Platelet transfusion refractoriness (PTR), defined as an unsatisfactory post‐transfusion platelet count increment, is a common complication of patients receiving multiple transfusions. Different ...strategies are described in the management of PTR. In this work, we demonstrate the efficacy of the detection and identification of anti‐HLA antibodies in the recipient using a threshold of 3000 mean fluorescence intensity (MFI), and the seek of donors not expressing HLA antigens against which the patient is immunized.
Summary Background Vascular endothelial growth factor (VEGF) inhibition is a valid therapeutic approach in renal cell carcinoma. Therefore, an investigation of the combination treatment of the ...humanised anti-VEGF monoclonal antibody bevacizumab with interferon alfa was warranted. Methods In a multicentre, randomised, double-blind, phase III trial, 649 patients with previously untreated metastatic renal cell carcinoma were randomised to receive interferon alfa-2a (9 MIU subcutaneously three times weekly) and bevacizumab (10 mg/kg every 2 weeks; n=327) or placebo and interferon alfa-2a (n=322). The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. An interim analysis of overall survival was prespecified after 250 deaths. On the basis of new second-line therapies that became available while the trial was in progress, which could have confounded analyses of overall survival data, we agreed with regulatory agencies that the pre-planned final analysis of progression-free survival would be acceptable for regulatory submission. The protocol was amended to allow the study to be unblinded at this point. The final analysis of progression-free survival is reported here. Efficacy analyses were done by intention to treat. This trial is registered with centerwatch.com , number BO17705E. Findings 325 patients in the bevacizumab plus interferon alfa group and 316 in the placebo plus interferon alfa group received at least one dose of study treatment. At the time of unblinding, 230 progression events had occurred in the bevacizumab plus interferon alfa group and 275 in the control group; there were 114 deaths in the bevacizumab plus interferon alfa group and 137 in the control group. Median duration of progression-free survival was significantly longer in the bevacizumab plus interferon alfa group than it was in the control group (10·2 months vs 5·4 months; HR 0·63, 95% CI 0·52–0·75; p=0·0001). Increases in progression-free survival were seen with bevacizumab plus interferon alfa irrespective of risk group or whether reduced-dose interferon alfa was received. Deaths due to adverse events were reported in eight (2%) patients who received one or more doses of bevacizumab and seven (2%) of those who did not receive the drug. Only three deaths in the bevacizumab arm were considered by investigators to be possibly related to bevacizumab. The most commonly reported grade 3 or worse adverse events were fatigue (40 12% patients in the bevacizumab group vs 25 8% in the control group) and asthenia (34 10% vs 20 7%). Interpretation The combination of bevacizumab with interferon alfa as first-line treatment in patients with metastatic renal cell carcinoma results in a significant improvement in progression-free survival, compared with interferon alfa alone.
The value of pretransplant splenectomy in patients with myelofibrosis (MF) is subject to debate, since the procedure may preclude subsequent allogeneic hematopoietic cell transplantation (allo‐HCT). ...To determine the impact of pretransplant splenectomy on the incidence of allo‐HCT, we conducted a comprehensive retrospective study of all patients with MF for whom an unrelated donor search had been initiated via the French bone marrow transplantation registry (RFGM) between 1 January 2008 and 1 January 2017. Additional data were collected from the patients' medical files and a database held by the French‐Language Society for Bone Marrow Transplantation and Cell Therapy (SFGM‐TC). We used a multistate model with four states (“RFGM registration”; “splenectomy”; “death before allo‐HCT”, and “allo‐HCT”) to evaluate the association between splenectomy and the incidence of allo‐HCT. The study included 530 patients from 57 centers. With a median follow‐up time of 6 years, we observed 81 splenectomies, 99 deaths before allo‐HCT (90 without splenectomy and nine after), and 333 allo‐HCTs (268 without splenectomy and 65 after). In a bivariable analysis, the hazard ratio 95% confidence interval (CI) for the association of splenectomy with allo‐HCT was 7.2 5.1‐10.3 in the first 4 months and 1.18 0.69‐2.03 thereafter. The hazard ratio 95% CI for death associated with splenectomy was 1.58 0.79‐3.14. These reassuring results suggest that splenectomy does not preclude allo‐HCT in patients with MF.
T cell therapy strategies, from allogeneic stem cell transplantation toward genetically‐modified T cells infusion, develop powerful anti‐tumor effects but are often accompanied by side effects and ...their efficacy remains sometimes to be improved. It therefore appears important to provide a flexible and easily reversible gene expression regulation system to control T cells activity. We developed a gene expression regulation technology that exploits the physiological GCN2‐ATF4 pathway's ability to induce gene expression in T cells in response to one essential amino acid deficiency. We first demonstrated the functionality of NUTRIREG in human T cells by transient expression of reporter genes. We then validated that NUTRIREG can be used in human T cells to transiently express a therapeutic gene such as IL‐10. Overall, our results represent a solid basis for the promising use of NUTRIREG to regulate transgene expression in human T cells in a reversible way, and more generally for numerous preventive or curative therapeutic possibilities in cellular immunotherapy strategies.
Allogeneic stem cell transplantation remains the only curative treatment for sickle cell anemia (SCA), but the place of myeloablative conditioning in the procedure remains to be defined. The aim of ...the present study was to analyze long-term outcomes, including chimerism, SCA-related events and biological data (hemoglobin, reticulocytes, HbS%), and fertility in a French series of 234 SCA patients under 30 years of age who, from 1988 to 2012, received a matched-sibling-donor stem cell transplantation following standardized myeloablative conditioning busulfan, cyclophosphamide and rabbit antithymocyte globulin (ATG). Since the first report of the series (1988-2004), 151 new consecutive patients with SCA have been similarly transplanted. Considering death, non-engraftment or rejection (donor cells <5%) as events, the 5-year event-free survival was 97.9% (95% confidence interval: 95.5-100%), confirming, since the year 2000, an at least 95% chance of cure. In the overall cohort (n=234, median follow up 7.9 years), event-free survival was not associated with age, but chronic-graft-
-host disease (cGvHD) was independently associated with recipient's age >15 years (hazard ratio=4.37;
=0.002) and lower (5-15
20 mg/kg) ATG dose (hazard ratio=4.55;
=0.001). At one year, 44% of patients had mixed chimerism (5-95% donor cells), but those prepared with ATG had no graft rejection. No events related to SCA occurred in patients with mixed chimerism, even those with 15-20% donor cells, but hemolytic anemia stigmata were observed with donor cells <50%. Myeloablative transplantation with matched-sibling donor currently has a higher event-free survival (98%) in patients under 30 years of age than that reported for non-myeloablative conditioning (88%). Nevertheless, the risk of cGvHD in older patients and the need to preserve fertility might be indications for a non-myeloablative conditioning.
The objective of this phase II trial was to assess the efficacy and toxicity of weekly paclitaxel for patients with metastatic or unresectable angiosarcoma.
Thirty patients were entered onto the ...study from April 2005 through October 2006. Paclitaxel was administered intravenously as a 60-minute infusion at a dose of 80 mg/m(2) on days 1, 8, and 15 of a 4-week cycle. The primary end point was the nonprogression rate after two cycles.
The progression-free survival rates after 2 and 4 months were 74% and 45%, respectively. With a median follow-up of 8 months, the median time to progression was 4 months and the median overall survival was 8 months. The progression-free survival rate was similar in patients pretreated with chemotherapy and in chemotherapy-naïve patients (77% v 71%). Three patients with locally advanced breast angiosarcoma presented partial response, which enabled a secondary curative-intent surgery with complete histologic response in two cases. One toxic death occurred as a result of a thrombocytopenia episode. Six patients presented with grade 3 toxicities and one patient presented with a grade 4 toxicity. Anemia and fatigue were the most frequently reported toxicities.
Weekly paclitaxel at the dose schedule used in the current study was well tolerated and demonstrated clinical benefit.
Background.
Angiosarcomas account for <2% of all soft tissue sarcomas. This subtype is one of the most aggressive forms of soft tissue sarcoma. The prognosis for angiosarcoma patients in the advanced ...phase remains poor with current cytotoxic agents (progression‐free survival PFS time of ∼4 months and overall survival OS time of ∼8 months). We investigated the antitumor activity of sorafenib in patients with metastatic or advanced angiosarcomas in a phase II trial.
Methods.
We conducted a stratified phase II trial. The primary endpoint was the progression‐free rate (PFR) at 9 months according to the Response Evaluation Criteria in Solid Tumors. A two‐stage design (optimal Simon design) was used. Patients received sorafenib (400 mg twice daily) for 9 months until unacceptable toxicity or tumor progression. Central pathological and radiological reviews were performed. Data on stratum A (superficial angiosarcoma) and stratum B (visceral angiosarcoma) are currently available. This trial is registered with ClinicalTrials.gov (identifier, NCT00874874).
Findings.
Strata A and B recruited 26 and 15 patients, respectively. The median age was 63 years (range, 31–82 years), with 17 male and 24 female patients. Fourteen cases arose in irradiated fields. Thirty patients (73.0%) had been pretreated with conventional chemotherapy. No unexpected toxicity occurred. The PFR at 9 months was 3.8% in stratum A and 0.0% in stratum B. The median PFS times were 1.8 months and 3.8 months, respectively, whereas the median OS times were 12.0 months and 9.0 months, respectively. No responses were observed in chemotherapy‐naïve patients, whereas a 40% tumor control rate and 23% response rate were observed in the pretreated population. In this cohort, no activating mutation of the KDR gene (exons 15, 16, 24) was detected.
Interpretation.
Sorafenib showed limited antitumor activity in pretreated patients only, for both visceral and superficial angiosarcoma, but tumor control was of short duration.
摘要
研究背景. 血管肉瘤在所有软组织肉瘤中所占比例不足2％。这种亚型是恶性程度最高的软组织肉瘤之一。接受目前的细胞毒性药物治疗的晚期血管肉瘤患者预后仍然较差无进展生存期(PFS)大约为4个月，总生存期(OS)大约为8个月。我们在II期临床试验中研究了索拉非尼治疗转移性或晚期肉瘤的抗肿瘤活性。
方法. 我们进行了分层II期临床试验。根据实体瘤疗效评价标准，主要终点为9个月时的无进展率（PFR）。采用两阶段设计（Simon最佳设计）。患者接受9个月的索拉非尼（400 mg，每天两次），直至出现不可接受的毒性或肿瘤进展。进行中心病理和影像学评价。目前得到了A层（浅表性血管肉瘤）和B层（内脏血管肉瘤）的数据。这项试验在ClinicalTrials.gov进行了注册（标识号，NCT00874874）。
结果. A层和B层分别纳入26和15例患者。年龄中位数为63岁（范围31‐82岁），男性患者17例，女性患者24例。共14例病灶出现在照射野。30例患者（73.0％）既往接受过常规化疗。未发生意外的毒性反应。9个月的A层和B层的PFR分别为3.8％和0.0％，中位PFS分别为1.8个月和3.8个月，而中位OS分别为12.0个月和9.0个月。既往无化疗史的患者表现为无缓解，而接受过化疗的患者，表现出40％的肿瘤控制率和23％的缓解率。在受试患者中，未检测到KDR基因（外显子15，16，24）的激活突变。
结论. 索拉非尼仅对既往接受过化疗的内脏和浅表性血管肉瘤患者表现出有限的抗肿瘤活性，但肿瘤控制作用的持续时间短暂。
The antitumor activity of sorafenib in patients with metastatic or advanced angiosarcomas was investigated in a phase II trial. Sorafenib showed limited antitumor activity in pretreated patients only, but tumor control was of short duration.
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