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Chronic graft-versus-host disease (cGVHD) is a long-term complication of allogeneic hematopoietic stem cell transplantation associated with poor quality of life and increased morbidity and mortality. Currently, there are several approved treatments for patients who do not respond to steroids, such as ruxolitinib. Nevertheless, a significant proportion of patients fail second-line treatment, indicating the need for novel approaches. Mesenchymal stem cells (MSCs) have been considered a potential treatment approach for steroid-refractory cGVHD. To evaluate the safety and efficacy of repeated infusions of MSCs, we administered intravenous MSCs every two weeks to ten patients with severe steroid-refractory cGVHD in a prospective phase I clinical trial. Each patient received a total of four doses, with each dose containing 1 × 10 6 cells/kg body weight from the same donor and same passage. Patients were assessed for their response to treatment using the 2014 National Institutes of Health (NIH) response criteria during each visit. Ten patients with diverse organ involvement were enrolled, collectively undergoing 40 infusions as planned. Remarkably, the MSC infusions were well tolerated without severe adverse events. Eight weeks after the initial MSC infusion, all ten patients showed partial responses characterized by the amelioration of clinical symptoms and enhancement of their quality of life. The overall response rate was 60%, with a complete response rate of 20% and a partial response (PR) rate of 40% at the last follow-up. Overall survival was 80%, with a median follow-up of 381 days. Two patients died due to relapse of their primary disease. Immunological analyses revealed a reduction in inflammatory markers, including Suppression of Tumorigenicity 2 (ST2), C-X-C motif chemokine ligand (CXCL)10, and Secreted phosphoprotein 1(SPP1), following the MSC treatment. Repeated MSC infusions proved to be both feasible and safe, and they may be an effective salvage therapy in patients with steroid-refractory cGVHD. Further large-scale clinical studies with long-term follow-up are needed in the future to determine the role of MSCs in cGVHD.

Graft-versus-host disease (GVHD) is a common complication following hematopoietic stem cell transplantation and can be life-threatening. Mesenchymal stem cells (MSCs), adult stem cells with immunomodulatory properties, have been used as therapeutic agents in a variety of ways and have demonstrated efficacy against acute GVHD (aGVHD); however, variability in MSC pro- and anti-inflammatory properties and the limitation that they only exhibit immunosuppressive effects at high levels of inflammation have prevented their widespread clinical use. The outcomes of GVHD treated with MSCs in the clinic have been variable, and the underlying mechanisms remain unclear. Therefore, the unique biological effects of Toll-like receptor 5 (TLR5) agonists led us to compare and validate the efficacy of MSCs primed with KMRC011, a TLR5 agonist. KMRC011 is a stimulant that induces the secretion of cytokines, which play an important role in immune regulation. In this study, we found that MSCs pretreated with KMRC011 increased the secretion of immunosuppressive cytokines indoleamine 2,3-dioxygenase (IDO) and cyclooxygenase-2 (COX2) and increased the expression of M2 macrophage polarizing cytokines macrophage colony-stimulating factor (M-CSF) and interleukin 10 (IL-10) in vitro . We investigated the immunosuppressive effects of TLR5 agonist (KMRC011)-primed MSCs on lymphocytes and their preventive and therapeutic effects on an in vivo mouse aGVHD model. In vitro experiments showed that KMRC011-primed MSCs had enhanced immunosuppressive effects on lymphocyte proliferation. In vivo experiments showed that KMRC011-primed MSCs ameliorated GVHD severity in a mouse model of induced GVHD disease. Finally, macrophages harvested from the spleens of mice treated with KMRC011-primed MSCs showed a significant increase in the anti-inflammatory M2 phenotype. Overall, the results suggest that KMRC011-primed MSCs attenuated GVHD severity in mice by polarizing macrophages to the M2 phenotype and increasing the proportion of anti-inflammatory cells, opening new horizons for GVHD treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Introduction: B-cell-activating factor (BAFF) is associated with donor-specific antibodies and chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the effects of BAFF on T-cell physiological function have not been fully elucidated in acute GVHD., Methods: We examined the effects of belimumab, a monoclonal antibody targeting BAFF, for the treatment of acute GVHD. We examined the effects of T cells and B cells separately when inducing GVHD in mouse model., Results: Therapeutic functional manipulation of endogenous BAFF can improve acute GVHD during the early post-transplant period. In this study, BAFF was shown to increase the proportions of CD4 + IL-17 + , CD4 + IL-6 + Th17, and CD4 + IFN-γ + Th1 cells and to reduce the proportion of regulatory T (Treg) cells. Furthermore, the belimumab therapy group showed increased B220 + IgD + IgM + mature B cells but decreased B220 + IgD - IgM - memory B cells, B220 + Fas + GL-7 + germinal center formation, and B220 + IgD - CD138 + plasma cells. These results indicate that BAFF can alleviate acute GVHD by simultaneously regulating T and B cells. Interestingly, the BAFF level was higher in patients with acute GVHD after HSCT compared with patients receiving chemotherapy., Conclusion: This study suggests that BAFF blockade might modulate CD4 +T-cell-induced acute GVHD early after allo-HSCT and the possibility of simultaneously controlling chronic GVHD, which may appear later after allo-HSCT., Competing Interests: Author SGC is founder of the company LucasBio. The remaining 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 © 2022 Jeon, Lim, Im, Kim and Cho.)

Despite the proven efficacy of anti-T-cell or antithymocyte globulin (ATG) for chronic graft-versus-host disease (GVHD) prevention in transplantation from an unrelated donor, dosing protocols and the effects of ATG on relapse and infection remain controversial. In the setting of transplantation from an HLA-matched sibling (MSD-T), few randomized studies have been conducted. We conducted a prospective, single-center, open-label, randomized study of low-dose thymoglobulin (2.5 mg/kg) for chronic GVHD prevention. A total of 120 patients with acute leukemia were randomly assigned in a 1:1 ratio. After a median follow-up of 27 months, the cumulative incidence of chronic GVHD in the ATG and non-ATG groups was 25.0% and 65.4% (p < 0.001), respectively. The ATG group had an increased relapse rate compared with the non-ATG-group (20.0% vs. 9.3%; p = 0.055), with risks that differed according to cytogenetic subgroup (high-risk, 29.6% vs. 9.3%, p = 0.042; non-high-risk, 12.2% vs. 9.2%, p = 0.596). Chronic GVHD-free and relapse-free survival (cGRFS) was higher in the ATG group (46.7% vs. 19.4%; p = 0.070), and the difference was significant in a cytogenetic non-high-risk subgroup (45.5% vs. 0%; p = 0.038). No differences were observed in other survival outcomes. Improved physical components in quality-of-life scores were observed in the ATG group at 12 months after transplantation. A higher rate of Epstein-Barr virus reactivation was observed in the ATG group (21.8% vs. 5.1%; p = 0.013), whereas no between-group differences for other complications. In conclusion, the low-dose thymoglobulin effectively prevented chronic GVHD in MSD-T, resulting in improvement in quality-of-life and cGRFS, whereas the necessity of caution for high-risk acute leukemia., (© 2021 Wiley Periodicals LLC.)

We assessed the impact of donor type on long-term outcomes of allogeneic hematopoietic cell transplantation (HCT) in 440 consecutive adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR1), particularly focusing on the donor type-specific difference in graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS). Donor sources were matched sibling donor (MSD; n = 199), matched unrelated donor (MUD; n = 110), 1-allele-mismatched unrelated donor (1-MMUD; n = 83), and cord blood (CB; n = 48). Cumulative incidence of severe chronic GVHD was 14.8% for MSD-HCT, 30.1% for MUD-HCT, 9.6% for 1-MMUD-HCT, and 4.2% for CBT, respectively (P < 0.001), while no difference was observed in grade III-IV acute GVHD. After a median follow-up of 58.1 months, cumulative incidence of relapse was 26.1% for MSD-HCT, 27.2% for MUD-HCT, 31.2% for 1-MMUD-HCT, and 7.2% for CBT, respectively (P = 0.042). Disease-free survival and overall survival were comparable among all donor sources. However, GRFS for MSD-HCT, MUD-HCT, 1-MMUD-HCT, and CBT was 33.1%, 14.5%, 42.1%, and 50.3%, respectively (P = 0.001). In multivariate analysis, CBT showed a comparable GRFS to MSD-HCT (HR, 0.78; P = 0.290), while MUD-HCT was associated with a poorer GRFS (HR, 1.53; P = 0.002). Given the encouraging GRFS of CBT, our data suggest that CBT remains a valid option for adult ALL in CR1.

Relapse is a major concern with reduced-intensity conditioning. We analyzed 257 patients with acute myeloid leukemia (AML) who received allogeneic stem cell transplantation (SCT) and fulfilled the following criteria: intermediate- or poor-risk disease by National Comprehensive Cancer Network guidelines (2017, version 3), in first complete remission (CR1) at SCT, received either myeloablative conditioning (MAC; busulfan plus cyclophosphamide or cyclophosphamide plus total body irradiation) or reduced-intensity conditioning (RIC; FluBu2TBI400) peripheral blood SCT from 8/8 matched sibling or unrelated donor, and having bone marrow Wilms tumor gene 1 (WT1) expression results before transplant. We and other groups serially published a predictive value for pretransplant WT1 expression in patients with AML to identify patients at higher risk of relapse. Among the total 257 patients, 191 (74.3%) and 66 (25.7%) patients received MAC and RIC transplants, respectively. WT1 ≥250 copies/10 4 ABL was defined as WT1 high . WT1 high before SCT was found to be an independent prognostic factor for inferior overall survival (OS), disease-free survival (DFS), and higher cumulative incidence of relapse (CIR). There were 201 patients with WT1 low expression based upon pretransplant analysis. There was no significant difference in OS, DFS, CIR, and nonrelapse mortality between MAC and RIC patients. To conclude, post-transplant survival or relapse was not different by conditioning intensity in AML CR1 patients whose WT1 level was below 250 copies per 10 4 ABL at transplantation., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to verify the feasibility of rabbit antithymocyte globulin (ATG; 5 mg/kg) in combination with 600 cGy of fractionated total body irradiation (fTBI; 3 doses of 200 cGy) and fludarabine (Flu; 150 mg/m 2 ) as a conditioning regimen for haploidentical stem cell transplantation from a related mismatched donor (haplo-SCT) in adult patients with severe aplastic anemia (SAA). We analyzed 47 consecutive patients who underwent haplo-SCT, including 24 patients from our previous pilot report. The median age was 36.0 years (range, 17 to 61 years), and 25 patients (53%) were very severe aplastic anemia (VSAA) at transplantation. All patients achieved primary engraftment. The cumulative incidence of grade ≥II acute graft-versus-host disease (GVHD) and chronic moderate or greater GVHD was 27.7% at 100 days and 13.5% at 3 years, respectively. With a median follow-up of 32.3 months, the 3-year probability of overall survival and failure-free survival was 91.0% and 88.6%, respectively. The 3-year GVHD- and failure-free survival (GFFS) was 71.6%. Offspring donor and lower comorbidity index were independent factors correlated with higher GFFS in multivariate analysis. In conclusion, the outcomes of haplo-SCT with fTBI 600 cGy/Flu/ATG-5 indicate that haplo-SCT can be an effective alternative option when a fully matched donor is not available or a patient with VSAA needs an urgent transplantation., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The recent improvements in the outcomes of severe aplastic anemia (SAA) patients who received allogeneic stem cell transplantation (SCT) from unrelated donors (URD) suggest the possibility of its alternative first-line treatment. To address this issue, results of adult SAA patients receiving allogeneic SCT were compared between the following three donor-type groups: 8/8-matched sibling (MSD; n = 153), 8/8 well-matched unrelated (WM-URD; n = 72), and 6-7/8 partially matched unrelated (PM-URD; n = 33). Proportion of patients who experienced immunosuppressive treatment failures was significantly higher in the URD groups than in the MSD group (P< 0.01). The incidences of graft failure and transplant-related mortality, and graft-vs.-host disease-free, failure-free survival rates of the MSD, WM-URD, and PM-URD groups were 14.6, 0, and 0% (P< 0.01); 6.1, 10.3, and 21.7% (P= 0.03); and 76.7, 55.5, and 51.5% (P< 0.01), respectively. The overall survival (OS) rate of the MSD group (93.9%) was higher than that of the PM-URD (78.3%; P < 0.01) group, but not to that of the WM-URD (86.2%; P= 0.18) group. Our study showed comparable OS between the MSD group and WM-URD group, which suggest that the URD-SCT can be used as a first-line treatment for adult SAA patients with WM-URD.

Graft-versus-host disease (GVHD) is a serious complication of allogeneic stem cell transplantation (SCT). Here, we report a rare case of GVHD involving the central nervous system (CNS). A 35-year-old woman was diagnosed with myelodysplastic syndrome unclassifiable and underwent allogeneic peripheral blood SCT for disease progression to myelodysplastic syndrome with excess blasts-2. One year following SCT, she experienced chronic oral and hepatic GVHD symptoms, which were managed with oral steroids and tacrolimus. Sixteen months after SCT, she developed sudden-onset, generalized, tonic-clonic-type seizures. Magnetic resonance imaging and cerebrospinal fluid evaluation showed multiple discrete white lesions and elevated IgG levels. Brain biopsy revealed periventricular plaques with the destruction of axons, representing a demyelinating disease of the CNS. We diagnosed the case as CNS GVHD. Neurologic symptoms gradually improved with methylprednisolone pulse therapy and total plasma exchange combined with a calcineurin inhibitor; the brain lesions nearly disappeared after decreasing steroid maintenance dosage, and were completely resolved 1 year after the onset of CNS GVHD. The patient is CNS GVHD-symptom-free, 3-year post-transplantation. Thus, CNS GVHD should be considered in cases of newly developed neurologic symptoms in SCT recipients showing evidence of preceding chronic GVHD.

Patients undergoing hematopoietic stem cell transplantation (HSCT) frequently receive empiric antibiotics during the neutropenic period before engraftment. Several recent studies have shown that anaerobes in the intestine are important mediators of intestinal homeostasis, and that commensal bacteria can be potent modulators of the severity of acute graft-versus-host disease (aGVHD). However, the relationships among the type of antibiotic used during the neutropenic period, changes in the intestinal microbiota, and subsequent occurrence of aGVHD are not clear. In this study, a total of 211 patients undergoing HSCT were stratified into 3 groups: patients not treated with any antibiotics during the neutropenic period (group 1; n = 43), patients treated with cefepime only (group 2; n = 87), and patients treated with carbapenem antibiotics, defined as meropenem or prepenem with or without previous cefepime therapy (group 3; n = 81). Intestinal microbiota analyses were performed on pre- and post-HSCT stool samples, and immunophenotypic analyses were performed on pre- and post-HSCT peripheral blood samples. Among the 211 patients, 95 (45%) developed aGVHD (grade ≥II), including 54 with intestinal GVHD. The incidence of intestinal GVHD was higher in group 3 compared with group 1 and group 2 (32.1%, 11.6%, and 26.4%, respectively; P = .044). After adjusting for potentially significant variables identified by univariate analysis, multivariate analyses identified broad-spectrum antibiotic use during the neutropenic period as associated with the occurrence of intestinal GVHD (hazard ratio, 3.25; 95% confidence interval, 1.13 to 9.34; P = .029). Accordingly, loss of bacterial diversity in terms of alterations in intestinal microbiota after HSCT was observed in patients who received broad-spectrum antibiotics. Moreover, alterations in the frequencies of several intestinal bacteria phyla were associated with the occurrence of intestinal GVHD. Evaluation of circulating immune cell subsets according to type of antibiotic used during the neutropenic period revealed delayed recovery of myeloid-derived suppressor cells in the broad-spectrum antibiotic use group. Our data indicate that the use of broad-spectrum antibiotics during the neutropenic period is associated with a higher incidence of intestinal GVHD via loss of microbiome diversity. Further studies are needed to determine whether maintaining bacterial diversity can help prevent the development of aGVHD., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still considered a definitive curative modality for refractory or relapsed non-Hodgkin's lymphoma (NHL). However, transplant-related morbidity and mortality remain a considerable challenge. The graft-versus-host disease (GVHD)-free with relapse-free survival (GRFS) rate and GRFS-related prognostic factors have not been fully examined for NHL alone. We evaluated 104 consecutive patients with refractory or relapsed aggressive NHL receiving allo-HSCT at a single institution. With a median follow-up of 31.5 months, the estimated 3-year overall survival (OS), disease-free survival (DFS), the cumulative incidence rates of relapse, and non-relapse mortality were 45.9%, 45.9%, 36.0%, and 17.0%, respectively. The patients with overall grades III-IV acute GVHD had markedly inferior OS and DFS (p = 0.040 for OS and p = 0.028 for DFS). However, patients with more than mild stage chronic GVHD showed superior OS and DFS (p = 0.004 and p = 0.008, respectively). The 1- and 3-year GRFS rates were 44.5% and 36.9%, respectively. The negative bone marrow involvement at diagnosis, chemosensitive disease status, and fewer exposure lines of chemotherapy before transplantation significantly increased the GRFS incidence. However, no transplant-associated factors were related to GRFS incidence. Furthermore, applying dynamic GRFS method which excepted patients whose chronic GVHD was fully resolved within short-period, survival rate significantly increased over time (36.9% vs. 41.9%, p = 0.045 for conventional GRFS vs. dynamic GRFS at 3 years after transplantation). In conclusion, these results suggest that GRFS is also a useful endpoint to assess transplant outcomes, and the dynamic GRFS calculation, including rapidly manageable chronic GVHD, is a more practical method for patients with refractory or relapsed heterogenous subtypes of NHL.

Interleukin (IL)-10-producing type 1 regulatory T (Tr1) cells, which are Foxp3 - memory T lymphocytes, play important roles in peripheral immune tolerance. We investigated whether Tr1 cells exert immunoregulatory effects in a mouse model of acute graft-versus-host disease (GVHD). Mouse CD4 + T cells were induced to differentiate in vitro into Tr1 cells using vitamin D3 and dexamethasone, and these donor-derived Tr1 cells were infused on the day of bone marrow transplantation. The Tr1 cell-transferred group showed less weight-loss and a twofold higher survival rate than the GVHD group, together with markedly decreased histopathologic grades. It was associated with the expansion of CD4 + IL-4 + type 2 T-helper (Th2) cells and CD4 + CD25 + Foxp3 + regulatory T (Treg) cells. Furthermore, Tr1 cells decreased the numbers of CD4 + interferon-γ + Th1 and CD4 + IL-17 + Th17 cells. Recipient mice harbored some Foxp3 + Tregs due to adoptive transfer of Tr1 cells, together with the upregulated expression of costimulatory molecules, including cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and inducible T-cell costimulator (ICOS); however, the Treg cells did not show the plasticity. Therefore, adoptive Tr1 cell therapy may be effective against manifestations of GVHD, exert immunomodulatory effects in a manner dependent on CTLA-4 and ICOS, and induce differentiation of the transferred Tr1 cells into Foxp3 + Treg cells.

Graft-versus-host disease-free, relapse-free survival (GRFS) is a composite endpoint that measures survival free of relapse or significant morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). Consecutive adult patients (N = 324) who received HSCT with fludarabine and busulfan-based conditioning for myelodysplastic syndrome (MDS) or secondary acute myeloid leukemia evolved from MDS were retrospectively analyzed. One-year and 3-year GRFS rates were 47.8% and 34.5%, respectively. Three fixed factors (circulating blast > 3%, high cytogenetic risk, and high comorbidity index) and 2 factors (which are) modifiable by clinicians (myeloablative conditioning [MAC] and low-dose [<7.5 mg/kg] antithymocyte globulin [ATG]) were independent factors for poor GRFS. Based on these 5 factors, 3 groups (3-year GRFS: 64.9% in low risk, 33.6% in intermediate risk, and 6.6% in high risk; P < .001) were identified. Fixed factor-adjusted GRFS in patients receiving reduced-intensity conditioning (RIC) plus high-dose ATG (≥7.5 mg/kg) was superior (P < .001) to those receiving MAC and/or low-dose ATG. Favorable influences of RIC plus ATG ≥ 7.5 mg/kg were evident in the low-risk group defined by fixed factors (3-year GRFS, 38.9% versus 4.4%; P < .001) but were not evident in the high-risk group (3-year GRFS, .0% versus 5.3%; P = .678). Conclusively, this study suggests that risk-adapted selection of conditioning intensity and ATG could improve qualified HSCT outcomes., (Copyright © 2018. Published by Elsevier Inc.)

Data regarding the optimal approach for second allogeneic hematopoietic stem cell transplantation (HSCT) after graft failure (GF) in acquired severe aplastic anemia (SAA) are still limited and heterogeneous. We examined 24 patients who underwent second HLA-matched sibling donor (MSD) peripheral blood HSCT for GF. The reconditioning regimen (TNI-750/ATG) consisted of a single dose of total nodal irradiation (TNI, 750 cGy) and antithymocyte globulin (ATG; Thymoglobulin ® , 1.25 mg/kg/day for 3 days). All but one patient achieved successful engraftment of neutrophils (median 12 days, range 5-21) and platelets (median 15 days, range 9-316). Two patients with subsequent secondary GF achieved successful engraftment after a third HSCT from the same MSD. After a median follow-up of 57.4 months (range, 11.2-155.2), the 5-year overall survival and failure-free survival were 95.7% (95% confidence interval [CI] 87.7-100%) and 87.5% (95% CI 75.2-100%), respectively. One patient developed grade II acute graft-versus-host disease (GVHD), and the 2-year cumulative incidence of chronic GVHD was 23.5% (95% CI 8.1-43.5%). This study demonstrated successful outcomes following a second MSD HSCT in SAA after GF, and the results suggest TNI-750/ATG is a feasible reconditioning option. Future studies with larger cohorts will validate our results.

Background/aims: Adoptive therapy with regulatory T (Treg) cells to prevent graft-versus-host disease (GVHD) would benefit from a strategy to improve homing to the sites of inflammation following hematopoietic stem cell transplantation (HSCT). Although donor-derived Treg cells have mainly been used in these models, third-party-derived Treg cells are a promising alternative for cell-based immunotherapy, as they can be screened for pathogens and cell activity, and banked for GVHD prevention. In this study, we explored major histocompatibility complex (MHC) disparities between Treg cells and conventional T cells in HSCT to evaluate the impact of these different cell populations on the prevention of acute GVHD, as well as survival after allogeneic transplantation., Methods: To induce acute GVHD, lethally irradiated BALB/c (H-2d) mice were transplanted with 5 × 105 T cell-depleted bone marrow cells and 5 × 105 CD4+CD25- splenic T cells from C57BL/6 (H-2b) mice. Recipients were injected with 5 × 105 cultured donor-, host-, or third-party-derived CD4+CD25+CD62L+ Treg cells (bone marrow transplantation + day 1)., Results: Systemic infusion of three groups of Treg cell improved clinicopathological manifestations and survival in an acute GVHD model. Although donor-derived Treg cells were immunologically the most effective, the third-party-derived Treg cell therapy group displayed equal regulation of expansion of CD4+CD25+- Foxp3+ Treg cells and suppressive CD4+IL-17+ T-helper (Th17) cells in ex vivo assays compared with the donor- and host-derived groups., Conclusion: Our findings demonstrate that the use of third-party Treg cells is a viable alternative to donor-derived Treg cellular therapy in clinical settings, in which human leukocyte antigen-matched donors are not always readily available.

Stem cell transplantation (SCT) from an unrelated donor (URD) is often considered in patients with severe aplastic anemia (SAA) whom immunosuppressive therapy failed and matched sibling donor is not available. To reduce the incidence of graft-versus-host disease (GVHD) in URD SCT, introducting antithymocyte globulin (ATG) into the conditioning regimen has been proposed. Although ATG was shown to play a role in reducing GVHD in a cohort with diverse hematologic diseases, its role in SAA remains uncertain. The aim of this study was to determine the efficacy and toxicity of ATG in URD SCT for adult patients with SAA. We investigated 83 adult patients with SAA who underwent URD SCT between 2003 and 2014. The transplantation strategy consisted of total body irradiation (total 800 cGy) and cyclophosphamide (total 100 mg/kg to 120 mg/kg), followed by tacrolimus and a short-term methotrexate. We divided patients into 2 groups: group 1 (n = 25), which received HLA-matched (8/8) bone marrow (BM) without ATG, and group 2 (n = 58), which received SCT from either an HLA-mismatched donor or peripheral blood (PB). Thereafter, group 2 was subdivided according to ATG use into group 2A (without ATG, n = 26), which served as a historical cohort, and group 2B (with ATG, n = 32). Rabbit ATG (Thymoglobulin; Genzyme-Sanofi, Lyon, France) was used in group 2B at a dose of 2.5 mg/kg. The median age of all patients was 30 years (range, 17 to 59 years). The incidence of GVHD was significantly lower in group 2B than group 2A, as demonstrated by the rate of grade II to IV acute GVHD at day 100 (31.2% versus 61.5%, P = .003) and the rate of chronic GVHD at 3 years (21.9% versus 65.4%, P = .002). The overall survival rates of the 3 groups were similar. However, GVHD-free, failure-free survival (GFFS) was significantly higher in group 2B than group 2A (P = .034). A multivariable model identified use of ATG as an independent factor affecting grades II to IV acute GVHD (hazard ratio [HR], 2.902; 95% confidence interval [CI], 1.417 to 5.942; P = .004), chronic GVHD (HR , 3.005; 95% CI, 1.279 to 7.059; P = .012), and GFFS (HR, 2.363; 95% CI, 1.162 to 4.805; P = .014). Toxicities, including infectious complications, were not different among the 3 groups. In conclusion, low-dose ATG (2.5 mg/kg) can reduce the incidence of acute and chronic GVHD and improve the quality of life in patients with SAA who receive stem cells from either an HLA-mismatched donor or PB; importantly, these benefits are achieved without increased toxicity. Furthermore, ATG can be considered in URD SCT from HLA-matched BM cells., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

This study explored the influence of mismatched inhibitory killer cell immunoglobulin-like receptor (KIR) ligands on the outcome of haploidentical transplantation using T cell-replete, granulocyte colony-stimulating factor-mobilized peripheral blood stem cells in adult patients with acute myeloid leukemia (AML). Three groups were examined: unidirectional graft-versus-host KIR ligand mismatched (GVH-KIR-MM; n = 33), bidirectional KIR ligand matched (KIR-M; n = 41), and unidirectional host-versus-graft KIR ligand mismatched (HVG-KIR-MM; n = 26). All recipients were treated with the same conditioning regimen (800 cGy total body irradiation, fludarabine, busulfan, and antithymocyte globulin). After a median follow-up of 26 months, the 2-year cumulative incidence of relapse was significantly higher in HVG-KIR-MM (40.3% ± 10.3%) versus others (18.9% ± 4.8%, P = .044). In the standard-risk group, the 2-year disease-free survival (DFS) was significantly lower in HVG-KIR-MM (51.8% ± 11.2%) compared with GVH-KIR-MM (88% ± 8.1%, P = .025). Multivariate analysis showed that HVG-KIR-MM was significantly associated with higher relapse (hazard ratio [HR], 10.7; P = .002) and lower DFS (HR, 3.4; P = .012). Subgroup analysis revealed increased DFS with higher doses of CD3(+)CD8(+) and CD3(-)CD56(+) grafts in GVH-KIR-MM (90.9% ± 8.7%, P = .006); there was no such effect in the other groups. Although our conclusions are limited by the absence of donor KIR genotype data, our study suggests unidirectional KIR ligand incompatibility in the host-versus-graft vector has a detrimental effect on T cell-replete haploidentical transplantation outcomes in adult patients with AML., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Chronic graft-versus-host disease (cGVHD) is a common complication following allogeneic hematopoietic stem cell transplantation (HSCT), which is characterized by autoimmune like inflammatory responses and reduced levels of regulatory T cells (Tregs). Recently, the use of low-dose IL-2 has been reported to selectively increase Tregs and therefore facilitate immune regulation and promote clinical improvements in cGVHD patients. In this report, we describe the case of a cGVHD patient who was treated with daily low-dose IL-2 therapy. Our observations demonstrate that low-dose IL-2 could induce significant expansion of Tregs in vivo leading to improved Treg/Th17 ratios. The patient showed moderate clinical benefits suggesting that multiple factors may be involved in the immunological responses. Therefore, while the therapeutic potential of low-dose IL-2 is promising, strategic approaches may be needed to induce a clinically significant and sustained Treg effect., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Therapeutic effects of combined cell therapy with mesenchymal stem cells (MSCs) and regulatory T cells (Treg cells) have recently been studied in acute graft-versus-host-disease (aGVHD) models. However, the underlying, seemingly synergistic mechanism behind combined cell therapy has not been determined. We investigated the origin of Foxp3+ Treg cells and interleukin 17 (IL-17+) cells in recipients following allogeneic bone marrow transplantation (allo-BMT) to identify the immunological effects of combined cell therapy. Treg cells were generated from eGFP-expressing C57BL/6 mice (Tregegfp cells) to distinguish the transferred Treg cells; recipients were then examined at different time points after BMT. Systemic infusion of MSCs and Treg cells improved survival and GVHD scores, effectively downregulating pro-inflammatory Th×and Th17 cells. These therapeutic effects of combined cell therapy resulted in an increased Foxp3+ Treg cell population. Compared to single cell therapy, adoptively transferred Tregegfp cells only showed prolonged survival in the combined cell therapy group on day 21 after allogeneic BMT. In addition, Foxp3+ Treg cells, generated endogenously from recipients, significantly increased. Significantly higher levels of Tregegfp cells were also detected in aGVHD target organs in the combined cell therapy group compared to the Treg cells group. Thus, our data indicate that MSCs may induce the long-term survival of transferred Treg cells, particularly in aGVHD target organs, and may increase the repopulation of endogenous Treg cells in recipients after BMT. Together, these results support the potential of combined cell therapy using MSCs and Treg cells for preventing aGVHD.

Graft-versus-host disease (GVHD) is a major complication associated with allogeneic hematopoietic stem cell transplantation. Despite the prominent role of the adaptive immune system, the importance of controlling the innate immune system in the pathogenesis of GVHD has recently been rediscovered. High-mobility group box 1 (HMGB1) is a crucial damage-associated molecular pattern signal that functions as a potent innate immune mediator in GVHD. In the present study, we investigated treatment of experimental GVHD through HMGB1 blockade using the compound cyclopentylamino carboxymethylthiazolylindole (NecroX)-7. Treated animals significantly attenuated GVHD-related mortality and inhibited severe tissue damage. These protective effects correlated with the decrease in HMGB1 expression and lower levels of reactive oxidative stress. Additionally, NecroX-7 inhibited the HMGB1-induced release of TNF and IL-6, as well as the expression of TLR-4 and receptor for advanced glycation end products. We also observed increased regulatory T cell numbers, which may be associated with regulation of differentiation signals independent of HMGB1. Taken together, these data indicate that NecroX-7 protects mice against lethal GVHD by reciprocal regulation of regulatory T/Th1 cells, attenuating systemic HMGB1 accumulation and inhibiting HMGB1-mediated inflammatory response. Our results indicate the possibility of a new use for a clinical drug that is effective for the treatment of GVHD., (Copyright © 2015 by The American Association of Immunologists, Inc.)

CD161 is a type II transmembrane glycoprotein with characteristics of the C-type lectin superfamily, which has recently been shown to promote T cell expansion. In this study, the role of T cells expressing CD161 as a predictor for the occurrence of acute graft-versus-host disease (aGVHD) after allogeneic stem cell transplantation (SCT) was investigated. Sixty-one patients who underwent first allogeneic SCT were enrolled. At engraftment, the expression of CD3, CD4, CD8, CD161, CD16, and CD56 was analyzed by flow cytometry. After adjusting for potential variables by univariate analysis, we performed a multivariate analysis, which revealed a low frequency of CD8(+)CD161(+) cells (P = .034) and a high ratio of CD4(+)CD161(+) to CD8(+)CD161(+) cells (P = .001) were associated with the occurrence of aGVHD with a grade of ≥ II. Moreover, the frequency of CD8(+)CD161(+) T cells was negatively correlated with aGVHD grade. A separate analysis for visceral aGVHD showed similar results, with a low frequency of CD8(+)CD161(+) T cells (P = .031) or a high ratio of CD4(+)CD161(+) to CD8(+)CD161(+)cells (P < .001), indicating a high risk. Also, the predictive role of serum IL-17 levels for the occurrence of aGVHD was identified, and RORγT was more highly expressed in CD4(+)CD161(+) T cells than in CD8(+)CD161(+) T cells after allogeneic SCT (P = .032). Although our study was limited by the heterogeneity and small number of patients, these results suggest that the CD8(+) subset of CD161(+) T cells may have regulatory effects and that they provide a basis for predicting the occurrence of aGVHD after allogeneic SCT., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Interleukin (IL) 21 plays a key role in the development of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation. Therapeutic manipulation of IL-21 activity may improve acute GVHD during the early-posttransplant period. We investigated the mechanisms regulating T- and B-cells during IL-21 blockade in acute GVHD. Interleukin 21 blockade enhanced regulatory T and T helper (Th) 2 cell differentiation and inhibited Th1- and Th17-derived transcription factors and cytokines as a modulator of activated T-cells. Interleukin 21(-/-) cell recipients showed increased mature B- and marginal-zone B-cells, but decreased memory B-cells, germinal center formation, and plasma cells that did not lead to immunoglobulin production. B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are involved in the induction and maintenance of T- and B-cell responses. We observed decreased levels of only BAFF during acute GVHD and confirmed that mammalian target of rapamycin complex 1 was reduced by the BAFF/BAFF-receptor pathway. Therefore, this study suggests that IL-21 blockade modulates activated T- and B-cell homeostasis via BAFF-pathway-mediated inhibition in acute GVHD following murine allogeneic bone marrow transplantation., (Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)

Establishment of mixed chimerism is an ideal approach to induce donor-specific tolerance while expanding its potential in various clinical settings. Despite the developments in partial conditioning regimens, improvements are still needed in reducing toxicity and bone marrow transplantation-related complications. Recently, cell-based therapies, including mesenchymal stem cells (MSCs), have been incorporated in establishing noncytoreductive mixed chimerism protocols; however, its efficacy is only partial and shows reversed immunosuppressive properties. This study demonstrates a novel approach to induce mixed chimerism and tolerance through combinatory cell-based immune modulation (CCIM) of MSCs and regulatory T cells (Tregs). We hypothesize that the interaction between these cells may lead to greater inhibition of host immune responses. Compared with single cell therapy, CCIM induced a higher engraftment rate and robust donor-specific tolerance to skin allografts across full major histocompatibility complex barriers. These regulatory effects were associated with inhibition of natural killer cell cytotoxic activity, CD4(+)IL-17(+) cells, memory B cells, plasma cells, and immunoglobulin production levels along with increased frequencies of CD4(+)Foxp3(+) cells, IL-10-producing mature B cells, and myeloid-derived suppressor cells. Furthermore, CCIM was able to regulate mortality in a graft-versus-host disease model through reciprocal regulation of Treg/Th17. Taken together, we suggest CCIM as a clinically applicable strategy for facilitating the induction of mixed chimerism and permanent tolerance.

Background: In unrelated donor allogeneic stem cell transplantation (URD-SCT), most studies reported that peripheral blood stem cells (PBSC) resulted in higher incidence of acute and/or chronic graft-versus-host disease (GVHD) without survival benefits compared with bone marrow (BM). To overcome these shortcomings of PBSC, we have used a risk-adapted GVHD prophylaxis for patients that received HLA-matched URD-SCT, which was adding low-dose rabbit antithymocyte globulin (Thymoglobulin(®) , 1.25 mg/kg for 2 d) to conditioning in the transplants with PBSC and not BM., Methods: To determine whether this strategy is effective, we analyzed 115 adult patients with acute myeloid leukemia who received HLA-matched URD-SCT with PBSC (n = 70) or BM (n = 45) using our risk-adapted GVHD prophylaxis strategy., Results: The PBSC group showed faster neutrophil (11 d vs. 13 d; P < 0.01) and platelet (12 d vs. 18 d; P < 0.01) engraftment compared with the BM group. No difference was observed in the incidence of acute GVHD grade II-IV at 100 d (54.3% vs. 64.4%; P = 0.38) and chronic GVHD at 4 yr (65.1% vs. 60.0%; P = 0.83). Other outcomes including the incidence of relapse (30.8% vs. 31.2%; P = 0.53), non-relapse mortality (13.5% vs. 6.9%; P = 0.24), disease-free survival (55.7% vs. 61.9%; P = 0.68), and overall survival (62.2% vs. 63.2%; P = 0.96) at 4 yr were not significantly different., Conclusion: Our risk-adapted GVHD prophylaxis strategy resulted in similar transplant outcomes including comparable incidence of GVHD between the PBSC and BM groups in HLA-matched URD-SCT., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Mesenchymal stem cells (MSCs) have been considered to be an ideal cellular source for graft-versus-host disease (GVHD) treatment due to their unique properties, including tissue repair and major histocompatibility complex (MHC)-unmatched immunosuppression. However, preclinical and clinical data have suggested that the immunomodulatory activity of MSCs is not as effective as previously expected. This study was performed to investigate whether the immunomodulatory capacity of MSCs could be enhanced by combination infusion of regulatory T (Treg) cells to prevent acute GVHD (aGVHD) following MHC-mismatched bone marrow transplantation (BMT). For GVHD induction, lethally irradiated BALB/c (H-2(d)) mice were transplanted with bone marrow cells (BMCs) and spleen cells of C57BL/6 (H-2(b)) mice. Recipients were injected with cultured recipient-derived MSCs, Treg cells, or MSCs plus Treg cells (BMT + day 0, 4). Systemic infusion of MSCs plus Treg cells improved clinicopathological manifestations and survival in the aGVHD model. Culture of MSCs plus Treg cells increased the population of Foxp3(+) Treg cells and suppressed alloreactive T-cell proliferation in vitro. These therapeutic effects were associated with more rapid expansion of donor-type CD4(+)CD25(+)Foxp3(+) Treg cells and CD4(+)IL-4(+) type 2 T-helper (Th2) cells in the early posttransplant period. Furthermore, MSCs plus Treg cells regulated CD4(+)IL-17(+) Th17 cells, as well as CD4(+)IFN-γ(+) Th1 cells. These data suggest that the combination therapy with MSCs plus Treg cells may have cooperative effects in enhancing the immunomodulatory activity of MSCs and Treg cells in aGVHD. This may lead to development of new therapeutic approaches to clinical allogeneic hematopoietic cell transplantation.

Mesenchymal stem cells (MSCs) have emerged as a therapeutic approach in a range of medical fields, including regenerative medicine, cancer, autoimmune diseases, and inflammatory diseases, because of their unique properties of tissue repair and major histocompatibility complex-unmatched immunosuppression. Because both in vitro and in vivo findings demonstrate that MSCs possess potent immunoregulatory functions, there has been increasing interest in the role of MSCs in allogeneic hematopoietic stem cell transplantation, especially in the prevention and treatment of graft-versus-host disease (GVHD). GVHD is a major cause of transplantation-related mortality, and conventional immunosuppressants frequently fail to treat patients suffering from GVHD. Following Ringden's pilot study that used third-party MSCs to treat a steroid-refractory GVHD patient, MSCs have created growing interest as a therapeutic agent for GVHD. There have been further studies which demonstrated the potentials of MSC treatment in steroid-refractory GVHD, de novo GVHD, and also GVHD prevention. However, MSCs still present limitations. The need for MSCs to be "licensed" in a pro-inflammatory environment, especially in the presence of interferon gamma, allows only a narrow window for their administration. Thus, their effects have been less clear as a preventive measure before the inflammatory environment of GVHD is established and also when administered during a chronic setting where MSCs may be alternatively licensed. In this review, we focus on the immunomodulatory properties of MSCs and their effects in relation to GVHD. Given the efficacy of MSCs in murine models of GVHD and their safety in clinical trials, it is crucial that larger clinical trials are conducted and further modifications are investigated.

Background: In this study we examined the in vivo and in vitro effects and mechanisms of action of curcumin on the development of acute graft-versus-host disease (GVHD) using a murine model., Methodology/principal Findings: Mixed lymphocyte reactions were used to determine the in vitro effects of curcumin. Treatment with curcumin attenuated alloreactive T cell proliferation and inhibited the production of interferon (IFN)-γ and interleukin (IL)-17. In a murine acute GVHD model, transplantation of curcumin-treated allogeneic splenocytes into irradiated recipient mice significantly reduced the clinical severity scores of acute GVHD manifested in the liver, skin, colon and lung as compared with animals receiving vehicle-treated splenocytes. c-Fos and c-Jun expression levels in the skin and intestine, which are major target organs, were analyzed using immunohistochemical staining. Expression of both proteins was reduced in epithelial tissues of skin and intestine from curcumin-treated GVHD animals. The IFN-γ-expressing CD4(+) splenocytes and IFN-γ-expressing lymph node cells were dramatically decreased in curcumin-treated mice. In contrast, CD4(+)Foxp3(+) splenocytes were increased in the curcumin-treated acute GVHD animals. Flow cytometric analysis revealed that animals transplanted with curcumin-treated allogeneic splenocytes showed increased populations of CD4(+) regulatory T cells (Tregs) as well as CD8(+) Treg cells, compared to animals administered vehicle-treated splenocytes. Curcumin-treated acute GVHD animals could have a change in B cell subpopulations., Conclusion/significance: In the present study, we investigated the efficacy and mechanism of action of curcumin treatment against acute GVHD. The acute GVHD mice administered with curcumin-treated splenocytes showed significantly reduced severity of acute GVHD. Curcumin exerted in vivo preventive effects on acute GVHD by reciprocal regulation of T helper 1 (Th1) and Treg (both CD4(+) and CD8(+) Treg) cell lineages as well as B cell homeostasis.

Using real-time quantitative PCR, we monitored Wilms tumor gene 1 (WT1) expression from diagnosis to hematopoietic stem cell transplantation (HSCT) in adult patients with cytogenetically normal acute myelogenous leukemia (CN-AML) and FLT3-ITD and NPM1 mutations. The values at diagnosis were evaluated in 104 patients. Data collected after induction chemotherapy were available for all patients, but only 68 patients were treated with HSCT. Significant WT1 expression cut-offs were determined by receiver operation characteristic curve analysis, and rates of overall survival (OS) and disease-free survival (DFS) were estimated. WT1 decrement ratios (DR) at postinduction chemotherapy and at pre- and post-HSCT compared with the diagnostic level were calculated. Higher WT1 expression at diagnosis, postinduction chemotherapy, and pre-HSCT showed inferior OS (P = .015, <.001, and .002) and DFS (P = .006, <.001, and .003). The cut-offs were determined at the median for diagnostic WT1 expression and at the 25% level from the top for other time points excluding post-HSCT. The WT1 DR ≥ 1-log after induction chemotherapy showed superior OS and DFS (P = .009 and .002) and WT1 DR ≥ 1-log preceding HSCT also showed superior OS and DFS (P = .009 and .003). Results of WT1 DR were consistently applicable in each subgroup with higher (≥ 1.0) and lower (<1.0) WT1 expression at diagnosis and also in NPM1-wild-type/FLT3-ITD-negative CN-AML. The WT1 DR therefore predicted survival outcomes after HSCT more accurately than did the diagnostic WT1 expression. WT1 expression may serve as a reliable marker for residual disease and WT1 DR as a prognostic indicator, particularly in NPM1-wild-type/FLT3-ITD-negative CN-AML. These measures may be applied throughout the course of treatment and even after HSCT., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Cytomegalovirus gastrointestinal (CMV-GI) disease in GI graft-versus-host disease (GI-GVHD) has not been properly evaluated in the era of preemptive therapy for CMV infection. We investigated 103 patients with GI-GVHD who underwent endoscopic biopsies with immunohistochemical staining for CMV. All recipients and/or donors were seropositive for CMV and monitored with a strategy of preemptive therapy based on real-time quantitative polymerase chain reaction. Twenty-six patients (25 %) developed CMV-GI disease, especially in HLA-mismatched transplants (P = 0.023) and with initial gut involvement of GVHD (P = 0.009). The CMV-GI diseases were diagnosed at follow-up endoscopies (n = 10, 39 %), comprising 19 % of 52 patients who underwent follow-up endoscopies, as well as initial endoscopies (n = 16, 61 %), comprising 16 % of all GI-GVHD patients. In seven cases, either at initial (n = 5) or follow-up endoscopies (n = 2), CMV-GI disease was diagnosed in the absence of histopathologic evidence for GI-GVHD. Notably, only 11 patients (42 %) had prior CMV DNAemia before the diagnosis of CMV-GI disease, while 12 (46 %) and three (12 %) had concurrent and no CMV DNAemia, respectively. Sixty-five percent of CMV-GI disease was resolved by additional antiviral therapies, but CMV-GI disease (P = 0.032) as well as severity of GVHD (P = 0.001) negatively affected GVHD-specific survival. In conclusion, our data demonstrate that CMV-GI disease was a cause of initial or persistent GI manifestations after the initiation of therapy in a considerable proportion of GI-GVHD. These suggest the necessity of novel strategies to reduce CMV-GI disease as well as an effort to confirm CMV with repeated endoscopies.

To weigh the pros and cons of familial-mismatched/haploidentical transplantation (FMT) in patients with high-risk acute myelogenous leukemia, we assessed outcomes of 23 patients who underwent FMT, using reduced-intensity conditioning with total body irradiation 800 cGy/busulfan/fludarabine/antithymocyte globulin without ex vivo T cell depletion, compared to 33 patients who underwent well-matched unrelated donor transplantation (WM-UDT) and 13 who underwent partially matched unrelated donor transplantation (PM-UDT) during the same period. The FMT patients had not only a similar pattern of engraftment and immune reconstitution as the WM-UDT and PM-UDT patients but also comparable incidences and severity of acute and chronic graft-versus-host disease. The FMT patients did not experience any form of engraftment failure. However, the cumulative incidence of cytomegalovirus DNAemia was significantly higher in the FMT group compared with the other groups (P = .036). After a median follow-up of 28 months, overall survival, disease-free survival, relapse, and nonrelapse mortality were 83%, 74%, 20%, and 7%, respectively, for WM-UDT; 51%, 51%, 31%, and 18% for PM-UDT; and 66%, 64%, 26%, and 10% for FMT. This demonstrates a trend for favorable survival outcomes of WM-UDT over FMT and of FMT over PM-UDT. However, we found no significant statistical differences in survival according to donor type. These data need to be interpreted cautiously because of limited power calculations due to the small number of each donor group. This pilot study suggests the feasibility of FMT using our novel regimen with careful evaluation of CMV DNAemia compared with WM-UDT and PM-UDT. Further trials with larger numbers of patients, comparing FMT directly with transplantation with other donor types, are needed., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The impact of National Institutes of Health consensus criteria (NCC) graft-versus-host disease (GVHD) on survival has rarely been investigated in a large cohort of patients with GVHD presenting before and after day 100 posttransplantation. We retrospectively investigated 775 patients who underwent allogeneic stem cell transplantation and assessed the GVHD effects on survival by the time-dependent covariates in Cox proportional hazards regression models. Using the NCC, the patients were classified into 4 groups: (1) no GVHD (n = 251); (2) acute GVHD (aGVHD) only (n = 199), including 26 patients with late aGVHD; (3) classic chronic GVHD (cGVHD; n = 232); and (4) overlap syndrome (OS; n = 93). Multivariate analyses showed that classic cGVHD (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.27-0.77) and OS (HR, 0.52; 95% CI, 0.28-0.96) were associated with significantly decreased risk of relapse, whereas aGVHD only was not associated with relapse rate (HR, 1.11; 95% CI, 0.76-1.63). All aGVHD events, including the period of aGVHD in patients who developed cGVHD after aGVHD, also did not affect the risk of relapse (HR, 0.74; 95% CI, 0.49-1.12). All types of GVHD were significantly associated with higher nonrelapse mortality in common. Finally, patients with aGVHD only had significantly lower overall survival and disease-free survival compared with those without GVHD, in contrast to favorable survival outcomes in patients with cGVHD without previous aGVHD. This study demonstrates that NCC GVHD type is associated with different graft-versus-tumor effects. Further studies are needed to investigate risk factors, pathogenesis, and biomarkers for each type of NCC GVHD., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

B cell activating factor (BAFF), also known as B cell survival and activation factor, is associated with autoimmune disease and chronic graft-versus-host disease (cGVHD). T cells are known to be modulated by soluble BAFF (sBAFF). Considering the possible association of sBAFF with T cell as well as B cell function, sBAFF during the peritransplantation period may affect the development of acute GVHD (aGVHD). To test this hypothesis, we evaluated 45 patients who had undergone myeloablative (MA) allogeneic stem cell transplantation (SCT) for hematologic malignancy. Serum sBAFF levels were measured before conditioning and on day 0, day +7, and day +14. Thirty-three of the 45 patients (cumulative incidence, 73%) developed aGVHD between 16 days and 98 days posttransplantation. Repeated-measures analysis of variance revealed significantly lower sBAFF levels during the peritransplantation period in patients with aGVHD than in those without aGVHD (P=.001). Receiver operating characteristic curve analysis revealed that sBAFF levels at every time point were available for the prediction of aGVHD development, and that patients with a sBAFF level >43 pg/mL at each time point (which could ensure 75% sensitivity and 73%-82% specificity for the prediction of aGVHD at every time point) had a significantly lower cumulative incidence of aGVHD. This study is the first to demonstrate that sBAFF level during the peritransplantation period not only may be predictive of aGVHD, but also may have a protective effect against aGVHD in humans. Further investigation is needed to confirm our findings., (Copyright 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

In this study, we investigated the effects of low-dose antithymocyte globulin (ATG, thymoglobulin) in the prevention of acute graft-versus-host disease (aGVHD) in mismatched, unrelated hematopoietic stem cell transplantations (uHSCTs) in patients with the single disease entity of acute myelogenous leukemia (AML). Patients (n = 103) with a variable risk for AML who received uHSCTs from available Asian and Caucasian donors were enrolled. First, we compared HLA-matched (group 1, n = 54) and HLA-mismatched (group 2, n = 49) transplantation patients. Then, we divided the patients in group 2, who had received transplants from allele(s)/antigen-mismatched donors, into 2 subgroups: patients who used ATG (group 3, n = 24) and those who did not (group 4, n = 25). To prevent the development of aGVHD, the patients in group 3 received ATG at a dose of 1.25 mg/kg body weight per day for 2 consecutive days, together with our standard regimen of methotrexate (MTX) and tacrolimus. The median CD34(+) cell infusion was 4.2 x 10(6)/kg (range: 1.2-34.4). The median patient age was 41 years (range: 16-57), and the median follow-up duration of patients who were event-free survivors was 23 months (range: 2-72). The overall incidences of aGVHD and chronic GVHD (cGVHD) were 38% and 56%, respectively. Of 48 evaluable patients in group 2, 10 (21%) developed moderate to severe aGVHD (grades II-IV). In contrast, 2 (8%) of the 24 patients in group 3 and 7 (29%) of the 24 evaluated patients in group 4 required therapy for aGVHD (grades II-IV; P = .038). The incidence of cGVHD was not different between groups 3 and 4. The estimated probabilities of overall survival (OS) and event-free survival (EFS) at 2 years for group 2 were 55% and 44%, respectively. In comparison, the estimated probabilities of OS and EFS at 2 years for groups 3 and 4 were 68% versus 38% (P = .043) and 58% versus 38% (P = .103), respectively. The overall cumulative incidence of nonrelapse mortality (NRM) was 29% in group 2. The cumulative incidence of NRM differed markedly between group 3 (16%; 95% confidence interval [CI], 4%-28%) and group 4 (44%, 95% CI, 34%-54%) (P = .013). We found no difference in cytomegalovirus (CMV) reactivation between groups 3 and 4. These results suggest that in mismatched uHSCT, a low dose of ATG (total 2.5 mg/kg) may prevent moderate to severe aGVHD, with comparable rates of relapse and CMV reactivation and a greatly decreased rate of NRM.

Background: We investigated the influence of killer cell immunoglobulin-like receptor (KIR) genes, based on the genotypes of inhibitory or activating KIR, in stem cell recipients with acute myelogenous leukemia and their human leukocyte antigen-matched sibling donors on acute graft-versus host disease (GVHD) after hematopoietic stem cell transplantation., Methods: We studied 53 consecutive donor-recipient pairs to determine the impact of KIR genotypes and their bidirectional KIR interactions., Results: All activating KIR genes in donors were important factors for determining outcome in a manner distinctive for each gene studied. Specifically, the 2DS2 gene and the 2DS4*003 allele were closely correlated with acute GVHD. The 2DS1 gene was associated with a better long-term survival, even if present only in the donor and not the recipient. The 2DS3-2DS5 dual genes were more often involved in a variety of transplant-related complications., Conclusions: In conclusion, these factors may help predict transplant outcomes and aid in our understanding of immunogenetic specificity.

The aim of the present study was to identify graft-versus-leukemia effects and the factors that affect outcome in 201 adults with acute lymphobalstic leukemia who received myeloablative allogeneic stem cell transplantation from matched sibling or unrelated donors (1995-2004). One hundred seventy-eight (88.6%) of these patients had high-risk criteria, and 151 (75.1%) patients were transplanted in first complete remission (CR). All patients received unmodified stem cell grafts (185 bone marrow and 16 peripheral blood) following total- body irradiation-containing myeloablative preparations. Graft-versus-host disease (GVHD) prophylaxis was uniformly attempted by administering calcineurin inhibitor plus methotrexate. After a median follow-up of 63 months (range: 25+ to 139+ months) for surviving transplants, disease-free survival at 5 years was 47.8% for all patients and 60.3% for patients in the first CR. No difference in transplantation outcome was observed between sibling and unrelated transplants in the first CR. The most powerful predictive factor affecting transplantation outcome was disease status at transplantation (the first CR versus beyond the first CR, P<.001). Chronic GVHD (cGVHD), especially limited type, was also found to have a significant antileukemic effect. Interestingly, the influence of cGVHD on relapse risk was prominent in patients with chromosomal translocations or normal cytogenetics.

Allogeneic hematopoietic stem cell transplantation following reduced-intensity stem cell transplantation (RIST) has enabled the treatment of older or medically infirm patients with myeloid malignancies; however, determining the value of RIST outcomes for myelodysplastic syndrome (MDS) is difficult because of the heterogeneity of the diseases included in most trials. To define the role of RIST in MDS, we performed RIST for 22 consecutive patients who had de novo MDS as classified by World Health Organization (WHO) criteria and who received an allograft with fludarabine/busulfan (Busulfex) or fludarabine/Busulfex/antithymocyte globulin (ATG) conditioning. Nineteen patients (86.4%) achieved engraftment. At a median follow-up of 18.9 months (range, 13.1-24.8 months), the estimated 2-year rates of overall survival, event-free survival (EFS), transplantation-related mortality, and relapse were 78.7%, 67.7%, 12.6%, and 22.5%, respectively. Acute graft-versus-host disease (GVHD) greater than grade II developed in 3 patients (15.8%). Chronic GVHD developed in 10 patients (55.6%), none of whom received ATG as a conditioning regimen. Variables influencing EFS were chronic GVHD, marrow blasts before transplantation, and the WHO criteria. The present study clarifies the benefits of the fludarabine/Busulfex-based conditioning regimen for de novo MDS diagnosed according to the WHO criteria and shows that chronic GVHD appears to have a beneficial effect on survival rates, which are strongly associated with graft-versus-tumor effects.