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After allogeneic hematopoietic cell transplantation (Allo-HCT) and conditioning, patients are typically placed in isolated hospital rooms to prevent neutropenic infections. Since 1998, we've offered an alternative: home care for patients living within a one to two-hour drive of the hospital. In Sweden this approach includes daily visits by an experienced nurse and daily phone consultations with a unit physician. When necessary, patients receive transfusions, intravenous antibiotics, and total parenteral nutrition at home. Our initial study report compared 36 home care patients with 54 hospital-treated controls. Multivariate analysis found that home care patients were discharged earlier to outpatient clinics, required fewer days of total parenteral nutrition, had less acute graft-versus-host disease (GVHD) grade II-IV, and lower transplantation-related mortality (TRM) and lower costs. Long-term follow-up showed similar chronic GVHD and relapse rates in both groups, with improved survival rates in the home care group. A subsequent comparison of 146 home care patients with hospital-treated controls indicated that home care and longer home stays were associated with lower grades of acute GVHD. Home care was found to be safe and beneficial for children and adolescents. Over two decades, 252 patients received home care post-Allo-HCT without any fatalities at-home. Ten-year outcomes showed a 14% TRM and a 59% survival rate. In 2020, an independent center confirmed the reduced risk of acute GVHD grades II-IV for patients treated in home care. Here, we report for the first time that home care patients also demonstrate a less inflammatory systemic cytokine profile. We found higher levels of IFN-γ, IL-2, IL-5, IL-13, GM-CSF, and G-CSF, but lower VEGF in hospital-treated patients, which may contribute to acute GVHD grades II-IV. In conclusion, home-based treatment following Allo-HCT yields multiple promising clinical outcomes and improved systemic inflammatory markers, which may contribute to less development of life-threatening GVHD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ringdén, Svahn, Moll and Sadeghi.)

Acute graft-versus-host disease (GVHD) is a frequent and potentially life-threatening complication following allogeneic hematopoietic cell transplantation (HCT). Mesenchymal stromal cells (MSCs), rare precursors found in all body tissues, possess immunosuppressive properties and can inhibit alloreactivity both in vitro and in vivo. Two decades ago, we introduced bone marrow-derived (BM) MSCs as a novel therapy for acute GVHD. While some patients responded to BM-MSCs, the response was not universal. Commercially available BM-MSCs are now used for acute GVHD treatment in Canada, Japan, and New Zealand. The fetus is protected from the mother's immune system by the placenta, and our research found that placenta-derived decidua stromal cells (DSCs) offer a stronger immunosuppressive effect than other sources of stromal cells. Safety studies in rabbits, rats, mice, and humans have shown negligible or no side effects from BM-MSCs or DSCs. In a phase I/II trial for severe acute GVHD, we treated 21 patients (median age, 49 years; range 1.6-72 years) with severe biopsy-proven gastrointestinal acute GVHD. The median cell dose of DSCs was 1.2 × 106 (range 0.9-2.9) cells/kg body weight, with a median of 2 (range 1-6) infusions given 1 week apart. The cell viability of DSCs was 93% (range, 69%-100%), and the median cell passage number was 4 (range, 2-4). All patients responded, with a complete response of acute GVHD in 11 patients and partial response in 10 and 1-year survival of 81%. Randomized trials are needed to prove the superiority of DSCs compared to ruxolitinib and/or other novel immunosuppressive therapies., (© The Author(s) 2024. Published by Oxford University Press.)

Post-transplantation cyclophosphamide (PTCy) has been shown to effectively control graft-versus-host disease (GvHD) in haploidentical (Haplo) transplantations. In this retrospective registry study, we compared GvHD organ distribution, severity, and outcomes in patients with GvHD occurring after Haplo transplantation with PTCy GvHD prophylaxis (Haplo/PTCy) versus HLA-matched unrelated donor transplantation with conventional prophylaxis (MUD/conventional). We evaluated 2 cohorts: patients with grade 2 to 4 acute GvHD (aGvHD) including 264 and 1163 recipients of Haplo and MUD transplants; and patients with any chronic GvHD (cGvHD) including 206 and 1018 recipients of Haplo and MUD transplants, respectively. In comparison with MUD/conventional transplantation ± antithymocyte globulin (ATG), grade 3-4 aGvHD (28% versus 39%, P = .001), stage 3-4 lower gastrointestinal (GI) tract aGvHD (14% versus 21%, P = .01), and chronic GI GvHD (21% versus 31%, P = .006) were less common after Haplo/PTCy transplantation. In patients with grade 2-4 aGvHD, cGvHD rate after Haplo/PTCY was also lower (hazard ratio [HR] = .4, P < .001) in comparison with MUD/conventional transplantation without ATG in the nonmyeloablative conditioning setting. Irrespective of the use of ATG, non-relapse mortality rate was lower (HR = .6, P = .01) after Haplo/PTCy transplantation, except for transplants that were from a female donor into a male recipient. In patients with cGvHD, irrespective of ATG use, Haplo/PTCy transplantation had lower non-relapse mortality rates (HR = .6, P = .04). Mortality rate was higher (HR = 1.6, P = .03) during, but not after (HR = .9, P = .6) the first 6 months after cGvHD diagnosis. Our results suggest that PTCy-based GvHD prophylaxis mitigates the development of GI GvHD and may translate into lower GvHD-related non-relapse mortality rate., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine whether treatment with tacrolimus plus sirolimus (Tac/Sir) as a prophylaxis for graft-versus-host disease worsens severe oral mucositis and delays healing compared to cyclosporine plus methotrexate (CsA/Mtx) following haematopoietic stem cell transplantation., Subjects and Methods: The study comprised 141 patients: 73 randomized to receive Tac/Sir and 68 to receive CsA/Mtx. The oral mucositis assessment scale and toxicity grading according to WHO were used to assess the severity, peak and duration of oral mucositis from the day -3 to day 24 post-transplant., Results: Eighty-seven patients developed oral mucositis in the first 24 days post-transplant. No significant difference in oral mucositis severity between the Tac/Sir and CsA/Mtx groups was observed. The peak oral mucositis score occurred on day 10 in both groups. Although oral mucositis scores had returned to baseline in the CsA/Mtx group on day 24 post-transplant, no significant difference compared with the Tac/Sir group was found., Conclusions: The introduction of tacrolimus/sirolimus as a graft-versus-host disease prophylaxis in haematopoietic stem cell transplantation increased neither the incidence nor severity of oral mucositis compared with cyclosporine/methotrexate. Furthermore, oral mucositis healing was not prolonged and followed the same time pattern as cyclosporine/methotrexate., (© 2020 The Authors. Oral Diseases published by Wiley Periodicals LLC.)

Following allogeneic hematopoietic cell transplantation (HCT), patients living near the hospital were treated at home instead of in isolation in the hospital. We analyzed cytokines using Luminex assays for the first 3 weeks after HCT and compared patients treated at home (n = 42) with matched patients isolated in the hospital (n = 37). In the multivariate analysis, patients treated at home had decreased GM-CSF, IFN-γ (p < 0.01), IL-13, IL-5 (p < 0.05), and IL-2 (p < 0.07). Bloodstream infections, anti-thymocyte globulin, G-CSF treatment, immunosuppression, reduced-intensity conditioning (RIC), related vs. unrelated donors, and graft source affected various cytokine levels. When patients with RIC were analyzed separately, home care patients had reduced G-CSF (p = 0.04) and increased vascular endothelial growth factor (VEGF, p = 0.001) at 3 weeks compared with hospital care patients. Patients with low GM-CSF (p < 0.036) and low IFNγ (p = 0.07) had improved survival. Acute GVHD grades III-IV was seen in 7% and 16% of home care and hospital care patients, respectively. One-year transplantation-related mortality was 7% and 16% and survival at 5 years was 69% and 57% in the two groups, respectively. To conclude, patients treated in the hospital showed varying increased levels of GM-CSF, IFN-γ, IL-13, G-CSF, IL-5, and IL-2 and decreased VEGF, which may contribute to acute GVHD.

Mesenchymal stromal cells (MSCs) are rare precursors in all organs of the body. MSCs have profound anti-inflammatory effects and reduce alloreactivity in vitro and in vivo . In pediatric allogeneic hematopoietic cell transplantation (HCT), MSCs have mainly been used to treat acute graft-versus-host disease (GVHD). MSCs are commercially available for this indication in Canada, Japan, and New Zeeland. More rare indications for MSCs in pediatric patients include graft failure and chronic GVHD. MSCs from bone marrow, adipose tissue, umbilical cord, Wharton's jelly, placenta tissue, and decidua have been used, but the optimal clinical stromal cell source has not been compared in clinical trials. More experimental clinical indications using MSCs, such as sepsis, acute respiratory distress syndrome, hemorrhages, pneumo-mediastinum, and neuroinflammation have primarily been explored in animal models or adult HCT patients. MSCs have almost no if any side-effects. In this pilot study we report the outcome of six children treated with decidua stromal cells (DSCs) for steroid refractory acute GVHD. At 6 months, complete response was seen in four patients and partial response in two patients. One child with high-risk ALL died from relapse and a boy with sickle cell disease died from a cerebral hemorrhage. Five-year survival was 67% and all survivors showed a Lansky score of 100%. To conclude, MSCs from various organs are well-tolerated and have shown an encouraging outcome for acute GVHD in pediatric patients., (Copyright © 2020 Ringdén, Gustafsson and Sadeghi.)

Acute and chronic graft-versus-host disease (GvHD) are the most important causes of treatment-related morbidity and mortality after allogeneic hematopoietic cell transplants for various diseases. Corticosteroids are an effective therapy in only about one-half of affected individuals and new therapy options are needed. We discuss novel strategies to treat GvHD using cellular-therapy including adoptive transfer of regulatory T-cells (T regs ), mesenchymal stromal cells (MSCs), cells derived from placental tissues, invariant natural killer T-cells (iNKTs), and myeloid-derived suppressor cells (MDSCs).These strategies may be more selective than drugs in modulating GvHD pathophysiology, and may be safer and more effective than conventional pharmacologic therapies. Additionally, these therapies have not been observed to substantially compromise the graft-versus-tumor effect associated with allotransplants. Many of these strategies are effective in animal models but substantial data in humans are lacking., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

There is a need for effective therapy with few side effects for severe acute graft-versus-host disease (GVHD). The placenta protects the fetus from the mother's haploidentical immune system during pregnancy. We found that maternal stromal cells from the fetal membrane, so-called decidua stromal cells (DSCs), are more immunosuppressive than other sources of stromal cells. We prospectively treated 21 patients (median age, 49 years; range, 1.6 to 72 years) for grade II-IV acute GVHD. All 21 patients had biopsy-proven gastrointestinal GVHD. The majority of patients were either steroid-refractory or had progressive GVHD, 11 patients after >7 days or with progression after 3 days, and 10 were refractory to steroids after >3 days. We used an improved protocol in which DSCs were thawed and infused in a buffer with 5% human albumin. DSCs were given at a median dose of 1.2 (range, 0.9 to 2.9) × 10 6 cells/kg body weight with a median of 2 (range, 1 to 6) doses, given 1 week apart. The median viability of thawed DSCs was 93% (range, 69% to 100%), and the median cell passage number was 4 (range, 2 to 4). Complete resolution of GVHD was seen in 11 patients, with a partial response in the other 10. The cumulative incidence of chronic GVHD was 52%. GVHD was mild in 6 patients, moderate in 4 patients, and severe in 1 patient based on National Institutes of Health chronic GVHD severity scoring. Nine patients died, including 3 from relapse and 1 each from acute GVHD and septicemia, Zygomycetes infection, liver insufficiency, cerebral hemorrhage, multiple organ failure, and chronic GVHD with obstructive bronchiolitis. Four-year transplantation-related mortality was 28.6%, and overall survival was 57%. Survival was similar (P = .33) to that for all 293 patients who underwent allogeneic hematopoietic cell transplantation during the same period (2012 to 2015), with 66% overall survival. DSC infusion is a novel therapy for acute GVHD grade II-IV, and a randomized trial is currently underway (ClinicalTrials.gov NCT02172937)., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic haematopoietic stem cell transplantation (HSCT). With new promising therapies, survival may improve for severe aGVHD., Objectives: We wanted to analyze the long-term outcome in patients who survive severe aGVHD., Methods: This study was a landmark analysis of 23 567 patients with acute Leukaemia who survived for more than 6 months after HSCT, 2002-2014. Patients alive after severe aGVHD (n = 1738) were compared to controls., Results: Patients with severe aGVHD had higher non-relapse mortality (NRM) and higher rate of extensive chronic GVHD (cGVHD) than the controls (P < 10 -5 ). The probability of relapse was significantly lower in the severe aGVHD group, but Leukaemia-free survival (LFS) and overall survival were significantly lower than for the controls (P < 10 -5 ). Five-year LFS in patients with severe aGVHD was 49%, as opposed to 61% in controls with no or mild GVHD and 59% in patients with moderate GVHD., Conclusions: HSCT patients who survive severe aGVHD have higher risk of developing extensive cGVHD, a higher NRM, a lower relapse probability, and lower LFS than other HSCT patients. This study is a platform for outcome analysis in patients treated with novel therapies for acute GVHD., (© 2017 The Association for the Publication of the Journal of Internal Medicine.)

Improvement of graft-versus-host disease prophylaxis remains an important goal in allogeneic hematopoietic stem cell transplantation. Based on reports of possibly preferential properties of sirolimus, we compared the standard regimen of cyclosporine and methotrexate (n=106) with a combination of tacrolimus and sirolimus (n=103) as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation in a prospective, open, randomized trial. The hypothesis was that the tacrolimus/sirolimus regimen would lead to less acute graft-versus-host disease and reduced transplant-related mortality. There was no significant difference in the cumulative incidence of acute graft-versus-host disease of grades II-IV (41% vs. 51%; P=0.19) or grades III-IV (13% vs. 7%; P=0.09) between the groups. Time to neutrophil engraftment (18 days vs. 17 days; P=0.24) was similar, but time to platelet engraftment was longer in cyclosporine/methotrexate patients (14 vs. 12 days; P<0.01). No significant differences in incidence of oropharyngeal mucositis, time to full donor chimerism, or number of cytomegalovirus infections were seen between the two treatment arms, and transplant-related toxicities were equally distributed. Triglyceride (P=0.005) and cholesterol (P=0.009) levels were higher in tacrolimus/sirolimus patients. Transplant-related mortality (18% vs. 12%; P=0.40) and 5-year overall survival (72% vs. 71%; P=0.71) were similar. Five-year relapse-free survival in patients with malignant diagnoses was 65% in the cyclosporine/methotrexate group and 63% in the tacrolimus/sirolimus group (P=0.73). We conclude that tacrolimus/sirolimus remains a valid and safe alternative to cyclosporine/methotrexate as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation, with comparable transplant-related outcomes. The trial was registered at clinicaltrials.gov identifier: 00993343., (Copyright© Ferrata Storti Foundation.)

The level of Epstein-Barr virus DNA in blood has proven to be a biomarker with some predictive value in allogeneic hematopoietic stem cell transplantation patients (HSCT). We evaluated the impact of EBV load on survival of 51 patients (32M/19F, median age: 32 years, from < 1 to 68 years old), who had received HSCT for different types of malignancies (49 cases) or non-malignancies (2 cases). The overall survival [1]was compared between patients with extreme and moderate cell bound EBV DNA levels. Different sources of stem-cells (peripheral blood stem, n = 39; bone marrow, n = 9; or umbilical cord blood, n = 3) were used. Twenty patients received reduced-intensity conditioning regimen while the other 31 received myeloablative conditioning. Patients with high or very low level of cell bound EBV-DNA levels had a shorter OS than those with moderate EBV load: OS at 5 years was 67% vs 90% (p < 0.03). There was a conspicuous relationship between EBV load and the reconstitution dynamics of total and EBV-specific T cells, CD4+ and CD4- CD8- (double negative) T cells in the few patients where it was analyzed. This was not statistically significant. Two other factors were associated to early mortality in addition to high or low EBV load: acute GVHD II-IV (p < 0.02) and pre-transplant conditioning with total body irradiation (TBI) ≥6 Gy, (p < 0.03). All the patients meeting all three criteria died within two years after transplantation. This points to a subgroup of HSCT patients which deserve special attention with improvement of future, personalized treatment., Competing Interests: The authors declare no conflict of interest.

Selective administration of mesenchymal stromal cells to the mesenteric arteries is a potential technique to overcome pulmonary trapping and increase the density of transplanted cells in extensive mural inflammation of the intestine, such as in inflammatory bowel disease and graft-versus-host disease. We injected 5 × 10(6) (111)In-oxine-labeled human decidual stromal cells (DSCs) to the rabbit superior mesenteric artery (SMA) using clinical routine catheters guided by an angiographical system under sterile conditions. We used longitudinal single-photon emission tomography at 6 h and at 1, 2, and 5 days to assess trafficking and distribution of DSCs. We used digital subtraction angiography, computed tomography, and hematoxylin and eosin stainings to determine biodistribution of cells and to assess safety end points. We found that selective injection of human DSCs to the rabbit SMA does not result in acute embolic complications. Furthermore, we found that IV administration resulted in extensive retention of the radiolabeled DSCs in the lungs, corroborating previous studies on pulmonary trapping. In sharp contrast, selective injections to the SMA resulted in uptake distributed in the intestine supplied by the SMA and in the liver, indicating that this approach could significantly increase the fraction of injected DSCs reaching the target tissue.

Background Aims: Human decidual stromal cells (hDSCs) may cure acute graft-versus-host disease (GVHD) in humans. We evaluated immunosuppression by xenogenic hDSCs in mice, both in vitro and in vivo., Methods: hDSCs inhibited mouse lymphocyte proliferation in allo- and xeno-stimulation assays in mixed lymphocyte culture (MLC) and after mitogenic stimulation. The immunosuppressive effect of hDSCs was dose-dependent and strain-independent. Trans-well experiments showed that hDSCs needed cell-to-cell contact to be immunosuppressive. In a GVHD model, Balb/c mice were transplanted with bone marrow and splenocytes from C57BL/6 a donor. Varying doses of hDSCs (10(5)-10(6) per mouse) were infused at different time points. Recipient mice showed lower GVHD scores than untreated mice, but they did not have consistently improved survival. Histopathological investigation of liver, gastrointestinal tract and skin of animals with GVHD did not show any significant improvement from hDSC infusion., Results: hDSCs were transduced with immunosuppressive genes including those encoding interleukin-10, prostaglandin-E2 receptor, indoleamine dioxygenase, interferon-γ and programmed death ligand-1. Transduced and untransduced hDSCs showed similar effects in vitro and in vivo. At a dose of 10(6)hDSCs per mouse, the majority of recipients died of embolism., Conclusions: hDSCs inhibit allo-reactivity, xeno-reactivity and mitogen-induced stimulation in mouse lymphocytes. Although the GVHD score was reduced by hDSC infusion, survival and GVHD histopathology were not improved. One reason for failure was fatal embolism., (Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Clinical outcomes after primary graft failure (PGF) remain poor. Here we present a large retrospective analysis (n=23,272) which investigates means to prevent PGF and early detection of patients at high risk. In patients with hematologic malignancies, who underwent their first myeloablative allogeneic hematopoietic cell transplantation, PGF was reported in 1278 (5.5%), and there was a marked difference in PGFs using peripheral blood stem cell compared with bone marrow grafts (2.5 vs 7.3%; P<0.001). A fourfold increase of PGF was observed in myeloproliferative disorders compared with acute leukemia (P<0.001). Other risk factors for PGF included recipient age <30, HLA mismatch, male recipients of female donor grafts, ABO incompatibility, busulfan/cyclophosphamide conditioning and cryopreservation. In bone marrow transplants, total nucleated cell doses ⩽2.4 × 10(8) per kg were associated with PGF (odds ratio 1.39; P<0.001). The use of tacrolimus-based immunosuppression and granulocyte colony-stimulating factor were associated with decreased PGF risk. These data, allow clinicians to do more informed choices with respect to graft source, donor selection, conditioning and immunosuppressive regimens to reduce the risk of PGF. Moreover, a novel risk score determined on day 21 post transplant may provide the rationale for an early request for additional hematopoietic stem cells.

Allogeneic mesenchymal stromal cells (MSCs) are widely used in regenerative medicine, but little is known about their immunogenicity. In this study, we monitored the therapeutic and immunogenic effects of decidual stromal cells (DSCs) from term placentas when used as a therapy for generalized severe junctional epidermolysis bullosa (JEB) (previously termed Herlitz JEB), a lethal condition caused by the lack of functional laminin-332. An 11-month-old JEB patient was treated with five infusions of allogeneic DSCs within a 3-month period. Amniotic membranes (AMs) were applied to severe wounds. After the treatment, wounds started to heal in the middle of the blisters, but the improvements were transient. After two infusions of DSCs, the JEB patient had developed multispecific anti-HLA class-I antibodies. No antibodies to laminin-332 were detected, but the patient had high levels of anti-bovine serum albumin antibodies, which could bind to DSCs. Peripheral blood mononuclear cells (PBMCs) from the patient had a higher proliferative response to DSCs than to third-party PBMCs, which contrasts with the pattern observed in healthy donors. Human DSCs and MSCs induced similar xenoreactivity in mice. Two of 16 allogeneic stem cell-transplanted patients, treated with DSCs for graft-versus-host disease or hemorrhagic cystitis, showed a positive flow cytometric crossmatch test. One patient had anti-HLA antibodies before DSC infusion, whereas the other had no anti-HLA antibodies at any time. AM and DSC infusions may have improved the healing process in the JEB patient, but DSCs appeared to induce anti-HLA antibodies. The risk of alloimmunization by DSCs seems to be low in immunocompromised patients.

Decidual stromal cells (DSCs) isolated from fetal membranes of term placentas are easily expanded and are highly immunosuppressive in vitro. These cells express high levels of integrins that are of importance in homing to inflamed tissues. In this study, we investigated DSCs as a cellular therapy for chronic graft-versus-host disease (cGvHD), a severe complication after allogeneic hematopoietic stem cell transplantation. Subsequent to transplantation, three patients developed severe extensive cGvHD and were treated with DSCs (1-2.8 × 10(6) cells/kg). One-third of the DSCs administered to two patients were labeled with (111)Indium, and the in vivo distribution was tracked for 48 h. The (111)In-labeled DSCs were initially located in the lungs, followed by dissemination to the liver and spleen. The DSCs induced a partial response in two of the patients. Blood samples from the patients were extensively evaluated by flow cytometry, luminex, and enzyme-linked immunosorbent assay. The nonresponder had the highest proportion of T-cells with Th17 and Th2 phenotypes and the highest median plasma concentrations of IL-17 and IL-4. The same patient also had high frequencies of HLA-DR(+) T-cells and regulatory T-cells. To conclude, DSCs are safe to infuse with no adverse effects. We determined how stromal cells are distributed in vivo after infusion in a cGvHD setting. The methods established for analysis of blood samples will be useful in determining the effect of DSCs in a study comprising a larger patient material. This pilot study may provide a basis for further controlled investigations with DSCs in a clinical setting.

In this issue of Blood, Kanakry and coworkers report on the use of posttransplant cyclophosphamide (Cy) as sole immunoprophylaxis against graft-versus-host disease (GVHD) in HLA-matched related or unrelated allogeneic hematopoietic stem cell transplant (HSCT).

Background: Female donors for male recipients worsen the outcome of allogeneic hematopoietic stem-cell transplantation. We wanted to find out whether a male human leukocyte antigen (HLA)-matched unrelated donor (MUD, 8/8, n=2,014) might be an alternative to a female HLA-identical sibling donor (n=2,656) for male patients with acute leukemia., Methods: This is a retrospective analysis from the Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation., Results: The relative risk (RR) of acute graft-versus-host disease (GVHD) of grades II to IV was increased in the MUD group with acute myeloid leukemia (AML) (RR, 1.47; P<0.001) and acute lymphoblastic leukemia (ALL) (RR, 1.76; P<0.001). There was no difference in incidence of chronic GVHD and nonrelapse mortality between the two groups. Probability of relapse was lower in the MUD group than in the sibling group in patients with ALL (hazards ratio [HR], 0.75; P=0.04) but not in the AML patients (HR, 0.89; P=0.17). Survival was not different between the groups. Leukemia-free survival (LFS) was also similar in the sibling and MUD groups in patients with AML (HR, 1.01; P=0.81) or ALL (HR, 0.93; P=0.45). Factors significantly associated with reduced LFS included active disease, poor cytogenetics, age, year of hematopoietic stem-cell transplantation, reduced-intensity conditioning, and the use of antithymocyte globulin., Conclusion: Male patients who received grafts from male MUDs demonstrated an increased incidence of acute GVHD and LFS same as when using HLA-identical female donors.

Few data have been published regarding posaconazole tissue concentrations in humans. We analyzed tissue concentrations in biopsy specimens taken at autopsy from seven patients who received posaconazole prophylaxis because of graft-versus-host disease. The results were compared to plasma concentrations collected before death. Tissue concentrations suggestive of an accumulation of posaconazole were found in the heart, lung, liver, and kidney but not in the brain., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Mesenchymal stromal cells (MSCs) have immunomodulatory effects and are increasingly being used for the treatment of acute and chronic GVHD. Although they seem immuno-privileged, they induce alloresponses, but the risk of immunization is poorly characterized. After infusion, they first reach the lungs, liver and spleen, and are then difficult to trace. Several mechanisms are involved in stromal cells suppressing alloreactivity, such as induction of regulatory T cells, but whether or not this will also affect leukemic relapse or increase infections is not known. Although several encouraging pilot studies have been published, there have been few prospective randomized trials. There may be a bias in the literature, as negative results are seldom published, and there have been few comparative studies with other immunosuppressive regimens. Most animal models have failed to show any effect on GVHD. Several questions remain to be answered for optimization of stromal cell therapy. Which source is optimal-BM, fat, cord or decidua? Can stromal cells be replaced by exosomes, which culture conditions are most appropriate and at what passage and how frequently should cells be administered? More research is required to move stromal cell therapy forward to become an established treatment for acute and chronic GVHD.

After ASCT, children are isolated in hospital to prevent neutropenic infections. Patients living within two-h drive from the hospital were given the option of treatment at home after ASCT. Daily visits by an experienced nurse and phone calls from a physician from the unit were included in the protocol. We compared 29 children and adolescents treated at home with 58 matched hospital controls. The children spent a median time of 13 days at home (range 2-24 days) and 6 (0-35) days in hospital. The cumulative incidence of acute GVHD grades II-IV was 21% in the home-care children and 39% in the controls (p = 0.1). Chronic GVHD and probability of relapse were similar in the two groups. TRM at five yr was 11% in the home-care patients and 18% in the controls. Overall survival at three yr was 77% and 62%, respectively (p = 0.33). None of the patients died at home. Median costs were 38,748 euros in the home-care patients and 49,282 euros in those treated in the hospital (p = 0.2). We conclude that it is safe for children and adolescents to be treated at home during the pancytopenic phase after ASCT., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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.

We report the long-term results of a prospective randomized study on the use of ursodeoxycholic acid (UDCA) for prevention of hepatic complications after allogeneic stem cell transplantation. Two hundred forty-two patients, 232 with malignant disease, were randomized to receive (n = 123) or not to receive (n = 119) UDCA from the beginning of the conditioning until 90 days post-transplantation. The results were reported after 1-year follow-up. UDCA administration reduced significantly the proportion of patients developing high serum bilirubin levels as well as the incidence of severe acute graft-versus-host disease (GVHD), liver GVHD, and intestinal GVHD. In the UDCA prophylaxis group, nonrelapse mortality (NRM) was lower and overall survival better than in the control group. After a 10-year follow-up, the difference in the survival and NRM in favor of the UDCA-treated group, seen at 1 year, was maintained (survival 48% versus 38%, P = .037; NRM 28% versus 41%, P = .01). A landmark analysis in patients surviving at 1 year post-transplantation showed no significant differences between the study groups in the long-term follow-up in chronic GVHD, relapse rate, NRM, disease-free survival, or overall survival. These long-term results continue to support the useful role of UDCA in the prevention of transplant-related complications in allogeneic transplantation., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The study included 110 consecutive patients with hematological malignancies receiving fludarabine-based reduced intensity conditioning (RIC) and hematopoietic stem cell transplantation (HSCT) from matched unrelated donors. The median age was 55 yr (range 11-68) and all but 15 patients received peripheral blood stem cell grafts. Antithymocyte globulin (ATG) (Thymoglobulin, Genzyme) at a total dose of 6 mg/kg (n = 66) or 8 mg/kg (n = 44) was given to all patients according to protocol. The ATG dose did not affect time-to-neutrophil or platelet engraftment. The incidences of acute GVHD grades II-IV were 34% and 18% (p = 0.11) and of chronic GVHD were 40% and 26% (p = 0.46) in patients receiving 6 and 8 mg/kg of ATG, respectively. The five-yr relapse-free survival (RFS) was 61% and 36% (p = 0.14) in patients, given low and high ATG dose, respectively. In patients given low-dose ATG, the incidence of relapse was lower compared to those given high-dose ATG, 19% vs. 41% (p = 0.04). In multivariate analysis, age >50 yr (p < 0.001), absence of acute (p < 0.001) and chronic GVHD (p = 0.001) were correlated to relapse, and low-dose ATG was associated with improved RFS (p < 0.05). A high dose (8 mg/kg) of ATG in RIC HSCT with unrelated donors increased the risk for relapse and reduced the RFS., (© 2013 John Wiley & Sons A/S.)

Risk factors associated with the development of aGVHD in the gastrointestinal tract have not been studied in depth. We retrospectively assessed 25 pediatric patients with MDS and JMML and compared the treatment outcome of two different conditioning regimens. Seventeen children (68%) underwent conditioning with busulfan (Bu), cyclophosphamide (Cy), and melphalan (Mel) and eight children (32%) with Bu and Cy. Gastrointestinal aGVHD stages II-IV (day 0-100) were observed in 47% (eight of 17) of the patients in the BuCyMel group and in none (0 of 8) in the BuCy group (p < 0.05). In patients who developed gastrointestinal aGVHD stages III-IV, a 24-h variation in the Bu concentration with a nighttime peak was noted. HC and liver aGVHD stages II-IV were observed in 47% (eight of 17) and 35% (six of 17) after BuCyMel conditioning and in 0% (0 of 17) and 12.5% (one of eight) after BuCy conditioning. The overall survival rate was 53% (nine of 17) in the BuCyMel group and 62.5% (five of eight) in the BuCy group. In conclusion, the addition of melphalan to the BuCy conditioning regimen resulted in severe gastrointestinal complications and did not improve overall survival., (© 2013 John Wiley & Sons A/S.)

The placenta protects the fetus from the mother's immune system. We have previously found that fetal membrane cells (FMCs) isolated from term placenta prevent alloreactivity in vitro. FMCs share many features with bone marrow-derived mesenchymal stromal cells (MSCs), which we previously introduced to treat severe acute graft-versus-host disease (GVHD). Here, we tested FMCs for treatment of steroid-refractory acute GVHD. After two passages in culture, approximately 10(9) FMCs were obtained from one single placenta, although not all cells from passage 0 and passage 1 were used for expansion. The FMCs were positive for CD29, CD44, CD73, CD90, CD105, and CD49d but were negative for hematopoietic, endothelial, and epithelial markers. Microsatellite polymorphism analysis showed that FMCs were of maternal origin. All FMCs used showed normal karyotype. Nine patients who had undergone hematopoietic stem cell transplantation (HSCT) and who had developed steroid-refractory grade III-IV acute GVHD were given 0.9-2.8 × 10(6) FMCs per kg at 15 infusions. Median age was 57 years. There was no toxicity from infusion of FMCs in eight patients. One patient had seizures after infusion. Two of eight evaluable patients had a complete response and four had a partial response, giving an overall response rate of 75%. Two patients showed no response at all. Three patients are alive from 6 to 21 months after HSCT. One patient is well and two have chronic GVHD. Thus, FMCs may be successfully used for immune modulation and tissue repair., (Copyright © 2013 AlphaMed Press.)

Patients are isolated in the hospital during the neutropenic phase after allogeneic hematopoietic stem cell transplantation. We challenged this by allowing patients to be treated at home. A nurse from the unit visited and checked the patient. One hundred forty-six patients treated at home were compared with matched hospital control subjects. Oral intake was intensified from September 2006 and improved (P = .002). We compared 4 groups: home care and control subjects before and after September 2006. The cumulative incidence of acute graft-versus-host disease (GVHD) of grades II to IV was 15% in the "old" home care group, which was significantly lower than that of 32% to 44% in the other groups (P < .03). Transplantation-related mortality, chronic GVHD, and relapse were similar in the groups. The "new" home care patients spent fewer days at home (P = .002). In multivariate analysis, GVHD of grades 0 to I was associated with home care (hazard ratio [HR], 2.46; P = .02) and with days spent at home (HR, .92; P = .005) but not with oral nutrition (HR, .98; P = .13). Five-year survival was 61% in the home care group as compared with 49% in the control subjects (P = .07). Home care is safe. Home care and many days spent at home were correlated with a low risk of acute GVHD., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

We evaluated the effect of acute and chronic GVHD on relapse and survival after allogeneic hematopoietic SCT (HSCT) for multiple myeloma using non-myeloablative conditioning (NMA) and reduced-intensity conditioning (RIC). The outcomes of 177 HLA-identical sibling HSCT recipients between 1997 and 2005, following NMA (n=98) or RIC (n=79) were analyzed. In 105 patients, autografting was followed by planned NMA/RIC allogeneic transplantation. The impact of GVHD was assessed as a time-dependent covariate using Cox models. The incidence of acute GVHD (aGVHD; grades I-IV) was 42% (95% confidence interval (CI), 35-49%) and of chronic GVHD (cGVHD) at 5 years was 59% (95% CI, 49-69%), with 70% developing extensive cGVHD. In multivariate analysis, aGVHD (≥ grade I) was associated with an increased risk of TRM (relative risk (RR)=2.42, P=0.016), whereas limited cGVHD significantly decreased the risk of myeloma relapse (RR=0.35, P=0.035) and was associated with superior EFS (RR=0.40, P=0.027). aGVHD had a detrimental effect on survival, especially in those receiving autologous followed by allogeneic HSCT (RR=3.52, P=0.001). The reduction in relapse risk associated with cGVHD is consistent with a beneficial graft-vs-myeloma effect, but this did not translate into a survival advantage.

This study analysed the effects of growth factor on outcome after haematopoietic stem-cell transplantation (HSCT) with >9 years follow-up. Of 1887 adult patients with acute leukaemia who received bone marrow from human leucocyte antigen (HLA)-identical siblings and were treated with myeloablative conditioning, 459 (24%) were treated with growth factor. Growth factor hastened engraftment of neutrophils (P < 0·0001), but reduced platelet counts (P = 0·0002). Graft-versus-host disease (GVHD)-free survival (no acute GVHD grade II-IV or chronic GVHD) at 10 years was 12 ± 2% (±SE) in the growth factor group, as opposed to 17 ± 2% in the controls [hazard ratio (HR) 0·81, P = 0·001]. Similar differences in GVHD-free survival were seen in patients with or without conditioning with total body irradiation (TBI). Non-relapse mortality (NRM) was higher in the growth factor group irrespective of whether or not TBI conditioning was included [HR = 1·48; 95% confidence interval (CI): 1·15-1·9; P = 0·002; HR = 1·59; 95% CI: 1·07-2·37; P = 0·02, respectively]. Both groups had similar probabilities of leukaemic relapse (HR = 0·96; 95% CI: 0·78-1·18; P = 0·71). Leukaemia-free survival (LFS) at 10 years was 35 ± 2% in those receiving growth factor prophylaxis, as opposed to 44 ± 1% in the controls (HR = 0·70; 95% CI: 0·60-0·82; P = 0·00001). Prophylaxis with growth factor increases the risk of GVHD, does not affect relapse, increases NRM and reduces LFS > 10 years after HSCT, regardless of conditioning with TBI., (© 2012 Blackwell Publishing Ltd.)

Thirty-one patients treated with mesenchymal stromal cells (MSCs) for acute graft-versus-host disease (aGVHD) or hemorrhagic cystitis between 2002 and 2007 were followed to investigate predictors of outcome, immunologic effects in vivo, and long-term survival. There was no correlation between in vitro suppression by MSCs in mixed lymphocyte cultures and outcome. Soluble IL-2 receptors were measured in blood before and after MSC infusion and declined significantly during the first week after MSC infusion (P = .03). Levels of interleukin-6 and HLA-G were unaffected. Infectious complications occurred several years after recovery from aGVHD. Cytomegalovirus viral load was high, and cytomegalovirus disease was common. Among patients recovering from aGVHD, 54% died of late infections, between 4 months and 2 years after MSC treatment. No increase in leukemia relapse or graft rejection was found. Children had a better survival rate than adults (P = .005). In GVHD patients, 1-year survival was 75% in patients who received early-passage MSCs (from passages 1-2) in contrast to 21% using later passage MSCs (from passages 3-4) (P < .01). We conclude that treatment with early-passage MSCs improved survival in patients with therapy-resistant GVHD. Death from infection was common in MSC-treated patients, but there was no increase in leukemia relapse., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

For prevention of graft-versus-host disease (GVHD), treatment of 24 haematopoietic stem cell transplantation (HSCT) patients with sirolimus and tacrolimus was compared to treatment of matched controls with cyclosporine-based regimens. The patients mainly had non-malignant disorders. Two-thirds of the donors were unrelated, and bone marrow was the most common source of stem cells. Rejection occurred in four patients in the sirolimus group and three in the control group. Donor chimerism for CD3, CD19 and CD33 was similar in the two groups. The cumulative incidence of grade II acute GVHD was 22% in the sirolimus patients and 17% in the controls (P=0.78). No patients developed acute GVHD of grades III-IV. The cumulative incidence of chronic GVHD was 25% and 37% in the two groups, respectively (P=0.40). Two patients in the sirolimus group developed Epstein-Barr virus lymphoma, and none in the controls. Side effects and toxicity were similar in the two groups. There was no transplant-related mortality at 5 yr in the sirolimus group, as opposed to 8% in the controls (P=0.47). Survival at 5 yr was 95% and 92%. Thus, sirolimus combined with tacrolimus is a promising immunosuppressive regimen in HSCT, also for non-malignancies, and its efficacy should be confirmed in prospective clinical trials., (© 2011 John Wiley & Sons A/S.)

Approximately 13% of patients lacking an HLA-identical sibling have a one-antigen-mismatched related donor (MMRD). Historically, outcomes from the use of a one-antigen MMRD were considered equivalent to those from the use of a matched unrelated donor (UD). Recent improvements in UD stem cell transplantation (SCT) resulting from better molecular HLA matching justifies investigating whether UD should be preferred over MMRD in adult patients with acute leukemia. Here, we compared the outcomes of MMRD (n = 89) and HLA-A, -B, -C, and -DRB1 allele-matched UD (n = 700) SCT reported to the Center for International Blood and Marrow Transplant Research between 1995 and 2005. The patients underwent transplantation for acute myelogenous leukemia or acute lymphoblastic leukemia in first or second complete remission. Donor type was not associated with hematologic recovery. Univariate and multivariate comparisons of MMRD versus HLA-matched UD transplants showed no statistically significant differences in overall survival, disease-free survival, treatment-related mortality, relapse, or 100-day grade III-IV acute graft-versus-host disease (GVHD). MMRD SCT was associated with a lower rate of chronic GVHD at 1 year (35% vs 47%; P = .03), which was confirmed by multivariate analysis (relative risk, 0.58; 95% confidence interval, 0.39-0.85; P < .01). According to our data, HLA-matched UD and MMRD SCT are associated with comparable survival. Given that less chronic GVHD was observed in the MMRD transplantations, this option, when available, remains the first choice in patients with acute leukemia without an HLA-identical sibling in need of allogeneic SCT., (Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

N-acetyl-L-cysteine (NAC) is a thiol antioxidant that stimulates glutathione synthesis in cells. Several studies indicate that NAC possesses immunomodulatory properties in vitro, but both inhibitory and activating effects on immunity have been reported. We observed that allogeneic stem cell transplantation (ASCT) patients who were randomized to receive NAC 100  mg/kg/day (n=73) had an increased prevalence of grade II-V acute graft-versus-host disease (GvHD) compared to patients who did not receive NAC (n=87), indicating that NAC has an immunostimulatory effect in vivo. When studying the effect of NAC on T-cell-mediated immunity in vitro, we found that moderate levels of NAC (0.4-3.2  mM) increased alloantigen-induced proliferation, expression of activation markers CD25 and CD71 on T cells, and production of IFN-γ and IL-10. In contrast, high concentrations of NAC (12.5-50  mM) were suppressive, which may explain previously conflicting data. NAC did not cause an increase in expression of CD86, CD80, and CD83 on mature DCs at any concentration, whereas high concentrations suppressed DC maturation. Furthermore, T cells exposed to suppressive concentrations of NAC in a primary stimulation were highly responsive when re-stimulated in the absence of NAC. To conclude, NAC appears to increase acute GvHD and has an immunostimulatory effect on alloantigen-specific T cells., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Severe congenital neutropenia (SCN) is an immunodeficiency characterized by disturbed myelopoiesis and an absolute neutrophil count (ANC) <0.5 × 10(9)/L. SCN is also a premalignant condition; a significant proportion of patients develop myelodysplastic syndrome or leukemia (MDS/L). Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for SCN., Procedure: Since 2004, eight HSCT have been performed in seven patients at our center. The indications were transformation to MDS/L (n = 2), granulocyte colony-stimulating factor receptor (CSF3R) mutation(s) (n = 2), granulocyte colony-stimulating factor (G-CSF) resistance (n = 2), and at the patient's own request (n = 1)., Results: The mean age at transplantation was 13 years (2.8-28 years) (mean follow-up 32 months, range 21-60). Three patients harbored ELANE mutations, three HAX1 mutations, and in one patient no causative mutation was identified. Two of the ELANE mutations were novel mutations. Three patients initially received myeloablative conditioning and four had reduced intensity conditioning (RIC). Three grafts were from HLA-identical siblings, three from matched unrelated donors and two were cord blood units. Engraftment occurred in all patients. Two of seven (29%) patients died; both had MDS/L and both were among the three that underwent myeloablative conditioning. One patient has chronic GVHD 2 years post-transplant., Conclusions: The role of HSCT should be explored further in patients with SCN. In particular, the influence of the conditioning regime needs to be evaluated in a larger cohort of patients., (© 2010 Wiley-Liss, Inc.)

We evaluated the results in 20 recent patients treated with a second hematopoietic stem cell transplantation (HSCT) after graft failure (GF). There were 10 children <18 yr of age. Ten patients had a non-malignant disease, and the other 10 had a malignant disease. In most of the transplantations, fludarabine-based reduced intensity conditioning (RIC) was given. Bone marrow was given to 11 patients, peripheral blood system cell (PBSC) in seven and cord blood to two patients. For the second transplantation (n = 20), a new donor was used in nine cases, while the initial donor was used in 11 transplants. Eight patients (40%) suffered from a second GF. Five of these patients were treated with a third HSCT. The probability of survival was 65% one yr and 60% three yr after the second HSCT. No difference in survival was found between patients transplanted with a new donor (56%) compared to those using the original donor (64%). The three-yr survival was 70% for children compared to 50% for adults (p = ns). Patients with a non-malignant disorder showed a three-yr survival of 90% compared to 20% in patients with a malignant disease (p = 0.005). We concluded that re-transplantation using RIC is a valid option for GF, especially in patients with non-malignant disorders., (© 2010 John Wiley & Sons A/S.)

Graft-versus-host disease (GVHD) prophylaxis of short duration (6 months) with low-dose cyclosporine A (CsA) starting at 1 mg/kg per day i.v. and four doses of methotrexate (MTX) were given to 171 consecutive leukaemic recipients of HLA-identical sibling transplants. In contrast, apart from MTX, retrospective controls received high-dose CsA, starting at 5-7.5 mg/kg per day i.v. and discontinued 1 yr post-transplant. In the low-dose CsA group, the probability of acute GVHD grades I-II (70% vs. 53%, P < 0.01), and chronic GVHD were increased (58% vs. 25%, P < 0.01), whereas the incidences of acute GVHD grades III-IV (9% vs. 5%, P = 0.62), and non-relapse mortality (20% vs. 22%, P = 0.58) were similar. Moreover, the probability of relapse was decreased (31% vs. 54%, P < 0.01), and both relapse-free (56% vs. 38%, P = 0.04) and overall survival (61% vs. 40%, P = 0.04) were markedly improved using the low-dose CsA regimen. In multivariate analyses, low-dose CsA was strongly associated with chronic GVHD [relative hazard (RH) 2.56, P < 0.01], which decreased the risk of relapse (RH 0.46, P < 0.01) and improved the probability of survival (RH 1.84, P < 0.01). In conclusion, a low-dose CsA regimen in leukaemic recipients of HLA-identical sibling transplants increases the rate of chronic GVHD, which seems to attenuate the risk of relapse, thereby improving patient survival owing to enhanced graft-versus-leukaemia effect.

The chimeric state after allogeneic hematopoietic stem cell transplantation provides a platform for adoptive immunotherapy using donor-derived immune cells. The major risk with donor lymphocyte infusions (DLIs) is the development of graft-versus-host disease (GvHD). Development of new DLI products with antitumor reactivity and reduced GvHD risk represents a challenging task in cancer immunotherapy. Although natural killer (NK) and NK-like T cells are promising owing to their antitumor activity, their low concentrations in peripheral blood mononuclear cells reduces their utility in DLIs. We have recently developed a system that allows expansion of clinical-grade NK and NK-like T cells in large numbers. In this study, the safety of donor-derived long-term ex vivo-expanded human NK and NK-like T cells given as DLIs was investigated as immunotherapy for cancer in five patients following allogeneic stem cell infusion. Infusion of the cells was safe whether administered alone or with IL-2 subcutaneously. No signs of acute GvHD were observed. One patient with hepatocellular carcinoma showed markedly decreased serum alpha-fetoprotein levels following cell infusions. These findings suggest that the use of ex vivo-expanded NK and NK-like T cells is safe and appears an attractive approach for further clinical evaluation in cancer patients.

Purpose: Acute graft-versus-host disease (GVHD) causes substantial morbidity and mortality after human leukocyte antigen (HLA)-identical sibling transplants. No large registry studies of acute GVHD risk factors have been reported in two decades. Risk factors may have changed in this interval as transplant-related techniques have evolved., Patients and Methods: Acute GVHD risk factors were analyzed in 1,960 adults after HLA-identical sibling myeloablative transplant for acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), or chronic myeloid leukemia (CML) reported by 226 centers worldwide to the Center for International Blood and Marrow Transplant Research from 1995 to 2002. Outcome was measured as time from transplant to onset of grade 2 to 4 acute GVHD, with death without acute GVHD as a competing risk., Results: Cumulative incidence of grade 2 to 4 acute GVHD was 35% (95% CI, 33% to 37%). In multivariable analyses, factors significantly associated with grade 2 to 4 acute GVHD were cyclophosphamide + total-body irradiation versus busulfan + cyclophosphamide (relative risk [RR] = 1.4; P < .0001), blood cell versus bone marrow grafts in patients age 18 to 39 years (RR = 1.43; P = .0023), recipient age 40 and older versus age 18 to 39 years receiving bone marrow grafts (RR = 1.44; P = .0005), CML versus AML/ALL (RR = 1.35; P = .0003), white/Black versus Asian/Hispanic race (RR = 1.54; P = .0003), Karnofsky performance score less than 90 versus 90 to 100 (RR = 1.27; P = .014), and recipient/donor cytomegalovirus-seronegative versus either positive (RR = 1.20; P = .04). Stratification by disease showed the same significant predictors of grade 2 to 4 acute GVHD for CML; however, KPS and cytomegalovirus serostatus were not significant predictors for AML/ALL., Conclusion: This analysis confirmed several previously reported risk factors for grade 2 to 4 acute GVHD. However, several new factors were identified whereas others are no longer significant. These new data may facilitate individualized risk estimates and raise several interesting biologic questions.

We studied the importance of human leucocyte antigen (HLA)-A, -B and -DRB1 high-resolution matching on the outcome of haematopoietic stem cell transplantation (HSCT) with matched unrelated donors (MUDs) vs single allele-mismatched unrelated donors. Fifty consecutive HSCT patients receiving an HLA-A, -B or -DR allele-level-mismatched unrelated graft (mmUD) were compared with a matched cohort of 100 patients with an HLA-A, -B and -DR-MUD. Rejection occurred in seven patients (14%) in the mmUD group and in four patients (4%) in the MUD group (P = 0.04), but this was mainly an effect of HLA-C mismatch. The cumulative incidence of acute graft vs host disease (GVHD) grades II-IV were 61%, 26% and 33% in the class I mmUD, class II mmUD and MUD groups, respectively. In multivariate analysis, HLA class I mismatch was associated with an increased risk of acute GVHD grades II-IV (2.09, P = 0.007) and transplant-related mortality (TRM) (1.99, P = 0.06). The 5-year overall survival was 81% in patients with a class II allele-mismatched donor compared with 52% (P = 0.025) and 50% (P = 0.017) in patients with a class I mismatch and a MUD. In multivariate analysis, HLA class II allele mismatch was associated with improved survival (3.38, P = 0.019). Relapse-free survival were 53%, 37% and 42% in patients with a class II mmUD, class I mmUD and a MUD, respectively (not significant). An HLA-C or -DQ mismatch had no significant impact on survival, TRM and relapse. In conclusion, compared with MUD, HLA class I allele mmUD had an increased risk of acute GVHD and TRM.

Recent studies have pointed towards an association between certain single nucleotide polymorphisms (SNPs) in the NOD2/CARD15 gene, and negative outcome of Allo-SCT. In this study, 198 patients and their corresponding donors were analyzed retrospectively for the occurrence of NOD2/CARD15 mutations to evaluate the impact on clinical results after Allo-SCT. In all, 7.6% of the patients and 11% of the donors were heterozygous for one of three SNPs 8, 12 or 13. Contrary to earlier findings, we found no significant impact on incidence of acute GVHD or TRM following Allo-SCT. These differences in results could be due to a lower mutation frequency in the studied population and/or a lower overall incidence of severe GVHD. On the basis of these findings we conclude that a consideration to NOD2/CARD15 mutation status is not pertinent when selecting a donor for Allo-SCT at our centre.

Background: Severe graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic transplantation with haemopoietic stem cells. Mesenchymal stem cells modulate immune responses in vitro and in vivo. We aimed to assess whether mesenchymal stem cells could ameliorate GVHD after haemopoietic-stem-cell transplantation., Methods: Patients with steroid-resistant, severe, acute GVHD were treated with mesenchymal stem cells, derived with the European Group for Blood and Marrow Transplantation ex-vivo expansion procedure, in a multicentre, phase II experimental study. We recorded response, transplantation-related deaths, and other adverse events for up to 60 months' follow-up from infusion of the cells., Findings: Between October, 2001, and January, 2007, 55 patients were treated. The median dose of bone-marrow derived mesenchymal stem cells was 1.4x10(6) (min-max range 0.4-9x10(6)) cells per kg bodyweight. 27 patients received one dose, 22 received two doses, and six three to five doses of cells obtained from HLA-identical sibling donors (n=5), haploidentical donors (n=18), and third-party HLA-mismatched donors (n=69). 30 patients had a complete response and nine showed improvement. No patients had side-effects during or immediately after infusions of mesenchymal stem cells. Response rate was not related to donor HLA-match. Three patients had recurrent malignant disease and one developed de-novo acute myeloid leukaemia of recipient origin. Complete responders had lower transplantation-related mortality 1 year after infusion than did patients with partial or no response (11 [37%] of 30 vs 18 [72%] of 25; p=0.002) and higher overall survival 2 years after haemopoietic-stem-cell transplantation (16 [53%] of 30 vs four [16%] of 25; p=0.018)., Interpretation: Infusion of mesenchymal stem cells expanded in vitro, irrespective of the donor, might be an effective therapy for patients with steroid-resistant, acute GVHD.

We analysed factors associated with moderate to severe acute GVHD in 111 patients treated with fludarabin-based reduced intensity conditioning (RIC) and allogeneic haematopoietic stem cell transplantation (HSCT). Most patients had a haematological malignancy. Donors were 97 HLA-A, -B and -DRbeta1 identical unrelated and 14 HLA-A, -B or -DRbeta1 allele mismatched unrelated donors. In the univariate analysis, we found ten factors associated with acute GVHD. These were diagnosis (P=0.06), GVHD prophylaxis with combinations other than CsA+MTX (P=0.006), graft nucleated (P<0.001) and CD34 (P<0.001) cell-dose, bidirectional ABO mismatch (P=0.001), conditioning (P=0.002), hospital vs home-care (P=0.06), ATG dose (P<0.001), donor herpes virus serology (P=0.07) and an immunized female donor to male recipient (P=0.05). In the multivariate analysis, three factors remained significant: a high CD34 cell dose (P<0.001), low dose (4 mg/kg) ATG (P<0.001), and an immunized female donor to male recipient (P<0.01). Patients receiving a CD34 cell dose > or =17.0 x 10(6) per kg had a higher incidence of GVHD, 53.7%, compared to 22.3% in patients receiving a lower dose (P=0.002). In patients without any of these risk factors (n=70), the incidence of acute GVHD was 14.1%, while it was 38.0 and 85.0% in patients with one (n=29) or two (n=10) risk factors (P<0.001). We concluded that risk factors for acute GVHD using RIC are similar as using myeloablative conditioning.

The aim of this study was to evaluate the effects and kinetics of IgG levels after allogeneic stem cell transplantation (SCT). This study retrospectively examines 179 consecutive patients undergoing SCT between 1995 and 2002. Diagnoses included acute and chronic leukemia (n=136), solid tumors (n=11), other malignancies (n=16) and non-malignant diseases (n=16). Standard myeloablative conditioning was given to 146 patients, and 33 patients received reduced intensity conditioning. Serum samples for measurement of IgG levels were collected 3, 6 and 12 months after SCT, and then yearly. IgG levels increased after SCT throughout the study period. Factors that were associated with low IgG levels after SCT were acute graft-versus-host disease (GVHD), patient age < or =30 years, female donor-to-male recipient, not receiving anti-thymocyte globulin and type of GVHD prophylaxis. Compared to patients with moderately low or normal levels as measured twice during the first year after transplantation, patients with low IgG levels (<4 g/l) showed a decreased survival rate (54 vs 71%, P=0.04) and an increased incidence of transplant-related mortality (27 vs 9%, P<0.01). IgG levels generally increase after SCT. Persistent low levels of IgG are a risk factor for death after SCT.

Mesenchymal stem cells (MSC) may be used to treat acute graft-versus-host disease and for tissue repair. In vitro expansion of MSC has been achieved in the presence of fetal calf serum (FCS). For safety and regulatory reasons, we explored if FCS could be replaced by human blood group AB serum. Proliferation and fold increase of MSC was higher in the presence of AB-serum, compared to FCS. Similar to cells generated in FCS media, MSC from AB-serum media were more than 95% positive for CD90, CD105 and human leukocyte antigen (HLA) class I, and negative for hematopoietic and endothelial markers CD14, CD31, CD34, CD45, and CD80. HLA class II expression was higher in MSC generated in AB-serum, but decreased with higher passage numbers. MSC generated in AB-serum suppressed lymphocyte proliferation in mixed lymphocyte cultures and after stimulation with phytohemagglutinin. MSC expanded in AB-serum and FCS have similar in vitro properties.

Cyclosporine A (CsA) therapy based on 2-h concentrations (C2) after oral administration has demonstrated low acute rejection rates after solid organ transplantation. We analysed the correlation between C2 and trough (C0) levels of oral CsA therapy in samples obtained twice in consecutive weeks from 58 patients during their first admission for allogeneic haematopoietic stem cell transplantation. Also 8-h concentration curves were obtained from 23 patients. The mean (range) CsA dose was 332 (167-763) and 255 (113-575) mg/day for patients with matched unrelated donor (MUD) and human leukocyte antigen identical sibling donor (Sib), respectively. Median (range) C0 and C2 were 254 (145-332) and 898 (419-1466) ng/ml in MUD patients, and 130 (93-265) and 554 (196-988) ng/ml in Sib patients. In MUD patients with either aGVHD grade < II or > or = II, the median C2 were 915 (419-1466) and 890 (519-1399) ng/ml, respectively. In Sib patients with aGVHD grade < II or grade > or = II, the median C2 were 552 (404-718) and 539 (196-988) ng/ml, respectively. The median C2 levels were comparable in patients with or without severe infections. Interindividual variations in CsA uptake and metabolism may explain the wide variation of C2 levels without prediction for increased risk for severe aGVHD or infectious complication when C0 guided the CsA dosing.

Severe hemorrhagic cystitis (HC) may be a life-threatening complication in allogeneic stem cell transplantation (SCT). In order to improve the strategies for prophylaxis and treatment, we retrospectively analyzed data on patients who underwent SCT at our center from 1990 through 2005. Patients with HC were identified through our database and their medical charts were reviewed. Grades 2-5 and 3-5 HC developed in 109/834 patients (13.1%) and 27/834 patients (3.2%), respectively. The frequency of HC decreased over the time from 18.0% in 1990-1992 to 9.5% in 2002-2005 (p = 0.005). HC started on a median of 35 (0-166) days post-transplant and persisted for a median of 23 (2-270) days. Transplant-related mortality was 21% in patients without HC, 15% in those with HC of grade 2, 55% in those with grade 3, and 71% in patients with HC of grades 4-5 (p < 0.001). In multivariate analysis, the risk factors for HC were myeloablative conditioning, busulphan, cytomegalovirus infection, hematological malignancy, and acute graft-versus-host disease (aGVHD). With four risk factors, the risk of HC development was 31%. Risk factors for severe HC of grades 3-5 were aGVHD and bacteremia.