bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modified Conditioning Regimen with Idarubicin Prior to Autologous Hematopoietic Stem Cell Transplantation in B-Cell Non-Hodgkin Lymphoma
Authors: Tian Chen , Li Yueyang , You M. James , Zhao Zhigang , Zhang Yizhuo , WANG Yafei 
Published: November 2019

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) has become a standard consolidation treatment for patients with invasive lymphoma. The combination of cyclophosphamide, carmustine, and etoposide (CBV) is a commonly used conditioning regimen prior to auto-HSCT for patients with invasive lymphoma. Many modifications of the CBV regimen, including the addition of idarubicin, have been employed, with varying results. We retrospectively analyzed the clinical characteristics and treatment outcomes of 36 patients with invasive B-cell non-Hodgkin lymphoma treated with a conditioning regimen prior to auto-HSCT between January 2015 and June 2018. For our analysis, the patients were divided into two groups: one group received the classic CBV conditioning regimen and the other group received idarubicin at a dose of 8 mg/m2 for 3 days in addition to the CBV regimen. Overall survival (OS), median progression-free survival (PFS), adverse reactions, and hematopoietic reconstitution time were compared between the two groups. OS and PFS were analyzed using the Kaplan-Meier method, and the log-rank test was used for comparison between groups. Cox regression was used for multivariable analysis of other clinical factors. The median follow-up time was 29 months. Among the 36 patients in the cohort, 19 were male and 17 were female, with a male-to-female ratio of 1.12 to 1. The median age of onset was 39.5 years; 18 patients were older than 40 years and 18 were younger than 40 years. Twenty-six patients (72%) had an international prognostic index score of 0-2 and 10 patients (28%) had a score of 3-5. According to Ann Arbor staging criteria, 9 patients (25%) had stage I-II disease and 27 patients (75%) had stage III-IV disease. A total of 21 patients achieved complete remission and 15 patients achieved partial remission before transplantation. There were no significant differences between the groups in terms of neutrophil counts (P = 0.795) or platelet reconstitution time (P = 0.551). Also, there was no difference in adverse reactions between the two groups, suggesting that the addition of idarubicin to the conditioning regimen did not aggravate adverse reactions. OS and PFS were significantly longer in the idarubicin group than among patients who did not receive idarubicin. In the multivariable analysis, the use of idarubicin and complete remission state before auto-HSCT were associated with improved prognosis. These results indicate that the use of idarubicin with the CBV conditioning regimen prior to auto-HSCT is a safe and effective choice for patients with invasive B-cell non-Hodgkin lymphoma.
Keywords: B-cell non-Hodgkin lymphoma; conditioning regimen; autologous hematopoietic stem cell transplantation; idarubicin

Disclosures
No relevant conflicts of interest to declare.
Management of Primary Gastrointestinal Non-Hodgkin Lymphoma with Lenalidomide
Authors: Tian Chen , Li Yueyang , Wang Yafei , You M. James 
Published: November 2019

Primary gastrointestinal non-Hodgkin lymphoma is a heterogeneous malignancy with limited data to guide management. We analyzed the clinical characteristics and treatment outcomes of patients with primary gastrointestinal non-Hodgkin lymphoma treated with or without lenalidomide in a single-center patient cohort. The Kaplan-Meier method was used for survival analysis. The log-rank test was used to perform univariate survival analysis, and Cox multivariable analysis was carried out to analyze significant (P < 0.05) factors from the univariate analysis. The cohort included 219 patients, of whom 140 (64%) had primary gastric lymphoma and 79 (36%) had primary intestinal lymphoma. Most tumors (205; 93%) were composed of predominantly B-cell lymphoma; diffuse large B-cell lymphoma was the most common pathologic type for both primary gastric lymphoma and primary intestinal lymphoma. Univariate analysis showed that lesion location, age, clinical stage, and sex were not associated with overall survival, but MYC rearrangement, tumor cell type, international prognostic index score, and malignant degree were associated with prognosis. Multivariable analysis showed that MYC rearrangement and tumor cell type were independent prognostic factors. The OS and PFS of patients with MYC rearrangement were shorter than that of patients without MYC rearrangement indicating that MYC rearrangement was associated with decreased survival. Neither overall survival nor progression-free survival differed between patients who received chemotherapy with surgery and those who received chemotherapy without surgery, but patients who received surgery alone had a poor prognosis. Surgery was mainly conducted to relieve tumor-related complications or to make the diagnosis. For patients with invasive B-cell lymphoma with MYC rearrangement, the addition of lenalidomide (25 mg daily, days 1-21) to chemotherapy were given. Both of the OS and PFS of patients with lenalidomide were prolonged compared with patients without lenalidomide indicating that lenalidomide could improve the prognosis of patients with invasive B-cell lymphoma with MYC rearrangement.
Keywords: primary gastrointestinal lymphomas, lenalidomide, prognosis

Disclosures
No relevant conflicts of interest to declare.
Evaluating Thrombocytopenia and Other Biomarkers in Multi-Organ Failure during Sickle Cell Crisis
Authors: Shanmugasundaram Krithika , Higgins Ixavier , El Rassi Fuad A , McLemore Morgan L. 
Published: November 2019

Background: In sickle cell anemia, very few markers of disease have been shown to correlate with activity and severity of crisis. We aimed to identify any patterns amongst biomarkers and co-morbidities that correlate with death from multi-organ failure when admitted for sickle cell crisis.
Methods: We identified 20 patients with sickle cell anemia who died of multi-organ failure at Grady Memorial Hospital from 2010-2016. We described baseline characteristics, such as hemoglobin phenotype, age, gender as well as features at presentation such as vital signs, laboratory data, clinical signs and symptoms (I.e. worsening pain), and co-morbidities. We examined bivariate associations between clinical characteristics and the length of survival after multi-organ failure. In a secondary analysis, we investigated clinical and demographic features that most accurately predict infection with gram-negative bacteria. To achieve this, we fit a multivariate logistic regression model and perform leave-one-out cross validation to assess the predictive performance of the fitted model on unseen data.
Results: At baseline, the average age of a patient is 43.8 years (sd=14.7 years). A majority of our cohort are women (60%), do not smoke (70%), and were not on hydroxyurea (80%). Time to death from multi-organ failure was 3.05 days (95% C.I.: 0.20, 5.90), and only 43% identified having "worsening pain." Among complications, 23% had a stroke and 25% had an infection with gram-negative bacteria. With regards to laboratory data, average WBC was 13.4 (95% C.I.: 11.04, 15.70), Platelets 155 (95% C.I.: 102.22, 208.38), d-dimer 12,892 (95% C.I.: -2498.47, 33437.87) and ferritin 3108 (95% C.I.: 795.07, 5421.63). When using a univariate analysis, we identified that stroke (p=0.008), age (p=0.022) and platelet count at the time of presentation (p=0.039) correlated with time to death. We also identified a statistically significant decrease in the platelet count from baseline to time of multi-organ failure (-105.6, p<0.001). Body mass index (BMI) and worsening pain jointly predict infection with gram-negative bacteria with small error (0.133).
Conclusion: We have described a cohort of patients with sickle cell anemia who died of multi-organ failure and found that some factors may have correlated with time to death. The most poignant factors include age, platelet count, and drop in platelet count from baseline. It is also interesting that a proportion of these patients developed a gram-negative bacterial infection, which is a common cause of mortality in sepsis. Although our cohort is small, these data may help guide future studies with larger cohorts of patients to identify what puts these patients at risk of death from multi-organ failure.

Disclosures
No relevant conflicts of interest to declare.
Anti-Leukemic Efficacy of Talazoparib and APE1 Inhibitor III Combined with Decitabine in Myeloid Malignancies
Authors: Kohl Vanessa , Brendel Susanne , Flach Johanna , Kleiner Helga , Weiss Christel , Seifarth Wolfgang , Nowak Daniel , Hofmann Wolf-Karsten , Fabarius Alice , Popp Henning D. 
Published: November 2019

Malignant hematopoietic cells of myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemias (CMML) and acute myeloid leukemias (AML) may be particularly vulnerable to inhibition of poly(ADP ribose) polymerase 1/2 (PARP1/2) and apurinic/apyrimidinic endonuclease 1 (APE1). PARP1/2 and APE1 are critical enzymes involved in single-strand break repair and base excision repair, respectively. Here, we investigated the cytotoxic efficacy of talazoparib and APE1 inhibitor III, inhibitors of PARP1/2 and APE1, as single-agents, combined with decitabine and combined with each other in CD34+ MDS/CMML cells and in CD34+ or CD34- AML cells in comparison to healthy CD34+ donor cells.
The surviving fraction of CD34+ MDS/CMML cells (n = 8; 4 MDS and 4 CMML), CD34+ or CD34- AML cells (n = 18) and healthy CD34+ donor cells (n = 8) was analyzed using the CellTiter-Glo luminescent cell viability assay (Promega, Southampton, UK). Cell proliferation of untreated MDS/CMML and AML cells was determined by trypan blue exclusion assay (Merck, Darmstadt, Germany). PARP1/APE1 mRNA expression was evaluated using validated primer sets for PARP1 (Hs_PARP1_1_SG QuantiTect Primer Assay, NM_001618) and APE1 (Hs_APEX1_1_SG QuantiTect Primer Assay, ENST00000216714) (Qiagen, Hilden, Germany). Immunofluorescence microscopy of γH2AX foci was performed using a JBW301-derived mouse monoclonal anti-γH2AX antibody (Merck).
Talazoparib and APE1 inhibitor III demonstrated critical anti-leukemic efficacy as single-agents in about 19-25% of MDS/CMML/AML cell samples (Figure 1A and B). Low doses of talazoparib and APE1 inhibitor III further increased the cytotoxic efficacy of decitabine in about 78-86% of MDS/CMML/AML cell samples. Moreover, low doses of APE1 inhibitor III increased the cytotoxic efficacy of talazoparib in about 68% of MDS/CMML/AML cell samples.
In summary, talazoparib and APE1 inhibitor III demonstrated substantial anti-leukemic efficacy as single-agents, in combination with decitabine and combined with each other. Hence, our findings support further investigation of these agents in sophisticated clinical trials.
Figure 1 Cytotoxic efficacy of talazoparib and APE1 inhibitor III in healthy CD34+ donor cells, in CD34+ myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (CMML) cells and in CD34+ or CD34- acute myeloid leukemia (AML) cells after 3 days of treatment. (A) The mean IC50 of talazoparib was significantly lower (*p = 0.016) in 1 MDS (MDS#2), 1 CMML (CMML#2) and 3 AML cell samples (AML#1, AML#2, AML#3) as compared to 8 healthy donor cell samples. (B) The mean IC50 of APE1 inhibitor III was substantially lower (p = 0.059) in 1 MDS (MDS#2) and 5 AML cell samples (AML#1, AML#2, AML#3, AML#6, AML#12) as compared to 8 healthy donor cell samples.
Figure 1

Disclosures
Fabarius: Novartis: Research Funding.
Clinical Study on Part Factors Affecting the Effect of Platelet Transfusion during Hematopoietic Stem Cell Transplantation
Authors: Yang Jie , Li Xiuwen , Chen Bao-An 
Published: November 2019

Objective :At present, patients with hematopoietic stem cell transplantation (HSCT) are gradually increasing due to hematological diseases. However, there are no further studies on the factors affecting the effect of platelet transfusion during HSCT. This study analyzed the possible factors that affect the platelet transfusion efficiency.
Methods: The clinical data of patients with HSCT were collected from the Department of Hematology, Zhongda Hospital Affiliated to Southeast University from March 2015 to March 2018. According to the inclusion and exclusion criteria, a retrospective statistical analysis on the factors affecting the infusion effect was taken in all patients from +1 d to the day that the peripheral blood granulocyte count was more than 0.5×109/L after transplantation. The factors are including gender, age, types of disease, whether initial treatment, platelet inventory days in the effective period, types of transplantation, duration of disease and transfusion times. Furthermore, non-conditional logistic regression analysis was performed on the mentioned factors with statistical significance.
Results: A total of 52 patients, 299 platelet transfusions were included in this study. The patients involve 28 men and 24 women, and there were 233 effective infusion and 66 invalid infusion. After chi-square test, the effects of gender, age, disease types, whether initial treatment, transplantation types, duration of disease and transfusion times on platelet transfusion were statistically significant(P<0.05), while platelet inventory days within the validity period had no statistically significant effect on platelet transfusion (P≥0.05). Furthermore, the results of non-conditional logistic regression analysis showed that gender, disease type and whether initial treatment had a statistically significant impact on the effect of platelet transfusion (P<0.05).
Conclusion: There are many factors related to poor platelet transfusion during HSCT, in which the gender, disease types and whether initial treatment are the main influencing factors.

Disclosures
No relevant conflicts of interest to declare.
Impact of Minimal Residual Disease Detected By Multiparameter Flow Cytometry on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia Patients in First Complete Remission
Authors: Konova Zoya V. , Parovichnikova Elena N. , Galtseva Irina V. , Kapranov Nikolay M. , Davydova Julia O. , Drokov Mikhail Yu. , Nareyko Maria V. , Popova Natalia N. , Dmitrova Anna A. , Maslikova Ulyana V. , Starikova Olga S. , Usikova Ekaterina I. , Mikhaltsova Ekaterina D. , Koroleva Olga M. , Vasilyeva Vera A. , Lobanova Tatiana I. , Kuzmina Larisa A. , Savchenko Valeriy G. 
Published: November 2019

Introduction.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be curative for acute myeloid leukemia (AML) patients. However, the disease relapse after allo-HSCT lead to poor outcomes almost in all cases. Minimal residual disease (MRD) is a strong prognostic marker of increased risk of relapse and reflects overall (OS) and relapse-free survival (RFS) in patients with AML. Immunophenotypic evaluation using multiparameter flow cytometry (MFC) is an important strategy for detecting MRD, because of its simplicity and wide availability.
Aim. Determine the impact of MRD detected by MFC before allo-HSCT on clinical outcomes.
Patients and methods.
To assess the impact of MRD status before transplantation we include 56 AML patients who underwent allo-HSCT in National Research Center for Hematology between July 2016 and June 2019. Patient's characteristics are shown in table 1. All these patients were in first compete morphologic remission at the time of allo-HSCT. MRD was evaluated by MFC. Bone marrow samples were obtained before allo-HSCT and were analyzed by 6-color MFC (BD FACS Canto II, USA). Positive MRD was identified as a cell population deviating from the normal patterns of antigen expression on specific cell lineages at specific stages of maturation for all patients. In addition, for patients with LAIP at diagnosis, positive MRD was also defined as a cell population carrying LAIP markers at diagnosis.
The probabilities of OS and RFS were estimated using the Kaplan-Meier method.
Results.
Among 56 AML patients before allo-HSCT (all were in CR at the time of MRD analysis). Median of follow-up was 9.3 months.11 patients (19,6%) were identified as MRD+ (0,011%-5,08%, mean 1%). And 5 of them relapsed (45,5%). Out of 45 MRD negative patients before HSCT relapse was registered in one (relapse rate 2,2%). Statistical analysis revealed significant differences between MRD- and MRD+ patients: MRD+ had much worse OS (22,9% vs. 85.5%, p=0.0047, Fig.1A) and RFS (26% vs. 97.4%, p<0,0001, Fig.1B).
Conclusions.
Despite the presence of morphological CR before allo-HSCT, MRD persistence can lead to worse probabilities of OS and RFS, which is comparable to patients who were transplanted in relapse. Because of the association between MRD and relapse risk, it can be assumed, that testing for MRD before allo-HSCT may help to identify a subgroup of patients at high risk of relapse who might benefit from preemptive posttransplantation treatment.

Disclosures
No relevant conflicts of interest to declare.
Prevalence of the Antiphospholipid Antibodies in Young Adults with Ischemic Stroke
Authors: Vaccarino Antonella , Pagliaro Maria , Rollone Clara , Melis Fabio , De Marco Federica , Savio Katia , Guido Marilena , Bazzan Mario , Imperiale Daniele , Pini Massimo 
Published: November 2019

Background: Ischemic stroke is rare in young adults, with an incidence of about 10-15% of all the ischemic strokes. In about one third of these patients a cause is missing. Among patients with antiphospholipid antibodies syndrome (APS), stroke is the first thrombotic event in about 13% of cases.
Aims of our project were: to evaluate the prevalence of antiphosfolipid antibodies (aPL),to investigate on the prevalence of conventional risk factors and to define the radiological characteristics of the ischemic lesion.
Materials and methods: this is a no profit, observational multicenter prospective study. Inclusion criteria were: age older than 18 and younger than 55 years, informed written consent, a clinical and radiological diagnosis of stroke.
Patient's data were collected at diagnosis and after 30 days from stroke. If any aPL positivity was found the patient was referred to our service to further/eventually confirm the diagnosis of APS. For each patient these data were collected: age, sex, body mass index, personal and familial history, concomitant co morbidities and therapies, cardiovascular risk factors, drug abuse.
CT scan or angioCT or MRI was always performed at diagnosis, aPL profile was determined at diagnosis and eventually confirmed after 12 weeks according to the Sapporo criteria. None of the patients had a previous diagnosis of APS.
Results: enrolled patients from January 2017 to December2018 were 46 out of 425 ischemic stroke (10.8%). We found 11/46 aPL positivity patients. Among these patients, 7 were confirmed at 12 weeks (15%). Baselines characteristics of the study population are detailed in table 1. We found a high prevalence of associated conventional cardiovascular risk factors: hypertension (56%), dyslipidemia ( 50%), obesity (55%), smoke ( 52%). We didn't find any correlation between APS and a clear radiological pattern on MRI and CT scan.
Conclusions: Prevalence of APS was 15% in our cohort of young patients with stroke, 85% of which had an high risk aPL profile. The detection frequency is similar to the recent APS-ACTION and literature findings. In our cohort stroke was a relapse of a previous ischemic event in 24% of the patients, while in 15% there was a stroke's relapse. Even if these data should be confirmed with a wider number of patients, it seems to be useful to evaluate the presence of aPL in a young patient with ischemic stroke .

Disclosures
No relevant conflicts of interest to declare.
Prognostic Value of Circulating Plasma Cells in Newly Diagnosed Multiple Myeloma
Authors: Chen Lijuan , Li Jianyong 
Published: November 2019

Multiple myeloma (MM) is biologically diverse and there is a significant variation in survival time from a few months to several years. The presence of circulating plasma cells (CPCs) is associated with a worse prognosis in patients with MM. This study retrospectively analyzed CPCs by 8-color multi-parameter flow cytometry in 108 cases of newly diagnosed MM patients to investigate its value for outcome prediction. Among them, 58 (53.7%) patients were CPCs positive expression. The optimum cutoff predicting for overall survival was determined as 0.29% by using a ROC analysis. Compared with patients with CPCs < 0.29% (n = 75, 69.4%), those with CPCs ≥0.29% (n = 33, 30.6%) showed lower Erythrocyte sedimentation rate(ESR) (P = 0.0032), but higher lactate dehydrogenase (LDH), ferritin (FER) , BM PCs and P53 deletion in BM by FISH (P = 0.001, 0.003, 0.014, and 0.001,respectively). With the median follow-up time 17 months (range, 2.0-37.0), the median PFS in the subgroups with CPCs<0.29% and ≥0.29% was not reached and17.0 months (95% confidence interval (CI):14.85-19.15), respectively, and the median OS was not reached and 12.5months (95% CI: 6.35-18.65), respectively. On multivariate analysis for OS, factors independently predictive of mortality were CPCs≥0.29% (hazard ratio (HR) 4.172; 95% CI, 1.61-10.79; P=0.003), Deletion P53(HR 11.54; 95% CI, 4.06-32.84; P<0.001). We further developed a convenient two-factor risk stratification based on CPCs and p53 deletion according to the results of log-rank test, univariate and multivariate analysis. The high-risk group was defined as both CPCs ≥ 0.29% and P53 deletion, accounting for 10% of the population, have a dire prognosis (median PFS = 5 months; OS = 10 months) despite modern therapies .These results identified CPCs as an unfavorable prediction for the outcome of MM. A combination of p53 deletion may screen out a high-risk subgroup which should be considered for novel therapeutic approaches.

Disclosures
No relevant conflicts of interest to declare.
Diplotype Analysis of NUDT15 Variants By Targeted Sequencing in Pediatric Acute Lymphoblastic Leukemia
Authors: Yu Chih-Hsiang , Chang Ya-Hsuan , Chou Wen-Chien , Wang Der-Shiun , Lin Shu-Wha , Chen Hsuan-Yu , Yang Yung-Li 
Published: November 2019

Background: The NUDT15 polymorphisms, V18_V19insGV and R139C, located on exon 1 and exon 3 were associated with intolerance of 6-mercaptopurine (6MP), which were frequently used during the maintenance therapy of childhood acute lymphoblastic leukemia (ALL). However, these two NUDT15 diplotypes with significant different biological activity, mono-allelic *1/*2 and complex homozygosity *3/*6, could not be distinguished from each other by direct Sanger sequencing of exon 1 and exon 3. We applied targeted sequencing of NUDT15 cDNA to clarify the diplotypes of complex homozygous of NUDT15. Methods: Thirty-five ALL patients who were diagnosed in National Taiwan University Hospital with both V18_V19insGV and R139C of NUDT15 were included in this study. A single amplicon (562 bp) covers all the coding regions of NUDT15 was amplified from cDNA and then sequenced by paired-end sequencing using MiSeq reagent kit v3 (600 cycles). For validation, the amplicons from complex homozygous NUDT5 were cloned into pCR-Blunt II-TOPO vector. Result: By targeted sequencing, thirty-three patients were identified as mono-allelic *1/*2. Two complex homozygous NUDT15, *3/*6 and *2/R34T, were identified in patient No.27 and No.37. We also cloned amplicons from these two patients into vector and the results were the same as targeted sequencing. These two patients with complex homozygous NUDT15 variants tolerated only 1~2 mg/m2 daily mercaptopurine doses. Conclusions: Targeted sequencing of NUDT15 cDNA is a simple method to determine the NUDT15 diplotype and helpful for the identifications of complex homozygous NUDT15, which should be identified before the administration of 6MP to avoid excessive myelosuppression caused by improper of 6MP dosage. Figure: (A) NUDT15 haplotypes. (B) The primers is used for direct Sanger sequencing and cDNA targeted sequencing. (C) The NUDT15 diplotype of patient No.27 is analyzed using cDNA cloning followed by Sanger sequencing.
Figure

Disclosures
No relevant conflicts of interest to declare.