bluuebunny/crossref_metadata_2025_split huggingface dataset:
Haploidentical Second Allogeneic Hematopoietic Stem Cell Transplantation for the Treatment of Acute Leukemia Relapse after First Allo-HSCT: A Retrospective Registry Analysis of 60 Patients on Behalf of the German Cooperative Transplant Group
Authors: Christopeit Maximilian , Tischer Johanna , Bornhäuser Martin , Uharek Lutz , Pfrepper Christian , Behre Gerhard , Niederwieser Dietger , Kröger Nicolaus , Rösler Wolf , Klein Stefan A. , Beelen Dietrich , Hausmann Andreas , Bethge Wolfgang , Schmid Christoph 
Published: October 2019

Abstract
Background: Relapse of acute leukemia (AL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is frequently treated with 2nd allo-HSCT. Donor change has not yielded a significantly different outcome over choosing the original HLA-identical donor (Christopeit et al., JCO 2013). Using a haploidentical donor at second allo-HSCT might represent a feasible option (Tischer et al., BMT 2014)
Study design and population: To define the role for second haploidentical allo-HSCT for AL relapsing after 1st allo-HSCT, a retrospective analysis was conducted 63 consecutive patients (female n=30, male n=33; AML n=51, ALL n=12) from 9 German centers were included. Median age was 40 years (range, 16-65). Grafts at 1st allo-HSCT were from matched related (32%), matched unrelated (33%), mismatch unrelated (18%), haploidentical donors (6%), and other donors, including cord blood (8%). Median duration of complete remission (CR) after 1st allo-HSCT was 414 days (range, 18-1633). Relapse was initially treated by cytoreductive chemotherapy in all cases; stage at start of conditioning for haploidentical second allo-HSCT was CR in 27%, active disease in 66% and not evaluated in 8%. Conditioning for second HSCT was myeloablative/reduced in 14%/86% To overcome the HLA barrier, 23 patients (36%) received ex vivo T-cell depletion (TCD), following either CD3/CD19 negative or CD34 positive selection. 4 patients received in vivo TCD only, two received no TCD at all, and 35 patients (55%) received high-dose cyclophosphamide post-transplant according to the Baltimore protocol.
Results: Neutrophil engraftment was achieved after a median of 12 days (range, 8-26). 50 patients (78%) achieved CR after 2nd haploidentical allo-HSCT, out of which 23 (46%) relapsed again. After a median follow-up of 425 days, 47 patents had died, 22 from leukemia, and 25 from treatment-related causes. Kaplan-Meier estimated overall survival at one and two years from haploidentical second HSCT was 41+/-6% and 19+/-6%.
Conclusions: Haploidentical second allo-HSCT is a promising approach to the treatment of AL relapse after first allogeneic transplant. OS rates at least comparable to alternative treatments were observed. Different strategies to overcome the HLA barrier seem feasible. This retrospective study was registered as NCT01997918 at clinicaltrials.gov.
Maximilian Christopeit and Johanna Tischer as well as Wolfgang Bethge and Christoph Schmid contributed equally to this work.

Disclosures
No relevant conflicts of interest to declare.
Phagocytic Function of Macrophages Is Impaired By Chronic Lymphocytic Leukemia and high–grade Lymphoma Progression and Can be Highly Effectively Restored for Chemo-Immunotherapy
Authors: Schwamb Janine , Reinart Nina , Vorholt Daniela , Ulas Thomas , Ristovska Vangica , Braun Christian J , Hemann Michael T , Schultze Joachim , Hallek Michael , Pallasch Christian P. 
Published: October 2019

Abstract
Macrophage polarity has recently been shown to play a pivotal role in progression and prognosis of human malignancies. In CLL the high dependence of the malignant cell to the tumor microenvironment has revealed macrophages as major mediators of leukemia cell survival. In contrast, macrophage activation also offers novel therapeutic strategies for leukemia cell targeting. Here we analyze the reciprocal relationship of leukemia cells and macrophages and the specific functional impact of phagocytosis in leukemia progression and therapy.
We employed the humanized hMB-Lymphoma and the Eµ-TCL1 CLL mouse model. Thioglycollate-induced macrophages, bone marrow derived murine macrophages and human monocyte derived macrophages were used for in vitroevaluation of phagocytosis either by bead based approaches or by ADCC.
Applying gene-expression profiling of macrophages in Eµ-TCL1 mice we could identify profound transcriptional alterations indicating a re-programming during leukemogenesis. Functional genomic analysis particularly revealed impaired phagocytic function induced during leukemia onset. In vivo and ex vivo phagocytosis assays of primary macrophages showed a significant reduced phagocytic activity during CLL progression. Human macrophages in co-culture with CLL cells in vitro compared to healthy B-cells similarly showed defects in phagocytosis. In the humanized leukemia model we similarly observed impaired phagocytosis resulting in resistance towards therapeutic antibody/macrophage mediated therapy. Resistance was actively induced by increasing leukemia cell infiltration in the bone marrow. Impaired macrophage function could be identified being mediated by secretory crosstalk such as release of PGE2 by leukemia cells and Cholecalciferol. We could restore phagocytic function by combination regimens involving therapeutic antibodies and chemotherapy. Specifically, an acute secretory activating phenotype (ASAP), releasing cytokines from leukemia cells induces macrophage infiltration and phagocytic activity in the bone marrow. Thus, malignant cells can be effectively targeted by modulation of macrophage polarization and function.
In conclusion, we have identified decreased phagocytic activity of macrophages as key functional aspect in leukemia and lymphoma associated macrophages. Inversely, enhancing phagocytosis rendered essential for the re-sensitization of refractory niches treatment towards monoclonal antibodies defined by macrophage polarity. Overall macrophage function represents a key therapeutic target in CLL and other B-cell malignancies.

Disclosures
No relevant conflicts of interest to declare.
In Vitro and in Vivo Imaging of Initial T-B Cell Interactions in the Setting of B Cell-Based Cancer Immunotherapy
Authors: Wennhold Kerstin , Klein-Gonzalez Nela , von Bergwelt-Baildon Michael , Shimabukuro-Vornhagen Alexander 
Published: October 2019

Abstract
In recent years, there has been a growing interest in the use of B cells for cellular immunotherapy, since B cell-based cancer vaccines have yielded promising results in preclinical animal models. Contrary to dendritic cells (DCs), we know little about the migration behavior of B cells in vivo. Therefore, we investigated the interactions between CD40-activated (CD40) B cells and cytotoxic T cells in vitro and the migration behavior of CD40B cells in vivo.
The dynamic interactions of human antigen-presenting cells and antigen-specific T cells were observed by time-lapse videomicroscopy. The migratory and chemoattractant potential of CD40B cells was analyzed by flow cytometry and standard transwell migration assays. GFP+ CD40B cells or CD40B cells isolated from Luciferase+mice were used for subsequent in vivo studies.
Murine CD40B cells show similar migratory and chemotactic characteristics compared to human CD40B cells. Upon CD40-activation, B cells upregulate the important molecules involved in lymh node homing (CD62L, CCR7/CDCR4), which are functional and induce chemotaxis of T cells in vitro. Striking differences were observed for interactions of human CD40B cells or DCs with T cells. Antigen-loaded CD40B cells differ from immature and mature DCs by displaying a rapid migratory pattern undergoing highly dynamic, short-lived (7.5 min) and sequential interactions with cognate T cells. In vivo, CD40B cells migrate to the spleen and the lymph nodes, where they enrich in the B cell zone before traveling to B cell/ T cell boundary close to the T cell zone.
CD40B cell interactions with T cells are dynamic and short-lived and thereby differ from DCs. Taken together, the migration behavior of CD40B cells and their interaction with T cells underline their potential as cellular adjuvant for cancer immunotherapy.

Disclosures
No relevant conflicts of interest to declare.
Conversion of Danger Signals into Cytokine Signals By Hematopoietic Stem and Progenitor Cells for Regulation of Stress-Induced Hematopoiesis
Authors: Zhao Jimmy L. , Ma Chao , O'Connell Ryan , Mehta Arnav , Wang Jun , Seet Christopher S. , Crooks Gay M. , Rao Dinesh S. , Heath James , Baltimore David 
Published: October 2019

Abstract
Mammals respond to infection by rapid production of innate immune cells. Hematopoietic stem and progenitor cells (HSPCs) have the ability to respond to pathogens directly through toll-like receptors. However, how the pathogen sensing ability of HSPCs may contribute to immune cell output remains unknown. Using a novel single-cell proteomic platform and mouse genetic models, we have shown that in response to toll-like receptor stimulation, short-term HSCs and multipotent progenitor cells produce copious amounts of diverse cytokines through NF-κB signaling. Interestingly, the cytokine production ability of HSPCs trumps mature immune cells in both magnitude and breadth. Among cytokines produced by HSPCs, IL-6 is a particularly important regulator of myeloid differentiation and HSPC proliferation. This is especially important in mediating rapid early myeloid cell recovery during neutropenia after chemotherapy or HSC transplant. This study has uncovered an important property of HSPCs that enables them to convert danger signals into versatile cytokine signals for the regulation of stress-induced hematopoiesis. To translate these findings into human hematopoietic system, we have recently developed a human cytokine chip and our preliminary analysis suggests that purified human bone marrow HSCs also have the capacity to secrete cytokines.

Disclosures
No relevant conflicts of interest to declare.
Concomitant Systemic and Neuro-Meningeal Non-Hodgkin’s Lymphoma: The Role of Consolidation with Intensive Chemotherapy and Autologous Stem Cell Transplantation. a Retrospective Study of 65 Cases
Authors: Damaj Gandhi , Ivanoff Sarah , Coso Diane , Ysebaert Loic , Choquet Sylvain , Houillier Caroline , Abarah Wajed , Marjanovic Zora , Garidi Reda , Diouf Momar , Gac anne Claire , Dupuis Jehan , Morschhauseur Franck , Ghesquieres Herve , Soussain Carole 
Published: October 2019

Abstract
Purpose
To determine the characteristics of Non-Hodgkin’s lymphoma (NHL) patients with concomitant systemic and central nervous system localization at diagnosis, as well as the impact of consolidation with high dose chemotherapy followed by hematopoietic stem cell rescue on outcome
Patients and Methods
Newly diagnosed NHL patients with concomitant systemic and cerebral or meningeal involvement at diagnosis have been included in this study. Patients were retrieved from the database of the participating centers of the LYSA and LOC study groups
Results
Sixty-five patients (37 males; 28 females) were included. Median age was 60 years (23-85). Histological subtype was mainly diffuse large B-cell lymphoma (n=54; 83%). The IPI was >2 in 43 (66%) patients. LDH level was elevated in 27 (55%) patients. Median number of extranodal positive sites was 2 (1-5) and bone marrow involvement was documented in 30 (46%) patients. CNS involvement was documented in 51 patients. Paravertebral and epidural compressive mass with (n=5) or without (n=2) CSF involvement were present. Five patients had both CNS and peripheral nervous system involvement. Anthracycline-based chemotherapy with high dose metothrexate with or without cytarabine was the most chemotherapy used. Autologous stem cell transplantation was performed in 21 patients in response. BEAM (n=9) or thiotepa-based (n=9) conditioning regimen was the most intensive chemotherapy used before autologous SCT
Post-chemotherapy ORR was 77%(CR69%;PR8%). 3-year overall survival (OS) and progression free survival (PFS) were 48±7% and 46±7% respectively. The consolidation strategy using high dose chemotherapy and autologous stem cell transplant positively impacted patient’s outcome. For the whole group as well as for patients ≤65 years, the 3-year OS and PFS were (77%vs29%;p=0.002) and (77%vs25%;p=0.001) and (75% vs 37%;p=0.002) and (75%vs32%;p=0.007) respectively.
In multivariate analysis and for the whole group of patients, the absence high dose therapy had a negative impact on 3-year OS and PFS [p=0.003;HR=5.05[1.76-14.49]) and PFS by [p=0.002;HR=5.46(1.91-15.26)] respectively. This is remained true for younger patients 65 years or less who had poorer 3-year OS [p=0.036;HR=3.41 (1.08-10.75)].
Conclusion
First line consolidative high dose therapy followed by autologous SCT in patients with systemic and neuro-meningeal NHL improve patient’s outcome

Disclosures
No relevant conflicts of interest to declare.
Ibrutinib Enhances the Anti-Tumor Immune Response Induced By Intratumoral Injection of a TLR9 Ligand
Authors: Sagiv-Barfi Idit , Kohrt Holbrook , Burckhardt Laura , Czerwinski Debra K , Levy Ron 
Published: October 2019

Abstract
We have designed a novel approach for treating tumors utilizing a combination of active immunotherapy and targeted kinase inhibition. We injected tumors with unmethylated CG-enriched oligodeoxynucleotides (CpG), an agonist for the toll like receptor 9 (TLR9). This in situ CpG injection resulted in local tumor eradication by NK cells and macrophages but on its own was not able to induce a systemic anti-tumor immune response. Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (Btk), a key enzyme in the signaling pathway downstream of B Cell receptor (BCR) is now known to also inhibit ITK, a key enzyme in the survival of Th2 T cells. By doing so, it can shift the balance to the more effective Th1 immune response.
In our murine model, the combination of in situ injection of CpG and systemic treatment with Ibrutinib resulted in eradication of tumor cells not only in the local site but also at distant sites. This anti-tumor immune response required both CD4 and CD8 T cells as the effect was lost in nude, scid and T cell depleted mice. Additionally, transferred T cells from animals previously treated with CpG and Ibrutinib protected na•ve mice from tumor challenge.
This immune-enhancing effect of Ibrutinib is unexpected. It reflects on the mechanism of action of the drug against B cell malignancies and it provides a novel way of enhancing anti-tumor immune responses against other types of cancer.
Figure 1 Figure 1.
A. six to eight weeks BALB/C mice were inoculated with 1x106 H11 cells s.c. into the right and left sides of their abdomen, tumor growth was monitored with a digital caliper. Therapy was started when tumors reached a size of 0.7-1cm in the largest diameter, CpG (100µg/injection) was given intratumorally to the left tumor every day in days 1-5, Ibrutinib (6mg/kg) was given daily, intraperitonealy (IP) on days 1-8. B. Growth curve of the right (non-treated) tumor C. Mice survival D. Mice at day 4 after treatment.

Disclosures
No relevant conflicts of interest to declare.
Cytoskeleton Regulator PAK4 Plays a Role in Growth and Survival of Myeloma with a Potential Therapeutic Intervention Using PAK4 Allosteric Modulators (PAMs)
Authors: Fulciniti Mariateresa , Bandi Rajya Lakshmi , Amodio Nicola , Cagnetta Antonia , Senapedis William , Baloglu Erkan , Anderson Kenneth C. , Munshi Nikhil C. 
Published: October 2019

Abstract
P21-activated serine/threonine kinase 4 (PAK4) is a major effector of Cdc42 and is essential for cytoskeleton reorganization. PAK4 is activated in cancer cells, promotes cell migration and anchorage-independent cell growth, and protects against apoptosis induction. With cellular migration playing a significant role in multiple myeloma (MM) cell growth and survival, we investigated the expression and subcellular localization of PAK4 in MM cells. We observed a high level of un-phosphorylated PAK4 in the cytoplasm and high levels of phosphorylated PAK4 in the nucleus. In a gain-of-function study, over-expression of PAK4-eGFP in PAK4-deficient MM cells (RPMI8226) significantly increased cell proliferation and survival. Conversely, in a loss-of-function study, conditional knock-down of PAK4 expression with TRIPZ-lentiviral vectors decreased MM cell proliferation and survival proportionally to the reduction in PAK4. With a significant impact of PAK4 on MM cell growth, we identified a class of orally bioavailable PAK4 allosteric modulators (PAMs; e.g. KPT-6604, -7189, -7657, -8752). We observed inhibition of MM cell growth and survival after treatment with PAMs even in the presence of bone marrow microenvironment. In addition, there is a significant correlation between PAK4 expression and the inhibition concentration (IC50s) of PAMs in proliferation assays. Moreover, inhibition of PAK4 induced receptor and mitochondrial-mediated apoptotic pathways via Caspase-3, -8, and -9 activation. PAMs had no significant effect on normal PBMCs, suggesting a favorable therapeutic index in MM treatment. Finally, in two murine models of human myeloma, orally bioavailable KPT-8752 given daily was able to inhibit tumor growth in vivo and prolong overall survival. In summary, PAK4 plays an important cellular and molecular function in myeloma and its inhibition with a new class of PAK4 allosteric modulators provides a novel therapeutic approach for the treatment of MM.

Disclosures
Senapedis: Karyopharm: Employment. Baloglu:Karyopharm: Employment. Anderson:Celgene: Consultancy; Sanofi-Aventis: Consultancy; Onyx: Consultancy; Acetylon: Scientific Founder, Scientific Founder Other; Oncoprep: Scientific Founder Other; Gilead Sciences: Consultancy.
Effects of Monoclonal Gammopathy of Undetermined Significance (MGUS) on Outcomes after Solid Organ Transplant
Authors: Goebel Teresa E , Schiltz Nicholas K , Pillai Aiswarya Chandran , Caimi Paolo , Koroukian Siran M , Woodside Kenneth J , Campagnaro Erica L 
Published: October 2019

Abstract

Background:
MGUS is a precancerous condition which can progress to multiple myeloma (MM) or other hematologic malignancy. MGUS increases the risk of developing MM approximately 25-fold, and increases lifetime risk of infection, venous thromboembolism (VTE), and skeletal related events (SRE). Solid organ transplant requires immunosuppression, which is associated with overlapping risks, including hematologic malignancy such as post transplant lymphoproliferative disease (PTLD). Hypothesizing that MGUS would further increase risk of PTLD and other complications after transplant, we described risk of these outcomes in patients with MGUS prior to solid organ transplant (MGUS+) compared to those without MGUS (MGUS-).
Methods:
We used the 2005-2011 California State Inpatient, Emergency, and Ambulatory Databases. MGUS and complications were identified by ICD-9 diagnosis codes, and solid organ transplant by ICD-9 procedure codes. Patients with the ICD-9 diagnosis code 273.1 documented on or before the day of solid organ transplant surgery were defined as MGUS+. We used logistic regression to analyze complications in MGUS+ versus MGUS- transplant patients.
Results:
Of 24,358,669 patients, we identified 22,062 solid organ transplant patients. Transplant patients were 8.8% African American, 29.5% Hispanic, 43.4% White, 15.1% other, and 3.2% had data missing. 72 were MGUS+ prior to solid organ transplant. Median age of MGUS+ was 61.5 years versus 51 years for MGUS-. Outcomes are shown in table 1.
Table 1. Transplant Patients Outcome MGUS + N=72 MGUS – N=21,990 Odds Ratio (95% CI) PTLD 0 161 n/a MM ≤10 37 34.90 (12.11, 100.61) Lymphoma 0 193 n/a VTE 20 3,202 2.26(1.35, 3.79) SRE 18 2,320 2.83(1.66, 4.83) Infection 50 11,612 2.03(1.23, 3.36)
*Frequencies ≤10 are reported as such per the data use agreement.
Conclusions:
Compared to MGUS-, MGUS+ solid organ transplant patients had higher risk of VTE, SRE, and infection, but did not have higher risk of PTLD or other lymphomas. MGUS+ transplant patients are more likely to develop MM than MGUS-; however, this risk is similar to that historically attributed to MGUS, in patients who have not undergone transplant. These data show increased risk of certain complications in MGUS+ patients, and do not support screening for MGUS to assess risk of PTLD prior to solid organ transplant.

Disclosures
No relevant conflicts of interest to declare.
The Benefit of FVIII Measurement: Tailored Treatment with Obi-1, a Recombinant Porcine Sequence Factor VIII, in Subjects with Acquired Hemophilia a
Authors: Oladapo Abiola , Epstein Joshua , Novack Aaron , Farin Heinrich D. 
Published: October 2019

Abstract

Introduction: A significant unmet need in the management of acquired hemophilia A (AHA) is a replacement therapy that can be used without consideration of anti-human FVIII titer and allows for the ability to measure FVIII levels. The ability to measure FVIII levels during treatment: (1) identifies treatment response and leads to the ability to individually tailor treatment; (2) reduces treatment safety concerns; and (3) optimizes the utilization of therapy during treatment to minimize cost impact. OBI-1 is a recombinant porcine sequence FVIII developed to meet this need.
Objective: To determine the impact of FVIII monitoring on OBI-1’s utilization during the treatment phase in the OBI-1 Phase 2/3 trial in AHA.
Methods: A post-hoc analysis of the utilization data from the prospective, open label, Phase 2/3 study of OBI-1 in AHA was conducted. Subjects were administered an initial dose of 200U/kg of OBI-1 and subsequent doses were based on subject’s post-infusion FVIII activity levels and clinical assessments. The impact of FVIII monitoring on OBI-1’s utilization was evaluated by comparing: (A) the initial administered dose to the subsequent doses infused in the treatment period; and (B) the initial total administered dose within the first 24 hours of treatment to the doses infused in the subsequent 24-hour period(s) in the treatment period. The magnitude and the statistical significance of the dose adjustment were determined using non-parametric statistics (signed rank test).
Results: Of the 29 subjects enrolled in the study, 65.5% (n=19) were males and median (range) age was 70 (42-90) years. Twenty-eight of the enrolled subjects had AHA while presence of anti-human FVIII titer could not be confirmed in the twenty-ninth subject. Of the subjects with AHA, 27 had a serious bleeding episode while one was enrolled for hemostatic cover for a planned surgery. Two subjects (7.1%) successfully responded requiring only the initial administered dose (100U/kg; 200U/kg). Two additional subjects were successfully treated within the first 24 hours. After the initial dose, subsequent doses indicated a median (IQR) dose reduction of 41.2% (50%) [n=26, p<0.01]. After the first 24-hour period, subsequent 24-hour periods showed a median (IQR) dose reduction of 65.4% (32.5%) [n=24, p<0.0001].
Conclusion: Study data indicate a significant reduction in the treatment dose after the initial dose or subsequent daily dosing after the first 24 hours. The ability to measure and monitor FVIII activity levels allow for the tailoring of OBI-1’s treatment dose and regimen. This measurability likely has a significant impact on dosing decisions to control the bleed.

Disclosures
Oladapo: Baxter Healthcare Corporation: Employment. Epstein:Baxter Healthcare Corporation: Employment. Novack:Baxter Healthcare: Employment. Farin:Baxter Healthcare: Employment.