bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Environmental Changes on Emergency Rooms Visits for Adult Sickle Cell Disease
Authors: Master Samip , Patel Abhishek , Mansour Richard Preston
Published: October 2019

Background:

Acute pain crises from vaso occlusive episodes are major cause of morbidity, hospitalization and emergency room visits for patients with sickle cell disease. Major causes of acute painful crises have been attributed to dehydration, infections and fever. Weather change has also been attributed as one of the major cause of acute pain crises by physicians and patients. Data on effects of environmental changes on acute pain crises in patients with sickle cell disease is mixed. Here we report our investigation to see if number of emergency room visits for adult patients with SCD were associated with environmental changes.

Method:

At our hematology clinic we take care of around 300 adult patients with SCD and we have on average around 11,000 emergency room visit per years from these patients. Electronically from EHR (Electronic health Record), we pulled out data on number of emergency room visit every day for adult patient with SCD in year 2015.We also gathered data on daily environmental changes from a national weather website for the year 2015 and collected data on daily temperature changes, humidity and precipitation/rain in our area. We did analysis to see if there was any correlation between the weather changes and emergency room visit.

Results:

As shown in graphs below, there was no correlation between the number of ER visits and weather changes in adult patient with SCD.

Conclusion:

Our analysis showed that there was no correlation between number of ER visit for adult patient with SCD and weather changes like -temperature, humidity and precipitation/rain.

ER Visits and Precipitation

ER visits, temperature and humidity

Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures

No relevant conflicts of interest to declare.
Prevalence of Disease Related Complications from in Adult Patients with Sickle Cell Disease
Authors: Master Samip , Patan Shajadi , Cingam Shashank , Mansour Richard Preston
Published: October 2019

Introduction: Sickle cell disease can lead to variety of complications like strokes, acute chest syndrome (ACS), sickle cell hepatopathy, priapism, renal dysfunction, avascular necrosis (AVN) ofjoints , pulmonary hypertension and leg ulcers. Average life expectancy of patient with SCD has improved with better treatments available. Most of literature on SCD in form pediatric literature and data on adults is considerably lacking. We did a retrospective analysis to investigate the prevalence of complications in adult patients with SCD.

Methods: We take care of around 300 adult active patients with SCD at our hematology clinic. We did a retrospective analysis from 458 adult patients seen at our clinic between 2001 and 2016. We collected data on gender, race, type of SCD, complications like stroke, acute chest syndrome, iron overload, leg ulcers, AVN, hepatopathy and renal dysfunction.

Results: A total of 458 adult patients with SCD were analyzed. 231 were female and 227 were males. The total number of patients with SC disease was 114, SS was 263, sickle beta thal was 75 and 4 had SS with hereditary persistence of Hemoglobin F (SS HPF). The number patient with complication has been listed in table below.

Conclusion: Adult Centers for the treatment of Sickle Cell Disease need to optimize care directed at these high frequency, life changing and life shortening complications. Multidisciplinary care teams have to focus on these chronic complications that include transfusion program, iron overload treatment and prevention, orthopedic care and Hepatitis C and B directed carealong with acute complication care. This retrospective study serves as the basis for our adult Sickle Cell Disease program at Louisiana State University Health Science Center in Shreveport, Louisiana.

Table Table.

Disclosures

No relevant conflicts of interest to declare.
Learning Not to Judge a Book By Its Cover: A Case Series of Malignancy Masquerading As Common Presentations of Sickle Cell Disease
Authors: Zaidi Ahmar Urooj , Martin Lo'Rell , Callaghan Michael U , Sarnaik Sharada A. , Taub Jeffrey W
Published: October 2019

Background: Sickle cell disease affects 100,000 people in the United States. Cancer does not appear to be more common in individuals with sickle cell disease however many presenting signs and symptoms of cancer overlap with signs and symptoms of sickle cell disease, complicating diagnosis. Furthermore, sickle cell disease can complicate surgical, chemo- and radio- therapies for malignancy.

Methods: We reviewed the past 46 years experience of cancers in children with sickle cell at a large urban pediatric referral center. We identified 5 cases and reviewed the presentations, treatments, response to therapy, sickle cell complication and laboratory values, including transfusion needs and effect of chemotherapy on fetal hemoglobin levels.

Results: We identified five cases of malignancies in children with sickle cell disease including cases of acute lymphoblastic leukemia (ALL), Hodgkin's lymphoma, Non-Hodgkin's lymphoma (NHL), Wilms tumor and renal cell carcinoma. An additional patient with sickle cell trait was diagnosed with metastatic renal medullary carcinoma. The patients were ages 6-18 years old at diagnosis and 4 were female. All had delays in diagnosis as their initial signs and symptoms overlapped with sickle cell disease (abdominal mass mimicking splenomegaly, low blood counts, fever and posterior reversible encephalopathy syndrome, hematuria). All five achieved complete remission with multi-modality therapy (excluding stem cell transplants) and are currently doing well 1- 20 years after treatment. Admissions for pain were reduced during and for some period after cancer therapy and 2 patients had marked, and in one case, prolonged elevation of fetal hemoglobin after therapy.

Discussion: Children with sickle cell develop cancers that can be confused for sickle cell related complications. Cancer therapy can be well tolerated and successful in children with sickle cell. Sickle cell complications are decreased during cancer therapy likely secondary to frequent therapy related transfusion and therapy induced increases in fetal hemoglobin.

Disclosures

Callaghan: Biogen: Honoraria; Bayer: Honoraria; CSL Behring: Honoraria; Baxalta: Honoraria, Research Funding; Grifols: Honoraria; Roche: Honoraria, Research Funding.
Comparison of the Diagnostic Power Between Cytokine Pattern and Procalcitonin for Predicting Infection in Pediatric Hematology/Oncology Patients
Authors: Tang Yongmin , Xia Tian , Xu Xiaojun , Zhao Ning , Luo Zebin
Published: October 2019

Objectives: Neutropenic fever is very common in chilidren with chemotherapy. Due to the fact that an infection is usually suggested, broad antibiotic therapy is usually administered. However, early diagnosis of the infection is usually difficult and the antibiotic therapy may not be alway appropriate. Furthermore, blood culture is usually negative for those heavily treated patients by antibiotics. So a sensitive biomarker for early recognition of inction is desired. Previous studies have shown that procalcitonin (PCT) is a good marker for predicting infection. However, in our experience, the sensitivity of infection recognition by PCT is low. Our previous studies have shown that cytokine profiles presented very high sensitivity and sepecificity for predicting infection in hematology-oncology children at the time of neutropenic fever. However, the diagnositic power between cytokine profiles and PCT in those patients has not been systemically compared. The aim of this study was to evaluate the diagnostic power of the cytokine pattern and serum PCT level for predicting infection in pediatric hematology/oncology patients.

Methods: In this retrospective study, a total of 3023 samples (2819 febrile episodes and 204 control samples) derived from 992 (including 164 afebrile patients as control) hospitalized hematology-oncology children. Th1/Th2 cytokines including Interleukin (IL)-2, Il-4, IL-6, IL-10, Tumor necrosis factor (TNF) α and interferon (IFN) γ were measured by a FACScalibur flow cytometer using cytometric bead array (CBA) techniques. According to the etiology, imaging and clinical symptoms, 2819 febrile episodes were divided into 5 groups including blood culture positive sepsis, clinical diagnosed sepsis, non-sepsis infection, viral infection and systemic fungal infection.

Results: IL-6 and IL-10 levels as well as positive rates in bacterial infection group were significantly higher than those in viral infection group and control group. In positive blood culture sepsis group, 92.8% (297/320) and 82.2% (263/320) patients had increased IL-6 and IL-10 levels that exceeded the upper limit of the normal range. However, the positive rates of PCT and C-reactive protein (CRP) in bacterial infection group were only 33.8% (108/320) and 73.1%(234/320), respectively, which were significantly lower than those of IL-6 and IL-10 (P<0.01). Based on the receiver operating characteristic (ROC) curves, PCT presented a poorer sensitivity in the diagnosis of severe infection, as compared with IL-6 and IL-10 (p<0.01). As for specificity, IL-6 and IL-10 was also significantly higher than PCT in the diagnosis of Gram-negative bacterial infection.

Conclusion: The specific cytokine pattern of highly elevated IL-6 and IL-10 shows higher diagnostic accuracy than PCT for bacterial and severe infection among febrile hematology-oncology children.

Disclosures

No relevant conflicts of interest to declare.
Synergistic Effects of a Procoagulant Bispecific Antibody and Rescue Therapies on Thrombin Generation- a Potential Safety Risk
Authors: Knappe Sabine , Hartmann Rudolf , Goldstein Brahm , Ewenstein Bruce M. , Valentino Leonard , Scheiflinger Friedrich
Published: October 2019

Background: Investigational non-factor products, such as ACE 910 (Emicizumab), offer potential new treatment options for hemophilia patients with inhibitors. However, their uncertain and unregulated mechanisms of action raise multiple concerns around safety and efficacy in specific clinical contexts. As an antibody to FIXa and FX, ACE 910 lacks the inherent regulatory characteristics that are present in replacement factor and bypassing agents in the context of hemostasis.

FEIBA is a plasma-derived, activated prothrombin complex concentrate developed to prevent and treat bleeding episodes in hemophilia A and B patients with inhibitors. There are more than 40 years of clinical experience with FEIBA. Extensive prospective clinical study data, as well as post-approval pharmacovigilance data demonstrated the product to be safe and highly effective. In an ongoing phase III study (NCT02622321), hemophilia A patients with inhibitors are treated with Emicizumab. To evaluate the treatment options for ACE910-treated patients experiencing breakthrough bleeding, we studied, in-vitro, the thrombin generation profile of various combinations of FEIBA with a biosimilar version of ACE910.

Methods: A biosimilar antibody to Emicizumab (BS-Em) was expressed in mammalian cells, purified and extensively biochemically characterized. Therapeutic doses of BS-Em (200-600nM) in combination with several concentrations of FEIBA (0.1-1IU/ml) were analyzed in standard in-vitro thrombin generation (TG) experiments (1pM TF trigger) using 3 inhibitor patient plasma. A normal range of TG for the experimental conditions used was established using plasma from 34 healthy individuals.

Results: The combination of FEIBA and BS-Em resulted in peak thrombin values of >500nM (600nM BS-Em/1IU/ml FEIBA) while the normal range was established to span peak thrombin levels of ~50-120nM thrombin. Titration experiments established that at 600nM BS-Em, FEIBA concentrations of >0.2IU/ml led to peak thrombin values 4- 10-fold higher than the normal range.

Conclusions: Our in-vitro experiments demonstrate an excessive thrombin generation potential for the combination of BS-Em and FEIBA at concentrations expected to be generated in patients participating in this study. Caution and clinical judgement will be required when considering the use of ACE910 in hemophilia A patients with inhibitors as options to treat breakthrough bleeds if they occur might be reduced or lead to potential AE.

Disclosures

Knappe: Shire: Employment. Hartmann:Shire: Employment. Goldstein:Shire: Employment. Ewenstein:Shire: Employment. Valentino:Shire: Employment. Scheiflinger:Shire: Employment.
Intermediate-Dose Tertiary Prophylaxis Show a Better Joint Protection in Adults with Severe Hemophilia Than Low-Dose Patterns
Authors: Zhou Xuan , Huang Shunhua , Qiu Shiqiu , Liu Zhuqin , Sun Jing
Published: October 2019

Background and Introduction:

Prophylaxis treatment is considered optimal care for patients with severe hemophilia during childhood to prevent bleeding and reduce the incidence of joint disability. However, tertiary prophylaxis may also benefit Adults with Severe Hemophilia, but the optimal dose tailoring of FVIII is still unknown. We initiated a study to compare the low-dose and intermediate-dose regimen for tertiary prophylaxis in adults with severe hemophilia A.

Methods:

Patients with severe hemophilia A (F VIII < 1%) born between January, 1978, and January, 1988, who were treated at the hemophilia treatment centre at Nanfang hospital and treatment data available were eligible for enrollment in the study. The main exclusion criteria were a history of FVIII inhibitor (titer ≥ 0.6BU [Bethesda unit]), detectable FVIII inhibitors at screening (titer ≥ 0.4 BU), chronic liver disease, immunodficiency, another hemostatic defect and the need for major surgery. A total of 40 adults with severe hemophilia were enrolled, including 25 patients with low-dose prophylaxis (5-10 IU/kg twice a week) and 15 patients with intermediate-dose prophylaxis ( FⅧ 15-20 IU/kg twice a week). Breakthrough acute bleedings were treated according to the regular practice and guidelines.

Results:

The study was conducted over a 2-year period (January 2014 to December 2015).Compared to low-dose prophylaxis group, Intermediate-dose tertiary prophylaxis group reduced the annual number of total and joint bleeds (median 13 vs 5.5 and median 10 vs 4; P= 0.001, respectively), and annual target joint bleeding rate were also significantly lower (median 8 vs. 3.5, P =0.002). The breakthrough bleeding events were largely lower in intermediate-dose group than in low-dose group (P=0.03). After prophylaxis, the FISH score in Intermediate-dose group increased from median 21 (range 15-28) to median 24 (range 17-28) (P=0.02) and in low-dose group from median 22 (range 14-28) to median 24 (range 14-28) (P=0.02) respectively. The improvement of FISH score were different between two groups (P=0.04). Meanwhile, The Health-related Qualityof life (HRQoL) in patients with severe hemophilia were measured by the SF-36. The SF-36 score showed better results in terms of overall perceived health status between patients with Intermediate-dose and with low-dose prophylaxis (P < 0.01).

Conclusion:

Compared to low-dose prophylaxis, Intermediate-dose tertiary prophylaxis may show a better joint protection in Adults with Severe Hemophilia, for Intermediate-dose regimen not only means less joint bleeding, but also helps joint function restore and Quality of life improvement. Our study established that Intermediate-dose tertiary prophylaxis may be a better choice for adults in a number of hemophilia treatment centers in China.

Disclosures

No relevant conflicts of interest to declare.
Rivaroxaban As Treatment for Thromboembolic Venous Disease in Patients with Cancer or Neoplastic Hematology
Authors: Campos-Cabrera Gregorio , Campos-Villagomez Jose-Luis , Campos-Cabrera Salvador , Campos-Cabrera Virginia
Published: October 2019

Introduction: Patients with cancer or neoplastic hematology (CNH) has 6 fold risk of thromboembolic venous disease (TVD) than general population and accounts the 20 % of new cases. NCCN treatment recommendation for TVD is with heparin and vitamin K antagonists, however every institution develops its own guidelines and protocols, and the FRONTLINE-2 survey designed to evaluate how clinicians perceive the risk of venous thromboembolism in cancer patients and to provide insight into current strategies for thromboprophylaxis and management has interestingly results. The phase III studies from rivaroxaban that led to its approbation by the FDA in different indications included 6 % of the patients that had some type of cancer and their evolution among the TVD was not different than those without it. There are phase II and III studies where rivaroxaban has shown promising results in this setting.

Objective: describe the evolution in patients with CNH whom developed TVD during treatment and received rivaroxaban.

Material and methods: adults with CNH with TVD during treatment and received rivaroxaban according our protocol (Hematología 2015; 16 supl 1: 115-116).

Results: there are 73 patients receiving rivaroxaban for TVD, 20 patients (27.4 %) has CNH. Gender: 10 female and 10 male, ratio 1/1. Age 23 to 90 years old, mean 54.5. Diagnosis: 1 CLL, 3 ALL, 3 HL, 3 NHL, 1 amyloidosis, 3 low grade MDS, 1 AML-M3, 1 primary myelofibrosis, 4 non neoplastic hematology (brain, kidney, breast and unknown primary). All patients has TVD treatment related, in three of them catheter related (2 HL and 1 NHL). Four died from neoplastic disease (2 male and 2 female): 1 HL, 1 NHL, 1 brain and 1 unknown primary. Eleven patients continue on rivaroxaban for acute treatment and secondary prevention due high risk factors. Five are on aspirin as secondary prevention. In lymphoid neoplasia patients receive prophylactic fluconazol and no interactions were observed. Patient with AML-M3 switches to enoxaparin while taking tretinoin as maintenance. No patient needed dose adjustment. No recurrent TVD or bleeding were observed.

Conclusions: in this small group of patients rivaroxaban was well tolerated without adverse effects or mortality due to recurrent TVD or bleeding. No patients with MM or MPD were observed due the prophylactic use of aspirin. The knowledge of rivaroxaban interactions for adjustments or change in the anticoagulation is essential for a good evolution, permitting its rational use in institutional protocols and lowering costs for anticoagulation compared to enoxaparin.

Disclosures

No relevant conflicts of interest to declare.
Effect of the Adition of Metformin on the expressión of Multidrug-Resistance Genes (ABCB1, ABCG2) in Acute Lymphoblastic Leukemia: In Vitro and In Vivo Study
Authors: Ramos Peñafiel Christian Omar , Olarte Carrillo Irma , Cerón Maldonado Rafael , Santoyo Sánchez Adrián , Castellanos Sinco Humberto Baldemar , Montaño Figueroa Efreen , Queipo García Gloria , Martínez Tovar Adolfo
Published: October 2019

INTRODUCTION. The over expresión of the multidrug resistance genes (MDR) specifficaly ABCB1 and ABCG2 correlate with a poor prognosis in patients with ALL. Different drugs specially the chomotherapeutic agents are they substrates. This genes encode a family of different membrane transports that Works with energy specifically the ATP. Metformin is a biguanide whose mechanism of action is the activiation of AMPK and depletes the levels of ATP.

PRIMARY OBJECTIVE: Evaluate the efficacy of the use of Metformin on the levels of expression of the MDR genes (ABCB1 y ABCG2) by RQ-PCR in ALL cell lines and patients with ALL during a preinduction treatment with prednisone.

RESULTS.

In vitro study . The ALL cell lines RS4, ReH, MOLT4 and SUB15 were elavluated. After the addition of Metformin (10uM) the expression level of ABCB1, ABCG2 started to decrease after the 24hrs of culture (mean expression level of 0.3823 ABCB1 and 0.4265 of ABCB2) with a máximum effect at 48 hours (0.2415 ABCB1 and 0.3452 ABCB2) The difference of levels were statystically significant (p= 0.0045).

In vivo study . About 108 patients were evaluated, 44 (40.7%) in the arm of prednisone and 64 (59.3%) in the arm of prednisone plus metformin. Fort eh subanalysis of the MDR genes by RQ-PCR we select 25 patients (14 in the prednisone arm and 11 in the metformin arm). The mean levels of the genes was 0.1906 for the ABCB1 gene and 0.3371 of the ABDG2. At the moment of diagnosis about 32% were considerer with high level of expression (n=8), 28% (n=7) of low expression and 40% (n=10) do not express any of the both genes. After the treatment with Metformin 4 patients with high expression at diagnosis change the patter for low expression. Although there is no difference in means of the expression of genes in both arms (p = 0.391 , p = 0. 828) in the group of metformin the prognosis in the high expression group was better than in the prednisone arm (p=0.043). Fort he entire cohort the complete remission rate was higher in the Metformin cohort comparing with prednisone (86.4% versus 67.2%) and the refractoriness was higher in the group of prednisone (n=16, 25%) p=0.002. About the relapse, the addition of Metformin reduce the relapse rate ( 6 vs 21 patients, p = 0.027).

Conclusion. The addition of metformin in a controlled enviroment reduce the expression of the MDR genes, but in vivo the impact is primarily on the refractory leukemias and the relapse rate

Disclosures

No relevant conflicts of interest to declare.
Phloridzin Docosahexaenoate (PZ-DHA) : A Novel Naturally Derived Drug Active in T-Cell Acute Lymphoblastic Leukemia (T-ALL)
Authors: Arumuggam Niroshaathevi , Melong Nicole , Too Catherine K.L. , Berman Jason N. , Rupasinghe H.P. Vasantha
Published: October 2019

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant disease that accounts for about 15% of pediatric and 25% of adult ALL. Although risk stratification has provided more tailored therapy and improved the overall survival of T-ALL patients, clinical challenges such as suboptimal drug responses, morbidity from drug toxicities, and drug resistance still exist. Plant polyphenols have therapeutic efficacy as pharmacological adjuvants to help overcome these challenges. They can be acylated with fatty acids to overcome issues concerning bioavailability, such as poor intestinal absorption and low metabolic stability. Phloridzin (PZ), a flavonoid found in apple peels, was acylated with an omega-3 fatty acid, docosahexaenoic acid (DHA), to generate a novel ester called phloridzin docosahexaenoate (PZ-DHA). The cytotoxic effect of PZ-DHA was studied in the human Jurkat T-ALL cell line. PZ-DHA significantly reduced the viability and cellular ATP levels of treated cells. PZ-DHA was found to selectively induce apoptosis in Jurkat cells, while sparing normal murine T-cells. Apoptosis was further confirmed by demonstrating the ability of PZ-DHA to induce morphological alterations, DNA fragmentation, caspase activation, and the release of intracellular lactate dehydrogenase. PZ-DHA also significantly inhibited cell division in Jurkat cells. Furthermore, interferon-α-induced phosphorylation of the transcription factor, STAT3, was downregulated following PZ-DHA treatment. The in vitro efficacy of PZ-DHA was recapitulated in vivo in an established zebrafish xenograft model, where the proliferation of transplanted Jurkat cells was inhibited when PZ-DHA was added to the embryo water. Overall, these findings provide evidence for PZ-DHA as a novel therapeutic agent with activity in T-ALL. Studies examining the effect of PZ-DHA on patient-derived ALL cells engrafted in zebrafish are currently underway.

Disclosures

No relevant conflicts of interest to declare.
HLA Class I-Specific Effects in AML with Mutated Nucleophosmin
Authors: Kuželová Kateřina , Röllig Christoph , Racil Zdenek , Stickel Juliane S. , Brodská Barbora , Schetelig Johannes , Thiede Christian , Ehninger Gerhard , Helbig Grzegorz , Kyrcz-Krzemien Slawomira , Mayer Jiri , Cetkovsky Petr
Published: October 2019

Background

We have recently identified a skewed distribution of class I human leukocyte antigens (HLA) among patients with AML and mutated nucleophosmin gene (NPMc+ AML). A lower frequency of several HLA allelic groups in the NPMc+ AML patient cohort was in good correlation with the results of theoretical predictions for high-affinity immunopeptides derived from NPM1, suggesting that an anti-NPM1 immune response could prevent leukemia development in patients with a suitable HLA class I type.

Aim

We here present more detailed analysis of HLA-specific features, in a much larger cohort (N = 357) of AML patients with NPM1 mutation (type A/D) from several centers in the Czech Republic, Germany and Poland.

Results

Most importantly, we confirmed the lower incidence of B´40 and C´07 allelic groups in NPMc+ AML compared to the normal values. The moderate decrease of A´02 allelic group frequency became statistically significant in this larger patient cohort (see Table). On the other hand, no difference in HLA class II frequencies was found compared to the normal distribution.

Furthemore, patients with B´07 allelic group had a significantly better prognosis, but only in the absence of Flt-3-ITD mutations (p = 0.049, see Figure). HLA typing was performed by molecular methods in a subgroup of patients (N = 73), allowing for discrimination between C´07 alleles. In this subgroup, C*07:01, but not C*07:02/04 expression was associated with better overall survival (p = 0.036), in agreement with theoretical predictions.

Conclusion

Our results support the hypothesis that anti-NPM1 immune response reduces AML development and contributes to a better outcome of NPMc+ AML patients with suitable HLA class I type (including at least A´02, B´07, B´40 and C*07:01). Furthermore, NPMc+ immunogenicity is caused rather by its aberrant localization than by the generation of a unique aminoacid sequence.

Figure Figure.

Disclosures

Schetelig: Sanofi: Honoraria. Thiede:AgenDix: Employment, Other: Ownership.
FLT3-ITD As a Prognostic Factor for Chinese Patients with Acute Myeloid Leukemia
Authors: Sun Jie , He Jingsong , Wei Guoqing , Zheng Weiyan , Shi Jimin , Luo Yi , Huang He
Published: October 2019

Internal tandem duplication of the FLT3 gene (FLT3-ITD) is one of most common genetic mutations found in patients with acute myeloid leukemia (AML). Although FLT3-ITD has been widely studied and used as an important prognostic indicator of AML in the western world, its association with disease features and prognosis in Chinese AML patients to date has rarely been investigated.In this study, 177 Chinese patients with AML were enrolled including a FLT3-ITD mutation positive group (n = 83) and a FLT3-ITD mutation negative group (n = 94).In FLT3-ITD-positive AML patients, the number of patients whose peripheral blood leucocyte count (≥ 100 × 109/L) before treatment was significantly higher than in FLT3-ITD negative patients (32.1% vs 7.6%), but comparing to FLT3-ITD mutation negative patients, 1 year and 2 year event free survival rates (EFSR) of FLT3-ITD-positive AML patients was lower ((37.0% vs 56.0%) and (14.8% vs 38.4%)), and also their 1 year and 2 year OS rates were significantly lower ( (50% vs 100%) and (18.0% vs 36.5%)). However, it was found that the rate of induced remissions in FLT3-ITD-positive AML patients was much lower than in negative patients (39.4% vs 56.0%). The median survival time of the FLT3-ITD+/NPM1- group (n = 39) was superior to the FLT3-ITD+/NPM1+ group (n = 27) (16.1 months vs 5.8 months). Lastly, after comparing chemotherapy regimes, we found that the allogeneic hematopoietic stem cell transplantation treatment method significantly improved the survival rate of FLT-ITD positive AML patients (not reached vs 14.5 months). Therefore, for FLT3-ITD-positive Chinese patients with AML, the relative rate of complication with leucocyte was increased; both the event free and overall survival rates were lower, these characteristics are the same as the FLT3-ITD-positive patients in western countries. The lower induced remission rate and shorter survival time suggested FLT3-ITD+/NPM1+ mutation is inferior to FLT3-ITD+/NPM1- mutation, which is not consistant with most reports. In addition, allogeneic hematopoietic stem cell transplantation was clearly an effective treatment for patients with FLT-ITD positive AML in China.

Disclosures

No relevant conflicts of interest to declare.
Exploratory Introduction of Cognitive Computing to Clinical Sequencing in Hematological Malignancies
Authors: Yokoyama Kazuaki , Yusa Nozomi , Itoh Mika , Suzuki Asako , Nakamura Sosuke , Ogawa Miho , Jimbo Koji , Kobayashi Masayuki , Kawamata Toyotaka , Konuma Takaaki , Kasajima Rika , Yui Hiroaki , Shimizu Eigo , Koyama Takahiko , Ohno Nobuhiro , Imai Yoichi , Takahashi Satoshi , Uchimaru Kaoru , Yamaguchi Rui , Imoto Seiya , Furukawa Yoichi , Miyano Satoru , Tojo Arinobu
Published: October 2019

Next-generation sequencing (NGS) is an attractive tool for prospective use in the field of clinical oncology. However, for this purpose, further innovations are necessary including medical informatics which links somatic mutations to clinical intervention. This process is currently labor-intensive, involving experienced curators who pick up the relevant evidence among a growing body of knowledge and translate it into medical practice. We organized a clinical sequencing team, called as IMSUT Tumor Board, and have been integrating clinical and genomic information in hematological malignancies with the aid of a cognitive computing (CC) system. Genomic DNA was prepared from malignant cell fractions and normal tissues in each patient, and subjected to comparative NGS, mainly targeted deep sequencing with ready-made panels and, on demand, whole exome sequencing. Sequence data was analyzed using a pipeline of in-house semi-automated medical informatics, namely YOKOMON-GO. CC was used to identify candidate driver mutations and pathways in each patient, from which pathogenic information as well as applicable drug information was deduced. A summary of NGS data was reported and discussed in IMSUT Tumor Board to deliberate upon potentially actionable findings. Up to date, we have performed NGS analysis on 90 patients with AML, MDS, MPN, et al., among which informative and actionable findings could be obtained in 50 and 18 patients, respectively. Six patients actually received treatments motivated in IMSUT Tumor Board. Our preliminary results indicate that CC can be well suited to clinical sequencing.

Disclosures

Koyama: IBM: Employment.
CD44 over Expression Caused Drug Resistance in Activated B Cell-like Diffuse Large B-Cell Lymphoma
Authors: Zhou Qinjun , Wei Yongqiang , Wei Xiaolei , Wei Qi , Feng Ru
Published: October 2019

CD44, a transmembrane glycocoptotein, involved in tumor cell survival, migration , invasion, metastasis and prognosis of many cancers. This study was performed to investigate the effects of CD44 over expression on the biological function and the chemotherapeutic sensitivity of ABC-DLBCL. The full length CD44 cDNA was cloned into pEASY-T vector and then transfected into activated B cell-like diffuse large B-cell lymphoma cell line OCI-ly3. QPCR and western blot confirmed that the CD44 expression was up-regulated in both mRNA and protein levels in CD44-transfected OCI-ly3 cells. The cell proliferation of OCI-ly3-CD44 cells was significantly faster than that in OCI-ly3-GFP cells and the OCI-ly3 cells (p<0.001). Annexin V-APC/PI staining results showed that the apoptosis ratio wasn't difference among three groups (p=0.676). OCI-ly3-CD44 cells showed significantly higher migration ratio than OCI-ly3-GFP cells and the OCI-ly3 cells(p=0.031). The IC50 of doxorubicin in OCI-ly3-CD44 cells (0.348±0.072uM) was higher than that in OCI-ly3-GFP (0.348±0.072uM ) and OCI-ly3cells(0.138±0.029uM ) ( P<0.001). After treatment with doxorubicin for 24h, the OCI-ly3-CD44 cells showed lower apoptotic ratio than OCI-ly3-GFP and OCI-ly3 cells ( (17.5±1.33)% VS. (41.7±9.91) %, (41.8±7.23)%), P<0.001). In conclusion, CD44 plays a key role in cell growth regulation and chemo-resistance and is a potential target to overcome drug resistance and improve prognosis in DLBCL.

Disclosures

No relevant conflicts of interest to declare.
Use of Ibrutinib Via Nasogastric (NG) Tube & Percutaneous Endoscopic Gastrostomy (PEG) Tube
Authors: Maddox Jamie M , Majid Mohammed
Published: October 2019

We describe the successful administration of ibrutinib via nasogastic (NG) tube & percutaneous endoscopic gastrostomy (PEG)tube. It was not previously known by the manufacturer if this route of administration was possible.

Our patient was a 71 year old man diagnosed with a leukaemic variant mantle cell lymphoma. He was commenced on R-CHOP (rituximab, cyclophospahmide, doxorubicin, vincristine, prednisolone) chemotherapy however after 3 cycles of chemotherapy there was no reduction in his lymphadenopathy or splenomegaly despite a reduction in the peripheral blood lymphocytosis.

During the R-CHOP chemotherapy, the patient suffered left-sided facial shingles causing Ramsay Hunt syndrome. He was left with a residual neurological swallowing deficit requiring nasogastric feeding. Due to the lack of response to R-CHOP chemotherapy, we felt that ibrutinib could be a useful second line treatment, however we were not sure if the capsule could be opened to allow administration via his nasogastric tube. We contacted the manufacturer who said that there was no data about this method of administration and therefore it was not recommended. Our own research identified one ongoing clinical trial comparing suspension and sprinkle formulations of ibrutinib to the capsule formulation (NCT02390609). This trial was unreported however we felt encouraged that this method of administration did seem feasible.

It was felt that ibrutinib represented the best chance of a useful disease response so full dose treatment was commenced via the nasogastric tube. This was later changed to a percutaneous endoscopic gastrostomy (PEG) tube. The patient opened the capsule and flushed the contents down the tube with water.

A follow up blood count 2 weeks later showed a marked lymphocytosis (baseline lymphocyte count 0.4 x109/L, risen to 40.8 x 109/L), as would be expected with ibrutinib therapy. This reduced to near normal values over the following 3 months, accompanied by an improvement in the haemoglobin and platelet counts. Imaging at 3 months confirmed compete resolution of all pre-existing lymphadenopathy and the previous 25.6 cm splenomegaly.

Our patients' dramatic response suggests that capsule formulation ibrutinib can be successfully administered by NG or PEG tubes.

Disclosures

Maddox: Janssen: Other: Funding to attend ASH 2016 (travel, accommodation, registration); Boehringer-Ingelheim: Other: Funding to attend ASH 2014 (travel, accommodation, registration).
Primary Testicular Lymphoma:a Single Center Experience and Literature Review
Authors: Li Ling , Zhang Fangwen , Young Ken H. , Duan Wenjing , Li Zhaoming , Yan Jiaqin , Fu Xiaorui , Zhang Lei , Li Xin , Sun Zhenchang , Zhang Xudong , Chang Yu , Nan Feifei , Zhang Mingzhi
Published: October 2019

Background: Primary testicular lymphoma (PTL), a rare and aggressive lymphoma mainly affecting the elderly, makes up 1-2% of Non-Hodgkin's lymphomas (NHL). Diffuse large B cell lymphoma (DLBCL) is the most common histological type of PTL. At present, comprehensive management is used for the treatment of PTL, such as operation, chemotherapy and radiotherapy. Although there are multiple treatment methods for PTL, its prognosis is very poor.

Materials and Methods: We retrospectively studied clinical data of 28 patients who were 10 to 82 years old and were diagnosed with PTL between March 2006 and November 2014.The clinical data included clinical characteristic, staging, treatment and outcomes. All of the patients received therapy [rituximab, CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), intrathecal prophylaxis, or irradiation for the contralateral testis] after orchiectomy. The therapeutic effects were evaluated as complete response (CR), partial response (PR), progressive disease (PD) and stable disease (SD). The prognostic evaluation was based on age, lactic dehydrogenase (LDH), Eastern Cooperative Oncology Group Performance Status (ECOG PS) and staging.

Results: The main clinical features of the 28 patients were shown in Table 1. All patients had testicular mass. Nine patients achieved complete response (CR), 8 patients had partial response (PR), and progressive disease (PD) occurred in 3 patients after 13, 12 and 20 months after treatment, respectively(Table 2). Eight patients died. The median overall survival (OS) was 19.6 months and the median progression-free survival (PFS) was 19.4months(Figure 1,2).

Conclusion: PTL is a highly aggressive disease. Although there are multiple treatment methods for PTL, it readily recurs and its prognosis is very poor. From this study, we can see that age, LDH, ECOG PS and staging are the main factors to affect PFS and OS of the patients with PTL(Table 3).

Disclosures

No relevant conflicts of interest to declare.
Prognostic Impact of p190 and p210 Co-Expression in Early Molecular Response in Chronic Myeloid Leukemia (CML) Patients Treated with Tyrosin Kinase Inibitors
Authors: Catania Gioacchino , Trincheri Nicol , Gottardi Enrico Marco , Limberti Giulia , Ladetto Marco , Monaco Federico , Pini Massimo , Giai Valentina
Published: October 2019

Background: Expression of p190 BCR-ABL mRNA is generally considered to be confined to patients with acute lymphoid or more rarely myeloid leukemias, whereas p210 BCR-ABL mRNA is the hallmark of CML. In reality it is not uncommon the presence of p190 m-RNA in p210 CML in chronic phase, due to alternative or missplicing. Its presence seems to have no impact on prognosis in the pre-TKI era, although it may be expression of genomic instability.

Aim: Primary object of this study was to investigate if the co-expression might influence the rate of early outcome surrogate endpoints such as such as optimal molecular response (EMR; BCR-ABL < 10% (IS) at 3 month and BCR-ABL < 1% or 6 month). in patients treated with TKI.

Methods: Were evaluated patients with CML in chronic phase treated with TKI at our institution. We excluded cases with less than one year of treatment or treated with conventional chemotherapy. The fusion transcripts BCR-ABL were evaluated at diagnosis in peripheral blood by NESTED-PCR and the molecular response were evaluated in peripheral blood with Real-Time PCR. The patients were divided into two groups, "double transcripts" (DT) and "single transcript" (ST).

Results: A total of 34 patients were analyzed. The median age was 61 years (range 22-80) and 26 (68%) were male. Ten patients (29%) were DT and twenty-fouru(71%) ST. The distribution according to Sokal score was: 2 (10%), 5 (50%) 3(30%) patients for low, intermediate and high risk in the DT, whereas 13 (54%), 10 (41%) 1 (5%) low, intermediate and high risk in ST, respectively. The optimal response at 3 month was achieved in 3 patients with DT and 20 patients with ST ( 10% vs 83), at 6-month optimal response was achieved in 3 patients with DT and 20 patients with ST (10% vs 83). No patients with BCR-ABL > 10 % at 3 months, achieved molecular response at 6 months.

Summary/Conclusion: In our study the co-expression of p190 and p210 BCR-ABL transcripts influences the early molecular response to TKI and suggesting the need for a larger validation study

Disclosures

No relevant conflicts of interest to declare.
Aberrant Let7a/HMGA2 Signaling Axis with Unique Clinical Phenotype in JAK2-Mutated Myeloproliferative Neoplasms
Authors: Hsu Chia-Chen , Chen Chih-Cheng , Gau Jyh-Pyng , Huang Cih-En , You Jie-Yu , Lung Jrhau , Chen YI-Yang , Ho Hsing-Ying , Li Chian-Pei , Lu Chang-Hsien , Lee Kuan-Der
Published: October 2019

High mobility group AT-hook 2 (HMGA2) is an architectural transcriptional factor that is negatively regulated by Let-7 microRNA. Dysregulated HMGA2 has been shown to exhibit a myeloproliferative phenotype in engineered mice. To decipher the Let-7-HMGA2 axis in myeloproliferative neoplasms (MPN), we studied a cohort of 151 MPN patients. Overexpressed HMGA2 was detected in about one-fifth of the cases, and it was more commonly seen in ET (26.9%, vs. 12.7% in PV, p=0.044). Compared to their counterparts, HMGA2-overexpressing patients had higher platelet counts, increased thromboembolic risk, and inferior thrombosis-free survival. Fluorescence in situ hybridizationanalysis showed that chromosomal translocation was not a major cause of HMGA2 overexpression in MPN patients, yet there was an inverse correlation between the expression levels of let-7a and HMGA2. Furthermore, up-regulation of HMGA2 was significantly associated with MPN patients carrying JAK2V617F mutation. In vitro studies showed that Ba/F3 cells carried JAK2V617F (Ba/F3-JAK2V617F) had decreased let-7a and up-regulated HMGA2. Silencing of HMGA2 in Ba/F3-JAK2V617F cells resulted in growth inhibition coupled with a significant increase in apoptosis. Our findings suggest that, in a subset of JAK2-mutated MPN patients, Let-7-HMGA2 axis plays a prominent role in the pathogenesis of the disease that leads to unique clinical phenotypes.

Disclosures

Hsu: Ministry of Science and Technology (Taiwan): Research Funding; Chang-Gung Memorial Hospital: Employment, Research Funding. Chen:Ministry of Science and Technology (Taiwan): Research Funding; Chang Gung Memorial Hospital, Chiayi branch: Research Funding. Gau:Taipei Veterans General Hospital, Taipei, Taiwan: Employment. Huang:Chang-Gung Memorial Hospital: Employment, Research Funding. You:Lotung Poh-Ai Hospital, Yilan, Taiwan: Employment. Lung:Chang-Gung Memorial Hospital: Employment, Research Funding. Chen:Chang-Gung Memorial Hospital: Employment. Ho:Chang-Gung Memorial Hospital: Employment, Research Funding. Li:Chang-Gung Memorial Hospital: Employment, Research Funding. Lu:Chang Gung Memorial Hospital, Chiayi, Taiwan: Employment. Lee:Chang-Gung Memorial Hospital: Employment, Research Funding.
Metabolic Reprogramming of Mesenchymal Stem Cells upon Co-Cultivation with Primary CLL Cells Determined By Mass Spectrometry-Based Proteomics
Authors: Schwarzmeier Josef D. , Mayer Rupert L , Slany Astrid , Bilek Andrea , Christopher Gerner
Published: October 2019

Chronic lyhocytic leukemia displays a strong dependency on tumor-stroma interactions. CLL cells were found to rapidly die when cultivated in vitro, whereas co-cultivation with mesenchymal stromal cells promotes cell proliferation and ensures leukemia cell survival. It is therefore of great interest to obtain a thourough picture of the exact molecular players involved in this critical interplay. While a number of protagonists are already well described, there are still unresoved issues concerning the effect of stromal cells on the metabolism of CLL cells.

In this study we co-cultivated for one week primary CLL cells obtained from peripheral blood with mesenchymal cells (hMSC). Subsequently, hMSC were lysed and fractionated to obtain cytoplamic, nuclear and secreted proteins. To allow comparative analyses, B-cells from healthy individuals and hMSC were co-cultivated.

Mass spectrometry-based proteomic analysis resulted in the identification and relative quantification of more than 3700 proteins. Comparative analyses between co-cultures with CLL and healthy B-cells showed that already at a ratio of 0.25% CLL cells could induce a significant proteomic alteration in hMSC. Furthermore, hMSC were found to undergo a metabolic change upon co-cultivation with CLL cells, an effect which was most pronounced in the secreted protein fraction. Annotation analyses according to gene ontology revealed that proteins related to "generation of precursor metaboites" were significantly up-regulated in hMSC upon co-culture with CLL cells. This indicated that these stromal cells "feed" the leukemia cells by producing and secreting high energy metabolite, satisfying the elevated metabolic demands of the CLL cells.

Revealing the metabolic interactions between CLL cells and surrounding stromal cells by mass spetrometry-based methods should contribute to the development of innovative treatment strategies.

Disclosures

No relevant conflicts of interest to declare.
Does Hypogammaglobulinemia at Diagosis Effects Survival and Infection Risk in Chronic Lymphocytic Leukemia (CLL)?
Authors: Atilla Erden , Ataca Atilla Pinar , Civriz Bozdag Sinem , Toprak Selami Kocak , Topcuoglu Pervin , Ilhan Osman , Ozcan Muhit , Arslan Onder
Published: October 2019

Background: CLL is the most common leukemia in Western World. Hypogammaglobulinemia is the most common immune deficiency detected in CLL. Patients with CLL have increased risk of recurrent infections. Despite hypogammaglobulinemia reported as a cause of both infections and morbidity, controversy exists in its role.

Aim: In the present study, we have evaluated the impact of hypogammaglobulinemia at diagnosis on survival and infection risk in CLL.

Patients and Mathods: We have included 75 CLL patients diagnosed between 2000 and 2014 with B lymphocyte count >5000mm3, CD5, CD19, CD30, CD 23, CD79b positivity and surface Ig light chain restriction in flow cytometry at Ankara University School of Medicine Department of Hematology. The diagnosis and treatment criterias were depended on IWCLL 2008. The patient's performance status was evaluated by physician. If levels were considered decreased when values were below the normal ranges, defined as IgG 6.1-14.9 g/L, IgA 0.8-4.9 g/L and IgM 0.41-2.2 g/L. Overall survival (OS) was calculated by Kaplan-Meier method.

Results: The median age at diagnosis was 59 (range, 32-85). 47 patients (63%) were male. The frequencies of RAI staging from 0 to 4 were as follows; 17%, 13%, 25%, 13%, 32%. The ECOG performance status at diagnosis were stage 1 in 81%, stage 2 in %16, stage 3 in %3 of patients. FISH abnormality was detected in 19 patients (25%), del 13q was the most common. 39 patients (52%) (25 fit, 12 unfit, 2 unknown) received treatment. Fit patients got Rituximab-Fludarabine-Cyclophosphomide (R-FC) in first line whereas RFClite was preferred in unfit patients. 37 patients (49%) had any hypogammaglobulinemia at diagnosis; low IgG in 7 (9%), low IgM in 28 (37%), low IgA in 18 (24%) patients. During first year after diagnosis 26 patients (35%) had moderate to severe infections. Twenty five patients (68%) received intravenous immunoglobulin (IVIG) after diagnosis of hypogamaglobulinemia. No significant associations were found with Ig levels and infections. Six patients died during follow-up. 5-year OS in patients with normal and decreased gammaglobulin were 90% vs 86% (P=0.72). There were no survival advantage detected in low IgG, IgM, IgA subgroup analysis.

Conclusion: Hypogammaglobulinemia is considered predictive risk of infections. However we have not detected any significant increase of infections or decrease of survival in our cohort. Most of patients with hypogammaglobulinemia received IVIG after diagnosis which would effect our results.

Disclosures

No relevant conflicts of interest to declare.