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Objective: To study the prevalence of vitamin [B.sub.6] deficiency in common variable immunodeficiency and the impact of vitamin [B.sub.6] supplementation on immune function in the disorder. Design: Open, non-blinded. Setting: [...]

Author(s): T. Frigge [1]; B. Hafke [1]; T. Witte [1]; B. Krenzer [1]; C. Streubhr [1]; A. Samad Syed [1]; V. Miki Trontl [1]; I. Avigo [1]; P. Zhou [1]; [...]

Ovarian cancer (OC) is an aggressive disease, primarily diagnosed in late stages with only 20% of patients surviving more than 5 years. Liquid biopsy markers have great potential to improve current diagnostic and prognostic methods. Here, we compared miRNAs and DNA methylation in matched plasma, whole blood and tissues as a surrogate marker for OC. We found that while both cfDNA and cf-miRNAs levels were upregulated in OC compared to patients with benign lesions or healthy controls, only cf-miRNA levels were an independent prognosticator of survival. Following on our previous work, we found members of the miR-200 family, miR-200c and miR-141 to be upregulated in both plasma and matched tissues of OC patients which correlated with adverse clinical features. We could also show that the upregulation of miR-200c and -141 correlated with promoter DNA hypomethylation in tissues, but not in plasma or matched whole blood samples. As cf-miRNAs are more easily obtained and very stable in blood, we conclude that they might serve as a more appropriate surrogate liquid biopsy marker than cfDNA for OC., (© 2023. The Author(s).)

While in vivo T-cell depletion (TCD) is widely used, its benefit in patients with MDS still remains a matter of debate. This study evaluates the impact of TCD on outcomes, and compares ATG and alemtuzumab, in patients with MDS. 1284 patients from the EBMT registry were included in this study with 470 patients in the no-TCD group and 814 in the TCD group (alemtuzumab N = 168; ATG N = 646). At 6 months, aGVHD III-IV cumulative incidences (CI) for no-TCD, ATG or alemtuzumab groups were 13% vs 14% vs 11% (ns), respectively. At 5 years, CI of chronic GVHD were 64% vs 52% vs 51% (p < 0.00017); and CI of relapse was 23% vs 25% vs 39% (p < 0.0001) for no TCD, ATG and alemtuzumab respectively; OS was 47% vs 46% vs 34% (p = 0.009) respectively; and GRFS was 21% vs 28% and 20% (p = 0.045) respectively. In multivariable analysis, ATG improved GRFS, and alemtuzumab decreased OS. Both ATG and alemtuzumab decreased risk of chronic GVHD, but the increased risk of relapse with alemtuzumab is associated with a poor GRFS and suggest to not use alemtuzumab in the setting of allo-SCT for high risk disease., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

In gout, crystallization of uric acid in the form of monosodium urate (MSU) leads to a painful inflammatory response. MSU crystals induce inflammation by activating the complement system and various immune cell types, and by inducing necrotic cell death. We previously found that the soluble pattern recognition molecule C-reactive protein (CRP) recognizes MSU crystals, while enhancing complement activation. In the absence of CRP, MSU crystals still induced complement activation, suggesting additional CRP-independent mechanisms of complement activation. In the present study, we searched for additional MSU crystal-binding complement activators. We found that all healthy individuals, even unborn children, have MSU crystal-specific immunoglobulin M (IgM) in their blood. This indicates that innate IgM, also known as natural IgM, recognizes these crystals. In serum lacking IgM and CRP, MSU crystals showed negligible complement activation as assessed by the production of the anaphylatoxins C4a, C3a, and C5a (listed in order of production via the classical complement pathway). We show that IgM and CRP both activate the classical complement pathway on MSU crystals. CRP was more efficient at fixating active C1 on the crystals and inducing release of the most inflammatory anaphylatoxin C5a, indicating non-redundant functions of CRP. Notably, while CRP recognizes MSU crystals but not the related calcium pyrophosphate dihydrate (CPPD) crystals, natural IgM bound to both, suggesting common and distinct mechanisms of recognition of individual crystal types by complement activators., (© 2022. The Author(s).)

Allogeneic hematopoietic cell transplantation (allo-HCT) remains a treatment option for patients with chronic myeloid leukemia (CML) who fail to respond to tyrosine kinase inhibitors (TKIs). While imatinib seems to have no adverse impact on outcomes after transplant, little is known on the effects of prior use of second-generation TKI (2GTKI). We present the results of a prospective non-interventional study performed by the EBMT on 383 consecutive CML patients previously treated with dasatinib or nilotinib undergoing allo-HCT from 2009 to 2013. The median age was 45 years (18-68). Disease status at transplant was CP1 in 139 patients (38%), AP or >CP1 in 163 (45%), and BC in 59 (16%). The choice of 2GTKI was: 40% dasatinib, 17% nilotinib, and 43% a sequential treatment of dasatinib and nilotinib with or without bosutinib/ponatinib. With a median follow-up of 37 months (1-77), 8% of patients developed either primary or secondary graft failure, 34% acute and 60% chronic GvHD. There were no differences in post-transplant complications between the three different 2GTKI subgroups. Non-relapse mortality was 18% and 24% at 12 months and at 5 years, respectively. Relapse incidence was 36%, overall survival 56% and relapse-free survival 40% at 5 years. No differences in post-transplant outcomes were found between the three different 2GTKI subgroups. This prospective study demonstrates the feasibility of allo-HCT in patients previously treated with 2GTKI with a post-transplant complications rate comparable to that of TKI-naive or imatinib-treated patients., (© 2021. The Author(s).)

Gout is caused by crystallization of uric acid in the form of monosodium urate (MSU) crystals, which induce a sterile inflammatory response that is hardly distinguishable from microbe-induced inflammatory responses. It is unclear, if MSU crystals (like microbes) are recognized by specific pattern recognition receptors. To identify possible soluble pattern recognition molecules for MSU crystals, we purified MSU-binding proteins from human body fluids. We identified C-reactive protein (CRP) as a major MSU-binding protein. Binding of CRP was strong enough to specifically deplete CRP from human serum. We found that CRP was required for fixation of complement components C1q, C1r, C1s and MASP1. Thus, we have identified a pattern recognition molecule for MSU crystals that links to the activation of complement. Notably, CRP does not show an even binding to the complete surface of the crystals. It rather binds to edges or distinct faces of the crystals.

Although several risk factors exist for acute coronary syndrome (ACS) no biomarkers for survival or risk of re-infarction have been validated. Previously, reduced serum concentrations of anti-ß 1 AR Ab have been implicated in poorer ACS outcomes. This study further evaluates the prognostic implications of anti-ß 1 AR-Ab levels at the time of ACS onset. Serum anti-ß 1 AR Ab concentrations were measured in randomly selected patients from within the PLATO cohort. Stratification was performed according to ACS event: ST-elevation myocardial infarct (STEMI) vs. non-ST elevation myocardial infarct (NSTEMI). Antibody concentrations at ACS presentation were compared to 12-month all-cause and cardiovascular mortality, as well as 12-month re-infarction. Sub-analysis, stratifying for age and the correlation between antibody concentration and conventional cardiac risk-factors was subsequently performed. Serum anti-ß 1 AR Ab concentrations were measured in 400/799 (50%) STEMI patients and 399 NSTEMI patients. Increasing anti-ß 1 AR Ab concentrations were associated with STEMI (p = 0.001). Across all ACS patients, no associations between anti-ß 1 AR Ab concentration and either all-cause cardiovascular death or myocardial re-infarction (p = 0.14) were evident. However among STEMI patients ≤60 years with anti-ß 1 AR Ab concentration 1 AR Ab concentrations > median (14/198 (7.1%) vs. 2/190 (1.1%)); p = 0.01). Similarly, the same sub-group demonstrated greater risk of cardiovascular death in year 1, including re-infarction and stroke (22/198 (11.1%) vs. 10/190 (5.3%); p = 0.017). ACS Patients ≤60 years, exhibiting lower concentrations of ß 1 AR Ab carry a greater risk for early re-infarction and cardiovascular death. Large, prospective studies quantitatively assessing the prognostic relevance of Anti-ß 1 AR Ab levels should be considered.

A rare variant (BAFF-var) of the tumor necrosis factor superfamily 13b (TNFSF13B) gene has been recently associated with multiple sclerosis (MS) and systemic lupus erythematosus (SLE). The aim of this study was to investigate the association between TNFSF13B BAFF-var and susceptibility to rheumatoid arthritis (RA) and replicate that association in SLE. 6,218 RA patients, 2,575 SLE patients and 4,403 healthy controls from three different countries were included in the study. TNFSF13B BAFF-var was genotyped using TaqMan allelic discrimination assay. PLINK software was used for statistical analyses. TNFSF13B BAFF-var was significantly associated with RA (p = 0.015, OR = 1.21, 95% CI = 1.03-1.41) in the Spanish cohort. A trend of association was observed in the Dutch (p = 0.115) and German (p = 0.228) RA cohorts. A meta-analysis of the three RA cohorts included in this study revealed a statistically significant association (p = 0.002, OR = 1.24, 95% CI = 1.10-1.38). In addition, TNFSF13B BAFF-var was significantly associated with SLE in the Spanish (p = 0.001, OR = 1.41, 95% CI = 1.14-1.74) and the German cohorts (p = 0.030, OR = 1.86, 95% CI = 1.05-3.28), with a statistically significant p-value obtained in the meta-analysis (p = 0.0002, OR = 1.46, 95% CI = 1.09-2.32). The results obtained confirm the known association of TNFSF13B BAFF-var with SLE and, for the first time, demonstrate that this variant contributes to susceptibility to RA.

The International Prognostic Scoring System has been revised (IPSS-R) to predict prognosis of patients with myelodysplastic syndromes at diagnosis. To validate the use of the IPSS-R assessed before transplant rather than at diagnosis we performed a retrospective analysis of the EBMT database. A total of 579 patients had sufficient information available to calculate IPSS-R at transplant. Median overall survival (OS) from transplant was significantly different according to IPSS-R: very low 23.6 months, low 55.0 months, intermediate 19.7 months, high 13.5 months, very high 7.8 months (P<0.001). In a multivariate Cox model the following parameters were significant risk factors for OS: IPSS-R, graft source, age and prior treatment. Median relapse free survival also showed significant differences according to IPSS-R: very low: 23.6 months, low: 24.8 months, intermediate 10.6 months, high 7.9 months, very high 5.5 months (P<0.001). Multivariate risk factors for relapse-free survival (RFS) were: IPSS-R, reduced intensity conditioning, graft source and prior treatment. A trend for an increased relapse incidence was noted for very high risk IPSS-R. We conclude that the IPSS-R at transplant is a useful prognostic score for predicting OS and RFS after transplantation, capturing both disease evolution and response to prior treatment before transplant.

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.

In 2013, recommendations for a standardized practice in the prophylaxis and treatment of GvHD were adopted and published by the European Society for Blood and Marrow Transplantation and the European LeukemiaNet. One year later, all 341 European Society for Blood and Marrow Transplantation centres performing allogeneic haematopoietic stem cell transplantation were contacted for a change-control analysis and asked to fill in a questionnaire; 111 centres (33%) responded. Of these, 83% had been aware of the recommendations. Paediatric centres (P=0.004), centres with shorter programme duration (P=0.049), not JACIE (the Joint Accreditation Committee of the International Society for Cellular Therapy and the European Society for Blood and Marrow Transplantation)-accredited centres (P=0.010) and centres from middle-income countries (P=0.033) were more likely to be unaware of the recommendations. Thirty-eight per cent of the centres regarded the recommendations as relevant guidelines affecting their policies, 61% as interesting information. Thirty per cent had decided to make changes in their institutional protocols based on the recommendations. More than 80% were willing to use the recommendations for a control arm in randomized studies. This survey shows that the published recommendations had some, though insufficient, impact on the strategies and methods of allogeneic haematopoietic stem cell transplantation applied by the centres. It also identified some of the weaknesses to be addressed when releasing recommendations in the future.

Treatment of PBMC with the CD4-specific mAb BT-061 induces CD4 down-modulation of T cells. Here we report that addition of BT-061 to purified T cells did not confer this effect, whereas incubation of T cells in BT-061 coated wells restored CD4 down-modulation. These results implied that Fcγ receptor mediated cell-cell interactions played a role. In consistence with this hypothesis PBMC depleted of CD64(+) monocytes did not confer CD4 down-modulation of BT-061 decorated T cells. Strikingly, CD4 down-modulation was observed in BT-061 treated synovial fluid punctuated from patients' inflamed joints that comprised enhanced numbers of CD64(+) cells. In contrast, in a circulating whole blood system injection of BT-061 did not induce CD4 down-modulation, due to CD64 saturation by serum IgG. Similarly, tonsil derived mononuclear cells devoid of CD64(+) cells did not show CD4 down-modulation, whereas addition of blood derived monocytes restored the effect. Thus, the interaction of BT-061 decorated T cells with CD64(+) cells is needed for CD4 down-modulation, implying that in patients BT-061 would primarily induce CD4 down-modulation at inflammatory sites. These results highlight the need not only to examine the interaction of a given mAb with single FcγR, but also the immunological environment that is appropriate to support such interactions.

In patients treated with allogeneic stem cell transplantation (SCT) for malignant disease who suffer from a relapse after the transplantation, the role of second allogeneic SCT is often uncertain. In a retrospective analysis, 2632 second allogeneic transplantations carried out for a relapse after the first transplantation were analyzed to define indications and identify predictive factors. Fifteen percent of the patients remained relapse-free until 5 years after the second SCT. Patients with CML had a better survival than patients with other diseases. In a multivariate analysis, factors associated with better survival were low disease burden, longer remission duration after the first transplantation, longer interval between the transplantations, younger age, absence of grade II-IV acute GvHD or chronic GvHD after the first transplantation, and later year of transplantation. The European Society for Blood and Marrow Transplantation risk score predicted the outcome. Using the same donor as in the first transplantation vs another donor had no predictive value for survival. Sibling donor was a favorable predictive factor. In conclusion, second allogeneic SCT offers a reasonable option especially for young patients with a long remission after the first transplantation and a low disease burden. The present findings do not support the usefulness of changing the donor for the second transplantation.

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.

Previous studies have shown that obtaining complete hematologic remission (CR) in multiple myeloma is an important predictor of PFS and OS. This applies both to autologous and allogeneic transplantation. However, the importance of CR obtained before vs after second transplant or following allogeneic vs autologous transplantation is not clear. We investigated the role of CR analyzing data from the EBMT-NMAM2000 interventional prospective study comparing tandem autologous/reduced intensity conditioning allogeneic transplantation (auto/RICallo) to autologous transplantation-single or double (auto/auto). Allocation to treatment was performed according to availability of a matched sibling donor. Cox regression and multi-state models were applied. The long-term probability of survival in CR was superior in auto/RICallo, both comparing groups according to treatment allocated at start (28.8 vs 11.4% at 60 months, P=0.0004) and according to actual administration of second transplant (25.6 vs 9.6% at 60 months, P=0.008). CR achieved before the second transplant was predictive for PFS (hazard ratio (HR)=0.44, P= 0.003) and OS (HR 0.51, P=0.047) irrespective of the type of second transplant. CR achieved after auto/RICallo was more beneficial for PFS (HR=0.53, P=0.027) than CR after auto/auto (HR=0.81, P=0.390), indicating a better durability of CR obtained after an allotransplant procedure.

The faster hematopoietic recovery after autologous peripheral blood SCT (APBSCT) in patients with AML may be offset by an increased relapse risk as compared with autologous BMT (ABMT). The EORTC and GIMEMA Leukemia Groups conducted a trial (AML-10) in which they compared, as second randomization, APBSCT and ABMT in first CR patients without an HLA compatible donor. A total of 292 patients were randomized. The 5-year DFS rate was 41% in the APBSCT arm and 46% in the ABMT arm with a hazard ratio (HR) of 1.17; 95% confidence interval=0.85-1.59; P=0.34. The 5-year cumulative relapse incidence was 56% vs 49% (P=0.26), and the 5-year OS 50% and 55% (P=0.6) in the APBSCT and ABMT groups, respectively. APBSCT was associated with significantly faster recovery of neutrophils and platelets, shorter duration of hospitalization, reduced need of transfusion packed RBC and less days of intravenous antibiotics. In both treatment groups, higher numbers of mobilized CD34+ cells were associated with a significantly higher relapse risk irrespective of the treatment given after the mobilization. Randomization between APBSCT and ABMT did not result in significantly different outcomes in terms of DFS, OS and relapse incidence.

GVHD remains the major impediment to broader application of allogeneic haematopoietic SCT. It can be prevented completely, but at the expense of other complications, rejection, relapse or delayed immune reconstitution. No optimal prevention or treatment method has been defined. This is reflected by enormous heterogeneity in approaches in Europe. Retrospective comparisons between different policies, although warranted, do not give definite answers. In order to improve the present situation, an European Group for Blood and Marrow Transplantation and the European LeukemiaNet working group has developed in a Delphi-like approach recommendations for prophylaxis and treatment of GVHD in the most common allogeneic transplant setting, transplantation from an HLA-identical sibling or unrelated donor for standard risk malignant disease. The working group proposes these guidelines to be adopted as routine standard in transplantation centres and to be used as comparator in systematic studies evaluating the advantages and disadvantages of practices differing from these recommendations.

Outcomes and prognostic factors of reduced intensity-conditioned allo-SCT (RIC allo-SCT) for multiple myeloma (MM) relapsing or progressing after prior autologous (auto)-SCT are not well defined. We performed an analysis of 413 MM patients who received a related or unrelated RIC allo-SCT for the treatment of relapse/progression after prior auto-SCT. Median age at RIC allo-SCT was 54.1 years, and 44.6% of patients had undergone two or more prior auto-SCTs. Median OS and PFS from the time of RIC allo-SCT for the entire population were 24.7 and 9.6 months, respectively. Cumulative non-relapse mortality (NRM) at 1 year was 21.5%. In multivariate analysis, CMV seronegativity of both patient and donor was associated with significantly better PFS, OS and NRM. Patient-donor gender mismatch was associated with better PFS, fewer than two prior auto-SCT was associated with better OS, and shorter time from the first auto-SCT to the RIC allo-SCT was associated with lower NRM. The results of this study identify patient and donor CMV seronegativity as the key prognostic factor for outcome after RIC allo-SCT for MM relapsing or progressing after prior auto-SCT.

This randomized-controlled trial studied the efficacy of palifermin in a chemotherapy-only, high-dose Melphalan (HDM) transplant setting, to reduce oral mucositis (OM) and its sequelae measured by patient-reported outcomes (PRO) and medical resource use. Palifermin, relative to placebo was given either pre-/post-HDM or pre-HDM in patients with multiple myeloma (MM) undergoing auto-SCT at 39 European centers. Oral cavity assessment (WHO) and PRO questionnaires (oral mucositis daily questionnaire (OMDQ) and EQ 5D) were used in 281 patients (mean age 56, ± s.d.=8 years). 57 patients received placebo. One hundred and fifteen subjects were randomized to pre-/post-HDM receiving palifermin on 3 consecutive days before HDM and after auto-SCT and 109 patients were randomized to pre-HDM, receiving palifermin (60 μg/kg/day) i.v. for 3 consecutive days before HDM. There was no statistically significant difference in maximum OM severity. Severe OM occurred in 37% (placebo), 38% (pre-/post-HDM) and 24% (pre-HDM) of patients. No significant difference was observed with respect to PRO assessments or medical resource use, but more infections and fever during neutropenia were reported in pre-/post-HDM vs placebo (for example, 51 and 26%). To conclude, palifermin was unable to reduce OM or OM-related patient's burden in MM transplant patients.

Peripheral blood used as a source of stem cells for transplantation (PBSCT) is known to exert stronger immune-mediated effects compared with BM (BMT). We decided to retrospectively analyze the impact of stem cell source on the OS of CML patients who relapsed after either matched related donor PBSCT (N=168) or BMT (N=216) and were treated with donor lymphocyte infusions (DLI). Univariate analysis revealed a lower probability of OS after DLI in patients relapsing after PBSCT vs BMT (66% vs 79% at 5 years, P=0.013). However, a multivariate Cox analysis did not reveal any significant impact of PBSCT as a risk factor for decreased OS for patients transplanted in first chronic phase (CP1; hazard ratio (HR) 1.036, 95% confidence interval (CI) 0.619-1.734). A statistical interaction term suggested that the impact of stem cell source on OS after DLI was different for those transplanted in advanced phases (negative impact of previous PBSCT-HR 2.176, 95% CI 0.930-5.091). In summary, the stem cell source does not affect the OS of CML patients who underwent PBSCT in CP1, relapsed and were treated with DLI. However, when the patients were transplanted in advanced phases, previous PBSCT seems to negatively affect OS after DLI compared with BMT.

In this multicenter retrospective study, the long-term outcomes of 878 adults with AML and refractory anemia with excess blasts (RAEB) with BM blasts <10% who underwent transplantation with an HLA-identical sibling donor between 1998 and 2004 were analyzed according to four regimens of conditioning intensity: reduced-intensity conditioning (RIC) (either intermediate RIC (IntermRIC) or non-myeloablative (NMA) RIC), and myeloablative conditioning (MC) in 718 patients (either conventional MC or hyperintense MC. In multivariate cox analysis, patients undergoing NMA transplantation had lower non-relapse mortality risk in the first 100 days after transplantation (P<0.01), but a higher risk beyond day +100 (P=0.02), as well as higher relapse incidence in the first 12 months (P<0.01), but the risk was similar in all groups beyond 12 months. The probabilities of PFS and OS up to 7 years were significantly lower only in the NMA subgroup (P0.01 for both). The 7-year OS was 53%, 29%, 56% and 51%, respectively. Our data suggest that prospective studies comparing RIC regimens (especially IntermRIC) with MC are appropriate in patients with AML and RAEB who are in a non-advanced disease status.

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.

A total of 654 centers from 48 countries were contacted for the 2010 survey. In all, 634 centers reported a total of 33 362 hematopoietic SCT (HSCT) with 30 012 patients receiving their first transplant (12 276 allogeneic (41%) and 17 736 autologous (59%)). Main indications were leukemias: 9355 (31%; 93% allogeneic), lymphoid neoplasias specifically Non Hodgkin's lymphoma, Hodgkin's lymphoma and plasma cell disorders: 17 362 (58%; 12% allogeneic), solid tumors: 1585 (5%; 6% allogeneic) and non-malignant disorders: 1609 (6%; 88% allogeneic). There were more unrelated donors than HLA-identical sibling donors (53% versus 41%); the proportion of peripheral blood as stem cell source was 99% for autologous and 71% for allogeneic HSCT. Cord blood was primarily used in allogeneic transplants (6% of total) with three autologous cord blood HSCT being reported. The number of transplants has increased by 19% since 2005 (allogeneic 37% and autologous 9%) and continued to increase by about 1100 HSCT per year since 2000. Patterns of increase were distinct and different. The data show the development of transplantation in Europe since 1990, with the number of patients receiving a HSCT increasing from 4200 to over 30 000 annually. The most impressive trend seen is the steady increase of unrelated donor transplantation, in parallel to the availability of unrelated donors through donor registries.

Systemic amyloid light-chain (AL) amyloidosis is a protein conformation disorder caused by clonal plasma cell dyscrasias. Symptoms result from fibrillar extracellular deposits in various tissues. The deposits disrupt organ function and ultimately lead to death. The prognosis is poor and depends mostly on the severity of cardiac involvement. The treatment is derived from the therapy of multiple myeloma with the main goal being to reach a complete hematological remission (CR). High-dose melphalan (HDM) and autologous hematopoietic cell transplantation can induce CR rates in about 40%. The main concern was the high transplant-related mortality of up to 40% due to organ dysfunction, which could be reduced to <12% by careful patient selection in experienced centers. However, >50% of patients in CR survive longer than 10 years, suggesting that HDM has the potential to change the natural course of the disease. As there is evidence that 'graft-versus-plasma-cell-dyscrasia' effects are active in AL amyloidosis, allogeneic hematopoietic cell transplantation might be an option for younger patients with preserved organ functions who have relapsed after HDM.

We studied GVHD after donor lymphocyte infusion (DLI) in 328 patients with relapsed CML between 1991 and 2004 . A total of 122 patients (38%) developed some form of GVHD. We analyzed GVHD by clinical presentation (acute or chronic GVHD) and onset time after the first DLI (early (< or =45 days) or late (>45 days)). There was a significant overlap between onset time and clinical presentation. Some form of GVHD occurred at a median of 104 days, acute GVHD at 45 days and chronic GVHD at 181 days after DLI. The clinical presentation was acute GVHD in 71 patients, of whom 31 subsequently developed chronic GVHD subsequently. De novo chronic GVHD was seen in 51 patients. OS for all patients was 69% (95% confidence interval (CI) 63-75) at 5 years, DLI-related mortality was 11% (95% CI 8-15) and disease-related mortality was 20% (95% CI 16-25). Risk factors for developing GVHD after DLI were T-cell dose at first DLI, the time interval from transplant to DLI and donor type. In time-dependent multivariate analysis, GVHD after DLI was associated with a risk of death of 2.3-fold compared with patients without GVHD. Clinical presentation as acute GVHD and early onset GVHD were associated with increased mortality.

The European Group for Blood and Marrow Transplantation regularly publishes special reports on the current practice of haematopoietic SCT for haematological diseases, solid tumours and immune disorders in Europe. Major changes have occurred since the first report was published. HSCT today includes grafting with allogeneic and autologous stem cells derived from BM, peripheral blood and cord blood. With reduced-intensity conditioning regimens in allogeneic transplantation, the age limit has increased, permitting the inclusion of older patients. New indications have emerged, such as autoimmune disorders and AL amyloidosis for autologous HSCT and solid tumours, myeloproliferative syndromes and specific subgroups of lymphomas for allogeneic transplants. The introduction of alternative therapies, such as imatinib for CML, has challenged well-established indications. An updated report with revised tables and operating definitions is presented.

Autologous hematopoietic stem cells (HSCs) harvested as back-up prior to allogeneic hematopoietic SCT (HSCT) may potentially be useful in the treatment of graft failure or in cases with severe GVHD. Here, we studied the general policies and indications for autologous back-up harvest among the European Group for Blood and Marrow Transplantation centers in the year 2003. The outcome of patients receiving autologous back-up transfusion between 1998 and 2002 was evaluated retrospectively. The responses from 94 centers showed that 48 centers had a general policy with variable indications for autologous back-up harvest. Thirty-five patients with graft failure (25), GVHD (8) or relapse (2) retransplanted with autologous back-ups were reported. Autologous back-up transfusion was performed at a median of 35 days (patients with graft failure) or 90 days (patients with GVHD) after allogeneic HSCT. Within 100 days after autologous HSCT, 21 patients died from treatment-related complications (19) or relapse (2). Estimated overall survival at 1 year was 16% (95% CI 0-32%) for patients treated for graft failure and 13% (95% CI 0-37%) for GVHD patients. In conclusion, our data demonstrate that the indication for autologous back-up harvests is limited and that general storage and use cannot be recommended unless in selected prospective studies.

Mucosal damage to the intestines induced by myeloablative conditioning for allogeneic PBSC transplant (PBSCT) can be determined by the concentration of citrulline, which is a functional marker of small intestinal enterocytes. Low citrulline concentrations in blood coincide with and are a response to severe mucosal barrier injury. We treated 29 patients with high-dose melphalan 200 mg/m(2) (Mel-200) to prepare for an autologous PBSCT and collected plasma samples from each patient starting before the myeloablative regimen and three times per week thereafter until discharge. The baseline citrulline concentration was 27.6 mM+/-4.0 (mean+/-95% confidence interval; CI), and citrulline concentrations declined rapidly thereafter reaching a nadir averaging 6.7 mM+/-2.7, 12 days after starting Mel-200. Citrulline concentrations, only increased gradually and were still low (12 mM+/-4) at discharge. A total of 20 patients developed fever, which was associated with bacteraemia in 10 cases. Their mean citrulline concentrations were lower at 5.5 mM+/-1.5 than were those of patients without bacteraemia (10.2 mM+/-3.9). Importantly, neither the number of preceding neutropenic days nor the mean C-reactive protein (CRP) concentration at the onset of fever was different between these two groups. In conclusion, citrulline concentrations rapidly decline after Mel-200 reflecting intestinal mucosal barrier injury. Low citrulline, rather than the duration of neutropenia, is associated with bacteraemia indicating the importance of an intact mucosal barrier in neutropenic patients.

Donor lymphocyte infusion (DLI) after allogeneic SCT induces complete remissions in approximately 80% of patients with relapsed CML in chronic phase, but some patients do not respond to DLI. We studied absolute numbers of dendritic cell (DC) subsets and chimerism in T cells and two subsets of blood DCs (myeloid DCs (MDCs) and plasmacytoid DCs (PDCs)) in relation to DLI-induced alloreactivity. Based on T cell and DC chimerism, we identified three groups. Four patients were completely donor chimeric in T cells and DC subsets. These patients had an early stage of relapse, and three of the four patients attained complete molecular remission (CMolR) without significant GVHD. Six patients were completely donor in T cells and mixed chimeric in DC subsets. All patients entered CMolR, but this was associated with GVHD in four and cytopenia in three patients. Five patients had mixed chimerism in T cells and complete recipient chimerism in MDC; only two patients entered CMolR. Our data suggest that the combination of donor T cells and mixed chimerism in DC subsets induces a potent graft-versus-leukemia (GVL) effect in association with GVHD. DLI in patients with an early relapse and donor chimerism in both T cells and DC subsets results in GVL reactivity without GVHD.

We report the results of 65 patients with treatment-related myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) who were transplanted from an autograft and reported to the EBMT. The median age was 39 years (range, 3-69), and stem cell source was bone marrow (n = 31), or peripheral blood progenitor cells (n = 30), or the combination of both (n = 4). The primary disease was solid tumors (n = 37), Hodgkin's disease (n = 13), non-Hodgkin's lymphoma (n = 10), acute lymphoblastic leukemia (n = 2) or myeloproliferative syndromes (n = 3). The types of MDS were as follows: RAEB (n = 1; 2%), RAEB-t (n = 3; 5%), or AML (n = 56; 87%). The median time between diagnosis and transplantation was 5 months (range, 3-86). The Kaplan-Meier estimates of the probability of 3-year overall and disease-free survival were 35% (95% CI: 21-49%) and 32% (95% CI: 18-45%), respectively. The median leukocyte engraftment was faster after transplantation with peripheral blood stem cells than with bone marrow: 12 (range, 9-26) vs 29 (range, 11-67) days (P<0.001). The cumulative incidence of relapse was 58% (95% CI: 44-72%) and of treatment-related mortality 12% (95% CI: 6-38%). Lower relapse rate was seen in patients transplanted in first complete remission (CR1 vs non-CR1: 3 years: 48 vs 89%; P = 0.05). Furthermore, age beyond 40 years resulted in a higher treatment-related mortality (47 vs 7%; P = 0.01). In a multivariate analysis, transplantation in CR1 age as well as their interaction influenced overall survival significantly. Autologous transplantation may cure a substantial number of patients with treatment-related MDS/AML, especially if they are in CR1 and of younger age.

In a multicentre retrospective EBMT database study, we analysed factors influencing outcome in 38 patients with MDS/sAML who were transplanted with stem cells from their syngeneic twin and compared those to 1444 patients who were transplanted from an HLA-identical sibling. The median time to leukocyte and platelet engraftment was faster in the twin group: 14 vs 17 (P=0.02) and 16 vs 26 days (P=0.09), respectively. The 5 years cumulative incidence of treatment-related mortality (TRM) was higher in the sibling than in the twin group (38 vs 27%; P=0.05). The 5 year cumulative incidence of relapse was 32% (95% CI: 29-35%) for the siblings and 39% (95% CI: 26-60%; P=0.6) for the twins. A trend for better 5-years disease-free and overall survival was observed in the twin group: 34% (95% CI: 14-54%) vs 28% (95% CI: 25-31%; P=0.2) and 36% (95% CI: 15-57%) vs 32% (95% CI: 29-35%; P=0.09), respectively. In a multivariate analysis, stem cell transplantation from identical twins had a lower TRM: HR: 0.4 (95% CI: 0.2-0.9; P=0.03). The relapse rate was similar for both groups with a HR of 1.2 (95% CI: 0.07-2.1; P=0.5), with a better survival for the twins: HR 0.6 (95% CI: 0.4-1.0; P=0.07). We conclude that twin transplantation in MDS/sAML is associated with a similar relapse risk, a lower TRM and a trend for better overall survival in comparison to transplantation from HLA-identical siblings.

We retrospectively analysed the outcome of voluntary unrelated donor (VUD)-SCT in 56 patients after conditioning without or with ATG. All received partially lymphocyte-depleted grafts. Four of 17 patients (24%) who were not given ATG rejected their grafts, as did one of 33 (3%) conditioned with ATG (P=0.02). The incidences of acute graft-versus-host disease grade III/IV were 29 and 6%, respectively (P=0.02), and probabilities of 1-year transplant-related mortality were 64% (95% CI, 44-84%) and 27% (95% CI, 12-42%), respectively (P=0.004). Projected at 3 years, probability of survival was 18% (95% CI, 2-34%) after conditioning without ATG and 60% (95% CI, 43-70%) after conditioning with ATG (P=0.002). Probabilities of disease-free survival (DFS) were 18% (95% CI, 2-34%) and 45% (95% CI, 27-63%), respectively (P=0.005). Patients who did not receive ATG had a probability of current DFS of 18% (95% CI, 3-34%) and this was 60% (95% CI, 43-77%) for the patients conditioned with ATG (P<0.001). We conclude that the addition of ATG to the conditioning regimen is associated with a significantly more favourable outcome in recipients of partially T-cell-depleted grafts from VUDs., (Copyright 2004 Nature Publishing Group)