bluuebunny/crossref_metadata_2025 huggingface dataset:
Possible Factors on Efficacy and Safety of CAR-T Therapy in Relapsed or Refractory Aggressive B-Cell Lymphoma
Authors: Huang Haiwen , Jiang Yibin , Jin Zhengming , Li Caixia , Wu Depei
Published: October 2019

Background:

Recent advances have improved the treatment of B-cell malignancies, but patients who have disease resistant to primary or salvage treatment or who relapse after transplantation have an extremely poor prognosis. Studies of chimeric antigen receptor T-cell (CAR-T) therapy have shown high response rates and long response duration in refractory B-cell lymphomas after the failure of conventional therapy, which suggest that this therapy may be potentially curative. To explore the possible factors on efficacy and safety of CAR T-Cell therapy in relapsed or refractory aggressive B-cell lymphomas, we conducted the clinical trial of CAR-T Cell Treating Relapsed/Refractory B-cell lymphomas (NCT03196830).

Methods:

From March 2017 to April 2018, 25 patients were enrolled into our clinical trial. According to the surface expression of tumor cells by either flow cytometry or immunohistochemistry, different targets of CAR T-cells were infused, ionly anti-CD19 (n=11), sequential infusion of anti-CD22 and anti-CD19 (n=8), and sequential infusion of anti-CD20 and anti-CD19 (n=6). Patients received conditioning treatment (low-dose cyclophosphamide, 300 mg/m² per day, and fludarabine, 30 mg/m² per day) on days -5, -4, and -3 before the administration of autologous CAR T-cells. The primary endpoint was the proportion of patients with an objective response. Secondary endpoints included safety and biomarker assessments.

Results:

Among the 25 patients who were enrolled, response was successfully evaluated

for 24. The objective response rate was 75%, and the complete response rate was 33%. With a median follow-up of 3.2 months, 54% of the patients continued to have a response, with 25% continuing to have a complete response. Grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 24% and 16% of the patients, respectively. One of the patients died during treatment. Serum biochemical index analysis confirmed the associations of peak serum interleukin-2, -6, -10, INF-γ, ferritin, C-reactive protein (CRP) concentrations and the level of lactate dehydrogenase (LDH) before therapy with the grade 3 or higher CRS, as well as peak serum interleukin-6, -10, INF-γ, CRP, ferritin and the level of LDH before therapy with grade 3 or higher neurologic events.

Conclusion:

Our study demonstrates the efficacy and safety of CAR-T therapy relapsed or refractory aggressive B-cell lymphoma. The level of LDH before therapy was higher in patients who developed grade 3 or serious CRS, which suggest that we should improve safety by reducing tumor burden before CAR T-cells infusion. Due to the small number of enrolled cases, no significant improvement of efficacy was observed, this result needs to be further confirmed by expanding the number of study cases.

Figure. Figure.

Disclosures

No relevant conflicts of interest to declare.
Omalizumab: Efficacy and Safety in Mast Cell Disorders
Authors: Lemal Richard , Fouquet Guillemette , Terriou Louis , Vaes Mélanie , Livideanu Cristina , Frenzel Laurent , Barete Stéphane , Canioni Danielle , Lhermitte Ludovic , Bay Jacques-Olivier , Rossignol Julien , Arock Michel , Lortholary Olivier , Hermine Olivier
Published: October 2019

Background. Patients with mast cell diseases may suffer from various distressing symptoms, which can be insufficiently controlled with available therapies, severely affecting quality of life. There is thus a need for new and safe treatment options for these patients.

Objectives. We aimed to evaluate safety and efficacy of omalizumab administration in patients with a systemic mast cell disorder.

Methods. We included 56 patients with a systemic mast cell disorder who received omalizumab treatment between January 2015 and December 2017, after a pluridisciplinary review at the French National Reference Center for Mastocytosis (CEREMAST).

Results. A complete response was achieved for 1 patient (1.8%), a major response for 30 patients (53.6%) and a partial response for 12 patients (21.4%), resulting in an overall response rate of 76.8% (43/56 patients). The response was persistent at least 3 months in 33 patients (58.9%). Median time to first response was 2 months and median time to best response was 6 months. Omalizumab was dramatically effective on all superficial and general vasomotor symptoms and on most gastrointestinal or urinary symptoms, and partially effective on most neuropsychiatric symptoms (Figure 1). Safety profile was acceptable, except for one severe adverse event (cervical edema and dyspnea after the first injection of omalizumab). Side effects were reported in 16 patients (28.6%), mainly of low to mild intensity, yet causing interruption of treatment in 6 patients (10.7%).

Conclusion. Omalizumab is an effective treatment option in systemic mast cell disorders, and displays a favorable safety profile. Prospective studies remain necessary to confirm these encouraging results.

Disclosures

No relevant conflicts of interest to declare.
Retrospective Observational Study from the Experience in Our Center of the Employment of Daratumumab in Multiple Myeloma
Authors: Morente Constantin Estefanía , Romero Garcia Pablo , Garcia-Ruiz Maria Almudena , Rios Rafael , Clavero Sanchez Esther , Jurado Manuel
Published: October 2019

INTRODUCTION

Daratumumab is an anti-CD38 monoclonal antibody which is a recent success in the treatment of multiple myeloma (MM). It binds to the CD38 protein, which is highly expressed in MM tumor cells.

It is indicated in monotherapy in patients with relapsed MM, being refractory to treatment and having previously received a proteasome inhibitor and an immunomodulatory agent, with progression of the disease since the last treatment.

It can also be used, as stated recently in its data sheet, in combination with Lenalidomide and Dexamethasone or Bortezomib and Dexamethasone for the treatment of patients with MM who have received at least one previous treatment. It is being tested in combination with other drugs, which shows its enormous potential.

OBJECTIVES

We expose the experience with this drug in our center in recent years.

MATERIALS AND METHODS

We have evaluated patients treated with Daratumumab, recording: demographic data, previous number of lines of treatment, use in monotherapy or combination, date of initiation of treatment, response to it, date of suspension (if it occurred) and its cause, as well as total duration of the treatment (figure 1 and 2).

RESULTS

We studied 12 patients, 6 men and 6 women, treated with Daratumumab between 2016 and 2018. The average age is 63.75 years (range between 57 and 72).

On average, it was used in the 4th line of treatment, ranging between 2 cases in which it was the 2nd and 1 in which it was the 7th. In all patients, it was used in monotherapy.

Currently, 3 out of the 12 patients are still being treated with Daratumumab and they are in remission (objectified by PET-CT in 1 patient with only 4 months of treatment). 2 other patients are in partial remission (with 23 and 4 completed months of treatment, respectively). It was necessary to suspend the drug in 8 patients, in 7 cases due to progression of the disease. The remaining patient suffered, in the 1st administration, an adverse reaction of type III that was refractory to the symptomatic treatment and to the decrease of the infusion rate, which forced to withdraw the drug.

In 4 cases, the drug was discontinued and the result was "stable disease", so it remained until progression was evidenced. The average maintenance of the drug until progression was 4 months, ranging between 2 and 6 months. In the remaining 3 patients the disease progressed, so the drug was discontinued.

CONCLUSIONS

The MM treatment has to be individualized and adapted to the risks. The data obtained from our patients indicate that Daratumumab is a potentially valuable drug among the therapeutic arsenal against this pathology. However, we believe that the results would be much better if the treatment is started in earlier lines.

Disclosures

Rios: Amgen, Celgene, Janssen, and Takeda: Consultancy.
Reconstituted Bay 81-8973 Factor VIII Stability Supports Its Suitability for Continuous Infusion for up to 24 Hours
Authors: Teare John M. , Trefethen Jared , Garger Stephen , Mathew Prasad
Published: October 2019

Continuous infusion (CI) is used in many treatment centers as an option at the time when patients with hemophilia A undergo major surgical procedures. Benefits of CI versus bolus infusion (BI) of factor VIII (FVIII) in patients undergoing surgery include avoiding unnecessarily high peaks and low troughs of FVIII levels and reducing FVIII consumption during and after surgery, partially due to decreased clearance. Stability and long-term potency of FVIII products under CI conditions have been shown to exhibit variability. Thus, it is important to demonstrate stability for each product used in CI applications.

BAY 81-8973 (Kovaltry®, Bayer, Berkeley, CA) is an unmodified, full-length recombinant human FVIII product with a primary amino acid sequence identical to that of sucrose-formulated recombinant FVIII (rFVIII-FS; Kogenate® FS, Bayer). rFVIII-FS was shown previously to be stable in solution for up to 7 days, to be safe and effective for CI during surgery, and to be suitable for pediatric and adult patients. The present study investigated whether BAY 81-8973 has adequate potency and purity up to 24 hours after reconstitution, which may indicate suitability for CI applications.

BAY 81-8973 drug product in 250-IU and 500-IU vial sizes was tested 0, 4, 8, 12, and 24 hours after reconstitution with sterile water for injection and storage at room temperature in 30-mL polypropylene syringes (BD Plastipak™, BD, Franklin Lakes, NJ). The drug product was tested for potency (chromogenic assay), purity (high performance liquid chromatography - size exclusion chromatography [HPLC-SEC]), total protein content, pH, solution clarity, and subvisible particulates (high accuracy liquid particle counting - subvisible particles [HIAC-SVP]).

There were no changes in potency, pH, clarity, aggregation, chain dissociation, subvisible particles, or total protein with either 250- or 500-IU BAY 81-8973 for up to 24 hours. Results were also consistent with the demonstrated safety and efficacy of rFVIII-FS for CI during surgery. These data indicate that BAY 81-8973 may be suitable for CI applications for up to 24 hours.

Disclosures

Teare: Bayer: Employment. Trefethen:Bayer: Employment. Garger:Bayer: Employment. Mathew:Bayer: Employment.
Phosphatidylinositol-3,4-Bisphosphate-Akt Signaling Pathway Promotes Platelet Activation
Authors: Marjanovic Jasna , Rumancik Brad , Weber Luke , Wangmang Felix , Fickes Dane , Postnov Dmitri , Nguyen Dung , Lee Yoon , Ngo-Lam Richard , Wilson Monita
Published: October 2019

Phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P2) is a messenger that accumulates in platelets in a phosphoinositide 3-kinase and platelet aggregation-dependent manner. PtdIns(3,4)P2 is broken down by inositol polyphosphate 4-phosphatases, type I (INPP4A) and type II (INPP4B). These enzymes do not catalyze hydrolysis of phosphoinositides other than PtdIns(3,4)P2, and therefore provide unique means for studying the role of this lipid in platelet activation. We have found that the dominant isoform of 4-phosphatases expressed in platelets is INPP4A and we have generated radiation chimera mice with the deficiency in INPP4A restricted to hematopoietic cell lineage. Compared to wild type platelets, agonist-stimulated INPP4A-deficient platelets accumulated higher levels of PtdIns(3,4)P2. An increase in platelet aggregation in INPP4A-deficient platelets was observed with all tested agonists. To study platelet function in vivo, we performed carotid artery injury mouse thrombosis model experiments. Time to occlusion was dramatically reduced in mice with INPP4A deficiency. These data support the hypothesis that by regulating PtdIns(3,4)P2 levels, INPP4A downregulates platelet aggregation and thrombus formation. To investigate mechanisms mediating INPP4A-dependent signals, we compared levels of phosphorylated Akt and phosphorylated glycogen synthase kinase (GSK) in wild type and INPP4A-deficient platelets in response to agonist stimulation. An increase in phospho-Akt levels was observed in INPP4A-deficient platelets, suggesting that in addition to its well-characterized regulator, PtdIns(3,4,5)P3, PtdIns(3,4)P2 can promote Akt activation. Interestingly, this was not accompanied by a significant increase in phospho-GSK levels, suggesting a possible novel mechanism involved in platelet aggregation.

Disclosures

No relevant conflicts of interest to declare.
A Novel Recombinant Eklf-GATA1 Fusion Protein Reduces Sickling of Cultured Mouse Erythrocytes
Authors: Zhu Jianqiong , Li Hongzhen , Aerbajinai Wulin , Kumkhaek Chutima , Chin Kyung , Rodgers Griffin
Published: October 2019

β-hemoglobinopathies are inherited disorders caused by mutations/deletions in the β-globin chain that lead to structurally defective β-globin chains or reduced (or absent) β-globin chain production. These diseases affect multiple organs and are associated with considerable morbidity and mortality, representing a major public health challenge. Current gene therapy approaches for the treatment of hemoglobinopathies involve viral transduction of hematopoietic stem cells with antisickling globin genes. Hemoglobin A2 (HA2, α2δ2), expressed at a low level due to the lack of Eklf binding motif in its promoter region, is fully functional and could be a valid anti-sickling agent in sickle cell disease, as well as a substitute of hemoglobin A in β-thalassemia. We had previously demonstrated that two Eklf-GATA1 fusion proteins could significantly activate δ-globin expression in human CD34+ cells. Here we report the effects of Eklf-GATA1 on hemoglobin expression and phenotypic correction using erythrocytes cultured from mouse hematopoietic progenitor cells with sickle cell disease. We found that enforced expression of Eklf-GATA1 fusion protein enhanced globin gene expression in the erythrocytesas compared with vector control. The long-form Eklf-GATA1 up-regulated β-globin gene expression 1.8-fold, δ-globin gene expression 3.3-fold, and γ-globin gene expression 1.7-fold. The medium-form EKLF-GATA1 up-regulated δ-globin gene expression 2.6-fold and γ-globin 1.3-fold, but had no significant effect on β-globin gene expression. HPLC revealed a percentage of HA2 was increased from 2.1 % in vector-transduced cells to 8.9% in medium-form Eklf-GATA-transduced-cells (p<0.01) and 6.3% in long-form Eklf-GATA-transduced-cells (p<0.01). Upon deoxygenation, the percentage of sickling erythrocyte was lower to 30.6% in medium-form Eklf-GATA-transduced cells as compared with 40.7% in vector-transduced-cells (p<0.05). Flow cytometry analyses of CD71/GPA and thiazole orange staining indicated that erythroid cell differentiation and enucleation were not affected by Eklf-GATA1. ChIP-sequencing analysis has demonstrated that Eklf-GATA1 fusion proteins and GATA1 having a similar protein-DNA binding pattern at a global level. Our results have found that the long form Eklf-GATA1 fusion protein has a major effect on δ-globin induction than β-globin; the medium form Eklf-GATA1 is able to elevate δ-globin expression without having an effect on β-globin expression. The above findings indicate that these fusion constructs could be a valuable genetic therapeutic tool for hemoglobinopathies, and warrant further preclinical study and evaluation.

Disclosures

No relevant conflicts of interest to declare.
Tigit Expression Defines a Subset of Activated Treg Cells with Prognostic Relevance in Follicular Lymphoma
Authors: Yang Zhi-Zhang , Kim Hyo Jin , Jalali Shahrzad , Wu Hongyan , Price-Troska Tammy , Ansell Stephen M.
Published: October 2019

T cell Ig and ITIM domain (TIGIT) is an immune checkpoint molecule that is expressed on a variety of cell types including NK cells, effector and memory T cells, and Treg cells. Upon ligation with CD155, TIGIT delivers an inhibitory signal and negatively regulates anti-tumor responses. While important in normal T-cell biology, the pathological significance of TIGIT expression and function in the tumor microenvironment of the patients with follicular lymphoma (FL) is largely unknown. The present study sought to phenotypically and functionally characterize TIGIT+ T cell subsets in FL. While its expression is not detected on resting T cells in peripheral blood, we found that TIGIT is highly expressed on intratumoral T cells from FL. Treatment with cytokines such as IL-4 and TGF-β downregulated TIGIT expression on T cells. We found that TIGIT is predominantly expressed on effector memory T cells (TEM) with an activation/exhausted phenotype, and TIGIT+ T cells have higher expression levels of CD69 and PD-1 when compared to TIGIT- T cells. Functionally, TIGIT+ T cells displayed reduced capacity of cell proliferation and cytokine production (IFN-γ and IL-2). Using mass cytometry (CyTOF), we observed that TIGIT is abundantly expressed on some intratumoral Treg (CD4+CD25+Foxp3+) cells, while other Treg cells lack TIGIT expression in FL, forming two subsets of Treg cells: CD4+CD25+TIGIT+ and CD4+CD25+TIGIT-. These two subsets are phenotypically distinct in that CD25+TIGIT+ cells exhibited increased expression of activation/costimulatory markers such as CD69, CD27 and CD28 compared to CD25+TIGIT-, suggesting an activated Treg subset of CD25+TIGIT+ cells. This CD25+TIGIT+ subset had increased suppressive function and could more effectively inhibit activation and proliferation of CD8+ T cells than CD25+TIGIT- cells. Furthermore, we found that lymphoma B cells promoted the development of TIGIT-expressing T cells as TGF-β-mediated downregulation of TIGIT on T cells was inhibited when CD19+ lymphoma cells were present. Using a cohort of 31 FL patients, we found that intratumoral TIGIT-expressing T cells were associated with a favorable prognosis. Patients with TIGIT+ T cell numbers greater than 50% had better overall survival than patients with TIGIT+ T cell numbers less than 50%. Taken together, our results reveal a role of TIGIT in defining Treg cell subsets with different immune function and TIGIT expression may be useful in predicting patient outcome in FL.

Disclosures

Ansell: Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Merck & Co: Research Funding.
Effect of Metabolic Reprogramming on the Biological Activity of Acute Myeloid Leukemia Cells
Authors: Liu Tongyuan , Li Dengju , Zhou Jianfeng
Published: October 2019

ABSTRACT

Metabolic reprogramming of acute myeloid leukemia (AML) cell lines has been described as a compensatory adaptation to fulfill their energy requirements for its rapid proliferation. In this study,we examined the role of the glutamine (Gln) removal or inhibition of glutaminase by GLS inhibitor bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol- 2-yl) ethyl sulfide(BPTES) in AML cell lines SKM-1 to Observe whether it has an effect on the biological activity of SKM-1 cells. Our results indicated that inhibit glutamine uptake or utilization can inhibit cell growth and induce apoptosis in AML. we used Long non-coding RNAs (LncRNAs) Gene Microarray to analyze gene expression after Gln deprivation treatment. We found that the expression of MT2A, MT1X, MT3, MT1H, MT1F and MT1E in the metallothionein (MT) gene family was significantly upregulated and the expression of AGT、CSF1R、PAK7、MYCN、ARG1 was significantly downregulated . We further analysed the expression of MT isogenes by quantitative real-time PCR (RT-PCR). The results showed that the gene expression of the MT gene family was upregulated, consistent with the results of the Gene Microarray. These findings indicate that metallothionein may play an important role in the glutamine metabolic pathway of AML cells. metformin, a commonly used antidiabetic drug, play an important role in Glucose Metabolism.We observed that Metformin alone exhibited a dose-dependent anti-leukemic activity in SKM-1 cell lines and its anti-leukemic activity was enhanced when used in combination with Gln deprivation or Cytarabine. These findings show that Gln deprivation or Metformin enhance the sensitivity of SKM-1 cell line to chemotherapeutic agents. Taken together , targeting amino acid metabolism and glucose metabolism are promising new therapeutic strategies to enhance the efficacy of chemotherapeutic agents in AML.

Conflict of interest

No relevant conflicts of interest to declare.

Acknowledgments:

Tongyuan Liu analyzed the data, plotted the tables and figures and wrote the paper; Dengju Li designed projects and revised the paper. This work was supported by the National Natural Science Foundation of China (Grant no. 81770168).

Disclosures

No relevant conflicts of interest to declare.
Nonbiological Factors Affecting Outcomes in Adolescent and Young Adults with Lymphoma
Authors: Xavier Ana C. , Costa Luciano J
Published: October 2019

Background: Lymphoma is one of the most common cancers in adolescent and young adults (AYA). Although histology, stage, age, and gender are known to affect outcome, little is known about nonbiological factors (NBF) that may affect access to care on survival.

Objectives: To determine the impact of NBF in the survival of AYA with classical Hodgkin lymphoma (cHL) or non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), lymphoblastic lymphoma (LL), and anaplastic large cell lymphoma (ALCL).

Design/Methods: The impact of NBF (insurance status, median household income, and educational achievement in the county of residence) along with biological factors (histology, stage, gender, age, and race/ethnicity) on survival of AYA lymphoma patients was analyzed using a SEER-18 (Surveillance, Epidemiology, and End Results) cohort diagnosed between 2007 and 2014.

Results: There were 8,173 cases of cHL and 4,973 cases of NHL with a median follow-up of 44 months and 32 months, respectively. Five-year overall survival (OS) for AYA patients with localized cHL according to insurance status was 98% vs. 91% vs. 92% for insured, Medicaid, and uninsured patients, respectively (P < 0.001). The 5-year OS for advanced stage cHL was 91.5% vs. 85% vs. 85% for insured, Medicaid, and uninsured patients, respectively (P < 0.001). In multivariate analysis, the increase risk of death was associated with Medicaid (HR 2.23, 95% C.I. 1.76-2.81), and uninsured (HR 1.88, 95% C.I. 1.38-2.55), after adjustment for age, gender, histology and stage (P<0.001). Five-year OS for AYA patients with localized NHL according to insurance status was 90% vs. 76.5% vs. 84.5% for insured, Medicaid, and uninsured patients, respectively (P < 0.001). The 5-year OS for advanced stage NHL was 76% vs. 57%, and 62% for insured, Medicaid, and uninsured patients, respectively (P < 0.001). In multivariate analysis, the increased risk of death in AYA NHL was associated with Medicaid (HR 1.95, 95% CI 1.67-2.27), and uninsured (HR 1.48, 95% CI 1.18-1.84) (P<0.001) and county level of income in the second (HR 1.33, 95% C.I. 1.07-2.64), third (HR 1.54, 95% C.I. 1.25-1.90), and forth (HR 1.57, 95% C.I. 1.27-1.93) (P< 0.001) lower quartiles (P<0.001), after adjustment for age, gender, histology, and stage.

Conclusion: Lack of insurance or Medicaid insured status and lower income are associated with increased mortality in AYA lymphomas, indicating an opportunity to increase outcomes by addressing NBF.

Disclosures

Costa: Karyopharm: Research Funding; Amgen: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Research Funding; Sanofi: Honoraria; BMS: Research Funding.
Prognostic Value of Serum Beta-2 Microglobulin during and after Completing Chemotherapy in Marginal Zone Lymphoma
Authors: Yoon Byung Woo , Hong Jung Yong , Yoon Dok Hyun , Lee Kyoung Min , Kim Shin , Park Jung Sun , Park Chan-Sik , Huh Jooryung , Park Chan-jeoung , Jang Seongsoo , Ryu Jin-Sook , Lee Sang Wook , Suh Cheolwon
Published: October 2019

Background Baseline serum beta-2 microglobulin (B2M) has been suggested as a prognostic factor for marginal zone lymphoma (MZL). However, there have been no reports on the prognostic value of sequential serum B2M during and after chemotherapy. Herein, we retrospectively reviewed sequential values of serum B2M: baseline (B2Mb), maximum during chemotherapy (B2Mm), end of chemotherapy (B2Me), and the first increased value after completing chemotherapy (B2Mfi).

Methods Between January 2000, and June 2018, a total of 94 patients with MZL treated with rituximab, cyclophosphamide, vincristine, and prednisolone (R-CVP) were identified from the database of Asan Medical Center, Seoul, Korea. Respective serum B2Ms less than 2.5 mg/L were considered normal. The cutoff value for differences between serum B2Mb and sequential values of serum B2M were calculated by using the optimal point from the receiver operating characteristic curve.

Results Median age of the study population was 55 year-old (range, 10-83) and 54 (57%) patients were male. Fifteen (16%) patients had nodal MZL, 76 (81%) had extranodal MZL and 3 (3%) had splenic MZL. In univariate analysis, serum B2Mb and B2Mfi above 2.5 mg/L were associated with poor prognosis with a hazard ratio (HR) of 2.3 (95% confidence interval (CI): 1.1-4.9; p=0.024) and a HR of 3.3 (95% CI: 1.6-7.0; p=0.001), respectively. In addition, the difference between serum B2Mb and B2Mfi greater than the optimal cutoff value of 0.6 mg/L (area under curve=0.58) was also associated with poor prognosis, with a HR of 4.0 (95% CI: 1.9-8.3; p<0.001). In multivariate analysis, serum B2Mfi above 2.5 mg/L was the only independent adverse prognostic factor in terms of progression-free survival (PFS) with a HR of 4.0 (95% CI: 1.2-14.1; p=0.023). The median time of serum B2Mfi measurement was 5.6 months from the end of chemotherapy (range, 0.5-25.1 months).

Conclusion To the best of our knowledge, this is the first report of measuring sequential serum B2M, starting from baseline to its first rise after completing chemotherapy in MZL. In MZL patients treated with R-CVP, the first increased serum B2M above 2.5 mg/L after completing chemotherapy is a powerful prognostic factor for PFS.

Disclosures

No relevant conflicts of interest to declare.
Pediatric Langerhans Cell Histiocytosis (LCH) Clinical Outcome in Hospital Civil De Guadalajara, México
Authors: Rojas Rodríguez Katterine , Soto Veronica , Rodriguez-Galindo Carlos , Friedrich Paola M. , Guzmán Edwin , Sanchez Fernado , Gonzalez-Ramella Oscar
Published: October 2019

Pediatric Langerhans cell histiocytosis (LCH) clinical outcome in Hospital Civil de Guadalajara, México.

Introduction : LCH results from clonal proliferation of functionally and immunophenotyped inmature round Langerhans cells along with eosinophiles, machrophages, lymphocytes and ocasionally multinucleated giant cells (1). Its incidence is 2-10 cases by million of children below 15 yr in US (2). Our objective was to describe the clinical characteristics and treatment outcome of patients with LCH at Departement of Hematology-Oncology of Hospital Civil de Guadalajara México.

Methods: It was a retrospective design and 41 pediatric patients below 18 yr were included. The diagnosis was corroborated by pathology and immunohistochemistry. Variables as age, gender, localised vs systemic disease, risk organ commitment, global survival (GS) and event free survival (EFS) were analysed. We used descriptive and inferencial statistics with SPSS program.

Results: There were included 41 patients from January 1st 2012 to December 31st 2017. Relation male:female was 1.1:1. Mean presentation was localised disease (58%). Bone was the principal affected structure (34%) and it was 71% to be combined with lung, lymph node and CNS compromise. Risk organ commitment was presented in 32%, being more frecquent bone marrow and liver in 22% each one. Time induction treatment was equal or below 12 weeks in 66% of patients. The 25% of patients had reactivation of LCH, with similar lesions to the beggining in 19.5%. We found statistically significant differences between dead patients (DP) (14.6%) and not dead patients (NDP) (85.4%) in clinical presentation: localised (0% in DP vs 69% in NDP) and systemic disease (100% vs 31%) (p=0,003) and risk organ commitment (100% in DP vs 20% in NDP) (p=0,000). Median age of 13 vs 24 months was for DP and NDP respectively.

Conclusion: Dead patients were younger than 13 months old, with systemic disease, and risk organ commitment. We found a later asking of medical advice in DP (6 months) vs NDP (2 months).

Keys words: langerhans cell histiocytosis, multisystem disease, risk organ

Figure. Figure.

Disclosures

No relevant conflicts of interest to declare.
Can Childhood Hodgkin International Prognostic Score Mitigate Interim Positron Emission Tomography and Predict Survival of Children with Hodgkin Lymphoma in Resource Limited Countries?
Authors: Khedr Reham , Mahfouz Sally , Fathy Hoda , Shalaby Lobna
Published: October 2019

Background & aim: Although 'interim' positron emission tomography (PET) may inform therapeutic decisions, Risk stratification at diagnosis allow earlier and potentially better modification during the treatment of HL. In this study, we aimed to identify the prognostic role of both the IPET and the CHIPS in predicting the prognosis of HL in our center. Patients and methods: This is a retrospective, single-center study done at the National Cancer Institute (NCI) Cairo University starting January 2011 to the end of December 2015. A total of 140 patients with newly diagnosed Hodgkin lymphoma were enrolled for analysis of all clinical, pathological and Laboratory Data. Only 83 patients were eligible for analysis of both IPET and CHIPS scoring. PET scan was performed at baseline and after two cycles of chemotherapy. Treatment was not changed according to the results of the interim scan. Childhood Hodgkin International Prognostic Score (CHIPS), was evaluated. Log-rank testing was used to compare EFS for each CHIPS (0-3). Results: Eight three scans out of 140 patients were eligible for analysis of both IPET and CHIPS scoring. Twenty-six patients were scored positive (31.3%) and 57 (68.7%) as negative. The 5- years overall survival (OS) was 94%, 83% for patients with interim positive scans and 97% for patients with interim negative scans (P 0.01). The 5-year Event-free survival (EFS) rate was 86.7% for the whole study population, 76% for patients with interim positive scans and 91% for patients with interim negative scans (P 0.04). The 5 year OS was 100% for patients with CHIPS = 0, 80.4% for patients with CHIPS = 1, 75% for patients with CHIPS = 2, and 100% for patients with CHIPS = 3 (a very limited number of patients), with a p-value of (0.055). Hemoglobin level </= 10) and initial Total Leucocytic count(</= 15,000) were independent prognostic predictors; OS P- value (0.003 and <0.001 ) respectively- and EFS P- value (0.03 and <0.001 ) respectively. Conclusion: The prognostic role and validity of using the interim PET scan response have been confirmed to be strongly related to treatment outcome by the present study; however, the use of CHIPS is a good inexpensive approach to predicting risk in patients with HL that may improve ability to tailor therapy to risk factors known at diagnosis. Other Variables including TLC as well as Hb level will need further larger studies to identify their impact.

Figure. Figure.

Disclosures

No relevant conflicts of interest to declare.
10-Day Low Dose Decitabine Regimen for Elderly Acute Myeloid Leukemia Patient Maintenance Treatment
Authors: Liu Jia , Peiyan Kong , Gao Li , Zhang Cheng , Liu Yao , Yan Hongju , Zhu Lidan , Gao Shichun , Lei Gao , Zeng Defu , Zhang Xi
Published: October 2019

Background

Acute myeloid leukemia (AML) is a malignant hematologic disease with high incidence in the elderly peoples. The median age of onset is 65 years. There is no standard chemotherapy regimen for elderly AML, especially for AML patients older than 70 years old. Six to eight courses of low-dose or reduced-dose chemotherapy were commonly used in clinical treatment. However, most patients. However, most patients relapsed within six months after chemotherapy. How to prolong the survival of elderly patients with AML is a realistic problem that needs to be urgently solved.

Patients and Methods

From Jan 2017 to May 2018, six elderly patients with AML in our center include in the study. The median age was 74 (70-78) years. According to cytogenetics and molecular mutation, 1 patient were favorable risk with t (8, 21) and AML1-ETO, 3 patients were intermediate risk with karyotype abnormality, and 2 patients were unfavorable risk with complex karyotype and FLT3-ITD mutation. One patient received complete remission (CR) after IA induce scheme, and then, he received 4 courses of DA regimen for consolidation therapy. At last, he stopped chemotherapy because of severe atrial fibrillation and heart failure. Other 5 patients treated with 4-8 courses of decitabine (Dec) +CAG or HAG regimen. Minimal residual disease (MRD) of four patients were negative and two patients were positive before include in the study. Six patiens were given 10-day low dose Dec regimen treatment (5mg/m2/day×10 days) for every six weeks, until AML progress.

Results

For 2 MRD positive patients, after 10-day low dose Dec regimen treatment, one patient MRD turn to negative, one patient MRD remained positive, and died after 4 months. Till Jul 2018 (median observation time 10 months), 5/6 patients remained CR and survival with better quality of life. the most common treatment-emergent adverse events (TEAEs) were related to hematocytopenia. The most significant reduction of blood cells was hypoleucocytosis, and mainly in the first 2 courses of G-Dec treatment.

Conclusion

Preliminary research shows 10-day low dose Dec regimen treatment has Significant effect and mild side effect on the survival of elderly AML patients. The multicenter, randomized controlled clinical study will conduct to further verify its effectiveness and safety.

Disclosures

No relevant conflicts of interest to declare.
Lncrna RP1-68D18.2 Promotes K562 Cell Line Resistance to Imatinib through CD44 and Its Downstream Signal Molecules
Authors: Yan Tianyou , Gong Yuping
Published: October 2019

As the first-generation tyrosine kinase inhibitor specifically targeting the BCR-ABL oncoprotein, imatinib has been successfully used in the therapy for chronic myelogenous leukemia (CML) with a significant response and good compliance. However, imatinib resistance becomes the main reason for failure of the treatment of CML. In addition to the common BCR-ABL dependence of imatinib resistance, e.g. BCR-ABL kinase domain mutations and BCR-ABL gene amplification, BCR-ABL independence also plays important roles, which involves alteration of dynamics of drug import and efflux, persistent or compensatory activation of signaling pathways etc. Recently, several studies have reported the correlation of lncRNA with resistance of chemotherapeutic drugs in many cancers. Here, we report, for the first time, discernible overexpression of lncRNARP1-68D18.2 and CD44 mRNA in the imatinib resistant chronic myelogenous leukemia cell line K562R, using lncRNA and mRNA microarray, and further verify it using qPCR. Knockdown of RP1-68D18.2 in K562R cell lines increased their sensitivity to imatinib, and simultaneously caused a decrease in CD44 and c-Myc protein levels. Correspondingly, overexpression of RP1-68D18.2 in K562, a sensitive cell line, led to a slightly decrease in imatinib sensitivity and partially reverse downregulation of c-Myc, p-ERK and p-MEK caused by imatinib treatment. Analysis of correlations revealed positive correlation between RP1-68D18.2 and CD44 mRNA expression in the primary CML blasts and hematological malignant cell lines. We conclude that overexpression of RP1-68D18.2 could promote imatinib resistance in the K562R cell line through the regulation of CD44 and its downstream signal molecules.

Disclosures

No relevant conflicts of interest to declare.
hnRNP K: A Regulator of Global Transcription and Translation That Drives Lymphomagenesis
Authors: Malaney Prerna , Gallardo Miguel , Hornbaker Marisa J , Zhang Xiaorui , Link Todd , Shah Vrutant , Alybayev Sanzhar , Wu Meng-Han , Pageon Laura R , Ma Huaxian , Jacamo Rodrigo , Yu Li , Xu-Monette Zijun Yidan , Steinman Haley , Lee Hun Ju , Sarbassov Dos , Rapado Inmaculada , Barton Michelle , Martinez-Lopez Joaquin , Bueso-Ramos Carlos E. , Young Ken H. , Post Sean M
Published: October 2019

hnRNP K is an RNA binding protein that controls a multitude of cellular processes and is aberrantly expressed in cancers. We have previously shown that hnRNP K functions as a haploinsufficient tumor suppressor in AML patients with 9q deletions. However, overexpression of hnRNP K is the more commonly observed clinical phenomenon. We have recently discovered that hnRNP K overexpression in patients with diffuse large B-cell lymphoma correlates with dismal outcomes and directly resulted in the development of lymphomas in transgenic mice.

To understand the mechanistic basis for the oncogenicity of hnRNP K overexpression and to identify therapeutic vulnerabilities, we performed RNA-sequencing, RNA immunoprecipitation following by sequencing (RIP-Seq), mass spectrometry, and polysome assays. We observed that hnRNP K regulates both global transcription and translational processes within the cell via modulation of 7SK and translation initiation proteins (such as the eIFs and PABP), respectively. Consequently, we hypothesized that aberrant hnRNP K expression primarily perturbs oncogenes with short half-lives. Mechanistically, we identified that hnRNP K binds to the RNA and regulates the expression of a plethora of critical oncogenes and tumor suppressors involved in hematologic malignancies such as c-Myc, RUNX1, and Cyclin D1. As proof of concept for clinical applications, we have demonstrated that hnRNP K-driven c-Myc overexpression renders tumors susceptible to bromodomain inhibition.

Given that hnRNP K directs global transcription and translation, it is likely that hnRNP K overexpressing tumors will also be sensitive to transcriptional and translational inhibitors such as CDK9 inhibitors and omacetaxine mepesuccinate, respectively. However, since hnRNP K also regulates a plethora of additional cellular processes that extend far beyond mRNA and protein synthesis, there is a need to develop hnRNP K-specific inhibitors that will only target these activities. Thus, we have recently begun to identify small molecule compounds that can directly inhibit hnRNP K-RNA binding function on specific targets using an in vitro fluorescent binding assay. Using this assay, we are currently screening a library of 70,000 small molecule compounds to identify agents that can prevent hnRNP K-RNA interactions.

In summary, we have established that hnRNP K is a bona fide oncogene that drives lymphomagenesis. Global analyses have revealed therapeutic vulnerabilities of hnRNP K overexpressing tumors. Furthermore, using our in vitro RNA binding assays, we anticipate identification of novel hnRNP K-specific inhibitors.

Disclosures

No relevant conflicts of interest to declare.
Building Capacity for Relapsed/Refractory ALL Patients Needing CAR-T Cells: How Do We Prepare?
Authors: Khalife Roy , Montroy Joshua , Limvorapitak Wasithep , Broady Raewyn , Fergusson Dean , Atkins Harold , Holt Robert , Lalu Manoj , Kekre Natasha
Published: October 2019

Introduction: The prognosis of relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL) remains poor in adults. Response rates and survival following anti-CD19 chimeric antigen receptor (CAR) T-cells in r/r ALL have exceeded those of other available agents, but comparative studies are still lacking. Although this therapy shows great promise, it involves complex and expensive manufacturing and administration. Our study seeks to understand the response and survival outcomes of a cohort of Canadian patients with ALL treated with current standard therapies to help the Canadian health care system build capacity for anti-CD19 CART therapies for r/r ALL.

Methods: We conducted a retrospective chart review of all patients diagnosed with ALL at 2 large Canadian academic hospitals between 2010 and 2015 (Ottawa and Vancouver). All patient, therapy and outcome-based factors were extracted. Included patients were then cross-checked against the eligibility criteria for completed anti-CD19 CART cell trials in r/r ALL, but with an upper age cut-off of 75.

Results: 173 patients were diagnosed with ALL over a 5-year period, with median age of 50 (range 16-88). 159 (92%) patients had CD19 reported by flow cytometry, of which 141 were positive at diagnosis. 124 patients (72%) achieved complete remission with induction chemotherapy and 74 patients (43%) relapsed after a median of 11.8 months (range 1-85.6) from diagnosis, of which 29 patients (17%) experienced a second relapse. A total of 63 patients (36%) had an allogeneic stem cell transplant, of which 22 (13%) relapsed after transplant. Patients who relapsed at any point in time survived 5.4 months (range 0.2-55.4). A total number of 62 patients (35.8%) would have been eligible for currently approved anti-CD19 CAR T cell therapy. Reasons for ineligibility were not limited to remission status, but also included CNS involvement, previous solid malignancy, undocumented CD19 status or CD19 negativity, and evidence of kidney or liver dysfunction. The median event-free and overall survival for patients who would have been eligible for FDA-approved anti-CD19 CART cells were 10.3 months (range 0.4-52.3) and 17.3 months (range 0.4-72.6), respectively.

Conclusion: Anti-CD19 CAR T cell therapy has shown very promising results based on early phase data in patients with r/r ALL. Canadian patients are expecting this therapeutic option to be available soon, but our health care system needs to prepare for the complexity of this therapy. Our study helps provide "real-world" eligibility and outcomes of adult patients with r/r ALL. This data suggests that about one-third of cases of ALL could be eligible for this new therapy and should help centers build capacity according to how many new cases of ALL are seen per year.

Disclosures

No relevant conflicts of interest to declare.
Vitamin C Stabilizes CD8iTregs and Enhances Their Therapeutic Potential in Controlling GvHD and Leukemia Relapse
Authors: Iamsawat Supinya , Daenthanasanmak Anusara , Yu Xue-Zhong
Published: October 2019

Graft-versus-host disease (GvHD) remains a leading cause of non-relapse mortality after allogeneic hematopoietic cell transplantation (allo-HCT). The imbalance between T effector (Teffs) and regulatory cells (Tregs) is a defined characteristic of GvHD. Therefore, promoting Tregs for controlling GvHD has drawn an intense interest in preclinical and clinical studies of allo-HCT. Although CD4 Tregs (CD4+Foxp3+) have been shown to effectively prevent GvHD, they impaired graft-versus-leukemia (GVL) effect. Our lab has previously demonstrated that CD8 iTregs (CD8+Foxp3+) not only suppressed allogeneic T-cell responses, but also possessed the GVL activity themselves. However, instability of Foxp3 in CD8 iTregs is a major obstacle to translate this Treg population into clinic application.

Vitamin C has been reported to promote Foxp3 stability by accelerating its demethylation. In the current study, we asked whether vitamin C could stabilize CD8 iTregs and enhance their therapeutic potential in controlling GvHD. Addition of vitamin C in the culture significantly increased the generation of allo-reactive CD8 iTregs in vitro (Fig. 1A). These CD8 iTregs generated with vitamin C had strikingly increased demethylation on Foxp3 CpGs (Fig. 1B) and superior suppressive activity (data not shown) compared to control-treated CD8 iTregs. We further evaluated the capability of vitamin C-treated CD8 iTregs in preventing GvHD in allo-HCT. Using a MHC-mismatched murine BMT model, vitamin C-treated CD8 iTregs could significantly alleviate GvHD reflected by a marked reduction of recipient mortality (Fig. 1C) and clinical scores (data not shown).

To determine the Foxp3 stability in vivo, we analyzed the transferred CD8 iTregs and allogeneic Teffs in recipient spleens 7 days after allo-HCT. Vitamin C-treated CD8 iTregs (Ly5.2+) remarkably suppressed Teff (Ly5.1+) expansion and maintained higher Foxp3 expression compared to the control iTregs (Fig. 1D). To address a critical question whether vitamin C-treated CD8 iTregs can preserve the GVL activity, we performed a haploidentical transplant with a leukemia relapse model, and found that vitamin C-treated CD8 iTregs not only attenuated GvHD severity, but also prevented recipients from tumor relapse (Fig. 1E). In conclusion, our studies provide a rationale and mean to use stabilized CD8 iTregs with vitamin C for controlling GvHD and leukemia relapse in the clinic.

Disclosures

No relevant conflicts of interest to declare.
Bendamustine Conditioning Alters Host Dendritic Cell Composition and Function
Authors: Molina Megan Stanley , Stokes Jessica , Hoffman Emely , Katsanis Emmanuel
Published: October 2019

Background

A largely understudied strategy for reducing graft-versus-host disease (GvHD) is the modification of conditioning regimens. We have demonstrated that pre-transplant bendamustine (BEN) used in combination with total body irradiation (TBI) significantly reduces GvHD compared to the more commonly used cyclophosphamide (CY) + TBI. The short half-lives of BEN/CY (<4h), which are given 48h prior to transplant, indicate that these drugs do not directly affect the donor cells. Therefore, the striking improvement in GvHD by substituting CY with BEN must be due to differential effects on the host cells. Conditioned host immune cells diminish over time, but are the majority early after transplant and are able to critically interact with the infused donor cells at the earliest stages of GvHD pathogenesis.

Methods

Using an MHC-mismatched murine model of bone marrow transplantation (BMT) with C57BL/6 donors into BALB/c recipients (H2Kb into H2Kd), we evaluated the differential effects of BEN conditioning on host dendritic cells (DCs) early after transplant, as compared to CY conditioning. Transplant recipient mice were conditioned with BEN or CY on day -2 pre-BMT, and supplemented with 400cGy of total body irradiation on day -1. On days 1, 3, and 5 post-BMT, splenic pan-DCs were isolated and analyzed by flow cytometry to evaluate host (H2Kb-) DC phenotype and activation state. Further, on day 0 (without BMT), circulating leukocytes and splenic pan-DCs were isolated from conditioned mice and analyzed by flow cytometry, qPCR and allogeneic mixed leukocyte reactions.

Results

We found that BEN-conditioned pan DCs are less stimulatory of allogeneic T-cells than CY-treated DCs. BEN conditioning significantly alters host DC composition compared to CY conditioning, resulting in a significantly higher frequency and number of host CD8α+ DCs on days 1 and 3 post-BMT. BEN-conditioned CD8α+ DCs also display a highly regulatory phenotype (CD80highCD86low) and have greater suppressive ability compared to CY-conditioned CD8α+ DCs. Analysis of host DCs on day 0 (without BMT) revealed a significantly greater percentage of BEN-conditioned DCs positively expressing the Flt3 receptor compared to CY.

Conclusions

These findings advocate a potential role of Flt3L-dependent DCs, particularly CD8α+ DCs, in the mechanism by which BEN alters GvHD pathogenesis to limit morbidity and mortality. Thus, BEN may have advantages as an alternative agent to CY for pre-transplant conditioning in allogeneic BMT.

Disclosures

No relevant conflicts of interest to declare.