Risk factors for treatment failure after allogeneic transplantation of patients with CLL: a report from the European Society for Blood and Marrow Transplantation.

For young patients with high-risk CLL, BTK-/PI3K-inhibitors or allogeneic stem cell transplantation (alloHCT) are considered. Patients with a low risk of non-relapse mortality (NRM) but a high risk of failure of targeted therapy may benefit most from alloHCT. We performed Cox regression analyses to identify risk factors for 2-year NRM and 5-year event-free survival (using EFS as a surrogate for long-term disease control) in a large, updated EBMT registry cohort (n= 694). For the whole cohort, 2-year NRM was 28% and 5-year EFS 37%. Higher age, lower performance status, unrelated donor type and unfavorable sex-mismatch had a significant adverse impact on 2-year NRM. Two-year NRM was calculated for good- and poor-risk reference patients. Predicted 2-year-NRM was 11 and 12% for male and female good-risk patients compared with 42 and 33% for male and female poor-risk patients. For 5-year EFS, age, performance status, prior autologous HCT, remission status and sex-mismatch had a significant impact, whereas del(17p) did not. The model-based prediction of 5-year EFS was 55% and 64%, respectively, for male and female good-risk patients. Good-risk transplant candidates with high-risk CLL and limited prognosis either on or after failure of targeted therapy should still be considered for alloHCT.

Long-term survival of patients with CLL after allogeneic transplantation: a report from the European Society for Blood and Marrow Transplantation.

Even with the availability of targeted drugs, allogeneic hematopoietic cell transplantation (allo-HCT) is the only therapy with curative potential for patients with CLL. Cure can be assessed by comparing long-term survival of patients to the matched general population. Using data from 2589 patients who received allo-HCT between 2000 and 2010, we used landmark analyses and methods from relative survival analysis to calculate excess mortality compared with an age-, sex- and calendar year-matched general population. Estimated event-free survival, overall survival and non-relapse mortality (NRM) 10 years after allo-HCT were 28% (95% confidence interval (CI), 25-31), 35% (95% CI, 32-38) and 40% (95% CI, 37-42), respectively. Patients who passed the 5-year landmark event-free survival (N=394) had a 79% probability (95% CI, 73-85) of surviving the subsequent 5 years without an event. Relapse and NRM contributed equally to treatment failure. Five-year mortality for 45- and 65-year-old reference patients who were event-free at the 5-year landmark was 8% and 47% compared with 3% and 14% in the matched general population, respectively. The prospect of long-term disease-free survival remains an argument to consider allo-HCT for young patients with high-risk CLL, and programs to understand and prevent late causes of failure for long-term survivors are warranted, especially for older patients.

Long-term follow-up of a retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic transplantation from matched related donors in myelodysplastic syndromes.

This study shows the long-term updated outcomes of a multicenter retrospective study which analyzed 843 patients with myelodysplastic syndrome (MDS) who underwent transplantation with an HLA-identical sibling donor with either reduced-intensity conditioning (RIC) in 213 patients, or standard myeloablative conditioning (MAC) in 630 patients. In multivariate analysis, the 13-year relapse rate was significantly increased after RIC (31% after MAC vs 48% in RIC; HR, 1.5; 95% CI, 1.1-1.9; P=0.04), but with no differences in overall survival (OS) (30% after MAC vs 27% in RIC; P=0.4) and PFS (29 vs 21%, respectively, P=0.3). Non-relapse mortality was higher in MAC (40 vs 31%; P=0.1), especially in patients older than 50 years (50 vs 33%, P<0.01). In addition, long-term follow-up confirms the importance of other variables on 13-year OS, mainly MDS risk category, disease phase, cytogenetics and receiving a high donor cell dose, irrespective of the conditioning regimen used.

Comparison of upfront tandem autologous-allogeneic transplantation versus reduced intensity allogeneic transplantation for multiple myeloma.

We performed a retrospective analysis of the European Group for Blood and Marrow Transplantation database comparing the outcomes of multiple myeloma patients who received tandem autologous followed by allogeneic PSCT (auto-allo) with the outcomes of patients who underwent a reduced intensity conditioning allograft (early RIC) without prior autologous transplant. From 1996 to 2013, we identified a total of 690 patients: 517 patients were planned to receive auto-allo and 173 received an early RIC allograft without prior autologous transplant. With a median follow-up of 93 months, 5-year PFS survival was significantly better in the auto-allo group, 34% compared with 22% in the early RIC group (P<0.001). OS was also significantly improved in the auto-allo group with a 5-year rate of 59% vs 42% in the early RIC group (P=0.001). The non-relapse mortality rate was lower in the auto-allo group than in the early RIC group, with 1- and 3-year rates of 8% and 13% vs 20% and 28%, respectively (P<0.001). The relapse/progression rate was similar in the two groups, with 5-year rates of 50% for auto-allo and 46% for early RIC (P=0.42). These data suggest that planned tandem autologous allograft can improve overall survival compared with upfront RIC allograft alone in patients with multiple myeloma.

Investigation on the ability of an ultrasound bubble detector to deliver size measurements of gaseous bubbles in fluid lines by using a glass bead model.

Detectors based on ultrasonic principles are today's state of the art devices to detect gaseous bubbles that may be present in extracorporeal circuits (ECC) for various reasons. Referring to theoretical considerations and other studies, it also seems possible to use this technology to measure the size of detected bubbles, thus offering the chance to evaluate their potential hazardous effect if introduced into a patient's circulation. Based on these considerations, a commercially available ultrasound bubble detector has been developed by Hatteland Instrumentering, Norway, to deliver bubble size measurements by means of supplementary software. This device consists of an ultrasound sensor that can be clamped onto the ECC tubing, and the necessary electronic equipment to amplify and rectify the received signals. It is supplemented by software that processes these signals and presents them as specific data. On the basis of our knowledge and experience with bubble detection by ultrasound technology, we believe it is particularly difficult to meet all the requirements for size measurements, especially if these are to be achieved by using a mathematical procedure rather than exact devices. Therefore, we tried to evaluate the quality of the offered bubble detector in measuring bubble sizes. After establishing a standardized test stand, including a roller pump and a temperature sensor, we performed several sets of experiments using the manufacturers software and a program specifically designed at our department for this purpose. The first set revealed that the manufacturer's recommended calibration material did not meet essential requirements as established by other authors. Having solved that problem, we could actually demonstrate that the ultrasonic field, as generated by the bubble detector, has been correctly calculated by the manufacturer. Simply, it is a field having the strongest reflecting region in the center, subsequently losing strength toward the ECC tubing's edge. The following set of experiments revealed that the supplementary software not only does not compensate for the ultrasonic field's inhomogeneity, but, furthermore, delivers results that are inappropriate to the applied calibration material. In the last set of experiments, we were able to demonstrate that the signals as recorded by the bubble detector heavily depend upon the circulating fluid's temperature, a fact that the manufacturer does not address. Therefore, it seems impossible to resolve all these sensor related problems by ever-increasing mathematical intervention. We believe it is more appropriate to develop a new kind of ultrasound device, free of these shortcomings. This seems to be particularly useful, because the problem of determining the size of gaseous bubbles in ECC is not yet solved.

Application of a new dynamic flow model for investigating the biocompatibility of modified surfaces.

An in vitro model was developed to compare the biocompatibility of four different coating methods (three heparin and one nonheparin) under hemodynamic conditions. Fresh human donor blood (heparin 5 IU/ml) was recirculated in a standardized experimental circuit. All circuit components were either coated or remained uncoated for control purposes. The aim of the study was to investigate a wide spectrum of effects on blood; coagulation parameters (e.g., fibrinogen, ATIII, thrombin-antithrombin-complex), complement parameters (C1rsC1 Inh, C3b(Bb)P, SC5b-9, C5a), differential blood analyses, platelet activation (flow cytometric investigations), PF 4, and PMN-elastase release were examined by showing possible trends. All heparin coated systems reduced platelet stimulation in comparison to untreated biomaterials. Leukocyte activation was reduced to different degrees depending upon the coating method used. Complement activation was markedly reduced by all coated systems. The results obtained indicate that the pump driven, dynamic blood flow model is suitable to characterize the biocompatibility of surface modified biomaterials. Advantages lie in the integration of the different polymers as parts of the circuit, the low priming volume, and the generation of blood flow conditions similar to those that occur in clinical applications.

Prophylaxis and treatment of GVHD after allogeneic haematopoietic SCT: a survey of centre strategies by the European Group for Blood and Marrow Transplantation.

Recommendations on indications for allogeneic haematopoietic SCT have been presented, but transplantation techniques remain poorly standardized. Pre-transplant risk factors are well defined, and reported outcomes vary markedly among patients with similar risk characteristics. It would be of importance to know the impact of differences in treatment procedures. To study properly the different components of allogeneic transplantation, standardization of at least some central procedures would be needed. As the first step, the European Group for Blood and Marrow Transplantation (EBMT) performed a survey among all its 372 member centres performing allogeneic transplantations about their strategies in preventing and treating GVHD. Responses from 79 centres (21% return) from 25 countries (60% return) were received. Although some trends toward more uniform policies compared with a survey carried out 15 years earlier were observed, the present survey still showed marked variability in the GVHD prophylaxis and treatment strategies. On the basis of these findings, EBMT is developing a consensus process aiming at a standardized strategy.