.09/100,000 people. The highest morbidity of 2.7/100,000 recorded among women under 40 years of age. While in men there was a gradual increase in the incidence from 1.09 to 2.5/100,000 people over the age of 60 years. The result obtained is comparable with the data of the registers of other European countries. An analysis of incidence in the sex‐age strata showed that men have a tendency to an increase in the incidence of ITP from 1.09 at the age of 40, to 2.98 at the age of 60. Similar changes in the incidence in women of different age groups not detected. It is noteworthy that in the age group over 60 years, the incidence in men and women is almost the same, whereas data from epidemiological studies in other European countries showed a significant predominance in this group of men.

There was a significant relationship between the risk of development, the degree of bleeding and the number of platelets in the onset of the disease: the severity of hemorrhagic syndrome increases with the number of platelets below 50x109/l (p < 0.0001). In 92.2% of cases glucocorticosteroid hormones prescribed as the first line of therapy. Analysis of methods of treatment used as a second line therapy demonstrated that the probability of splenectomy the last 3 years decreased from 26 to 17%, while the number of patients receiving thrombopoetin receptors agonists increased from 5.9 to 45.7%.

Summary/Conclusion:

The epidemiological data are comparable with those in other European countries. Geographical variations of incidence in different regions of the Russian Federation require further study.
PS1105 CONGENITAL DEFICIENCY OF COAGULATION FACTOR VII IN THE SOUTH OF TUNISIA: ABOUT 88 CASES
Authors: Kacem S. , Megdiche F. , Ghorbel M. , Maalej S. , Fakhfakh Y. , Kassar O. , Frikha I. , Kotti F. , Chaabane H. , Elloumi M. , Kallel C.
Published: June 2019

Background:

Congenital factor VII deficiency (FVII) is the least rare among uncommon hereditary bleeding disorders (1:500 000). This coagulopathy, inherited in an autosomal recessive pattern, is characterized by a bleeding tendency, varied prognosis and a lack of correlation between clinical phenotypes and biological analysis.

Aims:

The objective of our study was to describe and to explore the clinical and the biological features of FVII deficiency in the South of Tunisia.

Methods:

Our FVII‐deficient cohort consisted of 88 patients whose FVII activity was less than 50% and who were referred to our laboratory from January 2000 to December 2018 because of a prolonged prothrombin time (PT) or hemorrhagic manifestations. The FVII deficiency was considered as severe for FVII coagulant activities (FVII:C) <2%, moderate for rates between 2 and 19% and minor for values between 20 and 49%. The statistical analysis was based on Chi‐squared test.

Results:

The mean age of the patients was 22 years old ranging between 21 months and 63 years old and the sex ratio was about 0.83. Among 88 patients, belonging to 58 unrelated Tunisian families, 45 cases (51.2%) were diagnosed accidentally during presurgical screening, 28 cases (31.8%) were noticed following family screening and 15 patients (17%) were discovered due to bleeding accidents. Clinically, 64 patients (72.7%) were asymptomatic whereas the bleeding frequency was about 27.3%. Clinical examination revealed several bleeding manifestations as follows : gingivorrhagia noticed in 12 patients (50%), followed by epistaxis in nine patients (37.5%). Four cases had hematemesis (16.6%), hematoma was found in three (12.5%) and one of the patients had a cerebral haemorrhage (4.2%). Added to that, some bleeding signs, not commonly related to the FVII deficiency, had been noticed such as: menorrhagia, haemoperitoneum, hematuria and bruising. The laboratory severity of each patient was also determined : FVII deficiency was classified as severe in 3.4%, moderate in 14.8% and minor in 81.8% of cases. With reference to statistics, results showed a weak correlation between clinical data and biological levels of FVII:C (p = 0.004). In fact, 15 patients with a minor FVII deficiency had presented haemorrhages with a variable bleeding severity; while one of the patients was asymptomatic despite the severity of his defect.

Summary/Conclusion:

Our study, in accordance with the literature, revealed a great interindividual heterogeneity of the clinical phenotype of FVII deficiency. In addition, bleeding severity did not necessarily correlate with FVII:C and varies markedly between individuals with a similar FVII:C. This would explain the delay and the underestimation of the diagnosis. In addition, the family screening had a prominent effect in improving the earliness of the diagnosis and in ensuring an adequate monitoring of these Tunisian patients.
PS1106 A RETROSPECTIVE ANALYSIS OF IMMUNE THROMBOCYTOPENIA PATIENTS TREATMENT RESULTS AFTER SEQUENTIAL SWITCHING OF THROMBOPOIETIC RECEPTOR‐AGONISTS
Authors: Ptushkin V. , Vinogradova O. , Tkachenko N. , Pankrashkina M. , Chernikov M. , Perova V. , Shikhbabaeva D.
Published: June 2019

Background:

Immune thrombocytopenia (ITP) is an immune‐mediated disease characterized by increased platelet destruction and impaired platelet production with transient or persistent decrease in the platelet count and increased risk of bleeding. Romiplostim (R) and Eltrombopag (E) are the first thrombopoietic receptor‐agonists (TPO‐ra) with demonstrated efficacy against ITP. So far, very few data are available about the potential contribution of switching from romiplostim to eltrombopag or vice versa in terms of efficacy or tolerance.

Aims:

To evaluate the reasons for and result of TPO‐ra switching in adult ITP patients

Methods:

We retrospectively analyzed all patients who received sequential treatment with both TPO‐RA between 2014 and 2018 in Moscow city hematology center (Botkin hospital).

Results:

Thirty‐three pts with primary ITP were included; 19 received first Romiplostim and 15 received first Eltrombopag. Reasons for switching were inefficacy (n = 30) and adverse events (n = 3). All patients (33) had previously received multiple courses of corticosteroids and IV Ig infusions, four (10%) received immunosuppression (rituximab), and five (14%) performed splenectomy. The median platelet count at the administration of the second TPO‐ra was 17x109/l (range 3–25x109/l). Twenty‐five (76%) patients had bleeding symptoms before the second TPO‐ra administration.

From 33 included patients partial response (> 50x109/l without platelet transfusions and bleeding) was achieved in 16 (70%). PR was seen in sixteen from 19 (84%) in E to R group and seven from 15 (47%) in R to E group. Complete response (>100x109/l without pl. transfusions and bleeding) were achieve in 17 from 33 (52%). Twelve pts from 19 (63%) achieve CR in E to R group and five from 15 (30%) in R to E group. Two of 17 (10%) pts achieved a CR within 1–3 months, 11 (67%) pts in 3–12 months, and four (23%) pts later than 1 year from the start of switching to second TPO‐ra therapy.

Three pts (2 in E group due to repeated thrombosis, and 1 in R group due to persistent increased liver enzymes) with recommendation of switching to second TPO‐ra due to adverse events resolved rapidly and maintained remission on alternative drug.

In nine pts (28%) the switching to second TPO‐ra therapy was ineffective (blood platelet level was less than 30x109/l pl). All of them were resistant to first TPO‐ra.

Summary/Conclusion:

Our results confirmed that switching from one thrombopoietic receptor‐agonist to another could be beneficial for patients with chronic immune thrombopenia who failed to respond. Yet longer follow‐up and larger number of pts enrolled are required to fully assess the potential benefits of such therapy change.
PS1180 FOLLOW‐UP OF LOWER DOSE DASATINIB 50MG DAILY AS FRONTLINE THERAPY IN NEWLY DIAGNOSED CHRONIC PHASE CHRONIC MYELOID LEUKEMIA (CML‐CP)
Authors: Naqvi K. , Jabbour E. , Skinner J. , Anderson K. , Yilmaz M. , Ferrajoli A. , Bose P. , Thompson P. , Alvarado Y. , Jain N. , Takahashi K. , Burger J. , Estrov Z. , Borthakur G. , Pemmaraju N. , Dellasala S. , Paul S. , Cortes J. , Kantarjian H.
Published: June 2019

Background:

Dasatinib, a potent BCR‐ABL tyrosine kinase inhibitor (TKI), is approved for the treatment of chronic phase CML (CML‐CP) in the frontline and salvage settings. Notable side effects include pleural effusions and myelosuppression. We previously reported dasatinib 50 mg daily to be active and better tolerated than the approved 100 mg daily dose (CANCER. 2018 Jul 1;124(13):2740–2747).

Aims:

An update on the efficacy and toxicity profile of lower dose dasatinib 50 mg orally daily in patients with early CML‐CP.

Methods:

All patients presenting to our institution in early CML‐CP were eligible to participate. Prior TKI therapy for up to 1 month was allowed. Responses were assessed according to the European LeukemiaNet guidelines (Baccarani et al. Blood 2013 122.872:884).

Results:

From March 2016 to March 2018, 81 patients have been enrolled. Median age is 47 years (20–84). Patients categorized by Sokal risk are: low 53; intermediate 22 and high 6. Median follow‐up is 18 months (9–31). Cumulative response rates (n = 81) over time are shown in the gragh below.

At 3 months, 96% patients achieved early molecular response (BCR‐ABL PCR ≤10%). Median time to CCyR was 4.6 months, MMR 6.0 months, MR4.0 11.4 months and MR4.5 12.2 months. Eighteen patients had treatment interruption: pleural effusion 4 (possibly related 3, unrelated 1 due to pneumonia); gastrointestinal bleed 2; thrombocytopenia 3; transaminitis 2; renal dysfunction 1; asthma exacerbation 1; pneumonitis 1; lower extremity edema 1; myalgias 1, and pregnancy 2. Four patients had dose reductions: pleural effusion 3; myalgias 1. Four patients had dasatinib dose increased to 100 mg: lack of CCyR at 6 months, 3; lack of MMR at 12 months, 1. Four patients are off study: no response 2, pneumonitis 1, and insurance 1. None of the patients have transformed or died.

Summary/Conclusion:

These updated results continue to support dasatinib 50 mg daily as an effective and safe dose for early CML‐CP.

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PS1321 INHIBITION OF NOTCH SIGNALING RESTORES SENSITIVITY TO IMMUNOCHEMOTHERAPY IN AN IN VITRO MODEL OF ACQUIRED RESISTANCE TO R‐CHOP
Authors: Di Pinto G. , Masiero M. , Li D. , Banham A.H. , Lawrie C.H.
Published: June 2019

Background:

Diffuse large B‐cell lymphoma (DLBCL) accounts for almost 40% of all lymphomas. One‐third of DLBCL patients either initially fail to respond to Rituximab plus anthracycline based therapy CHOP (R‐CHOP) or suffer a relapse (i.e. acquired resistance). The Notch pathway is involved in cell proliferation, differentiation and survival in a wide range of cancers.

Aims:

We investigated the role of Notch signaling in an in vitro model of acquired resistance to R‐CHOP treatment.

Methods:

We developed an in vitro model of acquired R‐CHOP resistance using different DLBCL cell lines (SU‐DHL‐4, SU‐DHL‐10 for GCB‐like subtype; RIVA and U2938 for ABC‐like subtype). Using gene expression microarrays, we screened parental and R‐CHOP resistant cell lines to identify putative genes responsible for acquired resistance. Notch1/2 and JAG1 expression levels were validated by qPCR and flow cytometry in R‐CHOP resistant U2932 cells. We treated U2932 cells with a neutralising anti‐JAG1 antibody (clone J1–65D, 10ug/ml) or with the γ‐secretase inhibitor dibenzazepine (DBZ, 100 nM). We then evaluated cell viability after 72 h of R‐CHOP treatment at 400 ng/ml (corresponding to the GI50 of the resistant clones).

Results:

Our microarray analysis showed many genes were differentially expressed. We focused particularly on the U2932 cell line, where overexpression of NOTCH1, NOTCH2 and JAG1 were independently confirmed by qPCR and flow cytometry. We evaluated the viability of U2932 after 72 h treatment with R‐CHOP and we found that the treatment of the resistant clones with DBZ or anti‐JAG1 restored sensitivity to RCHOP, compared to DMSO (vehicle) or IgG controls.

Summary/Conclusion:

We have demonstrated that blocking of Notch signaling, either by preventing JAG1 ligand binding or impeding the cleavage of the intracellular Notch domain, can restore sensitivity to R‐CHOP at levels comparable to the parental control. These preliminary results may suggest Notch signaling as new therapeutic target for resistant DLBCL.
PS1387 CARFILZOMIB IN RELAPSED AND REFRACTORY MULTIPLE MYELOMA (RRMM): FRAILTY SUBGROUP ANALYSIS FROM PHASE 3 ASPIRE AND ENDEAVOR
Authors: Facon T. , Niesvizky R. , Weisel K. , Bringhen S. , Ho P.J. , Obreja M. , Yang Z. , Klippel Z. , Blaedel J. , Mezzi K. , Siegel D.
Published: June 2019

Background:

Carfilzomib (K)‐based regimens improved progression‐free survival (PFS) and overall survival (OS) in relapsed and refractory multiple myeloma (RRMM) patients (pts) in ASPIRE (K [27 mg/m2]‐lenalidomide‐dexamethasone [KRd] vs Rd) and ENDEAVOR (K [56 mg/m2]‐dexamethasone [Kd56] vs bortezomib‐dexamethasone [Vd]), regardless of age. Frailty scores have been developed based on age, comorbidities, and functional status (Palumbo Blood 2015;125:2068–74; Facon Blood 2015;126:4239).

Aims:

We assessed post‐hoc pt outcomes by frailty status.

Methods:

PFS, OS, and safety were assessed by treatment arm and frailty score (based on age, medical history‐derived Charlson Comorbidity Index, and ECOG performance status); frailty scores: 0 = fit, 1 = intermediate (int), and ≥2 = frail.

Results:

Pt frailty status was balanced between treatment arms in ASPIRE and ENDEAVOR. Median PFS and OS were longer with K‐based regimens vs controls in ASPIRE and ENDEAVOR across frailty subgroups (Table). Rates of treatment‐emergent adverse events are summarized in the Table.

Summary/Conclusion:

Kd56 and KRd consistently improved outcomes vs Vd and Rd, respectively, in all frailty subgroups as defined by the algorithm above. These findings support the favorable benefit‐risk profile of KRd and Kd56 regardless of frailty score.

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PS1471 MYELOPROLIFERATIVE NEOPLASMS IN KOREAN CHILDREN AND YOUNG ADULTS
Authors: Choi H.S. , Hong J. , Lee J.H. , Bang S.M.
Published: June 2019

Background:

Myeloproliferative neoplasms (MPNs) are a rare, heterogeneous group of clonal hematopoietic stem cell disorders, characterized by aberrant proliferation of one or more myeloid lineages leading to an overproduction of both mature and immature cells. Three major components of classical BCR‐ABL‐negative MPNs are polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (pMF). They may be transformed to either secondary MF (sMF) or secondary acute myeloid leukemia (sAML). In addition, they can have second cancers during follow up (FU). These classical MPNs primarily occur in middle and advanced age adults, and are exceptionally rare in pediatric age.

Aims:

We conducted an epidemiologic study to elucidate clinical course of MPNs in children and young adults under 30 years of age focusing on disease transformation as well as thromembolism and second cancers.

Methods:

We analyzing data from the Health Insurance Review and Assessment Service (HIRA) database which includes almost all hospital‐based patients’ information in Korea.

Results:

A total of 352 patients who were diagnosed as one of the three kinds of MPNs from Jan. 2008 to Dec. 2016 (242 patients for ET, 104 for PV, and 6 for pMF) were included. Six pMF patients were excluded from further analysis. The incidence was 0.148 per 100,000 for ET and 0.064 per 100,000 for PV. Among 242 ET patients, the male‐female ratio was 119 to 123, and median age at diagnosis was 22 years (range 13–29). Four ET patients (1.65%) underwent any transformation during the study period (median FU duration 49.5 months); ET→PV (i.e., initially diagnosed ET but changed to PV later; N = 2), and ET→sMF (N = 2). Among 104 PV patients, the male‐female ratio was 96 to 8, and median age at diagnosis was 24 years (range 11–29). No PV patients were transformed into sMF during the FU period (median 45.9 months). sAML did not develop in both ET and PV patients. Solid cancers occurred in 5 ET patients and 3 PV patients. Cumulative incidence of arterial and venous thromboembolism were 6.98% and 1.71% in ET, 16.69% and 4.77% in PV, respectively. Five‐year overall survival and transformation‐free survival (to PV, MF and cancer) were 98% and 96.12% in ET, 100% and 97.29% in PV, respectively.

Summary/Conclusion:

This is the first population‐based epidemiologic study in Korean children and young adults with MPNs. The incidence of MPNs is very low in this age group. ET is more common than PV, whereas pMF is very rare. Transformations of ET to PV or MF occurred in a small number of patients. Considering long latency to transformation in MPNs, continuous observation is needed. In addition, second solid tumors should also be carefully observed. Further research is necessary in this patient group, including studies involving other complications such as bleeding.
PS1552 THE INCIDENCE RATES AND RISK FACTORS OF ATYPICAL INFECTIONS IN PATIENTS WITH LYMPHOMA WHO RECEIVED AUTOLOGOUS STEM CELL TRANSPLANTATION
Authors: Lee H.S. , Kim D.J. , Jung S.M. , Lee H. , Jeong S. , Kong S.G. , Lee S.
Published: June 2019

Background:

Autologous stem cell transplantation (ASCT) is an intermediate risk group for infections according to National Comprehensive Cancer Network (NCCN) guideline. Based on the risk of infection, experts recommend prophylaxis for fungal infections with fluconazole or micafungin if mucositis is accompanied, and prophylaxis for Pneumocystitis jirovecii (P. jirovecii) infection with trimethoprim‐sulfamethoxazole (TMP‐SMX) for 3 to 6 months after transplantation. For varicella zoster virus (VZV) reactivation, acyclovir or famcyclovir or valacyclovir is recommended as prophylaxis for 6 to 12 months after ASCT. However, there is a lack of evidence to support this guideline.

Aims:

In this study we performed a nationwide population‐based study to provide information regarding the incidence and risk factors of atypical infections such as fungal, viral or PJP in patients were performed ASCT in the South Korea.

Methods:

Using the Korean Health Insurance Review and Assessment Service database, the patients with lymphoma who received ASCT from 2003 to 2016 were retrospectively analyzed. Atypical infection is identified by international classification of disease (ICD) codes of each infection or ATC(Anatomical Therapeutic Chemical) codes of medicines for treatment. Oral Candidiasis, Herpes simplex virus (HSV), and Epstein‐Barr virus (EBV) infection were excluded because these are considered to non‐pathogenic in clinical field. The patients undergoing allogenic stem cell transplantation (AlloSCT) were excluded.

Results:

The total number of patients with lymphoma undergoing ASCT was 2147, median age was 48 years (range 2–70). The cumulative incidence of fungal infection is 10.4%, viral is 20.0% and PJP is 5.5% in lymphoma. In multivariate analysis, TBI (HR 1.702, p = 0.0390), and previous fungal infection (HR 1.701, p = 0.0398) were independent significant risk factors for fungal infection. The multivariate analysis showed that TBI (HR 2.524, p < 0.0001), previous infection history (HR 1.351, p = 0.0046) and prophylaxis (HR 1.633, p = 0.0001) were independent risk factors for viral infection. The multivariate analysis showed that prophylaxis (HR 2.647, p = 0.0002) were independent risk factors for PJP infection.

Summary/Conclusion:

In this study, patients with lymphoma who underwent ASCT showed relative high risk of viral infection (CIR 20.0%) and previous viral infection, TBI conditioning and non‐prophylaxis were independent risk factors for viral infection. So patients with lymphoma who planed ASCT should be considered prophylaxis for 2years after ASCT. Especially, patient who treated with TBI conditioning and have previous viral infection should receive prophylactic anti‐viral agents.