bluuebunny/crossref_metadata_2025 huggingface dataset:
Late-Onset Cytopenias and Therapy Related Myeloid Malignancies in a Cohort of Patients with Lymphoproliferative Disorders at Instituto Nacional De Cancerologia- Mexico
Authors: Palacios Campos Adriana , Corona Herrera Judith Monserrat , Fabián Morales Eunice , Candelaria Myrna
Published: October 2019

Background:

The increasing survival rate of patients with non-Hodgkin lymphoma has allowed the diagnosis of long-term complications including therapy related myeloid malignancies (t-MDS/t-AML).

Methods:

To determine the frequency of late-onset cytopenias, as well as t-MDS/t-AML in patients with lymphoproliferative malignancies, a cohort followed from Jan 2011-Dec 2016 including patients with either Follicular Lymphoma (FL) or Diffuse Large B Cell Lymphoma (DLBCL) was reviewed. Inclusion criteria: patients that received full treatment at Instituto Nacional de Cancerología (INCAN), who achieved full hematologic recovery at the end of treatment, and thereafter developed any degree of cytopenia (according to the CTCAE v4.0). Exclusion criteria: Follow-up less than 6 months and previous treatment before receiving medical care at INCAN. Initially peripheral causes (vitamin deficiencies, viral infections, liver autoimmune diseases, among others) were discarded. Thereafter, bone marrow aspiration was performed for morphologic analysis (including cellularity), karyotype and FISH panel. Baseline data was compared between groups with cytopenias and without it, with X2 method. A Cox-regression model evaluated the factors involved in the development of cytopenias. Survival was estimated with Kaplan-Meier method.

Results:

Of 840 patients enrolled, 35 developed cytopenias (4.16%) (23-DLBCL & 12-FL). Causes of cytopenia were: medullar hypoplasia (n=4, 11.4%), transitory cytopenia (n=4, 11.4%), t-MDS (n=8, 22.8%), t-AML (n=2, 5.7%) among others. In patients with FL, only hemoglobin <12 g/dL (p=0.032) and >6 nodal areas (p=0.037) at diagnosis were statistically significant factors for the development of cytopenia; no factor was significant in patients with DLBCL. It is of interest that 80% of patients developing t-MDS also received radiotherapy. Anemia was the most frequent cytopenia in patients with DLBCL (22.8%) and pancytopenia was the most frequent in FL (54.5%). For patients with t-MDS or t-AML (table 1), there was a gender predominance in women (66.7%). Patients with complex karyotype were associated with progression to t-AML, those with t(11q23) and -7 had aggressive clinical course and shorter survival. Treatment details and outcomes are summarized in table 1.

Conclusions:

The incidence of t-MN is increasing as more patients survive their primary cancers. It is quite important to get further knowledge on the molecular biology of the group of therapy-related disorders not only for a better diagnostic and classification criteria, which may help in selecting individualized treatments, but also to investigate potential chemopreventive strategies.

Disclosures

No relevant conflicts of interest to declare.
Evaluation of Endocrine Complications in Beta-Thalassemia Intermedia Patients: A Cross Sectional Multi-Center Study
Authors: Karimi Mehran , Zarei Tahereh , Haghpanah Sezaneh , Azarkeivan Azita , Kattamis Christos , Ladis Vassilis , Kilinc Yurdanur , Daar Shahina , Alyaarubi Saif , Yasseen Duaa , Yassin Mohamed A , Soliman Ashraf Tawfiq , Canatan Duran , Obiedat Maha , Remawi Hala , Mariannis Demetris , Christodoulides Constantinos , Christou Soteroula , Tzoulis Ploutarchos , De Sanctis Vincenzo
Published: October 2019

The diagnosis of beta thalassemia intermedia (BTI) is mainly based on the severity of clinical phenotype. It is associated with a wide range of specific complications including extramedullary hematopoiesis, leg ulcers, gallstones, hypercoagulable state, pulmonary hypertension (PHT), endocrine disorders and osteoporosis. The commonest endocrine complication in beta thalassemia major (TM) patients is hypogonadism followed by hypothyroidism and diabetes but the data on endocrine disorders in BTI patients are scarce. The aim of this study is to determine the prevalence of endocrine complications in a large series of BTI patients.

Methods: In this multi-countries cross-sectional study, all BTI patients registered at 12 thalassemic treatment centers in Iran (2 Centers), Italy (2 Centers), Greece, Turkey (2 centers), Oman, Qatar, Jordan, Cyprus and United Kingdom were enrolled during 2017. Non transfusion- dependent beta-thalassemia patients or those who received blood transfusion 3-4 times or less annually, were evaluated. Required information was collected from medical records using a designed questionnaire. Demographic data, clinical characteristics and laboratory data included age, sex, splenectomy, type of treatment (blood transfusion, iron chelation, hydroxyurea), hormonal assays, bone mineral density, calcium -phosphorous metabolism, serum ferritin, liver function tests, fetal and total hemoglobin levels,, platelet and nucleated red blood cell counts, were collected.

Results: A total of 721 BTI patients were enrolled in the survey from 9 countries. The most prevalent disease-related complications were osteoporosis (21.6%) and hypogonadism (12.6%) followed by: central hypothyroidism (8.3%), non-insulin-dependent diabetes mellitus (7.8%), primary hypothyroidism (5.5%), insulin-dependent diabetes mellitus (4.2%), hypoparathyroidism (2.2%), growth hormone deficiency (1.1%), adrenal mass (1%) and thyroid cancer (0.5%).

Conclusion: This study evaluated the largest cohort of BTI patients with endocrine disorders. Although BTI patients are non-transfusion dependent or only occasionally transfused, iron-overload due to increased intestinal iron absorption and enhanced bone marrow activity cause endocrine disorders and osteoporosis. This study demonstrate that although endocrine complications are less common in patients with BTI compared to data reported in literature in TM patients , a regular monitoring with timely diagnosis and proper management underscoring on osteoporosis and gonadal disorders are crucial to prevent endocrine complications in these patients.

Disclosures

No relevant conflicts of interest to declare.
Influence of FLT3-ITD Mutation and Length on the Treatment Response and Prognosis in Cytogenetically Normal AML Patients
Authors: Jiang Xuejie , Yin Changxin , Sun Junya , Cheng Jiaying , Wang Qiang , Yu Guopan , Jiang Ling , Xu Dan , Liu Xiaoli , Feng Ru , Liu Qifa
Published: October 2019

BACKGROUND : Mutations of internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD) contributed to poor prognosis in cytogenetically normal acute myeloid leukemia (CN-AML). FLT3 tyrosine kinase inhibitor sorafenib in combination with chemotherapy was applied to treat FLT3-ITD AML patients with limited efficacy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was considered as a potent therapeutic regimen in FLT3-ITD patients, but additional sorafenib maintenance was indispensable to support their long-term survival after allo-HSCT. Studies showed that increasing ITD size may be accompanied with decreasing OS and RFS in AML patients, but it remained controversial about the prognostic implication of ITD mutant lengths, the prognostic influence was important to evaluate in determining the therapeutic strategy for AML patients with different ITD lengths.

METHODS: Total 185 CN-AML patients with and without FLT3-ITD mutations were enrolled in this study. We retrospectively studied the clinical characteristic, treatment response, survival and relapse risk after chemotherapy or allo-HSCT plus sorafenib in these patients. Distribution of ITD lengths detected in AML patients suggested two groups including long (≥70bp) and short ITD length (<70bp). Influence of FLT3-ITD mutation and its length were investigated after chemotherapy or allo-HSCT plus sorafenib.

RESULT: FLT3-ITD mutations were detected in 15 percentage of AML patients, and associated with leukocytosis, high blast percentage in bone morrow (BM) and increased risk of treatment failure. FLT3-ITD mutations indicated decreased complete remission (CR) rate, overall survival (OS) and relapse-free survival (RFS), and increased relapse risk (RR) in AML patients after chemotherapy plus sorafenib. Patients with long ITD length (≥70bp) had worse OS and RFS, and more relapse probability than these with short ITD length (< 0bp) or FLT3-WT, but patients with short ITD length and FLT3-WT had the similar RFS and RR after chemotherapy. Allo-HSCT plus sorafenib maintenance significantly prolonged OS and RFS, decreased RR in FLT3-ITD patients, especially in these with long ITD length instead of those with short ITD length.

CONCLUSION: Our findings indicated that FLT3-ITD mutation and long ITD length had negative effect on treatment response and prognosis in CN-AML patients. Allo-HSCT plus sorafenib maintenance was an effective strategy to improve survival and decrease relapse probability, abrogated disadvantage from long ITD length in FLT3-ITD patients.

Disclosures

No relevant conflicts of interest to declare.
Long-Term Stability of the Adult Sickle Cell Quality of Life Measure (ASCQ-Me)​
Authors: Roach Keesha L. , Yao Yingwei , Suarez Marie L. , Angulo Veronica , Shuey David , Ezenwa Miriam O. , Schlaeger Judith M. , Fillingim Roger B. , Wang Zaijie J. , Molokie Robert E. , Wilkie Diana J.
Published: October 2019

Aim: The Adult Sickle Cell Quality of life Measure (ASCQ-Me) is a relatively new tool with increasing frequency of use, but no published reports of its long-term stability. The aim of this study was to examine reliability of ASCQ-Me in a sample of adults with sickle cell disease (SCD). Evidence of reliability of this new tool is important for credible use in longitudinal studies of SCD, especially those with interventions intended to improve quality of life (QOL) for patients with SCD.

Methods: In a comparative study, 141 adults with SCD (mean age 37±11 years [ranged from 19 to 74 years]; 100% African ancestry; 60% female; 74% SS, 20% SC and 6% Other) provided demographic information and completed the ASCQ-Me questionnaire twice, separated by 1 year so that data were collected in the same season. The 30-item ASCQ-Me has 6 subscales focused on: pain episodes (frequency and severity), pain impact, emotional impact, sleep impact, social functioning impact, and stiffness impact. Its scores range from (0 low QOL) to 100 (high QOL) and are normed at a mean of 50 and SD of 10. Because the scores are reversed for pain episodes (frequency, severity), higher scores indicate more suffering. Descriptive and bivariate statistical analysis were conducted using the R statistical software package.

Results: Table 1 presents the complete findings for the ASCQ-Me subscale domains, mean (SD) scores at baseline and one-year, intra-class coefficients (ICC), and Cronbach's alphas at baseline and one-year. Generally in this sample, the subscale scores across time did not differ by more than 2.4 points (Table 1). The internal consistency alphas at baseline ranged from 0.64 to 0.93 and at one-year ranged from 0.62 to 0.93. The long-term stability (ICC) ranged from 0.43 to 0.64.

Conclusions: Over a one-year time span, the stability of the ASCQ-Me subscale scores was fair to good, with pain severity being less stable as would be expected for a condition known for recurrent pain episodes as well as chronic pain. Mean scores in this sample are similar to published scores associated with moderate to high severity SCD. Several domains showed ICC of 0.53 and higher, suggesting adequate stability for use of ASCQ-Me as a treatment outcome measure. While worsening disease has been associated with an increased number of pain episodes, in this sample, over the one-year period, the quality of life remained relatively stable. ASCQ-Me may be used to help describe chronic pain phenotypes in patients with SCD and as a longitudinal measure of treatment outcomes.

Disclosures

No relevant conflicts of interest to declare.
Efficacy of a New Small-Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) in Preclinical Models of B-Cell Lymphoma and Acute Myeloid Leukemia
Authors: Perez-Salvia Montserrat , Eneko Aldaba , Yosu Vara , Myriam Fabre , Cristina Ferrer , Carme Masdeu , Aizpea Zubia , Eider San Sebastian , Dorleta Otaegui , Pere Llinàs-Arias , Margalida Rosselló-Tortella , Maria Berdasco , Fernando Setien , Catia Moutinho , Alberto Villanueva , González-Barca Eva , Muncunill Josep , Navarro Jose Tomas , Piris Miguel Angel , Fernando Cossio , Esteller Manel
Published: October 2019

Histone deacetylase 6 (HDAC6) is a protein modifier that is an increasingly attractive pharmacological target. Interestingly, the observation that the HDAC6 knock-out mouse is not lethal, in contrast to those undergoing complete loss of class I, II and III HDACs, suggests that specific HDAC6 inhibitors may be better tolerated than pan-HDAC inhibitors or drugs that target the other HDAC classes. In this regard, the compound ACY-1215 (Rocilinostat), the described selective HDAC6 inhibitors, is undergoing clinical trials for the treatment of multiple myeloma. Taking into account the previous information about HDAC6 inhibitor structures, the structural differences between HDAC6 and other HDAC isoforms and also the structural information of other developed HDAC inhibitors, we have previously designed and synthesized a new potential HDAC6 selective inhibitor, QTX125 with growth inhibitory effects in mantle cell lymphoma (MCL) cell lines, mouse models and ex vivo treatment of primary samples obtained from patients with MCL. Herein, we have extended these findings to show that the newly identified HDAC6 inhibitor QTX125 is also able to inhibit the growth of preclinical models of other B-cell lymphomas such as follicular lymphoma and Burkitt's cell lymphoma, but also of acute acute myeloid leukemia. In addition beyond a-tubulin, a well known HDAC6 target, we have developed a pharmacological and proteomic screening to identify other proteins modified by HDAC6 that can contribute to the described lymphoma and leukemia phenotypes.

Disclosures

Eneko: Quimatryx: Employment. Yosu:Quimatryx: Employment. Myriam:Oncomatryx: Employment. Cristina:Oncomatryx: Employment. González-Barca:Roche: Speakers Bureau; Celtrion: Consultancy; Gilead: Consultancy; janssen: Consultancy, Speakers Bureau. Fernando:Quimatryx: Consultancy.
Induced Transdifferentiation of Leukemia B-Cells to Macrophages Involves Reconfiguration of the DNA Methylome
Authors: Bueno-Costa Alberto , Piñeyro David , Soler Marta , Javierre Biola Maria , Martínez-Climent José Angel , Esteller Manel
Published: October 2019

The epigenomic changes that occur during the process of cellular differentiation, such as in the blood cell lineage, are currently not well understood, especially at distant regulatory regions such as enhancer sequences. To study the effects of DNA methylation on cellular (de)differentiation, we have used a human B Cell Acute Lymphoblastic Leukemia model of transdifferentiation (BLaER1), which has an estradiol-inducible CEBPA construct that allows the conversion of leukemic B cells to non-tumorigenic macrophage-like cells. By analyzing the DNA methylation landscape of these cells at different time points of transdifferentiation with an Illumina EPIC methylation array, we have found enhancer-associated CpGs that shifts their methylation levels at the end of the transdifferentiation. By merging these results with the data obtained by Genome-wide Chromosome Conformation Capture Capture (Hi-C) in naive B cells and macrophages, we studied the putative interaction between several gene-promoters and our differentially methylated CpGs. We then proceed further to characterize the impact of the observed interactions on gene expression. We have identified the DNA methylation dependent enhancer interactomes of B-cells and macrophages. These target genes are related with vesicle trafficking, endocytosis and immune response. Our data highlight the role of DNA methylation to determine cell identity in the blood cell lineage.

Disclosures

No relevant conflicts of interest to declare.
Autoimmune Hemolytic Anemia and Checkpoint Inhibitors: 68 Cases from the FDA Database and Critical Review
Authors: Tanios Georges , Doley Peter B , Munker Reinhold
Published: October 2019

Immune checkpoint inhibitors (CPI) are widely used in modern oncology and have improved the prognosis of lung cancer, bladder cancer, malignant melanoma and other malignancies. Unlike cytotoxic chemotherapy, drugs like nivolumab, pembrolizumab and ipilimumab are associated with a high frequency of immune-related adverse effects. We recently observed a patient with lung cancer who developed a fulminant warm-antibody autoimmune hemolytic anemia (AIHA) and reviewed the literature and public databases of the Food and Drug Administration (FDA) to help understand the association between CPI use and AIHA. A total of 68 cases of AIHA were identified in the FDA database during the time period 2012-2018; 43 associated with nivolumab, 13 with pembrolizumab, 7 with ipilimumab and 5 with atezolizumab administration (see Table 1). All episodes of AIHA were listed as serious. If the total number of adverse effect cases reported to the FDA is taken as a reference, AIHA is rare, but occurred more frequently with PD-1 or PDL1 targeting agents (0.15 to 0.25%) than with CTLA4-inhibitors (0.06%). The underlying cancer diagnoses corresponded mostly to the approved indications for CPI (32 cases of malignant melanoma, 24 cases of lung cancer). In about a quarter of cases with AIHA other immune related side effects were reported. In addition to our case, the literature review identified 10 similar cases. AIHA can occur earlier and later after the administration of CPI (median of 10 weeks, range 2- 78). Most cases of AIHA responded to steroids, but 2/11 were fatal. In conclusion, we describe AIHA as a rare and serious immune-related side effect of checkpoint inhibitors. Because of its seriousness and the underlying comorbidities, early aggressive management is necessary.

Disclosures

No relevant conflicts of interest to declare.
Development of a Pegylated Dimeric Recombinant Factor VIII-Fc Fusion Protein for the Treatment for Hemophilia a Patients
Authors: Liu Bin , Wang Xiaoshan , Li Xueqin , Yan Haixia , Wang Shuya , Zhu Xi , Wang Pengju , Gao Jie , Wang Yali , Su Hongsheng
Published: October 2019

Hemophilia A is a hereditary bleeding disorder resulting from reduced factor FVIII activity. It occurred in 1/5000 male. Currently, the treatment option is with the factor FVIII replacement therapy. A long-acting recombinant monomeric FVIII-Fc fusion protein product (Eloctate®) has been approved in 2014 by the US FDA, it requires to infuse the drug for every 3 days or twice a week. There is a clinical need to develop longer half-life product to extend the treatment option to once a week infuse for hemophilia A patients. Recently, we have developed a dimeric recombinant factor VIII-Fc (drFVIII-Fc) fusion protein therapeutic candidate, which is entering the clinical development in China. To generate a longer half-life recombinant FVIII product, we have developed a PEGylation method to PEGylated this drFVIII-Fc fusion protein to PEGdrFVIII-Fc. We have analyzed and characterized the fusion protein by various analytic methods, as well as in vivo animal tests. It was shown that PEGdrFVIII-Fc fusion protein has been modified with about five Y type of 40kd PEG; the remaining activity is around 700 IU/mg, and the in vivo tests in cynomolgus monkey demonstrated that the fusion protein has a half-life of about 37 hours. The data also showed that there was no detectable affinity binding activity of vWF to a PEGdrFVIII-Fc fusion protein, as compared with the binding activity of 5.16X10-4M for the molecule of a drFVIII-Fc fusion protein. In conclusion, we are able to generate a PEGylated form of a drFVIII-Fc molecule with the relevant specific activity and has been shown the molecule with the prolonger half-life in the in vivo tests. The further biochemical analysis demonstrated PEGdrFVIII-Fc fusion protein with no detectable vWF binding activity, which might explain why its half-life is longer than vWF's ~15hours half-life in vivo. This molecule is likely to be used as a once-weekly treatment option for hemophilia A patients. Currently, we are in the development stage of an IND filing in China.

Disclosures

No relevant conflicts of interest to declare.
Defective Autophagy Process and Increased ROS Formation in Primary Myelofibrosis
Authors: Shi Guanfang , Kodali Sreenath , Wong Ching , Gotlieb Vladimir K. , Wang Jen-Chin
Published: October 2019

Introduction: We and others have reported markedly increased ROS formation in primary myelofibrosis (MF) including post-ET or PV-MF when compared with essential thrombocytosis (ET), polycythemia vera (PV) and normal controls. A growing body of evidence illustrates the interdependency between the Keap1-Nrf2 pathway and p62-mediated selective autophagy, are playing an important role in major cellular defense mechanisms against oxidative and electrophilic stress ; dysregulation of p62-Keap1-Nrf2 axis has been implicated in tumor development. Therefore, we studied p62 mediated autophagy and Nrf2 pathways in patients with MF ,ET and PV.

M aterials and Methods :33 patients including 15 patients with MF, 7 patients with PV, 11 patients with ET and 10 normal controls were studied. Cellular ROS measurement: Cellular ROS was determined by a dichlorofluorescein (DCF) assay. The oxidation of H2DCFDA was measured by flow cytometry. Real-time PCR assay: Total RNA was extracted from normal control or patient mononuclear cells using RNeasy Kits from Qiagen (Germantown, MD). Real-time PCR was performed using SsoAdvanced™ Universal SYBR® Green Supermix (Bio-Rad, Hercules, CA) on Bio-Rad iQ5 Multicolor Real-Time PCR Detection System. Western blotting: Total cell lysates were obtained from normal control or patient mononuclear cells. Primary antibodies against Beclin-1, LC3 and p62 were purchased from Cell Signaling Technology (Danvers, MA).

Results: Fig.1a shows significantly elevated ROS in MF (2127±261.6) when compared with PV (1090 ± 163.8) or ET (1031 ± 140.9) or controls (549.1 ± 52.50). Fig.1b. shows that Nrf2 protein levels (ratio to controls) was significantly reduced in MF (41.84 ± 29.33), PV (14.42 ± 2.96), ET (14.05 ± 3.02), than the controls ( 101.3 ± 7.64). Fig.1c shows that the RT-PCR values of p62 was significantly increased in MF (1.34 ± 0.06) and grouped PV (1.21 ± 0.07), ET (1.14 ± 0.08) and MF as MPN (1.27 ± 0.04) than controls (1.00 ± 0.05),( P<0.05); ET or PV were not significantly elevated than controls.

Conclusions: Patients with MF had increased levels of ROS when compared with PV and ET while Nrf2 levels were significantly reduced in all three( ET,PV, MF) which implies defective detoxification process in MPNs. P62, a marker for defective autophagy was significantly increased in MF than controls . This implies that there is a defective autophagy process in MF, contributing further to the formation of P62 and ROS. There is also a defective detoxification mechanism which further leads to more ROS formation and further DNA damage. Further studies are in progress on other autophagy markers which will enlighten more about the pathophysiology of MF.

Disclosures

Wang: INCYTE: Other: clinical trial.
Human Double-Negative Regulatory T Cells Modulate Effector Functions of Conventional T Cells By Selectively Blocking mTOR Signaling
Authors: Haug Tabea , Aigner Michael , Bruns Heiko , Peuser Moritz , Gebhardt Dorothea , Berger Jana , Koppitz Florentine , Mackensen Andreas , Voelkl Simon
Published: October 2019

Regulatory T cells play an important role in the maintenance of immune tolerance to self-antigens and are involved in modulating immune responses to promote resolution of inflammation. The population of TCRαβ+ CD4-/CD8- (double-negative, DN) T cells has attracted growing attention as a result of their potent immune regulatory function. In murine models, DN T cells were able to prevent rejection of allogeneic and xenogeneic organ grafts by effectively suppressing reactive T cells. In addition, DN T cells possess the capacity to resolve various inflammatory conditions, including graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation. Notably, first clinical studies in patients after stem cell transplantation demonstrated an inverse correlation between the frequency of circulating DN T cells and the severity of acute GvHD, suggesting a therapeutic potential of human DN T cells. To gain a better understanding of the molecular mechanism of suppression, we investigated whether human DN T cells modulate distinct signaling processes in conventional T cells. We found that DN T cells selectively block mTOR signaling but not activation of mitogen-activated protein kinases. Enforced activation of the mTOR pathway by a chemical activator rendered conventional T cells unsusceptible to DN T cell-mediated suppression, confirming the critical function of mTOR signaling. Given that mTOR is a major regulator of cellular metabolism, we further determined the impact of DN T cells on the metabolic framework of conventional T cells. Of interest, DN T cells diminished upregulation of the glycolytic machinery and glucose uptake in conventional T cells, whereas fatty acid uptake was not modified. Next, we investigated the fate and function of effector cells after DN T cell co-culture. Of importance, DN T cells suppressed proliferation but also altered expression of differentiation markers, transcription factors and homing receptors. Further analyses demonstrated that CD4+ T cells failed to produce effector cytokines IL-17 and IFN-γ after coculture with DN T cells, whereas IL-2 secretion was amplified. The selective modification was induced by a direct cell-cell contact dependent mechanism between CD4 and DN T cells and not as a consequence of competition for nutrients or growth factors. Together, our findings expand the understanding of DN T cell functionality and support that human DN T cells represent an interesting opportunity to limit and modulate T-cell reactivity.

Disclosures

No relevant conflicts of interest to declare.
Pegaspargase with Concurrent Radiotherapy in a Once-Every-Three-Weeks Schedule in Patients with Newly Diagnosed, Stage IE to IIE, Nasal, Extranodal NK/T-Cell Lymphoma: A Phase II Study
Authors: Wang Hua , Luo Wei , Lu Yue
Published: October 2019

Introduction: Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive form of non-Hodgkin's lymphoma,which is relatively more common in Asia and Latin America.Radiation therapy(RT) is widely administered for patients with localized nasal disease. However, local and systemic failures are observed frequently in patients who receive RT alone.Therefore, chemotherapy is needed in combination with RT to reduce the risk of recurrence. Concurrent chemoradiotherapy (CCRT) is expected to improve both local and systemic disease control and has been established as a standard therapy for several types of solid tumors. Therefore,we conducted a phase II study of pegaspargase-based CCRT to explore a more effective treatment for localized nasal natural killer (NK)/T-cell lymphoma.

Methods: Enrolment began in May 2016 for a phase II single-center clinical trial. Chemotherapy and RT were simultaneously started within 7 days after registration. The drug administration schedule were as follows: day1,deep intramuscular injection of 2000 unit/m2 pegaspargase at three different sites. Chemotherapy was planned to repeat every 3 weeks. Pegaspargase were administered only if the plasma fibrinogen level was greater than 0.75g/L. Six courses of chemotherapy were planned.All patients received three-dimensional (3D) conformal radiation therapy by using 4 or 6MV photons generated from a linear accelerator. The involved-field radiation (IFRT) dose was 50 Gy, which was given as 2.0 grays (Gy) per daily fraction with 5 weeks.

Results: Until May 2, 2018, we have completed the enrolment of 12 patients with newly-diagnosed untreated ENKTL. The main clinical characteristics of the 12 patients are presented in Table 1. All patients (n=12) have begun treatment and are evaluable for response. Of the 12 patients, complete remission (CR) rates is 100% to concurrent chemoradiotherapy alone. None of patients has experienced disease progression until now. Toxicities are recorded as the number of patients experiencing a certain adverse event.The most common grade 1-2 non-haematological (non-heme) adverse effects (AEs) are fatigue (n=2), nausea (n=1),oral mucositis (n=1) and increased transaminases (n=1).Eight (n=8) patients were confirmed to have decreased fibrinogen. Most of these were grade 1/2 and no bleeding or other adverse events were observed.There was no grade 3/4 non-heme toxicities during treatment. Grade 1-2 hematological (heme) AEs included neutropenia (n=6), anemia (n=5) and thrombocytopenia(n=2).Grade3-4 haematological AEs was anemia (n=1). No patients interrupted treatment for severe adverse events and no treatment-related deaths occurred.

Conclusions: Preliminary data indicate that pegaspargase with concurrent radiotherapy in newly diagnosed ENKTL patients was efficacious and well-tolerated, while the long-term outcome is required to be followed up.

Disclosures

No relevant conflicts of interest to declare.
Venous Thromboembolic Disease and Bone Marrow Transplant: A Remarkable Cause of Mortality and Morbidity — Potentially Preventable
Authors: Rivas Luque Marta , Morente Constantin Estefanía , Romero Garcia Pablo , Garcia-Ruiz Maria Almudena , Jurado Manuel
Published: October 2019

Thrombotic events are frequent in patients undergoing HSCT, being an important cause of morbidity and mortality. The highest incidence occurs three months after the transplant. There are several risk factors, which add to those already known for VTE: neoplasia, central venous catheters, immobilization, chemotherapy, infections, GVHD. In the series described, the frequencies are variable, between 0.5 and 23.5%, with an overall incidence of 5%. In patients with GVHD, this incidence increases, with up to 35% of events.

METHODS

A retrospective observational study that includes patients transplanted in our Unit between 2014 and 2017 has been conducted, with the objective of analyzing the incidence of VTE peri-TPH. Likewise, we have analyzed if it is associated to catheter, presence of CVRF, if there was a known medical history of thrombophilia, number of platelets at time of thrombosis, the heparin used and whether anticoagulation was maintained indefinitely or not.

RESULTS

Out of the 235 patients included in our series, 130 underwent an autologous transplant and 105 an allogeneic transplant. 18 thrombotic events occurred (9 men and 9 women, aged between 18 and 65 years), which means 7.5% (14 occurred between days 0-100, 12 in patients undergoing autologous hematopoietic stem cell transplantation). Three of them had thromboembolism and the rest deep vein thrombosis, 4 of which with catheter. The platelet count at the time of the event ranges from 21 to 409,000 / mm3. Regarding the heparin used, 2 were treated with Tinzaparin and the rest with Bemiparin. Only 1 of the patients presented prior VTE. Among the patients, there were some with CVRF and others without relevant medical history. Just in one patient, a family thrombophilia study had been performed prior to his hematological diagnosis, resulting in a deficit of protein S. In 8 of the patients, anticoagulation was maintained indefinitely with LMWH in the post-transplant period.

CONCLUSIONS

Our incidence approaches the literature, albeit the series of published cases are heterogeneous and with variable differences. Although the incidence of thrombosis in these patients is a cause of marked morbidity and mortality, the risk of bleeding also increases, therefore routine prophylaxis is not recommended in all patients. We must undergo an exhaustive analysis of the data to identify individually which patients may be candidates for prophylaxis, with the aim of reducing the incidence without raising the hemorrhagic risk of our patients.

Disclosures

No relevant conflicts of interest to declare.
Very High Efficacy of Bendamustine, Gemcytabine and Dexamethasone (BGD) in Relapsed/Refractory Classical Hodgkin Lymphoma
Authors: Swoboda Ryszard , Najda Jacek , Dulik Katarzyna , Kwiatkowska-Pamula Anna , Twardosz Maja , Giebel Sebastian
Published: October 2019

Introduction. Although Hodgkin lymphoma (HL) is one of the most curable malignancies, 10-30% of patients experience resistance or relapse following initial response. Treatment options for relapsed/refractory (R/R) disease include usually multi-agent chemotherapy followed by autologous hematopoietic stem cell transplantation (autoHSCT). Although many chemotherapy-based regimens are used as salvage, the optimal one has not been defined so far. The goal of this study was to evaluate efficacy and safety of bendamustine in combination with gemcitabine and dexamethasone (BGD) in R/R HL.

Patients and Methods. This was a retrospective, single center study, including 30 consecutive R/R HL patients treated between 2016 and 2018. Median age was 33 (19-82) years. Ten patients (33%) had been pre-treated with at least 2 lines of chemotherapy; 11 patients (37%) with radiotherapy, 6 patients (20%) with autoHSCT while 4 patients (13%) with allogeneic (allo)HSCT. Six patients (20%) were resistant to previous salvage treatment.

BGD therapy consisted of bendamustine 90mg/m2 on days 1 and 2, gemcitabine 800 mg/m2 on days 1 and 4, dexamethasone 40 mg on days 1-4. Best response after at least 2 courses of therapy was the primary study end-point.

Results. Median number of BGD cycles was 4 (2-7). Nineteen (63%) patients achieved complete remission (CR) confirmed by FDG-PET, while 6 patients (20%) achieved partial response (PR), accounting for 83% overall response (OR) rate. Stable disease was reported in 3 patients and progressive disease - in 2 cases. Many patients achieved CR (33%) or PR (33%) after 2 cycles of BGD. The OR rate was 85% for patients in whom BGD was administered as first salvage and 80% when used in more advanced stages of the disease. Fourteen patients proceeded to autoHSCT while 4 patients were subsequently treated with alloHSCT.

Six patients experienced infections of the upper respiratory tract while two patients had allergic skin reactions. No organ toxicity was reported. One patient required transfusion of red blood cells while none was treated with platelet transfusions.

Conclusion. BGD is a highly effective, well-tolerated salvage regimen for patients with R/R HL. The protocol may be used as a bridge to autoHSCT or alloHSCT. Further, prospective studies are warranted to define its role in future treatment algorithms.

Disclosures

No relevant conflicts of interest to declare.
Hedgehog Pathway Inhibitor for Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD)
Authors: Gupta Ridhi , Albabtain Abdulwahab , Arai Sally , Kwong Bernice , Weng Wen-Kai
Published: October 2019

Background: Sclerodermatous chronic GVHD (scGVHD) is a unique form of cutaneous GVHD that predominantly involves the skin, subcutaneous tissue, fascia and joints. Steroid-refractory scGVHD is especially challenging to manage since it is usually a progressive condition with devastating effects on the quality of life of affected patients. Inhibition of hedgehog signaling has been shown to be effective in the treatment of murine scGVHD. Here, we report a retrospective review of patients with scGVHD who were treated with hedgehog pathway inhibitor, Vismodegib, at Stanford University.

Results: A total of n=8 patients with steroid-refractory scGVHD were treated with Vismodegib 150 mg daily as an off-label use since 2016. The male:female ratio is 5:3 and median age was 49 (range 39-62) at time of start of Vismodegib. The median time from transplant to diagnosis of scGVHD was 26.9 months (range 8.9-37.5) and the median time from diagnosis of scGVHD to Vismodegib treatment was 14.4 months (range 2.7-45.2). All patients had GVHD involvement of other organ besides scGVHD and have received multiple lines of therapy prior to Vismodegib.

Hair thinning/alopecia and muscle cramps were noted in 100% of the patients. 75% (6/8) had dysgeusia, 88% (7/8) had fatigue (gr 2) and 1 patient had an asymptomatic elevated lipase level. All patients required dose reduction or drug holiday due to side effects (mainly muscle cramps). Four patients (50%) stopped the drug due to side effects (2/4) or lack of response (2/4). All Vismodegib-related side effects resolved after discontinuation of the drug. The median duration of Vismodegib treatment was 6.1 months (range 2.3-17.1) for the entire group. One patient received multiple courses of Vismodegib with benefit noted with each course.

Five patients (63%) had partial response including 1 patient responded to multiple courses of Vismodegib and 1 patient had subjective symptom improvement. The median time to clinical response was 103 days (range 24-145) and the duration of response was 7.8 months (range 1.6-13.4). Three patients had experienced prolonged clinical response off the Vismodegib. At the last follow-up visit, all patients were alive and 4 patients continued to take Vismodegib including 1 patient who had been tapered off systemic steroid.

Conclusion: Steroid-refractory scGVHD is an extremely difficult disease to manage with a high rate of morbidity. Our experience with hedgehog pathway inhibitor, Vismodegib, is very encouraging. Additional study to evaluate the optimal dosing, side effects and its efficacy is under way.

Disclosures

No relevant conflicts of interest to declare.
Risk Factors of Clostridium Difficile Infection in Hematopoietic Stem Cell Transplant Recipients: A Systemic Review and Meta-Analysis
Authors: Tariq Raseen , Furqan Fateeha , Jamshed Saad , Khanna Sahil
Published: October 2019

Introduction:

C. difficile infection (CDI) is a common nosocomial infection. Immune suppression is thought to be a major risk factor for CDI. Hematopoietic stem cell transplant (HSCT) recipients represent a major subgroup of immunologically vulnerable patients. It is unclear if these patients have novel risk factors for CDI development. We, therefore, performed a systematic review and meta-analysis to evaluate the predictors of CDI in HSCT recipients.

Methods:

A systematic search of Medline, Embase, and Web of Science was performed from January 2000 up to June 2018. All studies that assessed risk factors associated with CDI development in HSCT recipients were eligible for inclusion. Data on clinical characteristics and risk factors associated with CDI development were collected. Study quality was assessed using the Newcastle-Ottawa scale. Meta-analyses were performed using random effects models and pooled odds ratios with 95% confidence interval (CI) for risk factors reported in ≥ 2 studies were calculated.

Results:

Overall, 17 studies, including 6328 HSCT patients were included. Of those 874 patients developed CDI. The rate of CDI development in these patients was 13.81% with a follow up ranging from 1- 36 months. A total of 34 different risk factors were studied, of which 20 were identified in ≥ 2 studies. Our analysis showed that cephalosporin use (Odds ratio [OR] 2.21, 95% confidence interval [CI] 1.26-3.87), cord blood transplant (OR 1.36, 95% CI 1.01-1.83), graft versus host disease (GVHD) (OR 1.63, 95% CI 1.07-2.48) & prior hospitalization within 90 days of HSCT (OR 1.85, 95% CI 1.21-2.83) were associated with statistically significant increased risk of CDI in HSCT patients (Figure 1). On the other hand, many characteristics of HSCT patients including age, diabetes, lung disease, fluoroquinolones, proton pump inhibitors, rituximab, mucositis, myeloablative therapy, melphalan use before BMT, total body irradiation, growth factor use during admission, neutropenia, autologous vs allogenic transplant and use of matched related donor were not associated with increased risk of CDI.

Conclusion:

HSCT recipients are at an increased risk of CDI compared to general population. In addition to the common risk factors like cephalosporin use and prior hospitalization, these patients have novel characteristics including presence of GVHD and cord blood transplant that puts them at a higher risk of CDI. HSCT patients with these risk factors may warrant a closer surveillance for early detection and treatment of CDI.

Table 1. Table 1.

Disclosures

No relevant conflicts of interest to declare.
Research of miR-30b in Cisplatin Resistance of Human NK/T Cell Lymphoma Lines SNK-6 and YTS Cells By Targeting CCL22
Authors: Liang Rong , Wang Jian hong , Liu Fang , Duan Xiao hui , Hao Xia Cai , Zhang Liang , Wang Michael , Liu Xiang -xiang , Guo Yan Hua , Wang Zhe , Tang Hailong , Yang Ljie
Published: October 2019

Objective: To investigate the role and mechanism of miR-30b underlying cisplatin resistance of human NK/T cell lymphoma lines SNK-6 and YTS cells. Methods: Normal NK cells and SNK-6 and YTS cells were cultured, the levels of miR-30b and CCL22 were detected by real-time PCR assay, CCL22 expression was detected by western blot analysis. Transfected with miR-30b mimics and inhibitor in SNK-6 and YTS cells respectively, and then measured the effect of cisplatin resistance in SNK-6 and YTS cells by MTT assay, the activity of caspase-3 was detected by caspase-3 kit assay, the cells apoptosis ratio was detected using flow cytometry analysis. The target relationship of miR-30b and CCL22 were determined by dual-luciferase reporter gene assay. The expressions of CCL22. Furthermore, the effect of CCL22 on cisplatin resistance and caspase-3 were also evaluated. Results: The levels of miR-30b were significantly decreased in both SNK-6 and YTS cells, but with the increase in CCL22 expression. MiR-30b mimics decreased the cells activity, down-regulated the cisplatin resistance, increased cells apoptosis ratio and caspase-3 activity. The effects of miR-30b inhibitor were contrary to the mimics. Up-regulated miR-30b significantly decreased the luciferase activity in CCL22 3'-UTR transfected NK cells, but not in Mut-CCL22 3'UTR group, suggesting that CCL22 could act as a direct target of miR-30b. The expressions of CCL22 pathway proteins were down-regulated after SNK-6 cells transfected with miR-30b mimics, while the effects were restored by overexpression of CCL22. Moreover, CCL22 overexpression also increased the cells activity and decreased caspase-3 activity when SNK-6 cells were transfected with miR-30b mimics. Conclusion: MiR-30b inhibited cisplatin resistance of human NKTCL in SNK-6 and YTS cells by targeting CCL22.

Disclosures

Wang: Novartis: Research Funding; Kite Pharma: Research Funding; MoreHealth: Consultancy; AstraZeneca: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria; Juno: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding.
A Clinico-Genotypic Prognostic Index for De Novo Composite Diffuse Large B-Cell Lymphoma Arising from Follicular Lymphoma in the Rituximab Era
Authors: Lim Ryan Mao Heng , Chan Natalie Pei Xin , Khoo Lay Poh , Cheng Chee Leong , Tan Leonard , Poon Eileen Yi Ling , Somasundaram Nagavalli , Farid Mohamad , Tang Tiffany , Tao Miriam , Lim Soon Thye , Chan Jason Yongsheng
Published: October 2019

Aim

Composite follicular lymphoma with diffuse large B-cell lymphoma (FL/DLBCL) is an uncommon hematological neoplasm. The aim of this study was to examine clinico-pathological features of patients with FL/DLBCL and investigate relevant predictors of survival outcome.

Methodology

Patients with histologically-proven FL/DLBCL at diagnosis (n=106) and who were subsequently treated with Rituximab-based chemotherapy from 2002-2017 at the National Cancer Centre Singapore were retrospectively analyzed. Survival analyses were performed using the Kaplan-Meier method and multivariate Cox proportional models.

Results

The cohort consisted of 72 men and 34 women with a median age of 59 years (range, 24-82). The cell of origin by Han's algorithm was GCB in 37.7%, ABC in 58.5% and unknown in 3.8%. Eight patients (7.5%) were double-hit for c-MYC, BCL2 and/or BCL6 rearrangements. In a multivariate model inclusive of known clinico-pathological parameters at diagnosis, presence of B symptoms (p = 0.0122), stage 3 or 4 lymphoma (p = 0.0166) and double-hit genotype (p = 0.0045) were independently prognostic for worse overall survival (OS). These factors, excluding B symptoms, were similarly prognostic for progression-free survival (PFS). Including first-line treatment data in the multivariate model, lack of complete response (p < 0.0001) and use of chemotherapy regimens other than R-CHOP (p = 0.0360) alongside presence of B symptoms (p = 0.0022), were the only remaining independent prognostic variables for worse OS. Classification by cell of origin was not prognostic. A Clinico-Genotypic Index derived from point-wise addition of all five adverse parameters (score of 0, 1, 2, 3-4) revealed four prognostic risk groups accounting for 25%, 30%, 25% and 20% of the cohort, with a predicted 5-year OS of 100%, 95%, 57% and 19% respectively (p < 0.0001).

Conclusion

A Clinico-Genotypic Index derived from clinical and molecular factors can classify patients with composite FL/DLBCL into distinct prognostic groups. Han's algorithm has no prognostic value in this disease entity.

Figure. Figure.

Disclosures

No relevant conflicts of interest to declare.
Role of Rhoa G17V in Cell Migration and Transformation in Angioimmunoblastic T-Cell Lymphoma
Authors: Palomero Teresa , Cortes Jose R. , Cooke Anisha R. , Belver Laura , Bhagat Govind , Ferrando Adolfo A.
Published: October 2019

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive form of peripheral T-cell lymphoma derived from the malignant transformation of follicular helper T-cells (TFH), frequently associated with autoimmune disease and characterized by resistance to chemotherapy and poor prognosis. A recurrent RHOA G17V mutation in the RHOA small GTPase gene is characteristically present in 70% of AITL cases, frequently in association with loss of function mutations in the Tet2 epigenetic regulator. Expression of Rhoa G17V in CD4+ T cells in a conditional Rhoaco-G17V/+ knockin mice induces TFH cell specification and increased proliferation. A pathogenic role for Rhoa G17V in cooperation with loss of Tet2 is demonstrated by the development of AITL in a CD4+ specific Rhoa G17V Tet2 knockout mice. However, the specific effector mechanisms driving TFH specification and T-cell transformation downstream of Rhoa G17V remain largely unknown. Here we demonstrate a novel role for Rhoa G17V as a modulator of signaling cascades initiated by sphingosine-1-phosphate (S1P), an important lipid mediator of lymphocyte trafficking. Specifically we show that expression of Rhoa G17V results in impaired S1P receptor internalization with the consequent up-regulation of S1P-dependent signaling pathways. In addition, and of potential therapeutic relevance, targeted inhibition of S1P signaling in Tet2-/-RHOA G17V mouse AITL cells induces apoptosis and reduces tumor load in vivo. In all, these results uncover a previously unrecognized role for S1P signaling downstream of Rhoa G17V in AITL tumor cell migration and survival, and support the role of S1P receptors as potential therapeutic target for the treatment of this disease.

Disclosures

No relevant conflicts of interest to declare.