bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and Safety of a New Intravenous Immunoglobulin Product in Patients with Chronic Immune Thrombocytopenic Purpura.
Authors: Robak Tadeusz , Salama Abdulgabar , Kovaleva Lidia , Vyhovska Yaroslava I. , Davies Simon , Mazzucconi Maria G. , Zenker Othmar 
Published: October 2019

Abstract
Background Intravenous immunoglobulin (IVIG) is an accepted treatment for immune thrombocytopenic purpura (ITP). A new liquid 10% human IgG preparation stabilized with proline at a pH of 4.8 (trade name: Privigen) was recently developed. It can be stored at room temperature and is therefore always ready to use. Here we report its efficacy and safety in patients with chronic ITP.
Patients and Methods Fifty-seven patients with chronic ITP and a platelet count below 20 x 109/L were included in this open-label, single arm, multi-center Phase III trial. IVIG was given at a dose of 1 g/kg on 2 consecutive days at a maximum infusion rate of 4 mg/kg/min. A subset (56.1%) of the patients received premedication (acetaminophen or diphenhydramine) to avoid adverse events. The primary endpoint was the platelet response rate, defined as the percentage of patients showing an increase in platelet count to ≥50 x 109/L within 7 days of the first infusion. Secondary endpoints included platelet counts at specified time points, time to platelet response, duration of platelet response, and regression of hemorrhages at different bleeding sites. Safety was evaluated by the frequency and severity of adverse events.
Results The primary endpoint, an increase in platelet counts to ≥50 x 109/L, was achieved by 81% of the subjects (95% CI: 69–89%). The highest median platelet count (149 x 109/L) was observed on day 8. Median time to response was 2.5 days, with 43% of subjects responding within 1 day. Median duration of platelet response (days with platelet count ≥ 50 x 109/L) was 15.4 days. Regression rates for various bleeding sites ranged from 78% to 100%. Regression of bleeding correlated with increases in platelet counts. Adverse events were reported in 52 (91%) subjects. The most common adverse event was headache (67%), the incidence and severity of which was attenuated by premedication with acetaminophen/diphenhydramine. There were 3 serious adverse events, one of which (aseptic meningitis) was considered related to the study medication.
Conclusions The present study has shown the safety and significant efficacy of a novel, 10% liquid, ready for use IVIG preparation, in patients with chronic ITP. A rapid increase in platelet counts to a level where severe bleeding episodes become more unlikely was seen in the majority of patients, as expected with IVIG given at 1 g/kg on 2 consecutive days. The increase in platelet counts was associated with a regression of bleeding. Adverse events were generally mild to moderate in severity, corresponded to those expected with IVIG, and could be prevented with premedication.
A Phase 2 Open-Label, Sequential-Cohort, Dose-Escalation Study of AMG 531 in Japanese Patients with Chronic Immune Thrombocytopenic Purpura (ITP).
Authors: Shirasugi Yukari , Ando Kiyoshi , Hashino Satoshi , Nagasawa Toshiro , Kurata Yoshiyuki , Kishimoto Yuji , Iwato Koji , Sonehara Yusuke , Ohkura Masayuki , Ohtsu Tomoko , Nichol Janet L. 
Published: October 2019

Abstract
AMG 531 is a novel thrombopoiesis-stimulating peptibody that is being studied for its ability to increase platelet production by stimulating the thrombopoietin (TPO) receptor. This phase 2 study was conducted to identify the appropriate starting dose of AMG 531 for treatment of chronic ITP in adult Japanese patients. The study consisted of 2 phases: a 2-week cohort dose-escalation phase to determine the starting dose for subsequent phase 3 evaluation, and a treatment continuation phase (that lasted until completion of the dose-escalation phase) which provided continuation of treatment for those with a platelet response. Patients in the continuation phase received the dose of AMG 531 they had received in the dose-escalation phase with the option for subsequent dose adjustments. Twelve patients were enrolled with a mean platelet count of 11.8x109/L and a median age of 60.5 years (range 32 to 63); 8 were female. Four patients enrolled into each of 1μg/kg, 3μg/kg, or 6μg/kg dose cohorts and received AMG 531 by subcutaneous injection on days 1 and 8 with no dose adjustments. Cohort dose escalation was to be stopped in the event of an observed platelet count >1000x109/L. Comparison of dose cohorts showed that the proportion of patients achieving a platelet response (doubling of baseline counts and ≥50x109/L) was greater in cohorts receiving higher doses of AMG 531 (see Table). A dose response was also observed in the mean peak platelet counts, the mean fold changes from baseline in peak platelet counts, and the maximum platelet count. Because one patient in the 6μg/kg cohort had an excessively high platelet count (980x109/L), this dose was eliminated from consideration as the starting dose in phase 3 and further dose escalation to 10μg/kg dose cohort was stopped. Five of 7 eligible patients (3μg/kg, 1/4; 6μg/kg, 4/4) elected to enter the treatment continuation phase. There were no study withdrawals, and no serious adverse events (AEs) were reported during the study in either phase. The most common treatment-related AE in the cohort phase was headache (25%), and in the treatment continuation phase were arthralgia, contact dermatitis, and malaise (each 20%). No patients received rescue medications during the entire treatment period. No antibodies against either AMG 531 or endogenous TPO were detected. AMG 531 was well-tolerated and produced a dose-responsive increase in platelet counts. The phase 3 study in Japanese patients with ITP will be initiated with a starting dose of 3μg/kg based on the outcome of this study.
Key Measures of Platelet Response
Methylen Blue Photoinactivated Plasma vs Fresh Frozen Plasma in Thrombotic Thrombocytopenic Purpura Treatment: A Multicentric Prospective Cohort Study.
Authors: Alvarez-Larrán Alberto , Del Río-Garma Julio , de la Rubia Javier , Zamora Concepción , Galmés Antonio , Ramírez Consuelo , Rodríguez-Vicente Pilar , Martínez Clara , Alegre Adrian , Viejo Aurora , Arbona Cristina , Serrano Alfons , Castellá María Dolors , Corral Mercedes , Peña Francisco , Pereira Arturo 
Published: October 2019

Abstract
Plasma exchange (PE) with plasma infusion is the treatment of choice for Thrombotic Thrombocytopenic Purpura (TTP) but doubts remain as to whether all kinds of plasma are equally effective. Since October 2004, a multicentric prospective cohort study is being conducted in Spain to compare Methylene Blue Photoinactivated Plasma (MBPIP) with Fresh Frozen Plasma (FFP) in the treatment of TTP. Sixty-three first episodes of idiopathic TTP were included. MBPIP was used in 38 and FFP in 25. The treatment schedule consisted of daily PE (> 40 mL/kg of body weight) and costicosteroids (1.5 mg/kg/d). Response was defined as the achievement of a platelet count >= 150 x 109/L for at least three consecutive days, normal LDH level and absence of TTP-related symptoms and signs. Recurrence was defined as a fall in platelet count below 50 x 109/L or below 50% of the highest count achieved after response. Response lasting for more than 15 days was considered as remission. The prognostic significance of the kind of plasma used was investigated by logistic regression analysis after adjustment for other variables that had previously been found to influence on response to PE (gender; the Rock score; days from first medical attendance to PE; volume of plasma infused in the first 7 days of treatment). Both groups were comparable with regard to clinical and biological parameters at diagnosis. A severe deficit in ADAMTS13 activity was found in 9 out 12 (75%) patients treated with MBPIP and in 12 out of 16 (75%) patients treated with FFP. When compared to FFP, patients treated with MBPIP required a higher number of PEs (16±13 vs 9±7, p=0.004) and a larger volume of plasma (763±678 ml/kg vs 413±326 ml/kg, p=0.02) to achieve a remission and presented more recurrences while on PE treatment (21 out of 38 vs 6 out of 25, p=0.02). Splenectomy or rituximab was required in eight patients (21%) treated with MBPIP to achieve a remission vs in none out of the 25 patients treated with FFP (p= 0.02). After adjustment for other prognostic variables, patients in the MBPIP group had a lower likelihood of remission by the 8th treatment day (OR: 5.1; 95% CI: 1.6 – 15.9) and a higher risk of recurrence while on PE treatment (OR: 4.2; 95% CI: 1.3 – 13.5). In conclusion, MBPIP is less effective than FFP in the treatment of TTP.
Initial and Long-Term Outcomes of Splenectomy in Adult Immune Thrombocytopenic Purpura (ITP) Patients: A Systematic Review and Meta-Analysis.
Authors: Mikhael Joseph , Kessler Craig M. , Danese Mark , Deuson Robert 
Published: October 2019

Abstract
Splenectomy serves as a common therapy in treating adults with chronic ITP. Laparoscopic splenectomy was introduced in 1991 with the goal of reducing complication rates. This study was designed to estimate both the initial surgical non-response rate and the long-term relapse rate of splenectomy in the post-laparoscopic era. A systematic literature review was conducted by searching PubMed for articles published between January 1, 1991 and October 3, 2006. Selection criteria included: chronic ITP, study enrollment in 1990 or later, ≥12 months of follow-up, ≥15 patients with ITP, ≥75% of patients at least 14 years of age, not HIV positive, and not undergoing a second splenectomy. Response rates for surgery were collected according to an author-defined platelet response criterion (platelet counts <50x109/L or <30x109/L in 75% of studies). Relapse rates post-splenectomy (using the same platelet response criteria) were also collected. A meta-analysis was conducted to estimate a pooled surgical non-response rate as well as a pooled relapse rate in responders by weighting the study-specific estimates by the inverse of their variances, using Stata 9™. The pooled relapse rate was converted to a probability using the exponential formula, e(-rate x time). We identified 161 articles for detailed review. Of these, 24 met our inclusion criteria, all of which were observational studies. These studies represent 1,138 laparoscopic splenectomies (66 or 5.8% were converted to open splenectomy during surgery), and 317 open or undefined splenectomies. The average surgical non-response rate across 21 studies reporting data was 12.2% (95% CI: 10.3–14.3%). The average long-term relapse rate per person year across all studies was 53 per 1,000 patient years (95% CI: 45.0–62.0%). This corresponds to a 5% per year failure rate, or 32% failure rate after 5 years, for all patients initiating surgery. Initial non-response rate to planned splenectomy is 12% in adults with ITP. For patients undergoing laparoscopic splenectomy, 6% required conversion to open splenectomy. The 5 year relapse rate post-splenectomy is 32%. Splenectomy, although the current standard of care, is not always initially successful and does not provide a durable response in all patients. The benefits and risks of splenectomy must be weighed in light of newer options of therapy currently available.
Relapse Rate per 1,000 Patient-years of Follow-up for Each Study Relapse Rate per 1,000 Patient-years of Follow-up for Each Study
Health-Related Quality of Life (HRQoL) in Patients with Chronic Immune Thrombocytopenic Purpura (ITP): Interim Results from an Open-Label Study of AMG 531.
Authors: Tarantino Michael D. , Henry David H. , Go Ronald S. , Lefrere Francois , Lichtin Alan E. , Terebelo Howard R. , Viallard Jean-Francois , Mathias Susan D. , Deeter Robert , Nie Kun , Nichol Janet L. 
Published: October 2019

Abstract
The ITP Patient Assessment Questionnaire (ITP-PAQ) was developed to complement clinical data by assessing multiple facets of disease-specific HRQoL in adult patients with chronic ITP (Mathias et al., Health Qual Life Outcomes, 2007). Here we present interim results from an ongoing, open-label extension study that will evaluate the ability of AMG 531 to improve their HRQoL in the long-term. AMG 531 is a novel thrombopoiesis-stimulating peptibody that is being studied for its ability to increase platelet production by stimulating the thrombopoietin receptor. Adult chronic ITP patients receiving AMG 531 completed the ITP- PAQ at baseline, and weeks 4, 12, 24, and every 12 weeks thereafter. The ITP-PAQ consists of 44 items and 10 scales. Data have been assessed for this interim analysis through week 48, a time-point with reasonable patient numbers at the time of the data cut-off. Mean scores at each assessment, and changes in mean scores from baseline to week 48 were calculated, with positive changes in mean score indicating improvement in HRQoL. Compliance rates for the ITP-PAQ were 95% at baseline, 93% at week 4, and 83% at week 48. Over the 48-week period, results demonstrated an upward trend for the scale scores (see Table). The greatest improvements were reported in the Symptoms, Bother, Activity, Reproductive Health, and Overall Quality of Life scales, particularly during the first 4 weeks of the study. Changes in mean score from baseline to week 48 were significantly increased for Symptoms, Bother, Fatigue, Activity, Fear, Psychological Health, Work, Social Activity, and Overall Quality of Life. ITP patients receiving AMG 531 had an initial, yet sustained, improvement in ITP-PAQ scores. Subsequent analyses of results collected in this ongoing study will be used to substantiate our findings, and the therapeutic benefit of AMG 531 on HRQoL in patients with chronic ITP will be provided by correlations with clinical data.
ITP-PAQ Scale Scores a by Assessment and Change in Mean Scores from Baseline
Platelet Production Rate Predicts the Response to Prednisone Therapy in Patients with Idiopathic Thrombocytopenic Purpura.
Authors: Houwerzijl Ewout , Louwes Henk , Sluiter Wim , Smit Jan , Vellenga Edo , de Wolf Joost 
Published: October 2019

Abstract
The thrombocytopenia in ITP is predominantly caused by autoantibodies that recognize antigens on platelets and megakaryocytes resulting in accelerated platelet destruction and a decreased platelet production rate (PPR). ITP patients with a predominantly suppressed PPR might respond differently to therapy than patients with predominantly peripheral platelet destruction. Tests and/or patient characteristics that can make a distinction between a reduced platelet half life and a reduced PPR could therefore influence diagnostic and therapeutic strategy in ITP. Therefore, in the present study the predictive value of clinical and platelet kinetic parameter for treatment outcome in idiopathic thrombocytopenic purpura (ITP) was investigated. Seventy-five patients with severe ITP (platelets ≤20 × 109/L) were studied. Median age was 46 (range 16–89) years and 34 (45%) patients were males. Median platelet count was 8 (1–20) × 109/L. The mean platelet life was 1 (0.1–6.5) days, and the PPR 160 (2–4670) × 109/day (normal 223 (100–355) × 109/day, p = 0.7). PPR was decreased (<100 × 109/day), normal (100–355 × 109/day) and increased (>355 × 109/day) in 33%, 48%, and 19% of the patients, respectively. All patients started with prednisone at diagnosis (1 mg/kg/day). Initial complete and partial response (CR/PR) was 84% and a durable CR/PR (defined as CR/PR for ≥6 months without treatment) was attained in 44% of the patients. Apart from a higher proportion of patients with a decreased PPR in the group that responded to prednisone therapy (p=0.03), there were no significant differences regarding clinical and platelet kinetic parameters between responders and nonresponders. A durable CR/PR was noticed in 64% of the patients with a decreased PPR (median follow-up of 81 months (18–92)), compared to 34% of the patients with normal or increased PPR (median follow-up 141 (10–284) months (HR: 0.47 [95% CI (0.24–0.92)], p = 0.03). Splenectomy was performed in 32% of the patients with decreased PPR and in 62% of patients with normal or increased PPR (p = 0.03). In addition, patients with a decreased PPR showed significantly less splenic sequestration and a significantly longer mean platelet life than patients with a normal or increased PPR, which underscores that in these patients peripheral destruction of platelets contributes relatively less to thrombocytopenia than suppressed platelet production. Thirty-nine of 42 nonresponders to prednisone underwent splenectomy. Durable CR/PR postsplenectomy was reached in 74%. There were no significant differences with regard to patient characteristics between responders and nonresponders to splenectomy. In conclusion, ITP patients with suppressed PPR have a significant higher durable CR/PR rate to prednisone therapy and are less frequently exposed to splenectomy, than those with a normal or increased PPR.
Constitutive Activation of the Canonical NF-κB Signaling Pathway and Expanded Populations of Splenic Marginal Zone B Cells Characterize Em-BCL10 Transgenic Mice.
Authors: Li Zhaoyang , Xue Liquan , Shin Dong-Mi , Qi Chen-Feng , Zhang Quangeng , Xu Wu , Morris Stephan W. , Morse Herbert , Wang Hongsheng 
Published: October 2019

Abstract
The BCL10 gene was isolated from the breakpoint region of the t(1;14)(p22;q32) chromosomal translocation, a recurrent chromosomal abnormality in mucosa-associated lymphoid tissue (MALT)-type lymphomas. The translocation results in constitutive over-expression and nuclear location of the BCL10 protein. To understand the physiological and pathogenic roles played by BCL10 in B-cell biology, a transgenic (TG) mouse model was developed with a human BCL10 gene driven by Em. The TG was expressed in thymic but not peripheral T cells and in the spleen; lymph nodes were negative. Although the lymphoid compartments of the TG mice were grossly normal, histologic studies showed the splenic marginal zone (MZ) to be significantly expanded and, in older mice, to compress the white pulp. In addition, about 10% of animals developed B-cell neoplasms by 18 months of age. By FACS analyses, the number of MZ B cells was increased nearly 2-fold, and both MZ and follicular (FOL) B cells exhibited a marked down-regulation of CD23 expression. In the peritoneum of TG mice, the B1a B-cell population was markedly reduced while the B1b subset was increased over 2-fold. Studies of purified MZ and FOL B cells from normal and TG mice showed that MZ B cells from TG mice had a survival advantage in culture. Studies of the canonical NF-κB signaling pathway that lies downstream from BCL10 showed that it was constitutively activated with high levels of nuclear p50 and p65 protein identified by Western blotting. Quantitative real-time RT-PCR analyses of purified splenic B cells from normal and TG mice for expression of 384 genes identified 44 with significant differences in expression. Almost half of these genes were known NF-κB targets and included genes known to influence B-cell survival (BAFF, IL-10) or associated with MZ lymphomas (S100A9). These results indicate that constitutive expression of BCL10 in B cells is not sufficient to induce transformation alone and that as-yet-unknown secondary mutations are required. Nonetheless, expression of BCL10 clearly resulted in constitutive activation of the canonical NF-κB signaling pathway and a prominent expansion of the MZ B-cell population, thereby setting the stage for later development of lymphomas.
Bendamustine Is Safe and Effective in Patients with Rituximab-Refractory, Indolent B-Cell Non-Hodgkin Lymphoma.
Authors: Kahl Brad , Bartlett Nancy L. , Leonard John P. , Ganjoo Kristen , Williams Michael E. , Czuczman Myron S. , Robinson K. Sue , Joyce Robin , van der Jagt Richard H. , Cheson Bruce D. 
Published: October 2019

Abstract
Background: Bendamustine (Treanda®) is a purine analog/alkylator hybrid with single-agent activity in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), multiple myeloma, and breast cancer. The objective of this phase 3 multicenter study was to evaluate the efficacy and safety of single-agent bendamustine HCl in patients with relapsed, rituximab-refractory NHL.
Methods: Eligible patients had previously treated, rituximab-refractory, indolent-histology NHL. Rituximab-refractory was defined as no response or progression within 6 months of
first dose of rituximab induction, completion of rituximab maintenance therapy or progression before the next scheduled rituximab dose, or completion of a combination of rituximab and chemotherapy.
Patients received bendamustine 120 mg/m2 intravenously over 60 minutes on days 1 and 2 every 21 days for 6 cycles (2 additional cycles at investigator discretion; max 8). Tumor response was determined by modified International Working Group Response Criteria for NHL. The primary endpoint was overall response rate (ORR) with secondary endpoints of response duration (RD) and progression-free survival (PFS).
Results: Results for the first 38 of 100 enrolled patients are presented. The median age was 60 years, 63% were male, and 63% had stage III/IV disease. Histologies included follicular (53%), CLL/small lymphocytic lymphoma (26%), and marginal zone (21%) lymphoma. Patients had received a median of 3 prior courses of treatment (range 1–10) and 2 prior rituximab-containing courses (range 1–6). Prior alkylator or purine analog-based treatment was administered to 79% and 37% of patients, respectively. Eighteen (47%) patients were considered to be chemoresistant. Four (11%) patients received prior radioimmunotherapy. The ORR in the primary analysis population was 84%, including 29% complete responses (CR), 3% CR unconfirmed, and 53% partial responses. The median RD was 9.3 months and the median PFS was 9.7 months. The primary hematologic toxicity was reversible myelosuppression; grade 3/4 hematologic side effects included leukopenia (60%), neutropenia (60%), thrombocytopenia (24%), lymphocytopenia (95%), and anemia (5%). Febrile neutropenia was not observed. Common nonhematologic adverse events (grades 1/2, 3, 4) were nausea (68%, 5%, 0%), vomiting (42%, 0%, 0%), and fatigue (42%, 13%, 3%).
Conclusions: In this multicenter study, single-agent bendamustine was well tolerated and produced a high rate (84%) of durable responses. It is the first chemotherapeutic agent to demonstrate significant clinical activity in rituximab-refractory indolent lymphoma. These results compare favorably with prior reports of radioimmunotherapy in this patient population. An updated analysis of all 100 patients will be available for the annual meeting.