bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long Term Efficacy of Rituximab in B-Cell Post Transplantation Lymphoproliferative Disorders (B-PTLD): Update of the Multicenter, Open Label, Phase II Trial (M39037 TRIAL).
Authors: Choquet Sylvain , Herbrecht Raoul , Stoppa Anne-marie , Vandenberghe Peter , Feremans Walter , Morschhauser Franck , Salles Gilles Andre , Jaccard Arnaud , Lamy Thierry , Lebranchu Yves , Offner Philippe , Oksenhendler Eric , Raphael Martine , Leblond Veronique , Milpied Noel-Jean 
Published: October 2019

Abstract
Background:
B-PTLD is a rare but severe complication observed after organ transplantation. There is no consensus on treatment modalities in this setting but Rituximab monotherapy has been presented as an effective and well tolerated treatment. Long term efficacy is unknown.
Aim:
We recently published results of the first prospective study on PTLD treatment, using four weekly injection of Rituximab in progressive or non responding tumours after immunosuppression diminution (Blood2006; 107; 3053–7). We present here update results up to 6 years after inclusion.
Methods:
From may 2000 to December 2001, 43 PTLD after solid organ transplantation have been enrolled in M39037, a franco-belgian multicentric prospective trial. The primary end point was day 80 response rate and one year results were also presented. Participating centres were contacted in order to obtain update data on surviving patients at one year, especially for their tumour status (complete response (CR), partial response (PR) or progressive disease (PD)), date of last information, eventual death and cause of death.
Results:
At one year, on 43 included patients, 26 were still alive, 12 in CR or Cru, one in PR, 10 in PD and two with insufficient information. At this time, update data are available on eight patients, six were in CR or Cru at one year and two in PD. Five patients died by organ failure (n=1), graft rejection (n=1), sudden death (n=2) or heart biopsy complication (n=1); all but one were in CR at this time. Three patients are still alive and in CR. No relapse has been diagnosed and median survival is 1188 days (with a median follow up of 1689 days for surviving patients). Final analysis on all patients will be presented at the ASH meeting.
Conclusion:
Rituximab in monotherapy seems to have a durable efficacy on PTLD after solid organ transplantation with a follow up of more than 4,5 years. Complete results will be presented at the ASH Meeting.
Treatment of 22 Patients with Amyothrophyc Lateral Sclerosis, Grafting Stem Cells through Neuroendoscopy.
Authors: De Bellis Roberto , Cordoba Alvaro , Muxi Pablo J. , Bello Laura , Caneiro Ada 
Published: October 2019

Abstract
Introduction: experimental and clinical research have shown the plasticity of Stem Cell in varied conditions of tissular damage. Amyothrophyc Lateral Sclerosis (ALS) is a degenerative disorder, culminating in a respiratory insufficiency and death. We have designed a trial in order to implant stem cells, in the spinal cord and in the cerebrospinal fluid (CSF), through a neuroendoscopic procedure minimally invasive.
Material and Methods: 22 patients with ALS met the inclusion criteria for this study. Spirometry with forced expiratory volume and forced vital capacity ratio not inferior to 60% was required. All patients were measured with ALS function scale to settle an individual initial score. Peripheral blood stem cells were collected through a central venous catheter by a continuous flow apheresis equipment. CD34+ cells were tested and selected. In the operating room, the first step was to insert a spinal needle in the vertebral space between L4 – L5, to obtain 4 milliliters (ml) of CSF and to suspend 2 ml of stem cells in it, injecting the mixture in the subaracnoidal space. The second step was to locate the intervertebral space between D8 – D9 and to introduce percutaneously a flexible neuroendoscope to find the spinal posterior sulcus. Once 1 millimeter (mm) deep in the posterior side of the spine, 1 ml of concentrated stem cells were transplanted. After checking through the neuroendoscope, the graft is firmly attached, 2 ml of concentrated stem cells were injected in the perispinal space and the procedure was finished.
Results: 22 patients with ALS (17 males, 5 females); with an average of 57 years old (38 – 75); 27 months after diagnosis (8 – 36) were treated. The amount of CD34+ cells employed was 7.0×10–6 per kilogram (3.3 – 17.8). Periodically assessment of the evolution of the score points of the international ALS scale, revealed that 9 improved their initial scores, 11 kept the same condition with no progressive deterioration of their neurological performance and 2 decrease their neuromuscular status. In all cases a remarkable decrease of the neuromuscular fasciculations was observed.
Conclusions: The procedure was safe, feasible and easy to reproduce. No complications or morbility was observed. Improvement of the neurological condition was registered in 9 patients and stabilization of the progressive disease in other 11. In spite of the short follow up, we think it is an encouraging new approach for an up to now, always deadly disease.
Overexpression of Lipases Enables Specific Cytotoxicity by the Lipase Inhibitor Orlistat in Chronic Lymphocytic Leukemia Cells.
Authors: Pallasch Christian P. , Schwamb Janine , Schulz Alexandra , Debey Svenja , Kofler David , Schultze Joachim L. , Hallek Michael , Ultsch Alfred , Wendtner Clemens M. 
Published: October 2019

Abstract
Genome-wide gene expression profiling of chronic lymphocytic leukemia (CLL) cells in comparison to healthy donor CD5-positive B-cells revealed deregulated expression of lipase-associated genes. A set of 19 lipase activity defined genes, e.g. LPL, phospholipases A1, −A2, −C and −D2 family members and other lipase-associated genes were overexpressed in CLL. Recently lipoprotein lipase (LPL) was identified as prognostic factor in CLL. Here we show that the expression of LPL in CLL is induced by B-cell receptor (BCR) stimulus both in mutated and unmutated CLL samples. In native and BCR-stimulated CD5+ healthy B-cells no LPL-expression was detected. Antigenic stimulation via the BCR is thought to be functionally and prognostically relevant in CLL pathogenesis, LPL expression in CLL cells could reflect a permanent BCR-stimulus due to autoantigens including also unmutated IgVH cases.
We hypothesized that the overexpression of lipases and especially of LPL reveals a putative therapeutic target by lipase inhibition through the the FDA-approved obesity drug and lipase inhibitor orlistat (tetrahydrolipstatin), which is known to inhibit LPL as well. Treatment of CLL cells with orlistat in vitro revealed significant cytotoxicity and induction of apoptosis in primary CLL cells with an IC50 of 5.48 μM (n=18). In comparison, no significant cytotoxicity was seen with healthy PBMC’s (n=12; p<0.001), even using high doses of orlistat up to 100 μM. Induction of apoptosis induction was observed both in low-risk (ZAP70 negative, n=15) and high-risk (ZAP70-positive, n=10) CLL samples. Orlistat mediated cytotoxicity was slightly decreased by BCR stimulus while additive cytotoxic effects where observed in combination with fludarabine treatment. Susceptibility to orlistat treatment was not dependent on Binet stage.
In summary, we provide in vitro data for a criticial role of fatty acid metabolism in CLL pathogenesis and suggest a therapeutic potential of the lipase inhibitor orlistat. No severe systemic side effects of orlistat have been observed in several animal models and in the current clinical application as anti-obesity drug. Orlistat seems to be a promising candidate for an anti-leukemic therapy in CLL, ongoing in vivo experiments applying the TCL1 mouse model will further elucidate the therapeutic potential of orlistat.
Polyreactive Monoclonal Antibodies Synthesized by Some B-CLL Cells Recognize Specific Antigens on Viable and Apoptotic T Cells.
Authors: Catera Rosa , Hatzi Katerina , Chu Charles C. , Herve’ Maxime , Meffre Eric , Ferrarini Manlio , Oscier David Graham , Davis Zadie , Allen Steven L. , Rai Kanti R. , Chiorazzi Nicholas 
Published: October 2019

Abstract
B-cell chronic lymphocytic leukemia (CLL) is a disease characterized by uncontrolled clonal expansion of a CD5+/CD19+ B cell. Clones from different patients often express receptors/mAbs with remarkably similar VHDJH rearrangements, suggesting that the same antigen(s) or epitope(s) led to the initial clonal expansion. Although the specific antigens and epitopes remain to be identified, recent data indicate that B-CLL mAbs often bind autoantigens. In certain systemic autoimmune diseases, autoantibodies can react with cell surface molecules of viable lymphocytes (anti-lymphocyte mAbs) and with intracellular molecules of apoptotic cells that are transported to the cell membrane and function as autoantigens. Therefore, we expressed recombinant antibodies from B-CLL cells as IgG1 mAbs and tested them by flow cytometry for immunoreactivity with surface molecules on irradiated (apoptotic) and non-irradiated Jurkat cells, a human T-cell line. We chose to use T cells as our target for analysis to avoid difficulties that might arise from binding to FcgRIIb on B lymphocytes.
Initial screening indicated that 5 of 25 mAbs showed intense binding. Antibodies from CLL Nos. 141 and DO8 bound to live but not apoptotic cells; in contrast, CLL Nos. 014, 114, and DO13 bound to apoptotic but not live cells. These five antibodies express unmutated VH genes. CLL 141 and DO8 express VH4-34. CLL 014 expresses VH1-69, CLL 114 VH4-39 and DO13 VH1-02. Other antibodies expressing VH1-69 in its unmutated form also bound Jurkat cells, albeit weaker than CLL 014, whereas mAbs expressing different unmutated genes from the VH1 family did not react. Among the mAbs expressing VH1-02 that were tested, only DO13 showed reactivity. This indicates that the VH1-02 gene was not solely responsible for the observed binding, and that DJ and/or VLJL segments were also involved. Remarkably, none of the tested mAbs belonging to VH3 family recognize antigens on Jurkat cells; all of these VH3 mAbs were mutated. Only CLL 114 belongs to a previously identified stereotypic set. Of interest, although CLL 014 and 141 are polyreactive, binding ssDNA, dsDNA, insulin, LPS, and HEp-2 cell lysates, their reactivities with surface antigens were specific in that CLL 141 bound only live cells and CLL 014 reacted solely with apoptotic cells.
Our results indicate that, despite their inherent polyreactivity, certain B-CLL mAb bind specifically to antigenic epitopes on the surface of live as well as apoptotic Jurkat cells. The identity of these autoantigens is currently being investigated. These data highlight the importance of autoreactivity in the promotion and evolution of B-CLL.
Randomized Comparison of Cladribine Plus Cyclophsophamide with Fludarabine Plus Cyclophosphamide in Progressive Chronic Lymphocytic Leukemia: An Updated Report of Prospective PALG-CLL3 Study.
Authors: Robak Tadeusz , Blonski Jerzy Z. , Gora-Tybor Joanna , Jamroziak Krzysztof , Ceglarek Bernadetta , Konopka Lech , Calbecka Malgorzata , Kostyra Aleksandra , Stella-Holowiecka Beata , Kloczko Janusz , Warzocha Krzysztof , Seferynska Ilona , Dmoszynska Anna , Kowal Malgorzata , Lewandowski Krzysztof , Dwilewicz-Trojaczek Jadwiga , Wiater Elzbieta , Potoczek Stanislaw , Hellmann Andrzej , Skotnicki Aleksander , Sulek Kazimierz , Dybowicz Jacek , Zawilska Krystyna 
Published: October 2019

Abstract
Purine analogues, Cladribine (2-CdA) and Fludarabine (FA), are highly effective in treatment of chronic lymphocytic leukemia (CLL). This prospective randomized phase 3 trial was designed to compare the efficacy and toxicity of 2-CdA and cyclophsophamide (CC regimen) with FA and cyclophsophamide (FC regimen) in previously untreated progressive CLL. The primary end points of the study were complete response (CR) and overall response (OR) after completion of the therapy. The secondary end points were progression free survival (PFS), overall survival (OS) and treatment related toxicity. Eligible patients were assigned to receive 6 courses of either 2-CdA 0.12 mg/kg/d i.v. with cyclophosphamide 250 mg/m2/d i.v. for 3 consecutive days or FA 25 mg/m2/d i.v. with cyclophosphamide 250 mg/m2/d i.v. for 3 consecutive days administered at 28 day intervals. The treatment response and toxicity were evaluated according to NCI-SWOG guidelines. The study started in January 2004, and here we present updated results from the interim analysis of 227 evaluated patients performed in July 2006. As shown in the table, there were no significant differences in the rates of CR and OR between the treatment groups. Moreover, the treatment related toxicity, including grade ¾ thrombocytopenia, neutroepenia and infections was similar in patients receiving FC or CC regimens. Median time of progression free survival did not differ between both groups (11.0 months in CC arm and 11.2 months in FC arm, p=0.41). There were 5 deaths (3.2%) observed in CC arm and 15 (8.1%) in FC arm. In conclusion, the preliminary results of our study indicate that CC and FC protocols have similar activity and toxicity in previously untreated patients with CLL.
Characteristic CC arm FC arm p value Pts enrolled 158 174 Pts evaluated 105 122 OR (%) 88 (83.8) 99 (81.2) 0.60 CR (%) 41 (39.0) 49 (40.2) 0.86 Thrombocytopenia gr 3/4 (%) 12 (10.7) 17 (13.4) 0.53 Neutropenia gr 3/4 (%) 21 (18.8) 30 (23.6) 0.36 Infections gr 3/4 (%) 34 (30.4) 37 (29.1) 0.84
Significant Correlation between Survival Endpoints and Exposure to Ofatumumab (HuMax-CD20) in Chronic Lymphocytic Leukemia.
Authors: Coiffier Bertrand , Tilly H. , Pedersen L.M. , Plesner T. , Frederiksen H. , van Oers M.H.J. , Wooldridge J. , Kloczko J.S. , Holowiecki J. , Hellmann A. , Walewski J. , Flensburg M. , Petersen J. , Robak T. 
Published: October 2019

Abstract
Background: The fully human monoclonal IgG1 antibody HuMax-CD20 targets a novel epitope of the CD20 molecule on B-cells. HuMax-CD20 stops growth of engrafted B-cell tumors in SCID mice more efficiently than Rituximab and i.v. infusion of HuMax-CD20 in cynomolgus monkeys leads to profound, long lasting, dose-dependent B-cell depletion.
Aim: The objective of the present trial was to establish the safety, efficacy and the pharmacokinetics of HuMax-CD20 in patients with chronic lymphocytic leukemia.
Methods: Data are presented from an open label, dose-escalation, multicenter phase I/II clinical trial. 3 cohorts of 3 (A), 3 (B) and an extended cohort of 27 (C) patients with relapsed or refractory chronic lymphocytic leukemia (B-CLL) received 4 weekly i.v. infusions of HuMax-CD20 and were followed for 12 months. The first infusion was 100 mg, 300 mg and 500 mg in cohort A, B and C and the following 3 infusions were of 500, 1000 and 2000 mg, respectively. The endpoints were B-cell depletion, adverse events, objective response according to the NCI working group guidelines for CLL, time to progression, duration of response, time to next anti-CLL treatment, and pharmacokinetics. Data are presented from group C.
Results: Median age was 63 years (range, 27–82); median time since diagnosis was 6.1 years (range, 1–14). Maximum tolerated dose was not reached and none of the patients developed human anti human antibodies. 13 of 27 patients (48%) reported infections and infestations most frequently CTC grade 1 or 2 events of nasopharyngitis, gastroenteritis, sinusitis and upper respiratory tract infection without causal relation to ofatumumab. All patients had pronounced reduction of the leukemic CD19+CD5+ cell counts. Objective response rate was 46% (12 of 26 evaluable patients) with 1 nPR and 11 PR. Median time to progression (TTP) was 133 days (95 % CI 105–158) in the full analysis population and 161 days (95 % CI 140–220) in the subgroup of responders. The duration of response was 112 days (95 %CI 100–133). Time to next anti-CLL therapy was 366 days (95 % CI 258-N.A.). AUC (median 344697 μg/mL*h; range 62709–1362933) correlated significantly to both TTP and time to next anti-CLL therapy to which parameters the clearance (Cl) of ofatumumab (median 10 mL/h; range 3–42) correlated inversely.
Correlation between survival endpoints and PK Time to progression Time to next anti-CLL therapy ρ p-value n ρ p-value n ρ: Spearman correlation coefficient, n: number of observations AUC,μg/mL*h 0.55 0.005 24 0.62 0.001 24 Cl, mL/h −0.59 0.003 23 −0.58 0.003 23
Conclusion: This analysis of data from the first study of ofatumumab in CLL patients provides an indication of clinical benefit associated with high exposure and low clearance.
Alemtuzumab but Not ATG Decreases Natural Killer (NK) Cell Activity towards Tumor Targets in the Early Phase after Allogeneic Stem Cell Transplantation.
Authors: Penack Olaf , Fischer Lars , Stroux Andrea , Gentilini Chiara , Nogai Axel , Muessig Arne , Ganepola Susanne , Thiel Eckhard , Uharek Lutz 
Published: October 2019

Abstract
Background: In vivo T cell depletion with ATG or Alemtuzumab is effective to reduce the incidence of graft-versus host disease (GVHD) caused by alloreactive T cells. However, there is also a potential impact of these substances on the function of natural killer (NK) cells who are the predominant cells in peripheral blood in the early phase after hematopoietic stem cell transplantation (HSCT) and mediate beneficial graft-versus-tumor activity. Using a novel flow cytometric assay, which detects the lytic granule membrane protein CD107a as a marker for NK cell degranulation, we investigated the effect of T cell depletion with ATG and Alemtuzumab on NK cell function in the early phase after HSCT.
Methods: PBMCs of 34 patients (pts) at day +30 after allogeneic HSCT and of 16 healthy donors were coincubated at 37°C for 3 h with the NK sensitive cell line HL60. In each tube, containing 400μl effector/target suspension (2x106 cells), 20μl of PE-Cy5 conjugated anti-CD107a monoclonal antibody was added prior to incubation. After the first 1 h 10μl of the secretion inhibitor 2 mM monensin was added. At the end of coincubation cells were stained with mAbs (CD56, CD3) for flow cytometry. The percentage of CD107a expressing NK cells was assessed and the absolute number of degranulating NK cells/μl was calculated.
Results: Treatment Characteristics: Fourteen pts received ATG, ten pts were treated with Alemtuzumab and ten patients did not receive T cell depletion. The source of donor was: MRD 12 and MUD 22. NK cell count: The median NK cell count was: 250/μl in healthy individuals, 250/μl in pts without T cell depletion, 400/μl in pts with ATG and 100/μl in pts receiving Alemtuzumab (p<0.0005; Kruskal-Wallis test). NK cell activity: The median percentage of degranulating NK cells was 5.4% in healthy donors, 4,4% without T cell depletion, 2,8% when ATG was used and 0,8% when Alemtuzumab was given (p<0.0005). The absolute number of CD107a+ NK cells in response to the standardized tumor targets accounted for 13,4/μl (median) in normal donors, 12,9/μl in pts without T cell depletion, 7,6/μl in pts with ATG and 0,9/μl in pts with Alemtuzumab (p=0.001). The percentage and absolute number of CD107a+ NK cells were not significantly different between patients receiving ATG and patients not receiving T cell depletion (p=NS).
Conclusion: With a new and feasible method we were able to quantify and characterize tumor reactive NK cells after HSCT. We found that NK cell mediated cytotoxicity towards tumor targets is influenced by the type of T cell depletion: The NK cell activity in patients receiving Alemtuzumab was considerably reduced whereas ATG had only moderate impact on the NK cell activity in the early phase after HSCT.
Rituximab Reduces the Incidence of Acute Graft Versus Host Disease in an Unselected Series of Twenty-One Patients Undergoing Allogeneic Stem Cell Transplantation at a Single Center.
Authors: Christopeit M. , Mueller L. , Grothe W. , Weber T. , Muetherig A. , Theurich S. , Behre G. 
Published: October 2019

Abstract
Recent evidence highlights an implication of B lymphocytes in the development and sustainment of chronic graft versus host disease (cGvH). The monoclonal anti-CD20-antibody rituximab has proven effective against steroid refractory cGvH. Data on the role of B lymphocytes in acute GvH (aGvH) is sparse. We report on a reduction of the incidence of aGvH in patients receiving rituximab as an element of conditioning as compared to patients conditioned without rituximab. All 6 patients receiving rituximab suffered from CD20 positive Non-Hodgkin-Lymphoma (NHL) and received cyclosporine and mycophenolate immunosuppression. Immunosuppression in the other 15 patients was achieved either with cyclosporine and mycophenolate (N=11) or cyclosporine and methotrexate (N=4). All patients except for one received dose reduced conditioning. Only patients beyond day 25 are included in the analysis; as of july 20th, 2006 median follow up is 151 days (range 27 to 322 days). Out of six patients receiving rituximab as an element of conditioning, one (16.7 %) developed moderate aGvH. Out of 15 patients who did not receive rituximab during conditioning, 10 (66.7 %) developed moderate to severe aGvH. Two patients developed severe acute GvH after early cessation of immunosuppression and/or donor lymphocyte infusion for progressive disease. If removed from this analysis, 8 out of 13 patients (61.5 %) developed aGvH after conditioning without rituximab. Taken together, these data present a trend that in patients conditioned with rituximab acute GvH occurs less frequently. These are amongst the first data indicating that rituximab might suppress the development of acute GvH. They are in accordance with work published before yet this is the first study systematically comparing two groups of patients. At present, no data exploring the influence of CD20 positive B lymphocytes or the effect of rituximab on graft-versus-tumor effects exist. It therefore remains to be investigated whether the suggested suppression of GvH by rituximab benefits overall survival by reducing transplantation related mortality or whether it is associated with a higher relapse rate due to an abrogated graft versus tumor effect. Furthermore, it remains to be elucidated whether the administration of rituximab before transplantation or during the restoration of the allogeneic immune system exerts prophylactic effects against cGvH and whether this influences both graft versus tumor effects and survival. Finally, we conclude that the addition of rituximab to the treatment of severe steroid refractory acute graft versus host reactions has to be tested in randomized trials.