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We analyzed data relative to cell content in 88 consecutive patients receiving HLA haploidentical bone marrow (BM) transplants with post-transplantation cyclophosphamide (PT-CY). Median age was 54.5 (range, 17-72); diagnoses were acute leukemia (n = 46), lymphoproliferative disorders (n = 24), myelofibrosis (n = 11) and myelodysplastic syndromes (n = 5). Total nucleated cell (TNC) and CD34+, CD3+, CD4+ and CD8+ cell doses were stratified as higher than first, second and third quartile and the dose effect on various clinical outcomes was assessed. Median time to engraftment was 17 days for neutrophils and 24 days for platelets. To receive a dose of TNC ≥3.2 x 10 6 /kg or CD34+ cells ≥2.7 x 10 6 /kg significantly shortened the time to neutrophil and platelet engraftment and reduced the blood product requirements in the 30-day period after transplantation. Overall, TNC and CD34+ cell doses had no effect on acute graft-versus-host disease (GVHD) incidence, whereas patients receiving higher CD3+ and CD8+ cell doses seemed to have less chronic GVHD. No effect on non-relapse mortality, progression-free survival and overall survival was observed at different cell dose thresholds. These data suggest that in HLA haploidentical BM transplant with PT-CY, appropriate cell doses are relevant to the engraftment. The association between low CD3+/CD8+ cells and chronic GVHD deserves further investigation., Competing Interests: Declaration of Competing Interest The authors have no commercial, proprietary, or financial interest in the products or companies described in this article., (Copyright © 2020 International Society for Cell and Gene Therapy. Published by Elsevier Inc. All rights reserved.)

To avoid risk for allogeneic transfusions in healthy bone marrow (BM) donors, 1-2 preoperative autologous blood donations (PAD) are usually collected before the BM harvest. We analysed the haematological parameters in BM donors before and after the harvest, to assess the efficacy of this practice in limiting the postharvest anaemia. Overall, 102 consecutive donors underwent BM harvest preceded by one (26 cases) or two PAD (76 cases), which were infused during BM collection. We analysed the parameters related to donors, PAD timing and BM graft characteristics. PAD induced a significant decrease in Hb (from 14·6 g/dl, IQ range 13·3-15·5 to12·9 g/dl, IQ range 11·8-13·9; P < 0·0001) in all donors, with a median Hb loss at day -1 of 10·9% (IQ range 6·8-14·2). The PAD-related Hb decrease was independent of sex or number of PAD, and was inversely related to the time elapsed from first or last PAD. In comparison with values recorded at day-1, BM harvest produced an additional Hb decrease, accounting for a median Hb loss of 18·9% (IQ range 14·9-24·4). Overall, in comparison with pre-PAD values, Hb levels at day +1 were reduced of 28·9% (IQ range 23·6-32·2), independently if donors had 1 or 2 PAD reinfused. In conclusion, these data show that two PAD do not carry any advantage over one PAD. An eventual benefit of PAD can be achieved only if an adequate interval between PAD and BM harvest elapses. Prospective randomized studies could be worth to establish if any role for PAD does exist in BM donors., (© 2019 International Society of Blood Transfusion.)

We report a modified post-transplant cyclophosphamide (PT-CY) regimen, for unmanipulated haploidentical marrow transplants, in 150 patients with acute myeloid leukemia (AML). All patients received a myeloablative regimen, cyclosporine A (CsA) on day 0, mycophenolate on day +1, and PT-CY 50 mg/kg on days +3 and +5. The median age was 51 (range, 17-74) years, 51 (34%) patients had active disease at transplant, and the median follow-up of surviving patients 903 (range, 150-1955) days. The cumulative incidence (CI) of engraftment, acute graft-versus-host disease (GVHD) grade II to IV, and moderate/severe chronic GVHD was 92%, 17%, and 15%, respectively. The 4-year CI of transplant-related mortality (TRM) and relapse was 20% and 24%, respectively. Four-year survival for remission patients was 72% (74% versus 67% for <60 or ≥60 years of age) and 26% for advanced patients (17% versus 41% for <60 or ≥60 years of age). In a multivariate analysis, active disease at transplant was the only negative predictor of survival, TRM and relapse. The original PT-CY regimen can be modified with CsA on day 0, still providing protection against GVHD, low toxicity, and encouraging low relapse incidence in AML patients, also over 60 years of age., (Copyright © 2018. Published by Elsevier Inc.)

Haploidentical donors are now increasingly considered for transplantation in the absence of HLA-matched donors or when an urgent transplant is needed. Donor-specific anti-HLA antibodies (DSA) have been recently recognized as an important barrier against successful engraftment of donor cells, which can affect transplant survival. DSA appear more prevalent in this type of transplant due to higher likelihood of alloimmunization of multiparous females against offspring's HLA antigens, and the degree of mismatch. Here we summarize the evidence for the role of DSA in the development of primary graft failure in haploidentical transplantation and provide consensus recommendations from the European Society for Blood and Marrow Transplant Group on testing, monitoring, and treatment of patients with DSA receiving haploidentical hematopoietic progenitor cell transplantation.

Background: Incidence of graft-versus-host disease (GVHD) in haploidentical bone marrow (BM) transplants using posttransplantion cyclophosphamide (PT-Cy) is low, whereas GVHD using mobilized peripheral blood stem cells (PBSC) ranges between 30% and 40%., Methods: To evaluate the effect of stem cell source in haploidentical transplantation with PT-Cy, we analyzed 451 patients transplanted for acute myeloid leukemia or acute lymphoblastic leukemia reported to the European Society for Blood and Marrow Transplantation., Results: BM was used in 260 patients, and PBSC were used in 191 patients. The median follow-up was 21 months. Engraftment was lower in BM (92% vs 95%, P < 0.001). BM was associated with a lower incidence of stage II-IV and stage III-IV acute GVHD (21% vs 38%, P ≤ .01; and 4% vs 14%, P < .01, respectively). No difference in chronic GVHD, relapse, or nonrelapse mortality were found for PBSC or BM. The 2-year overall survival (OS) was 55% versus 56% (P = .57) and leukemia-free survival (LFS) was 49% versus 54% (P = .74) for BM and PBSC, respectively. On multivariate analysis, PBSC were associated with an increased risk of stage II-IV (hazard ratio [HR], 2.1; P < .001) and stage III-IV acute GVHD (HR, 3.8; P < .001). For LFS and OS, reduced intensity conditioning was the only factor associated with treatment failure (LFS: HR, 1.40; P = .04) and relapse (HR, 1.62; P = .02)., Conclusion: In patients with acute leukemia in first or second remission receiving haploidentical transplantation with PT-Cy, the use of PBSC increases the risk of acute GVHD, whereas survival outcomes are comparable. Cancer 2018;124:1428-37. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

We studied the impact of HLA mismatching on the outcome of 318 consecutive patients who received an unmanipulated haploidentical bone marrow transplant, followed by post-transplant cyclophosphamide (PTCy). The number of HLA-mismatched antigens was tested for its impact on overall survival (OS) and nonrelapse mortality (NRM), whereas HLA mismatches in the graft-versus-host (GVH) direction were tested for prediction of graft-versus-host disease (GVHD and relapse. Finally, we studied whether graft rejection correlated with the number of HLA mismatched antigens in host-versus-graft (HVG) direction. Two hundred thirty-one donor-recipient pairs (72%) had 4/8 mismatches at the -A, -B, -C, -DRB1 HLA loci. HLA mismatches did not predict the 2-year OS (hazard ratio, .83; P = .58) and NRM (subhazard ratio, 1.08; P = .93). The cumulative incidence of acute GVHD (P = .13), 1-year chronic GVHD (P = .84), and relapse rate (P = .26) did not correlate with univectorial GVH mismatches. Similarly, no correlation was observed between the amount of HLA mismatch in the HVG direction and graft rejection. In multivariate analysis advanced disease at transplant was the strongest predictor of survival, NRM, relapse, and graft rejection. In conclusion, the degree of HLA mismatching should not be used as a criterion to select family haploidentical donors when using bone marrow as stem cell source and PTCy for GVHD prophylaxis., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Standard front-line treatment for acquired aplastic anemia (AA) for patients is either immunosuppressive therapy (IST) or bone marrow transplantation (BMT), usually from an HLA identical sibling. Whereas long-term survival is comparable with either treatment, important differences remain: IST patients may have incomplete or no recovery, are exposed to late clonal disorders and relapse of the original disease. Transplantation is a curative treatment, but patients are exposed to transplant-related complications both acute and chronic, such as chronic graft versus host disease (cGvHD). In the year 2000, a study by the European Group for Blood and Marrow Transplantation (EBMT), looked at failure free survival (FFS), in patients receiving first-line BMT from an HLA identical sibling, or the first-line IST. Young patients with low neutrophil counts benefited of the first-line BMT; the opposite was true for older patients with higher neutrophil counts; and a third intermediate group of patients had comparable survival irrespective of the first-line therapy. We have now studied a more recent cohort of patients to assess whether things have changed over the years. We have found similar results, although overall survival has improved, as a consequence of changes in the IST and BMT protocols.

We explored the feasibility of unrelated donor haematopoietic stem cell transplant (HSCT) upfront without prior immunosuppressive therapy (IST) in paediatric idiopathic severe aplastic anaemia (SAA). This cohort was then compared to matched historical controls who had undergone first-line therapy with a matched sibling/family donor (MSD) HSCT (n = 87) or IST with horse antithymocyte globulin and ciclosporin (n = 58) or second-line therapy with unrelated donor HSCT post-failed IST (n = 24). The 2-year overall survival in the upfront cohort was 96 ± 4% compared to 91 ± 3% in the MSD controls (P = 0·30) and 94 ± 3% in the IST controls (P = 0·68) and 74 ± 9% in the unrelated donor HSCT post-IST failure controls (P = 0·02).The 2-year event-free survival in the upfront cohort was 92 ± 5% compared to 87 ± 4% in MSD controls (P = 0·37), 40 ± 7% in IST controls (P = 0·0001) and 74 ± 9% in the unrelated donor HSCT post-IST failure controls (n = 24) (P = 0·02). Outcomes for upfront-unrelated donor HSCT in paediatric idiopathic SAA were similar to MSD HSCT and superior to IST and unrelated donor HSCT post-IST failure. Front-line therapy with matched unrelated donor HSCT is a novel treatment approach and could be considered as first-line therapy in selected paediatric patients who lack a MSD., (© 2015 John Wiley & Sons Ltd.)

Mechanisms of hematopoietic reconstitution after bone marrow (BM) transplantation remain largely unknown. We applied a computational quantification software application to hybrid 18F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) images to assess activity and distribution of the hematopoietic system throughout the whole skeleton of recently transplanted patients. Thirty-four patients underwent PET/CT 30 days after either adult stem cell transplantation (allogeneic cell transplantation [ACT]; n = 18) or cord blood transplantation (CBT; n = 16). Our software automatically recognized compact bone volume and trabecular bone volume (IBV) in CT slices. Within IBV, coregistered PET data were extracted to identify the active BM (ABM) from the inactive tissue. Patients were compared with 34 matched controls chosen among a published normalcy database. Whole body ABM increased in ACT and CBT when compared with controls (12.4 ± 3 and 12.8 ± 6.8 vs 8.1 ± 2.6 mL/kg of ideal body weight [IBW], P < .001). In long bones, ABM increased three- and sixfold in CBT and ACT, respectively, compared with controls (0.9 ± 0.9 and 1.7 ± 2.5 vs 0.3 ± 0.3 mL/kg IBW, P < .01). These data document an unexpected distribution of transplanted BM into previously abandoned BM sites., (© 2015 by The American Society of Hematology.)

Although transplant practices have changed over the last decades, no information is available on trends in incidence and outcome of chronic graft-versus-host disease (cGVHD) over time. This study used the central database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to describe time trends for cGVHD incidence, nonrelapse mortality, and risk factors for cGVHD. The 12-year period was divided into 3 intervals, 1995 to 1999, 2000 to 2003, and 2004 to 2007, and included 26,563 patients with acute leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. Multivariate analysis showed an increased incidence of cGVHD in more recent years (odds ratio = 1.19, P < .0001), and this trend was still seen when adjusting for donor type, graft type, or conditioning intensity. In patients with cGVHD, nonrelapse mortality has decreased over time, but at 5 years there were no significant differences among different time periods. Risk factors for cGVHD were in line with previous studies. This is the first comprehensive characterization of the trends in cGVHD incidence and underscores the mounting need for addressing this major late complication of transplantation in future research., (Copyright © 2015 American Society for Blood and Marrow Transplantation. All rights reserved.)

This article addresses current transplant options for patients with acquired severe aplastic anemia (SAA). This discussion includes ongoing progress in the use of SAA in the setting of unrelated donor transplants, which now provide outcomes similar, though still not identical, to HLA-identical sibling transplants. Recent data on stem cell source, conditioning regimens, and graft-versus-host disease prophylaxis are outlined. Other donor types such as cord blood and haploidentical mismatched family donors are also discussed., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In this study, we investigated the factors affecting cell dose harvest and the role of cell dose on outcome. We analysed data from a cohort of 703 patients who underwent unrelated bone marrow transplantation facilitated by IBMDR in GITMO centers between 2002 and 2008. The median-infused cell doses is 3.7 × 10(8)/kg, the correlation between the nucleated cells requested from transplant centers and those harvested by collection centers was adequate. A harvested/requested cells ratio lower than 0.5 was observed only in 3% of harvests. A volume of harvested marrow higher than the median value of 1270 ml was related to a significant lower infused cell dose (χ(2): 44.4; P < 0.001). No patient- or donor-related variables significantly influenced the cell dose except for the recipient younger age (χ(2): 95.7; P < 0.001) and non-malignant diseases (χ(2): 33.8; P < 0.001). The cell dose resulted an independent predictor factor for a better outcome in patients affected by non-malignant disease (P = 0.05) while early disease malignant patients receiving a lower cell dose showed a higher risk of relapse (P = 0.05).

Fifty patients with high-risk hematologic malignancies, underwent an unmanipulated haploidentical bone marrow transplantation (BMT), followed by posttransplantation high-dose cyclophosphamide (PT-CY): the myeloablative (MA) conditioning consisted of thiotepa, busulfan, fludarabine (n = 35), or total body irradiation (TBI), fludarabine (n = 15). The median age was 42 years (range, 18-66 years); 23 patients were in remission, 27 had active disease, and 10 patients were receiving a second allograft. Graft-versus-host disease (GVHD) prophylaxis consisted in PT-CY on day +3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). Three patients died before engraftment, and 2 patients had autologous recovery: 45 patients (90%) had full-donor chimerism on day +30. The median day for neutrophil engraftment was day +18 (range, 13-30 days). The cumulative incidence of grade II-III acute GVHD (aGVHD) was 12%, and of moderate chronic GVHD (cGVHD) 10%. With a median follow-up for surviving patients of 333 days (range, 149-623 days), the cumulative incidence of transplantation-related mortality (TRM) was 18%, and the rate of relapse was 26%. The actuarial 22-month disease-free survival (DFS) rate was 68% for patients in remission and 37% for patients with active disease (P < .001). Causes of death were pneumonia (n = 3), hemorrhage (n = 3), sepsis (n = 3), and relapse (n = 7). In conclusion, an MA conditioning regimen followed by haploidentical BMT with PT-CY results in a low risk of aGVHD and cGVHD and encouraging rates of TRM and DFS., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: We analyzed the outcome of 100 patients with acquired severe aplastic anemia undergoing an alternative donor transplant, after immune suppressive therapy had failed., Design and Methods: As a conditioning regimen, patients received either a combination of fludarabine, cyclophosphamide, and antithymocyte globulin (n=52, median age 13 years) or this combination with the addition of low dose (2 Gy) total body irradiation (n=48, median age 27 years)., Results: With a median follow-up of 1665 and 765 days, the actuarial 5-year survival was 73% for the group that received fludarabine, cyclophosphamide, and antithymocyte globulin and 79% for the group given the conditioning regimen including total body irradiation. Acute graft-versus-host disease grade III-IV was seen in 18% and 7% of the groups, respectively. Graft failure was seen in 17 patients with an overall cumulative incidence of 17% in patients receiving conditioning with or without total body irradiation: 9 of these 17 patients survive in the long-term. The most significant predictor of survival was the interval between diagnosis and transplantation, with 5-year survival rates of 87% and 55% for patients grafted within 2 years of diagnosis and more than 2 years after diagnosis, respectively (P=0.0004). Major causes of death were graft failure (n=7), post-transplant-lymphoproliferative-disease (n=4) and graft-versus-host disease (n=4)., Conclusions: This study confirms positive results of alternative donor transplants in patients with severe aplastic anemia, the best outcomes being achieved in patients grafted within 2 years of diagnosis. Prevention of rejection and Epstein-Barr virus reactivation may further improve these results.

Background: Most allogeneic haematopoietic stem cell transplants now use peripheral blood progenitor cell transplantation (PBPCT) instead of bone-marrow transplantation (BMT). Long-term data on outcome and late effects of PBPCT compared with BMT are scarce. Here we present long-term data from a randomised study comparing PBPCT with BMT., Methods: Between February, 1995, and September, 1999, 329 patients with leukaemia received either PBPCT (n=163) or BMT (n=166) from HLA-identical sibling donors after central randomisation accounting for stratification criteria. Follow-up data were collected via questionnaires from 87% (176 of 202; 84 PBPCT, 92 BMT) patients who survived for more than 3 years (median of 9.3 years) after transplantation. Efficacy analyses included all patients who received treatment. This study is registered with ClinicalTrials.gov, number NCT01020175., Findings: 10-year overall survival was 49.1% for patients who underwent PBPCT and 56.5% for patients who underwent BMT (HR 0.83, 95% CI 0.60-1.15; p=0.27). Leukaemia-free survival was 28.3% with BMT versus 13.0% with PBPCT (0.61, CI 0.32-1.16; p=0.12) for acute lymphoblastic leukaemia; 62.3% with BMT versus 47.1% with PBPCT for acute myeloid leukaemia (0.67, 0.39-1.16; p=0.16); and 40.2% with BMT versus 48.5% with PBPCT for chronic myeloid leukaemia (1.12, 0.73-1.74; p=0.60). More patients developed chronic graft-versus-host disease after PBPCT (n=56, 73%) than after BMT (n=46, 56%; p=0.021), with more frequent involvement of skin, liver, and oral mucosa, and more patients who underwent PBPCT needed immunosuppressive treatment 5 years after transplantation (n=20, 26%) than patients who had BMT (n=10, 12%; p=0.024). Nonetheless, there was no difference in performance status, return to work, incidence of bronchiolitis obliterans, and haematopoietic function between the two groups. 14 cases of secondary malignancies occurred (five after BMT, nine after PBPCT), resulting in a cumulative incidence of 3% and 7% after BMT and PBPCT (p=0.17), respectively., Interpretation: More than 9 years after transplantation, overall and leukaemia-free survival remain similar in patients who underwent BMT and PBPCT. Differences in the incidence of chronic graft-versus-host disease and the duration of immunosuppression exist, but do not affect survival, general health status, or late events., Funding: No external funding was received., (2010 Elsevier Ltd. All rights reserved.)

Using the Center for International Blood and Marrow Transplant Research (CIBMTR) data, we compared the transplant outcomes of patients with chronic myelogenous leukemia (CML) who were nonsmokers (NS) and past or current smokers (PCS). There were 2193 NS and 625 PCS who received matched sibling and unrelated donor allografts for CML in first chronic phase. We looked for dose effects and identified low and high dose smoking groups (>10 pack years, >1 pack per day). Outcomes were adjusted for known prognostic variables including the European Group for Blood and Marrow Transplant (EBMT) risk score. In multivariate analyses of sibling allograft recipients, relapse risk (RR) was higher (RR=1.67, P=.003) in smokers than NS, but the dose effects were not consistent. High-dose smokers experienced a 50% treatment-related mortality (TRM) versus 28% in the NS group at 5 years on univariate analysis, and the RR was 1.57 (P=.005) on multivariate analysis. Overall survival (OS) at 5 years was 68% in NS versus 62% in the low-dose smoking group versus 50% in the high-dose smoking group (P < .001). Smoking did not significantly affect outcomes in unrelated donor recipients, but numbers were smaller. High-dose smoking is associated with a reduction in OS in patients having sibling allografts for CML. A prospective study with detailed demographic, pulmonary function, and quality-of-life data would improve our understanding of this issue.

The Italian Society of Hematology (SIE), the Italian Society of Experimental Haematology (SIES) and the Italian Group for Bone Marrow Transplantation (GITMO) commissioned a project to develop practice guidelines for the initial work-up, therapy and follow-up of classical Hodgkin's lymphoma. Key questions to the clinical evaluation and treatment of this disease were formulated by an Advisory Committee, discussed and approved by an Expert Panel (EP) composed of senior hematologists and one radiotherapist. After a comprehensive and systematic literature review, the EP recommendations were graded according to their supporting evidence. An explicit approach to consensus methodologies was used for evidence interpretation and for producing recommendations in the absence of a strong evidence. The EP decided that the target domain of the guidelines should include only classical Hodgkin's lymphoma, as defined by the WHO classification, and exclude lymphocyte predominant histology. Distinct recommendations were produced for initial work-up, first-line therapy of early and advanced stage disease, monitoring procedures and salvage therapy, including hemopoietic stem cell transplant. Separate recommendations were formulated for elderly patients. Pre-treatment volumetric CT scan of the neck, thorax, abdomen, and pelvis is mandatory, while FDG-PET is recommended. As to the therapy of early stage disease, a combined modality approach is still recommended with ABVD followed by involved-field radiotherapy; the number of courses of ABVD will depend on the patient risk category (favorable or unfavorable). Full-term chemotherapy with ABVD is recommended in advanced stage disease; adjuvant radiotherapy in patients without initial bulk who achieved a complete remission is not recommended. In the elderly, chemotherapy regimens more intensive than ABVD are not recommended. Early evaluation of response with FDG-PET scan is suggested. Relapsed or refractory patients should receive high-dose chemotherapy and autologous hemopoietic stem cells transplant. Allogeneic transplant is recommended in patients relapsing after autologous transplant. All fertile patients should be informed of the possible effects of therapy on gonadal function and fertility preservation measures should be taken before the initiation of therapy.

Acquired severe aplastic anemia can be treated successfully with either immunosuppressive therapy or bone marrow transplantation. Although immunosuppressive therapy can be readily administered to all patients, it is not a curative approach and is associated with a higher risk of clonal evolution than is transplantation, which yields rapid and long-lasting hematologic remission. This article reviews the key diagnostic and prognostic factors that influence the choice of therapy in patients with acquired aplastic anemia.

We analyzed the outcome of 692 patients with severe aplastic anemia (SAA) receiving transplants from HLA-matched siblings. A total of 134 grafts were peripheral blood progenitor cell (PBPC) grafts, and 558 were bone marrow (BM) grafts. Rates of hematopoietic recovery and grades 2 to 4 chronic graft-versus-host disease (GVHD) were similar after PBPC and BM transplantations regardless of age at transplantation. In patients older than 20 years, chronic GVHD and overall mortality rates were similar after PBPC and BM transplantations. In patients younger than 20 years, rates of chronic GVHD (relative risk [RR] 2.82; P = .002) and overall mortality (RR 2.04; P = .024) were higher after transplantation of PBPCs than after transplantation of BM. In younger patients, the 5-year probabilities of overall survival were 73% and 85% after PBPC and BM transplantations, respectively. Corresponding probabilities for older patients were 52% and 64%. These data indicate that BM grafts are preferred to PBPC grafts in young patients undergoing HLA-matched sibling donor transplantation for SAA.

Background and Objectives: The treatment of acquired aplastic anemia (AA) is based on allogeneic bone marrow transplantation (BMT) and immunosuppressive therapy. The aim of this study was to assess the outcome of children and adults with AA treated in the last decade, and to determine whether results have improved in two sequential time periods,1991-1996 and 1997-2002., Design and Methods: Two-thousands and seventy-nine consecutive patients with AA, classified according to first-line treatment: BMT (n=1567) or immunosuppressive therapy (n= 912), the patients for the two sequential time periods were studied. Analyses included variables related to patients, disease and transplant., Results: The actuarial 10-year survival was 73% and 68% for BMT or immunosuppressive treatment, respectively (p=0.002). BMT outcome improved significantly with time (69% and 77%, p=001) for both matched sibling donor (MSD) (74% and 80%; p=0.003 ), alternative donor (38% and 65% p=0.0001), and was better in children (79% versus 68%, p<0.0001). Multivariate analysis: favorable predictors (p<0.001) were younger age, transplant beyond 1996, MSD, a short interval diagnosis-transplant , no irradiation. IS: no significant improvement over time (69% and 73% p=0.29). Survival was significantly better in children (81% versus 70%, p=0.001), especially in vSAA(83% versus 62%, p=0.0002). Combined IS was superior to single drug treatment (77% versus 62%, p=0.002). Multivariate analysis: significant predictors of survival: age > or =16 years (p=0.0009), longer interval between diagnosis -treatment (p=0.04), single drug versus combined IS (p=0.02)., Interpretation and Conclusions: Outcome has improved in subsets of AA patients: those receiving first- line BMT and children with vSAA treated with IS. Age remains a major predictor for both treatments. Early intervention is associated with a significantly better outcome and is strongly recommended, whatever the first-line therapy.

Matching for HLA class I alleles, including HLA-C, is an important criterion for outcome of unrelated donor transplantation. However, haplotype-mismatched transplantations for myeloid malignancies, mismatched for killer immunoglobulin-like receptor (KIR) ligands in the graft-versus-host (GVH) direction, is associated with lower rates of graft-versus-host disease (GVHD), relapse, and mortality. This study investigated the effect of KIR ligand mismatching on the outcome of unrelated donor transplantation. The outcomes after 1571 unrelated donor transplantations for myeloid malignancies where donor-recipient pairs were HLA-A, -B, -C, and -DRB1 matched (n = 1004), GVH KIR ligand-mismatched (n = 137), host-versus-graft (HVG) KIR ligand-mismatched (n = 170), and HLA-B and/or -C-mismatched but KIR ligand-matched (n = 260) were compared using Cox regression models. Treatment-related mortality (TRM), treatment failure, and overall mortality were lowest after matched transplantations. Patients who received grafts from donors mismatched at the KIR ligand in the GVH or HVG direction and mismatched at HLA-B and/or C but matched at the KIR ligand had similar rates of TRM, treatment failure, and overall mortality. There were no differences in leukemia recurrence between the 4 groups. These results do not support the choice of an unrelated donor on the basis of KIR ligand mismatch determined from HLA typing.

This study reports outcomes of allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning (RIC) in 186 patients with chronic myeloid leukemia (CML) from the European Group for Blood and Marrow Transplantation (EBMT). The median age was 50 years, and 64% were in first chronic phase (CP1), CP2 13%, accelerated phase 17%, and blast crises 6%. The median EBMT transplant score was 3. The day 100 transplantation-related mortality (TRM) was 6.1% (confidence interval [CI], 3.4%-11%) but rose to 23.3% (CI, 14%-27%) at 2 years. Fludarabine, busulfan, and antithymocyte globulin (Fd/Bu/ATG) was associated with the lowest TRM of 11.6% (CI, 4.7%-11%) at 1 year. Acute graft-versus-host disease (GvHD) grade II to IV occurred in 32% and chronic GvHD in 43% (extensive in 24%). ATG was associated with a lower incidence of chronic GvHD (cGvHD). The overall survival (OS) and progression-free survival (PFS) at 3 years were 58% (CI, 50%-66%) and 37% (CI, 30%-45%), respectively. Adverse OS was associated with advanced disease (relative risk [RR], 3.4). PFS was inferior in advanced disease (RR, 2.7) and a trend to improved outcomes with Fd/Bu/ATG (RR, 0.58). RIC allografts are feasible in CML in first or second CP. Since no other RIC regimen demonstrated superiority, Fd/Bu/ATG should be considered as baseline in future prospective trials.

Background and Objectives: Transplant-related mortality (TRM) following allogeneic hematopoietic stem cell transplantation (HSCT) has been reported to be related to disease stage, duratiion of disease and type of donor. Furthermore, the outcome of transplants performed in the 1990s appears to be better than that of transplants done in the previous decade. The aims of this study were to determine whether these relationships still hold and whether the outcome of transplants is continuing to improve., Design and Methods: We analyzed 1180 consecutive patients with leukemia (n=979) or other hematologic malignancies (n=201) undergoing HSCT in 4 time periods: before 1990, 1991-1995, 1996-2000, and 2001-2002. Changes during these eras include increasing patient age, more unrelated transplants, more patients with advanced disease, different graft-versus-host disease (GvHD) prophylaxis, and different management of infections., Results: The actuarial 2-year transplant-related mortality (TRM) differed significantly between the transplant eras (p<0.001) with a significant interaction with disease phase (p=0.018). In patients in first remission (n=585) TRM was 34%, 25%, 21% and 6% in the four transplant eras. The reduction in TRM was less evident in patients in second remission (n=284) (37%, 35%, 30%, 25%) and absent in relapsed patients (n=311) (TRM=45%, 41%, 29%, 51%). This is a consequence of reductions in GvHD, infections and multiorgan failure among patients in remission but not among those who relapse. The actuarial 2-year survival has improved significantly in patients in first remission (54%, 66%, 72%, 78%) but not in those in second remission (38%, 46%, 52%,45%), or relapsed patients (31%, 25%, 36%, 21%)., Interpretation and Conclusions: In conclusion, TRM has been significantly reduced in first remission patients, suggesting an allograft should be considered in this phase, when appropriate, without delay. There has been no improvement in survival for patients beyond first remission, due to persisting high risk of infections and organ toxicity, a possible consequence of prolonged pre-transplant chemotherapy and neutropenia.

Background and Objectives: Graft-versus-host disease (GVHD) is a complex syndrome observed after bone marrow transplantation (BMT) affecting several organs including the lower genital female tract. We tried to evaluate the incidence of genital tract involvement and whether there are specific risk factors., Design and Methods: A retrospective study was conducted in order to describe genital manifestations of GVHD and evaluate its incidence, severity and remission among 213 females who underwent BMT. The risk factors studied were previous pregnancies, vaginal cultures just before BMT and hormonal replacement therapy (HRT)., Results: Genital lesions considered as expression of GVHD were found in 53 patients (24.9%). They appeared in the first 100 days after BMT in 12 women and beyond in 41 cases. Seventy-three percent of patients with such lesions showed some evidence of chronic GVHD elsewhere. The proposed grading, the first attempt of its kind, showed that genital chronic GVHD was minimal in 66%, moderate in 22% and severe in 12% of patients. Vaginal fibrosis, sometimes with complete obstruction, was seen in this last form. This occurred in 86.8% of patients after 2-157 months (median 22) while persistent GVHD was observed in 7 of them. In our sample no significant association was found between genital GVHD and previous pregnancies or vaginal infections at BMT, while HRT seems poorly associated with gynecological manifestations of GVHD (p=0.049)., Interpretation and Conclusions: Genital GVHD is not unusual after BMT. It can seriously affect female sexuality and the overall quality of life. We suggest stressing the importance of early detection of genital involvement in order to prevent the most serious lesions. Further studies are needed to identify the triggering factors associated with the development of genital GVHD.

Delayed hematopoietic recovery is the main factor precluding a wider use of cord blood (CB) transplants. We hypothesized that this delayed engraftment might not be related to an insufficient number of stem cells in the graft, but to an intrinsic difficulty of these cells to undergo differentiation. To test our hypothesis, 2 groups of children were compared; 12 received a CB transplant and 12 an adult bone marrow (BM) transplant. We studied neutrophil and platelet recovery and, at a median time of approximately 1 year after transplantation, the frequency of colony-forming cells (CFCs) and long-term culture initiating cells (LTC-ICs) in the BM of the 2 groups. Recipients of BM transplants received 1-log more cells and had significantly faster neutrophil and platelet recovery. Conversely, the frequency of committed and early progenitors was significantly higher in the BM of children given CB cells compared with BM transplant recipients (median count of CFC/2 x 10(4) BM mononuclear cells, 20 versus 11, P =.007; median count of LTC-IC/10(6) BM mononuclear cells, 8.2 versus 0.2 P =.001). CB, but not adult BM stem cells, can better restore the host hematopoietic progenitor cell reservoir; the delayed engraftment after CB transplantation may reflect the difficulty of CB progenitors to reprogram themselves toward differentiation.

We have studied the impact of cell dose on short- and long-term graft function and outcome in 905 patients undergoing an unmanipulated allogeneic bone marrow transplantation (BMT) from an HLA-identical sibling (n = 735), a one-antigen mismatched related donor (n = 35), or a matched unrelated donor (n = 135). Median number of nucleated cells infused was 3.4 x 10(8)/kg (25th percentile 2.4 x 10(8)/kg, 75th percentile 5 x 10(8)/kg). Patients were stratified according to cells infused in 3 groups: < or = 2.4 x 10(8)/kg (n = 247; low dose); >2.4 x 10(8)/kg and < or = 5 x 10(8)/kg (n = 452; intermediate dose); and >5 x 10(8)/kg (n = 206; high dose). Patients receiving high cell dose had significantly higher platelet counts on days +20, +50, +100, +180, and +365 after BMT (P <.01) and higher white blood cell counts on days +50, +100, and +180 after BMT (P <.01) as compared with other patients. The actuarial 5-year transplant-related mortality (TRM) was 41% versus 36% versus 28% (P =.01); overall survival was 45% versus 51% versus 56% (P =.0008); and disease-free survival was 41% versus 42% versus 48%, respectively, (P =.04) in patients receiving low, intermediate, or high cell dose. The cell dose effect was more pronounced in patients older than 30 years of age, with advanced disease, with chronic myeloid leukemia, and with alternative donors. In multivariate Cox analysis on TRM, cell dose was a significant predictor (P =.002; relative risk 0.6) together with donor type (P =.0001), year of transplantation (P =.0001), conditioning regimen (P =.02), and recipient age (P =.02). In conclusion, transplantation of high marrow cell dose is associated with reduced transplant mortality and improved survival and results in improved graft function both short and long term.

Purpose: Many attempts have been made to improve the results of allogeneic bone marrow transplantation (alloBMT) for patients with acute myeloid leukemia (AML) in first complete remission (CR1). Bone marrow cell dose has been reported to be an important factor in alloBMT; however, its true impact on relapse incidence (RI), leukemia-free survival (LFS), and nonrelapse mortality (NRM) in a large cohort of patients is unknown., Patients and Methods: From January 1992 to December 1999, 572 bone marrow transplantation recipients reported to the European Blood and Marrow Transplantation (EBMT) registry underwent allografting from an HLA-identical sibling donor with an unmanipulated bone marrow for AML in CR1., Results: The median number of nucleated cells (NCs) infused was 2.6 x 10(8)/kg. Estimated 5-year NRM, LFS, and RI for patients receiving more or less than 2.6 x 10(8) NCs/kg were, respectively, 18% +/- 5% v 30% +/- 5% (P =.001), 68% +/- 3% v 46% +/- 3% (P <.00001), and 14% +/- 4% v 24% +/- 5% (P =.004). The association of cell dose with the above outcomes was confirmed in multivariate analyses for NRM (relative risk [RR], 0.53; P =.0007), for LFS (RR, 0.53; P =.00008), and for RI (RR, 0.57; P =.02). The cell dose was also an important factor for neutrophil (RR, 0.76; P =.009) and platelet (RR, 0.77; P =.03) recoveries; however, it did not statistically influence the incidence of acute graft-versus-host disease., Conclusion: This study shows that marrow cell dose is one of the most important factors influencing relapse, NRM, and LFS after alloBMT for patients with AML in CR1. Therefore, increasing the marrow cell dose should substantially improve the survival of these patients.

Background and Objectives: Peripheral blood (PB) stem cell transplants are being increasingly used in the allogeneic setting, and are often preferred to the conventional bone marrow (BM) source. The aim of this report is to review available data on PB vs BM hematopoietic stem cell transplantation (HSCT). The discussion is restricted to unmanipulated HLA identical sibling transplants., Evidence and Information Sources: Data with appropriate follow-up are available only for this type of comparison: we have preliminary data on the use of PB from unrelated donors, and on the use of T-cell depletion/CD34+ selection methods. The latter are rapidly evolving and it may be difficult to find a concurrent group of patients receiving T-cell depleted or CD34-selected marrow., State of Art: The results of retrospective and prospective studies are quite similar: hematologic and immune recovery is faster after PB grafts, acute graft-versus-host disease (GvHD) is comparable, whereas chronic GvHD is increased in recipients of PB transplants. Transplant-related mortality (TRM) is similar in the two groups, whereas disease recurrence is lower after PB grafts., Perspectives: The general feeling is that PB grafts are indicated for patients with advanced disease, whereas for early phase patients the two sources may give comparable results.

Several lines of experimental evidence suggest that sex hormones may influence the development and activity of chronic graft-versus-host disease (cGVHD), which frequently occurs in patients undergoing allogeneic bone marrow transplantation (ABMT). Following ABMT, young women are commonly treated with hormone replacement therapy (HRT) because of irreversible gonadal failure. It seemed therefore worthwhile to investigate the effects of this therapy on the activity of cGVHD. Premenopausal women treated with ABMT for hematological malignancies between January 1997 and December 2000 were evaluated for cGVHD activity. They were divided into two groups, depending on whether or not they were treated with HRT. Seventy-one women qualified for the present study: 39 received HRT (treated group), while 32 did not (controls). In both groups of patients, cGVHD activity score was comparable before the start of HRT. No differences were observed in cGVHD activity score between the HRT group and controls after 3, 6, 12, and 24 months from the start of HRT. Furthermore, HRT did not induce any increase in the cGVHD activity score in the treated group of patients at any time from the start of HRT. According to present data, HRT did not appear to influence the activity of cGVHD in young women who underwent ABMT for hematological malignancies. Therefore, we can safely propose this therapy for women with gonadal failure after ABMT.

The Aspergillus galactomannan test was performed on cerebrospinal fluid and serum samples from 5 patients with probable cerebral aspergillosis and from 16 control patients. Cerebrospinal fluid galactomannan levels were significantly higher in aspergillosis patients, and most galactomannan was produced intrathecally. Comparison of serum galactomannan values in pulmonary and cerebral aspergillosis patients showed significant overlapping. Detection of Aspergillus galactomannan in cerebrospinal fluid may be diagnostic of cerebral aspergillosis.

Acquired severe aplastic anemia (SAA) is a rare hematologic disease associated with significant morbidity and mortality. Immune destruction of hemopoietic stem cells plays an important role in pathogenesis, as shown by successful treatment with immunosup-pressive agents, leading to transfusion independence or complete recovery of peripheral blood counts in a proportion of patients. Growth factors can be combined with immunosuppressive therapy (IST) and Clinical presentation may improve response rates, as recently shown with thrombopoietin analogs. Anabolic steroids may still play a role in combination with IST. The problem with IST is failure to respond and the development of late clonal disorders. Bone marrow transplantation (BMT) is the other therapeutic option: a matched sibling donor remains the best choice. For patients lacking a matched family donor, unrelated donors can be readily found, although mostly for patients of Caucasian origin. Other BMT options include unrelated cord blood or mismatched family donors. Acute and chronic graft-versus-host disease remain important complications of BMT. Patient age is a strong predictor of outcome for both IST and BMT, and must be considered when designing therapeutic strategies. Early diagnosis and treatment, as well as long-term monitoring, remain crucial steps for successful treatment of SAA. [ABSTRACT FROM AUTHOR]

Purpose. From a global perspective, the rates of allogeneic hematopoietic cell transplantation (alloHCT) are closely related to the economic status of a country. However, a potential association with outcome has not yet been documented. Thegoal of this study was to evaluate effects of health care expenditure (HCE), Human Development Index (HDI), team density, and center experience on nonrelapse mortality (NRM) after HLA-matched sibling alloHCTfor adults with acute lymphoblastic leukemia (ALL). Patients and Methods. A total of 983 patients treated with myeloablative alloHCT between 2004 and 2008 in 24 European countries were included. Results. In a univariate analysis, the probability of day 100 NRM was increased for countries with lower current HCE (8% vs. 3%; p = .06), countries with lower HDI (8% vs. 3%; p = .02), and centers with less experience (8% vs. 5%; p = .04). In addition, the overall NRM was increased for countries with lower current HCE (21% vs. 17%; p = .09) and HDI (21% vs. 16%; p = .03) and for centers with lower activity (21% vs. 16%;p = .07). Ina multivariate analysis, the strongest predictive model for day 100 NRM included current HCE greater than the median (hazard ratio [HR], 0.39; p = .002). The overall NRM was mostly predicted by HDI greater than the median (HR, 0.65; p = .01). Both lower current HCE and HDI were associated with decreased probability of overall survival. Conclusion. Both macroeconomic factors and the socioeconomic status of a country strongly influence NRM after alloHCT for adults with ALL. Our findings should be considered when clinical studies in the field of alloHCT are interpreted. [ABSTRACT FROM AUTHOR]

Background: In the setting of allogeneic human leukocyte antigen (HLA)-matched bone marrow transplantation, transplanting male patients with grafts from female donors has been associated with a higher incidence of graft-versus-host disease (GVHD) and of nonrelapse mortality (NRM). The aim of the current analysis was to compare transplantation outcomes in male patients given female unrelated cord blood (UCB) versus other gender combinations. Patients and methods: Data from 552 consecutive patients with acute myeloid leukemia (AML) given a single UCB transplantation between 2000 and 2014 were included. Results: In comparison with other gender combination, male patients given female UCB (n = 131) had a trend for a higher incidence of grades II-IV acute GVHD (33 versus 25 %, P = 0.08), a trend for a higher incidence of NRM (41 versus 33 %, P = 0.06), and a lower leukemia-free (LFS, 30 versus 41 %, P = 0.01) and overall survival (OS, 33 versus 45 %, P = 0.008). In multivariate analyses, taking into consideration all patients for which data on HLA-matching and cell dose transplanted were fully available (n = 363), male patients transplanted with a female UCB had a trend for a higher incidence of grade III-IV acute GVHD (hazard ratio (HR) = 2.0, P = 0.06), a trend for a higher NRM (HR = 1.5, P = 0.06), and a worse LFS (HR = 1.4, P = 0.04) and OS (HR = 1.3, P = 0.06). Conclusions: Our data suggest that male patients transplanted with female UCB might have higher risk of acute GVHD and of NRM leading to worse LFS and OS. These results should be confirmed in other large cohorts of patients before used for determining the choice of an UCB unit. [ABSTRACT FROM AUTHOR]

This study analysed the outcome of 563 Aplastic Anaemia ( AA) children aged 0-12 years reported to the Severe Aplastic Anaemia Working Party database of the European Society for Blood and Marrow Transplantation, according to treatment received. Overall survival ( OS) after upfront human leucocyte antigen-matched family donor ( MFD) haematopoietic stem cell transplantation ( HSCT) or immunosuppressive treatment ( IST) was 91% vs. 87% ( P 0·18). Event-free survival ( EFS) after upfront MFD HSCT or IST was 87% vs. 33% ( P 0·001). Ninety-one of 167 patients (55%) failed front-line IST and underwent rescue HSCT. The OS of this rescue group was 83% compared with 91% for upfront MFD HSCT patients and 97% for those who did not fail IST up-front ( P 0·017). Rejection was 2% for MFD HSCT and HSCT post- IST failure ( P 0·73). Acute graft- versus-host disease ( GVHD) grade II- IV was 8% in MFD graft vs. 25% for HSCT post- IST failure ( P < 0·0001). Chronic GVHD was 6% in MFD HSCT vs. 20% in HSCT post- IST failure ( P < 0·0001). MFD HSCT is an excellent therapy for children with AA. IST has a high failure rate, but remains a reasonable first-line choice if MFD HSCT is not available because high OS enables access to HSCT, which is a very good rescue option. [ABSTRACT FROM AUTHOR]

The article presents a retrospective multicenter study conducted by European Group for Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP) which focuses on the disease outcome for autologous stem cell transplantation (ASCT). Mentioued is the association of neuromyelitis optica (NMO) with ASCT as recorded by the EBMT from 2001 to 2011. Also explored is the disease progression after ASCT.

Background Extracorporeal photopheresis ( ECP) is an effective treatment for both acute and chronic graft-versus-host disease ( GVHD) in children and adults. Despite the large use of this treatment, a large heterogeneity in current application of ECP has been reported so far and recent evidence brought novel issues into some specific topics. Consensus-based recommendations ameliorate the appropriateness in daily clinical practice and, in turn, optimize the use of health care resources. Study Design and Methods Two Italian scientific societies, the Italian Society of Hemapheresis and Cell Manipulation ( SIdEM) and the Italian Group for Bone Marrow Transplantation ( GITMO), joined to develop and disseminate recommendations on appropriate application of ECP treatment in patients with GVHD. Accordingly, SIdEM and GITMO named an expert panel that first selected 16 questions that were considered relevant for clinical practice: the questions were subsequently addressed through a revision of the available literature and in consensus meetings. The whole group discussed the proposed recommendations according to the nominal group technique. Results The above-described approach in turn allowed the panel to agree on 47 practice recommendations. SIdEM and GITMO will disseminate such recommendations to the national transplant centers. Conclusion In conclusion, SIdEM and GITMO have made a scientific effort to provide a useful tool to physicians involved in the field, thus supporting daily clinical practice, as well as strategic decisions in the setting of ECP treatment of GVHD. [ABSTRACT FROM AUTHOR]

In order to assess the epidemiology of Hepatitis-Associated Aplasia (HAA) and compare treatment outcome of HAA with non-HAA patients, we evaluated 3916 aplastic anaemia patients reported to the European Registry between 1990 and 2007. Year, month, season of diagnosis, type and outcome of first-line therapy were analysed. Prevalence of HAA ( n = 214) in Europe was 5%. Compared to non-HAA patients, HAA patients were younger (15 vs. 20 years, P < 0·001), with a male prevalence (68% vs. 58% P = 0·002), and were treated earlier after diagnosis (46 vs. 62 d; P < 0·001). No significant differences were found regarding the year or month of diagnosis. No geographic clusters could be identified. Actuarial survival at 10 years after first-line immunosuppression was 69%, and did not differ according to aetiology. The 10-year actuarial survival after transplantation was 70%, and was comparable in HAA and non-HAA patients, when stratified for age and donor type. In a multivariate Cox analysis, increasing age and delayed treatment were significant negative indicators for survival. In conclusion, the incidence of HAA was 5% and was evenly distributed over time and geographic areas in Europe. Treatment outcome and predictive variables, were comparable in patients with or without HAA. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the study which suggests that posttransplantation cyclophosphamide (PT-Cy) in myeloablative bone marrow transplantation (BMT) of a mismatched unrelated donor (MMUD) was feasible for high-risk acute myeloid leukemia (AML) patients.

Abstract: This is an update of a randomized study on antithymocyte globulin (ATG; Thymoglobulin) before transplantation in patients undergoing unmanipulated marrow transplantation from unrelated donors. The median follow-up for surviving patients is 5.7 years. At last follow-up, chronic graft-versus-host disease (GVHD) was scored in 60% of non-ATG and in 37% of ATG patients (P = .05), and extensive chronic GVHD was present in 41% and 15%, respectively (P = .01). Chronic lung dysfunction was diagnosed in 51% versus 19% of patients (P = .005). Forced vital capacity decreased significantly with time in non-ATG patients (P = .005), but not in patients who received ATG (P = .30). The proportion of patients with Karnofsky scores of ≥90% at 4 years was 57% versus 89% in non-ATG versus ATG patients (P = .03). The actuarial 6-year survival for all patients randomized was 31% versus 44% (non-ATG versus ATG; P = .80). The cumulative incidence of transplant-related mortality was 51% versus 41% (P = .70) and of relapse was 32% versus 40% (P = .90). For patients who survived 1 year, transplant-related mortality was 25% versus 3% (P = .03), and actuarial survival was 58% versus 85% (P = .09). In conclusion, the addition of ATG to cyclosporine/methotrexate provides significant protection against extensive chronic GVHD and chronic lung dysfunction, reduces late transplant mortality, and improves quality of life in patients undergoing unrelated donor transplantation. [Copyright &y& Elsevier]

Graft versus host disease (GvHD) is a frequent complication of allogeneic hemopoietic stem cell transplantation (HSCT), and of donor lymphocyte infusions (DLI): the acute form occurs within 100 days from HSCT or DLI, the chronic form beyond day +100. GvHD should be prevented rather than treated. There are several ways to prevent GvHD: remove donor T cells from the transplant (ex vivo T-cell depletion), administer T-cell antibodies to the patient (in vivo T-cell depletion), administer immunosuppressive drugs such as methotrexate, cyclosporin, tacrolimus, and mycofenolate (post-transplant immunosuppression). New strategies of GvHD prophylaxis include the infusion of expanded mesenchymal stem cells and downregulation of host antigen-presenting cells. First-line treatment of established GvHD is based on low-dose corticosteroids (0.5-2?mg/kg). Second-line therapy for steroid refractory GvHD is unsatisfactory. The early administration of T-cell antibodies and/or TNF antibodies and TNF soluble receptor may be successful in some cases, but they do not seem to fulfill the expectations. High-dose chemotherapy has not been explored thoroughly. Acute GvHD is complicated by infections that cause significant morbidity and mortality: prophylaxis, early diagnosis and treatment of infections are an integral part of GvHD management. We have considerably reduced the risk of acute GvHD over the past three decades: we need to further improve these results, with the final goal of dissecting, if possible, the graft versus host from the graft versus tumor effect.The Hematology Journal (2004) 5, 189-196. doi:10.1038/sj.thj.6200399 [ABSTRACT FROM AUTHOR]