bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neutropenic and Non-Neutropenic Fever In Diffuse Large B-Cell Lymphoma Patients Treated With Rituximab-CHOP Chemotherapy
Authors: Park Silvia , Kim Won Seog , Kim Seok Jin , Hong Jung Yong 
Published: October 2019

Abstract

Introduction
Rituximab-CHOP (R-CHOP) is the standard chemotherapy in DLBCL patients. Febrile neutropenia (FN) is the major toxicity of this regimen, but we also observe non-neutropenic fever (NNF) during the recovery period after R-CHOP.

Method
Between September 20089 and January 2013, a total of 1142 lymphoma patients were registered in the prospective cohort. Among these, 397 DLBCL patients who had completed R-CHOP based chemo cycles as first line treatment were analyzed.

Results
Of the 397 patients, 160 (40.3%) and 39 (9.8%) experienced FN and NNF, and 24 (6.0%) exhibited both. Approximately 50% of the initial FN occurred after the 1st cycle whereas NNF was mainly observed around the 4th cycle (28.2%). Including multiple FN occurrences in 65 patients (40.9%), there were 276 FN events in 160 patients. Besides unexplained fever (47.8%), catheter related infection was predominated (14.2%) and Coagulase negative staphylococcus was the most common microorganism causing bacteremia (27.7%). Thirty nine patients with NNF exhibited a total of 42 episodes and atypical pneumonia comprised the highest proportion (54.8%). Of the identified organisms causing atypical pneumonia, PJP was most common (n=4), adenovirus (n=3), RSV (n=2), and CMV (n=1) came next.

Conclusion
FN and NNF during R-CHOP treatment showed different clinical manifestation regarding their timing of initial episode and causes.

Disclosures:
No relevant conflicts of interest to declare.
Interferon-Alpha With Or Without Rituximab Achieves a High Response Rate and Durable Responses In Relapsed FL: 17 years’ Experience In a Single Centre
Authors: Radesi-Sarghi Sinziana , Arbion Flavie , Dartigeas Caroline , Delain Martine , Benboubker Lotfi , Herault Olivier , Colombat Philippe , Gyan Emmanuel 
Published: October 2019

Abstract

Background
Maintenance interferon-alpha (IFNa) immunotherapy after induction chemotherapy prolongs progression-free survival (PFS) in untreated follicular lymphoma (FL). Little information is available about IFNa use in relapsed FL.

Objectives
To evaluate the benefit of IFNa as treatment for low-burden FL relapse.

Methods
In this single-centre retrospective study, we analysed all patients with molecular or clinical relapsed low- burden FL who received 3MIU IFNa three times a week alone (16 times) or in combination with 4-weekly rituximab (R) (11 times), without chemotherapy, according to the institution’s policy. All responses were evaluated according to the IWG 1999 criteria, except for molecular relapses which are described separately.

Results
20 patients (13 men, 7 women), treated for a total of 27 times with IFNa were identified, with a median follow-up of 85 months. At diagnosis, 17 patients had advanced III-IV stage and 5 of them a high tumour burden, according to GELA criteria. 5 patients were treated for molecular IGH-BCL2 relapses. The FLIPI score was intermediate or high risk in 37% of patients. The median age of patients at the first IFNa +/- R treatment was 51 years (range: 30-65). Patients had previously received a median of three lines of treatment (range: 1-6) and 59% had received anthracycline-based chemotherapy. In the 22 situations with measurable disease, the overall response rate (OR) was 70%, with 59% complete responses (CR). For patients with only detectable molecular disease (n=5), IFNa was used alone for a median duration of 15 months (range: 12- 21 months), MRD becoming negative in 4 patients. The only factor significantly correlated with maximum response was low FLIPI score calculated at study entry (p=0.02). Median PFS was 56.9 months, (95% CI: 0.8-113). The R-IFNa and IFNa subgroup outcomes did not statistically differ in response or PFS. The FLIPI score calculated at initiation of IFNa treatment was predictive of time to relapse (P=0.014). The overall survival at 5 years was 95 % (95%CI: 91-99): 100% in the IFNa group and 91% (95%CI: 82-100) in the R-IFNa group. Reported toxicity was low.

Conclusion
Interferon alpha with or without rituximab achieve high response rates in relapsed low burden follicular lymphoma. These results compare favorably with previous reports of the efficacy of R alone, and of R with IFNa in relapse. Further research is required to explore the role of IFNa in the management of FL.

Disclosures:
Gyan: Roche: Research Funding.
Resistance To Vorinostat In Hematological Malignancies May Involve Cytoprotective UPR and Correlates With Increased Sensitivity To Bortezomib-Induced Cell Death
Authors: Dupéré-Richer Daphné , Kinal Mena , Pettersson Filippa , Miller Wilson H. 
Published: October 2019

Abstract
Histone deacetylase inhibitors (HDACi) have shown promising activity against hematological malignancies in clinical trials and have led to the approval of vorinostat for the treatment of cutaneous T-cell lymphoma. However, as with many cancer therapies, de novoresistance is common and acquired resistance inevitably follows sensitivity. This issue is particularly difficult to resolve in HDACi therapy, as the mechanism of action is still unclear and may involve several components.
Our objective was to understand the molecular mechanisms underlying resistance to HDACi in order to design better combination strategies and to identify predictive biomarkers for response to HDACi therapy.
To gain insight into HDACi resistance, we developed vorinostat-resistant clones using a dose escalation protocol in the monocytic-like, histiocytic lymphoma cell line U937 and the diffuse large B-cell lymphoma SUDHL6. Indeed, resistant cells grow in 4 µM vorinostat without induction of cell death. Using a variety of targeted drugs, we evaluated the lethal dose (LD)50in the resistant cells versus their parental counterpart in order to screen for potential pathways involved in resistance to vorinostat.
We found that the vorinostat-resistant cells are cross-resistant to other HDACi but not all. Interestingly, the resistant cells exhibit increased sensitivity toward bortezomib, an inhibitor of the proteasome and to chloroquine, an inhibitor of autophagy. Both these drugs target protein processing, suggesting its importance in driving resistance to HDACi. We found that, in addition to elevated autophagy, vorinostat-resistant cells exhibit marks of ER stress, such as dilated ER when visualized by electron microscopy. Moreover, resistant cells have an increased protein synthesis rate and an accumulation of ubiquitinated proteins compared to their parental counterparts. Consistent with this, we observe activation of the UPR in the resistant cells.
We hypothesized that activation of UPR could be a mechanism of vorinostat resistance, because the UPR induces the upregulation of pro-survival genes and may induce autophagy. Understanding vorinostat resistance holds clinical relevance in terms of improving HDACi therapy and being able to identify subsets of patients who would benefit most from combination therapy, such as vorinostat with bortezomib.

Disclosures:
No relevant conflicts of interest to declare.
Evaluation Of Large Granular Lymphocytes and Endothelial-Cell-Related Biomarkers In Patients With Chronic Myeloblastic Leukemia: Comparison Among 3 TKIs
Authors: Ito Tomoki , Uoshima Nobuhiko , Maeda Yasuhiro , Hotta Masaaki , Yoshomura Hideaki , Fujita Shinya , Satake Atsushi , Ishii Kazuyoshi , Urase Fumiaki , Hayashi Kunio , Nomura Shosaku 
Published: October 2019

Abstract

Background
Tyrosine kinase inhibitors (TKIs) currently represent the main therapy for chronic myeloblastic leukemia (CML). Although they are therapeutically effective, some TKI-related events such as pleural effusion and elevation of large granular lymphocytes (LGL) have been reported. In addition, these events itself may affect the therapeutic response to TKIs. In the present study, we measured the levels of some cytokines, chemokines, soluble factors and coagulation markers in patients with CML, and investigated the relationship between these markers and TKI-related events.

Methods
The subjects were 48 patients with CML. Blood samples were collected and levels of cytokines (interleukin (IL)-6, tumor necrosis factor-α, high-mobility group box 1), chemokines (monocyte chemotactic protein (MCP)-1, RANTES), soluble molecules (soluble vascular cell adhesion molecule-1, soluble E-selectin, angiopoietin-2, vascular endothelial growth factor, and soluble thrombomodulin) and coagulation markers (plasminogen activator inhibitor (PAI)-1, platelet-derived microparticles (PDMP)) were measured by ELISA.

Results
Levels of all markers except IL-6 and MCP-1 were significantly increased in patients with de novo CML. Level of LGL/lymphocyte was significantly higher in dasatinib-treated CML patients compared to other TKI-treated patients. LGL/lymphocyte and many biomarkers exhibit the time-dependent increase after dasatinib treatment. In addition, LGL/lymphocyte was already increasing in patients with pleural effusion before dasatinib treatment.

Conclusion
These results suggest that LGL and endothelial-cell-related factors play an important role in the pathophysiology of CML and its response to TKIs.

Disclosures:
No relevant conflicts of interest to declare.
Identification Of Mutations In Bcr-Abl Gene In Newly Diagnosed Indian Patients With Chronic Myelogenous Leukemia (CML)
Authors: Shyam Aggarwal , Verma Binuja , Vyas Bijal , Jauhri Mayank 
Published: October 2019

Abstract

Background & Objectives
Mutations in Bcr-Abl gene is responsible for resistance after Imatinib treatment in 30-60% of the cases. Currently the data does not support testing for these mutations in Imatinib naïve cases. However there is a data emerging that suggest that base line mutations in the Bcr-Abl gene do exist even before Imatinib is started, especially in patients with high SOKAL score. In India the failure rate of Imatinib is higher in comparison to western literature because patients are detected for CML chronic phase (CP) at a later stage. This study was designed to identify mutations in Abl-KD in Indian CML patients with no previous exposure to tyrosine kinase inhibitor.

Methods
This study targeted a cohort of CML-CP patients (n=47) without prior TKI exposure. KD mutations were analyzed by direct sequencing.

Results
A total of 47 samples were evaluated, out of which 2 samples were identified to have the same variation. This heterozygous missense variation (A206D) in the Abl1 gene was located on SH2 domain of Exon 4. The change was from C>A in codon 206, which caused a protein change from Alanine to Aspartic acid (p.A206D). By using the mutation taster software, this change was predicted to be disease causing with a high probability of .99 (∞1). One of the patients died within one year of diagnosis in spite of imatinib treatment.

Interpretation & conclusion
A novel mutation with putative pathogenicity was identified in the TKI-naïve Indian CML patients, supporting the concept that naturally occurring KD mutations are present in leukemic cell prior to drug exposure.

Disclosures:
No relevant conflicts of interest to declare.
Real World Analysis Of Duration Of TKI Treatment Among Patients With Chronic Myeloid Leukemia
Authors: Henk Henry J , Woloj Mabel , Shapiro Mark , Whiteley Jennifer 
Published: October 2019

Abstract

Background
Chronic myeloid leukemia (CML) accounts for 10-15% of all adult leukemias in the US. CML treatment has improved in the past few years with the introduction of imatinib in 2001, which has improved overall survival in patients with CML. Despite its success, there remains a subset of individuals who are either imatinib-resistant or imatinib-intolerant. With the approval of 2nd generation TKIs (dasatinib, nilotinib) beginning in 2006, approximately 40–50% of imatinib-resistant and imatinib-intolerant patients achieve complete cytogenetic response (CCyR) when switching TKI. Few studies have estimated duration of TKI use since the approval of 2nd generation TKIs. The objective of this study is to explore current treatment patterns of TKIs by line of therapy in the US.

Methods
U.S. health plan claims data from 01 January 2007 through 31 December 2011 were used to examine duration of TKI treatment by line of therapy for patients with CML aged 18 and older. Patients were required to have a prescription fill for a TKI and a CML diagnosis (ICD-9-CM code 205.1). Duration of TKI use was determined based on a gap in TKI coverage of 180 or more consecutive days following TKI initiation or switch to another TKI within the 180 day window. To account for censoring due to disenrollment for the health plan or end of the study period, median duration of 1st and 2nd line treatment is estimated via the Kaplan-Meier estimator.

Results
We identified 695 who started TKI treatment and had diagnosis for CML from 2007 through 2011. More than half (58%) were male; mean age was 55 years (SD 14 years). The most common first line TKI was imatinib (82%) with dasatinib and nilotinib use equally distributed (9%). Of patients starting a 2nd line TKI, dasatinib represented 59% and nilotinib 37% (Table).
Since 2007, the median duration of 1st line TKI was 39 months and 2nd line TKI was 22 months. Median duration of treatment for 1st line (p=0.4342) and 2nd line treatment (p=0.1762) were not significantly different by TKI (Figure). Among those who initiated 2nd line TKI, the majority were switched from imatinib to dasatinib or nilotinib (86%). Mean time to switch was 12 months and did not differ when switching from imatinib to dasatinib or nilotinib (p=0.7233).

Conclusions
Duration of TKI therapy is an informative measure as it is a proxy measure of treatment effectiveness as well as patient adherence, which is important to maintain optimal therapeutic outcomes. Among CML patients, we found median duration of treatment in both the 1st and 2nd line to be similar by TKI.

Disclosures:
Henk: OptumInsight: Employment. Woloj:Pfizer Inc.: Employment. Shapiro:Pfizer Inc.: Employment. Whiteley:Pfizer Inc.: Employment.
Erosion Of The Chronic Myeloid Leukemia Stem Cell Pool By PPARγ Agonists
Authors: Prost Stephane , Relouzat Francis , Spenchian Marc , Massonnet Gérald , Beressi Jean-Paul , Verhoeyen Els , Maneglier Benjamin , Castaigne Sylvie , Chomienne Christine , Chretien Stany , Rousselot Philippe , Leboulch Philippe 
Published: October 2019

Abstract

Whether cancer is maintained by a small number of stem cells or is composed of proliferating cells with approximate phenotypic equivalency is a central question in cancer biology. In the stem cell hypothesis, relapse after treatment may occur by failure to eradicate cancer stem cells. The chronic myeloid leukemia (CML) is quintessential to this hypothesis. CML is a myeloproliferative disorder that results from dysregulated tyrosine kinase activity of the fusion oncoprotein BCR-ABL. During the chronic phase, this sole genetic abnormality (chromosomal translocation Ph1+: t(9;22)(q34;q11)) at the stem cell level causes increased proliferation of myeloid cells without loss of their capacity to differentiate. Without treatment, most patients progress to the blast phase when additional oncogenic mutations result in a fatal acute leukemia made of proliferating immature cells. Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that target the kinase activity of BCR-ABL have improved patient survival dramatically. However, fewer than 10% of patients reach the stage of complete molecular response (CMR), defined when BCR-ABL transcripts become undetectable in blood cells3. Failure to reach CMR results from the inability of TKIs to eradicate quiescent CML leukemia stem cells (LCSs). Here we show that the residual CML LSC pool can be gradually purged by the glitazones, antidiabetic drugs that are agonists of peroxisome proliferator-activated receptor gamma (PPARg). We found that activation of PPARg by the glitazones decreases expression of STAT5 and its downstream targets HIF2α and CITED2, which are key guardians of CML LSC's quiescence and stemness. When pioglitazone was temporarily given to three CML patients in chronic residual disease in spite of continuous treatment with imatinib, all of them achieved sustained CMR, up to 4.7 years after withdrawal of pioglitazone. This suggests that clinically relevant cancer eradication may become a generally attainable goal by combination therapy that erodes the cancer stem cell pool.

Disclosures:
No relevant conflicts of interest to declare.
A Murine Model Of Hemorrhagic Shock/Resuscitation Demonstrates Transfusion Related Acute Lung Injury (TRALI) Induced By Stored Platelet Transfusions
Authors: McKenzie Christopher G.J. , Kim Michael , Safavian Dana , Rotstein Ori D , Semple John W. 
Published: October 2019

Abstract
Transfusion related acute lung injury (TRALI) is one of the leading causes of transfusion fatalities. There have been several animal models of TRALI developed including ex vivo lung models demonstrating the importance of human anti-neutrophil antibodies in TRALI and in vivo transfusion models showing how biological response modifiers can induce recipient lung damage. In addition, an in vivo antibody-mediated TRALI model has also been established and has shown close similarities with human TRALI. Most of the animal models have a two-hit paradigm where the first hit is delivered in the form of a noxious substance such as lipopolysaccharide and the second hit is a transfusion of either a blood product or an antibody. Here we describe a novel clinically relevant two-hit model where the first hit is hemorrhagic shock followed by a second hit in the form of a platelet transfusion. Severe combined immunodeficient (SCID) mice were anesthetized and had half of their total blood volume was removed via a carotid cannula to instigate hypovolemic shock. After one hour of shock, the mice were reperfused with either Ringer’s lactate solution or fresh or three day aged platelets. 34-1-2s, a monoclonal anti-mouse MHC class I antibody known to induce TRALI was used as a positive reperfusion control. Two hours following reperfusion, the mice were sacrificed and blood was obtained via cardiac puncture in order to measure serum levels of the neutrophil chemoattractant macrophage inflammatory protein-2 (MIP-2). Lungs were removed to determine the percentage of accumulated neutrophils and to measure edema. Compared with control mice reperfused with Ringer’s lactate solution or mice administered fresh platelets, serum MIP-2 levels in mice administered with three day aged platelets were significantly elevated and were comparable to those observed in mice infused with 34-1-2s. Pulmonary neutrophil accumulation in the mice transfused with 3 day stored platelets was also elevated to levels observed in 34-1-2s treated mice. Pulmonary edema as measured by lung Wet/Dry ratios was elevated in mice receiving the 3 day aged platelets. In vivo administration of a MIP-2 antagonist (SB225002, 4mg/kg) intraperitoneally immediately before reperfusion significantly reduced all TRALI symptoms. These results show that an animal model of hypovolemic shock exhibits TRALI upon reperfusion with stored platelets and is dependent on MIP-2 production. This clinically-relevant model will be valuable in studying potential therapeutic interventions to prevent TRALI following transfusions,

Disclosures:
No relevant conflicts of interest to declare.
Calcineurin Inhibitor-Free GVHD Prophylaxis with Post-Transplant Cyclophosphamide and Brief-Course Sirolimus Results in Low Rates of Non-Relapse Mortality and Chronic GVHD Following Matched Related and Unrelated Donor Peripheral Blood Stem Cell Transplantation (PBSCT)
Authors: Sanacore Melissa , Bashey Asad , Sizemore Connie A. , Holland H. Kent , Morris Lawrence E. , Brown Stacey , Zhang Xu , Solomon Scott R. 
Published: October 2019

Abstract
Calcineurin inhibitors (CNIs) form the foundation of current GVHD prophylaxis regimens. Although advances in immunosuppressive regimens have had a significant impact on the incidence and severity of acute GVHD, it is noteworthy that CNIs have had little impact on chronic GVHD. We hypothesized that a CNI-free regimen consisting of post-transplant cyclophosphamide (Cy) and brief-course sirolimus would decrease the risk of chronic GVHD and non-relapse mortality and improve outcomes following reduced intensity allogeneic PBSCT. Twenty-seven patients with high risk hematologic malignancies were enrolled in the study: median age 61 years (25-73). All patients had a 10/10 locus matched donor; MRD=18, MUD=9. Conditioning consisted of fludarabine 30mg/m2 on days -9 to -6, IV busulfan 130 mg/m2 on days -5 to -4, and Cy 14.5 mg/kg on days -3 and -2 followed by unmanipulated PBSCT. Post-grafting immunosuppression consisted of Cy 50 mg/kg/day on days 3 and 4 and sirolimus starting day +5 and completing day+90 in the absence of GVHD. Donor engraftment occurred in all patients with a median time to neutrophil and platelet recovery of 15 and 30 days, respectively. The median day +90 donor T cell and myeloid chimerism was 94% (40-100%) and 100% (11-100%) respectively. Three patients received donor lymphocyte infusions for incomplete donor T cell chimerism. The cumulative incidence of grade II-IV acute GVHD, grade III-IV acute GVHD, all chronic GVHD, and severe chronic GVHD was 41%, 15%, and 32%, and 12% respectively. Non-relapse mortality (NRM) and relapse incidence at 2 years was 4% and 17% respectively. With a median follow-up of 18 months, the estimated 2 year overall and disease-free survival was 71% and 80% respectively for the whole cohort, while it was 87% and 89%, respectively in the subgroup of 18 patients receiving MRD transplants. Good immune reconstitution was evidenced by low cytomegalovirus reactivation rates, occurring in only 4 of 19 at-risk patients (21%). Transplant-related toxicity included BK virus-associated cystitis in 33% of patients and a non-fatal hepatotoxicity syndrome in three patients consisting of transaminase elevation and ascites, with resolution following discontinuation of sirolimus. CNI-free GVHD prophylaxis with post-transplant Cy and brief-course sirolimus achieves consistent donor engraftment, low rates of GVHD and NRM, and excellent outcomes in recipients of HLA-identical donor allogeneic PBSCT.

Disclosures:
Off Label Use:fludarabine, cyclophosphamide, and sirolimus are not FDA-labeled for stem cell transplantation.