bluuebunny/crossref_metadata_2025_split huggingface dataset:
Daclizumab-Associated Erythroderma Is Associated with Rebound Increases in CD25-Positive CD4 Cells Following Treatment of Aplastic Anemia and Pure Red Cell Aplasia.
Authors: Lemery Steven J. , More Kenneth F. , Young Neal S. , Sloand Elaine M. 
Published: April 2020

Abstract
We previously have reported success in treating patients with moderate aplastic anemia with daclizumab, a humanized monoclonal antibody that recognizes the interleukin-2 receptor (Blood.2003; 102(10):3584–6). Since our first report we have treated eighty-eight patients with moderate aplastic anemia, pure red cell aplasia and relapsed severe aplastic anemia with 1 mg/kg of monoclonal antibody every 2 weeks for 3 months. Although this drug has been used extensively in the management of solid organ rejection, erythroderma has not been reported. In our study, five patients developed a severe generalized erythema in a period of 20 to 70 days following the last dose of treatment. The cutaneous eruptions were characterized by severe pruritis and intense erythematous inflammation with spongiotic papules and plaques. Pathologic evaluation was possible for four of five patients and described focal spongiosis, dermal lymphocytic infiltration including some eosinophils, and no evidence of infection. All patients were negative for anti-nuclear antibody and had no arthritis, fever, or other systemic signs. HLA types were available on 83 of the 88 patients. HLA DR13 was more common in the patients that developed a rash; 80% versus 18% in those who did not develop rash (p = .0071, Fisher’s Exact Test). The rash was associated with a two to ten fold increase in the proportion of CD25-positive CD4 cells compared to pre-drug levels (p&lt;0.05). All patients required treatment with oral corticosteroids for periods of 2–6 weeks. Three patients who had partial or minimal responses to daclizumab elected to undergo a second course. The three patients who had a mild rash after the first course of treatment developed a more severe eruption with subsequent administration of the drug; rashes were delayed after each therapeutic administration of daclizumab. Two additional patients developed other autoimmune symptoms including inflammatory arthritis about three months following daclizumab administration. The absence of autoimmune complications following use of daclizumab in solid organ or allogeneic stem cell transplant recipients may be related to additional immunosuppression frequently administered to these patients. Our working hypothesis is that daclizumab associated rash is caused by an immune phenomenon. This is supported by the findings that CD4+CD25+ (effector) T cells are expanded at the time of the rash, the presence of a lymphocytic dermal infiltrate, and the relative preponderance of HLA-DR13 in the affected group. It is possible that treatment with daclizumab (an anti-CD25 antibody) results in a relative depletion of CD4+CD25+ regulatory T cells thereby permitting expansion of CD4+CD25+ effector T cells.
Prospective, Randomized, Multicenter Study Comparing Antithymocyte Globulin (ATG) Alone with ATG Plus Cyclosporine (CsA) for Treatment of Children with Nonsevere Aplastic Anemia (nSAA).
Authors: Yagasaki Hiroshi , Yabe Hiromasa , Ayukawa Hiroshi , Noguchi Yasushi , Ijichi Osamu , Kobayashi Ryoji , Tsuchida Masahiro , Mugishima Hideo , Ohara Akira , Morimoto Akira , Oga Shouichi , Bessho Fumio , Nakahata Tatsutoshi , Tsukimoto Ichiro , Kojima Seiji 
Published: April 2020

Abstract
In contrast to treatment for childhood severe aplastic anemia (SAA), there is no consensus on the treatment of childhood nSAA. Two thirds of patients progress to SAA, suggesting the need to consider early immunosuppressive therapy (IST). ATG+CsA was superior to ATG alone in a German randomized trial that enrolled both patients with SAA and nSAA. However, subgroup analysis revealed no advantage of adding CsA for patients with nSAA. These findings formed the basis for this prospective, randomized study comparing ATG alone with ATG+CsA for treatment of childhood nSAA. From 1997 to 2004, 62 children with newly diagnosed nSAA were enrolled. Interim analysis was done in April 2005. Patients were randomized to receive either horse ATG (Lymphoglobuline, 1.5vial/10kg/day for 5 days; n=31) or ATG+CsA (6mg/kg/day; n=31). CsA was added for non-responders at day+90 in ATG group. The endpoints were hematologic response at 6 months and failure-free survival (FFS). Complete response (CR) was defined as a neutrophil count &gt; 1.5x 109/L, a platelet count &gt; 100x109/L, and a hemoglobin level &gt; 11.0g/dl. Partial response (PR) was defined as a neutrophil count &gt; 1.0x 109/L, a platelet count &gt; 30x109/L, and a hemoglobin level &gt; 8.0g/dl. FFS was defined as survival with a response. Clinical profiles of two treatment groups were comparable. Median age was 11 years and 10 years in ATG+CsA group and ATG group, respectively. Median time from diagnosis to treatment was 20 days and 23 days in ATG+CsA group, and ATG group, respectively. After 6 months, CR was observed in ATG+CsA group in 5 patients (16%) and PR in 12 patients (39%). In ATG groups, 2 patients (6%) achieved CR and 13 patients (42%) achieved PR. However, 19 patients in the ATG group received additional CsA. There were 22 failures in ATG group and 14 failures in ATG+CsA group. A total of 10 patients who failed initial therapy (7 in ATG group and 3 in ATG+CsA group) received a second IST. Bone marrow transplant (BMT) was attempted in 4 non-responders in ATG group and 6 non-responders in ATG+CsA group. Requiring CsA was a cause of failure in 8 patients of ATG group. The probability of FFS was 54.8% in ATG+CsA group compared with 26.7% in the ATG group (p=0.001). There was 1 death in each group: 1 from BMT-related toxicity in ATG+CsA group and 1 from bacterimia in ATG group. The 5-year survival rate was 94.8% in ATG+CsA group and 96.7% in ATG group. Conclusion; the hematologic response rate at 6 months and overall survival rate are comparable between the two groups, however the combination of ATG and CsA is superior to ATG alone in term of FFS for children with nSAA.
RBC Hemolysis and Platelet Activation in Paroxysmal Nocturnal Hemoglobinuria Are Mediated by Oxidative Stress That Can Be Ameliorated by Antioxidants.
Authors: Fibach Eitan , Zelig Orly , Amer Johnny 
Published: April 2020

Abstract
Paroxysmal Nocturnal Hemoglobinuria (PNH) is an acquired stem cell disorder characterized by the unique triad of intravascular hemolysis, bone marrow failure and thrombosis. Complement-mediated hemolysis in PNH is explained by a deficiency in glycosylphosphotidylinositol (GPI)-anchored proteins, CD55 and CD59 on the RBC surface.
Using flow cytometry for simultaneous measurement of oxidative-state markers in RBC and platelets, we studied blood samples obtained from normal donors and PNH patients. Reactive oxygen species (ROS), reduced glutathione (GSH), membrane lipid peroxidation and phosphatidylserine (PS) exposure were measured by staining with dichlorofuorescein, mercury orange, fluor-DHPE and Annexin V, respectively, followed by gating based on size and granularity. The results of blood samples obtained from normal donors (N=25) and PNH patients (N=11) indicated that the RBC from the patients had higher levels of ROS (1.4-fold) and lipid peroxides (3.5-fold) and lower GSH levels (two-fold) than those of normal RBC. Similar results were obtained with platelets from the same samples, indicating that both cell types are in a state of oxidative stress. Within each cell type, cells with the PNH immunophenotype (CD55− CD59−) had higher ROS levels and PS exposure than cells with the normal (CD55+CD59+) phenotype. These results support the direct relationship between the PNH phenotype and intracellular oxidative stress. Oxidants, such as hydrogen peroxide, phenylhydrazine, hemin, ferric ammonium citrate, increased the oxidative status of the cells and caused concentration-dependent RBC lysis and platelet activation. Complement-containing plasma had a similar effect. The RBC lysis and platelet activation were preceded by a burst of ROS and were more prominent in cells with the PNH phenotype. Incubation of PNH-cells with antioxidants such as N-acetyl cysteine, vitamin C and tocotrinol, prevented the complement-mediated lysis.
We previously reported that cellular oxidative stress, prevalent in conditions such as thalassemia, may be associated with RBC hemolysis, platelet activation and a decreased PMN antibacterial potential. Oxidative stress in RBC, platelets and neutrophils in PNH could in part account for clinical manifestations such as hemolysis, a hypercoagulable state and recurrent bacterial infections. Our present results, indicating that incubation with antioxidants ameliorates such stress and its adverse consequences, suggest the possibility of using antioxidants for treatment of PNH and similar conditions.
Unexpected Fanconi Anemia Diagnosis in Patients with Bone Marrow Failure.
Authors: Pinto Fernando O. , Leblanc Thierry , Le Roux Gwenaelle , Dastot Helene , Santos Moema , Larghero Jerome , Rocha Vanderson , Esperou Helene , Socie Gerard , Baruchel Andre , Gluckman Eliane , Soulier Jean 
Published: April 2020

Abstract
Early diagnosis of Fanconi Anemia (FA) in patients with bone marrow failure is critical for optimal clinical management. However, the remarkably high clinical variability and the potential emergence of revertant hematopoietic cells (somatic mosaicism) can obscure and delay the diagnosis of FA. Here we addressed FA diagnosis in a prospective series of adult and pediatric patients who presented with bone marrow failure without clear overall clinical picture of FA.
Sixty-six patients were classified into three groups: (1) bone marrow failure likely to be congenital, based on dysmorphic features or a family history [n=18], (2) aplastic anemia likely to be idiopathic [n=32], (3) patients with intermediate clinical features not classified into the former groups [n=16]. Of note, FA patients with typical clinical features were not included in the present study. FA diagnosis was evaluated using chromosome breakage test and FANCD2 immunoblot in PHA-stimulated-PBL. In addition, skin primary fibroblasts were analysed in order to overcome potential hematopoietic FA reversion. For that purpose, and considering that chromosome breakage tests are barely efficient in fibroblasts, we used FANCD2 immunoblot and also developped a new flow cytometry test based on MMC-sensitivity in fibroblasts (to detect downstream FA/BRCA groups). Using these approaches, we detected FA in 4 previously undiagnosed patients: a 35-years old patient from the congenital-like group; a 10-years old patient presenting as an idiopathic aplastic anemia without any FA signs; and two patients from the intermediate group: a 10-years old patient with an isolated thrombocytopenia, and a 50-years old patient presenting with pancytopenia/MDS and complete hematopoietic reversion. Importantly, FA diagnosis was definitely excluded in all other patients. In conclusion, we could identify a few unexpected FA cases in a series of patients with bone marrow failure. Therefore, the comprehensive use of a large set of tests is useful for accurate FA diagnosis. Classical chromosomal breakage tests in PBL appeared to be sufficient to exclude FA in idiopathic aplastic anemia, whereas fibroblast analysis can be necessary to definitely diagnose or exclude FA in other patients.
Acquired Pure Red Cell Aplasia Associated with Alemtuzumab, Mycophenolate, and Daclizumab Immunosuppression after Pancreas Transplant.
Authors: Elimelakh Milena , Dayton Vanessa , Park Katharine S. , Gruessner Rainer W. , Gruessner Angelika C. , Sutherland David E. , Bland Barbara , Howe Robert B. , van Burik Jo-Anne , Asraani Aneel A. , Reding Mark T. , Singleton Tim P. , Key Nigel S. 
Published: April 2020

Abstract
Acquired pure red cell aplasia (PRCA) is a rare disorder that may be associated with malignancy, infections, connective tissue disorders, pregnancy and drugs. Recently, we observed PRCA in pancreas transplant patients treated with a new immunosuppressive regimen. Since 1966, the University of Minnesota Medical Center (UMMC) has performed 1577 pancreas transplants. Since February 2003, 280 pancreas transplants were treated with a new immunosuppressive protocol involving induction and maintenance with (n=190) or conversion to (n=90) alemtuzumab (humanized anti-CD52) and mycophenolate mofetil (MMF). Daclizumab (humanized anti-CD25, IL-2 receptor) was added when MMF dosing was limited by neutropenia. Between September 2004 and July 2005, 12 patients receiving the triple drug combination were diagnosed with PRCA. All 12 had prolonged exposure to MMF and/or a calcineurin inhibitor (cyclosporine, tacrolimus) prior to induction with [n=8] or conversion to [n=4] the above protocol. Eight subjects had bone marrow biopsies performed and reviewed at UMMC, and 4 additional patients received the diagnosis of PRCA at other institutions. All cases showed similar morphologic features, including dysgranulopoiesis, erythroid aplasia or marked hypoplasia with evidence of maturation, megakaryocytic hyperplasia with normal or low peripheral platelet counts, and atypical lymphoid aggregates in bone marrow trephine sections. Cytogenetic studies showed normal karyotypes. Severe reticulocytopenia was present in all subjects. In one subject, an extramedullary post-transplant lymphoproliferative disorder was diagnosed simultaneously. Another patient developed atypical reactive lymphadenopathy. Acute parvovirus infection was excluded by serology or polymerase chain reaction in 11 cases. Erythropoietin, when used, was started after the diagnosis or maintained through recovery of PRCA. Two patients died, one (post conversion) of PRCA associated with autoimmune hemolytic anemia and one (post induction) of ischemic heart disease. MMF was either discontinued (n=8) or dose reduced (n=2) in the remaining 10 subjects, with improvement in hemoglobin or decreased transfusion requirements in 8 patients. The single patient in whom a follow-up bone marrow biopsy was obtained after clinical recovery showed normal erythropoiesis. Ten patients developed infections with cytomegalovirus (n=7), BK virus (n=3), Zygomyces (n=1), Aspergillus versicolor (n=1), and Mycobacteria Simiae/Interjectum (n= 1). Hypogammaglobulinemia was a common finding. We conclude that reversible PRCA is associated with the immunosuppressive protocol including alemtuzumab, MMF, and daclizumab.
Analysis of Expanded Human Cytokine Induced Killer Cells for Cellular Therapy.
Authors: Baker Jeanette , Sheehan Kevin , Monterola Gina , Staines Nancy , Negrin Robert S. 
Published: April 2020

Abstract
We have previously reported on the ex vivo expansion of cytotoxic effector T cells termed Cytokine Induced Killer (CIK) cells. CIK cells demonstrate both in vivo and in vitro anti-tumor activity in murine models with limited potential for GVHD induction. Human CIK cells are readily expanded from peripheral blood mononuclear cells (PBMC) when cultured with IFNg, CD3 and IL-2 and show cytotoxic activity against a variety of tumor cell lines and fresh autologous tumor cells through an NKG2D dependent mechanism. Clinical application of CIK cells requires expansion of effector cells in GMP-compliant manner. In this study, PBMC were collected by apheresis from 9 healthy non-mobilized donors and placed in closed, continuous perfusion cultures using Aastrom RepliCell@biochambers for 21–28 days. Cultures were inoculated with 3x108–7.5x108 nucleated cells containing a median of 46% CD3+ cells (range 29%–71%). At culture harvest, the median cell count was &gt; 4x109 (range 2.6x109–8.7x109) with 97% CD3+ (86%–99%) and an average cell viability of 84.8% (range, 75%–99.6%). The average expansion of CD3+ cells in culture was &gt; 30-fold (range13–91). CD3+CD56+ are the subpopulation of cells that demonstrated the highest cytotoxicity against tumor cell lines in culture. The mean percentage of these cells was 1.8% however at harvest, the mean CD3+CD56+ was 14% representing an average 34-fold expansion (range 19–515). The majority of CD3+ cells were CD8+ (range, 33–82%), NKG2D was predominately expressed by cells recovered from most cultures (range 47–76%). CD56+ was expressed by 1% – 36% of cells in different cultures and CD8+NKG2D+ expression ranged from 21%–50% of harvested cells. There was a moderate up-regulation of the activation markers CD25 and CD69 and the NK markers CD16, CD161 and CD94. In all cultures, the majority of CD8+ and CD56+ cells co-expressed the selectin marker a4b7. Furthermore the majority of the CD3+CD8+ cells were effector memory cells expressing CD62L−CD44+ (50%–71%) while the central memory cells CD62L+CD44+ ranged from 10%–40%, almost no naïve cells were detected in time of harvest. Cytotoxicity assays against a panel of tumor cell lines (B and T cell lymphomas, uterine cancer, erythroleukemia, ovarian cancer and plasmacytoma) showed significant yet variable killing. This system allows for the rapid expansion of cytotoxic cell in GMP-compliant manner suitable for clinical application.
A Randomized Trial of High-Dose (HD) Imatinib Mesylate (IM) with or without Peg-Interferon (PEG-IFN) and GM-CSF as Frontline Therapy for Patients with Chronic Myeloid Leukemia (CML) in Early Chronic Phase (CP).
Authors: Cortes Jorge , Talpaz Moshe , O’Brien Susan , Ravandi Farhad , Verstovsek Srdan , Garcia-Manero Guillermo , Koller Charles , Andreeff Michael , Estrov Zeev , Kantarjian Hagop 
Published: April 2020

Abstract
Some studies suggest that HD IM may be more effective than standard dose in CP CML. Still, only a minority of patients (pts) may reach undetectable levels of Bcr-Abl transcripts, and the use of single agent therapy may eventually result in development of resistance. IFN is thought to be effective in CML due to its immunomodulatory properties and may be valuable for management of minimal residual disease. Pre-clinical studies suggest synergy with imatinib. GM-CSF combined with IFN is a potent stimulator of dendritic cells. We designed this randomized phase II study to investigate if adding PEG-IFN to imatinib may improve the rate of complete molecular responses and prolong remission duration. Pts with previously untreated CP CML started treatment with imatinib 800mg daily and randomized after 6 months (mo) of therapy to either continue HD IM alone or add PEG-IFN 0.5mcg/kg/week and GM-CSF 125 mg/m2 three times weekly. Pts were monitored with real-time PCR and cytogenetics (CG) every 3 mo for the 1st year and every 6 mo thereafter. Ninety-four pts have been registered to date: 49 randomized to IM alone and 45 to IM + PEG-IFN+GM. 70 (75%) have been followed for at least 6 months and 49 (52%) for 12 months. (First interim analysis done when 30 pts evaluable at 12 mo). Ten pts randomized to PEG-IFN did not start therapy (2 refused, 2 physicians decision, 6 off study before 6 mo because of noncompliance n=3, melanoma n=1, financial n=1, progressive disease n=1). Patient characteristics and response (intention to treat) are as follows:
No./No. Evaluable (%) p value Overall IM alone IM+PEGIFN+GM Median age (range), y 48 (19–73) 46 (19–73) 50 (19–73) 0.12 Sokal (% low/int/high) 71/20/9 63/25/12 79/16/5 0.17 CG CR Overall 73/84 (87) 40/45 (89) 33/39 (85) 0.74 @ 12 mo 44/49 (90) 27/31 (87) 17/18 (94) 0.63 12 mo BCR-ABL/ABL &lt;0.05% 20/49 (41) 10/31 (32) 10/18 (55) 0.13 Undetectable 5/49 (10) 3/31 (10) 2/18 (11) 1.0 Median (range) 0.1 (0–79.3) 0.12 (0–79.3) 0.04 (0–21.9) 0.51
Toxicity with HD imatinib was similar to previous reports. The most common grade ≥3 toxicity associated with PEG-IFN in the 26 pts included fatigue (n=7, 27%), rash (n=5, 19%), depression (n=3, 11%), and headache (n=2, 7%). Twelve pts have required dose reductions of PEG-IFN and 3 (13%) permanently discontinued it. The actual median (range) dose of IM at 12 months was 800 mg (600–800 mg) for IM alone and 800 mg (400–800 mg) for combination arm. Among pts randomized to PEG-IFN arm, the dose of IM had to be reduced after 6 mo (i.e., after start of PEG-IM) in 4 (16%) pts. We conclude that the combination of IM and PEG-IM as done here is associated with acceptable toxicity profile. There is a trend for improved response after 12 months with the combination.
Combination Treatment with Imatinib and Mitoxantrone/Etoposide Is a Suitable Preparative Regimen before Allogeneic Transplantation in Patients with Myeloid Blast Crisis of Chronic Myeloid Leukemia.
Authors: Fruehauf Stefan , Topaly Julian , Buss Eike C. , Lahaye Tanja , Ottmann Oliver G. , Fischer Thomas , Emmerich Bertold , Haus Ulrike , Hehlmann Rudiger , Ho Anthony D. , Hochhaus Andreas 
Published: April 2020

Abstract
In advanced BCR-ABL-positive leukemia, combination of chemotherapy with imatinib is expected to result in better reduction of leukemia cell load and may delay or offset clonal selection of resistant leukemia cells, thus improving the survival. We carried out a prospective phase I/II combination trial for patients (pts) with myeloid blast crisis of chronic myelogenous leukemia (CML). Pts were treated with imatinib+mitoxantrone/etoposide in four cohorts starting from mitoxantrone 10mg/m2/d and etoposide 100 mg/m2/d for 2 or 3 consecutive days and start of imatinib 600mg/d from day 15 (coh. 1 and 2) or from day 1 (coh. 3 and 4, respectively). After hematologic reconstitution following the cytopenic phase, cytarabine was administered at a dose of 10mg/m2/d s.c. in addition to imatinib as maintenance treatment.
A total of 16 pts (8 m, 8 f) are available for analysis, median age 59 years (range 37–74). All pts who received more intensive induction treatment (coh. 3 and 4, n=7) achieved a hematologic response (HR). In contrast, HR was achieved in 6 of 9 pts treated in coh. 1 and 2. The induction treatment was well tolerated with a treatment-related mortality rate of 12.5% (1 intracranial hemorrhage in coh. 1, and 1 pneumonia in coh. 4).
A median of 8 (2–18) red blood cell concentrates and a median of 5 (1–8) platelet concentrates were required. Antibiotic treatment for febrile episodes was administered for a median of 10d (0–38). Of note, CTC grade 3 or grade 4 mucositis did not occur. Pts who received imatinib on day 1 (coh. 3–4) had a longer duration of severe leukopenia (WBC &lt;1/nl) with a median of 19 days (0–23) vs. 2 (0–14) but without increase of infection incidence.
Six pts who achieved HR received an allogeneic stem cell transplantation with myeloablative conditioning. Three of 6 transplanted patients are alive and in complete cytogenetic remission at 735, 723, and 279 days after initiation of study treatment. Two patients died of transplant-related complications (GvHD and sepsis), 1 patient died from hematologic relapse. Of 10 pts who received only conventional treatment, 1 (coh. 1) is still alive and in a complete cytogenetic remission at day 1280 after initiation of study treatment. Median survival of transplanted pts was 486 days, and 142 days in the group with conventional treatment only (p=0.078).
We conclude that the combination of mitoxantrone/etoposide and imatinib is a well tolerated induction protocol with mild non-hematological toxicity even in older patients. Eligible pts have an advantage from an allogeneic stem cell transplantation following response to the induction treatment.