Tacrolimus-based Graft-versus-host Disease Prophylaxis Research Articles

Early Recovery of Myeloid-Derived Suppressor Cells After Allogeneic Hematopoietic Transplant: Comparison of Post-Transplantation Cyclophosphamide to Standard Graft-Versus-Host Disease Prophylaxis

Allogeneic hematopoietic cell transplantation (alloHCT) using haploidentical donors (haploHCT) with post-transplantation cyclophosphamide (PTCy) for augmented graft-versus-host disease (GVHD) prophylaxis has emerged as a robust platform to expand donor options with acceptable levels of GVHD and graft failure. The mechanism by which PTCy mitigates GVHD risk is partly explained by preferential cytotoxicity based on aldehyde dehydrogenase levels and up-regulation of regulatory T cells, but is incompletely understood. Myeloid-derived suppressor cells are important mediators of T-cell function and are up-regulated by cyclophosphamide exposure. We hypothesized that this cell type may play a role in GVHD protection in children undergoing haploHCT/PTCy. We prospectively collected samples in the first month after alloHCT from children undergoing standard of care (SOC) alloHCT with matched donors and tacrolimus-based GVHD prophylaxis (N=11) and PTCy recipients (N=11). MDSC recovery was compared using flow cytometry, and MDSC suppressive function was assessed at the peak of MDSC quantitative recovery post-alloHCT. Groups were well matched for conditioning regimen and stem cell source. PTCy recipients exhibited more robust MDSC recovery, particularly polymorphonuclear-MDSCs than SOC recipients, with preservation of T-cell suppressive function. This corresponded to significantly lower incidence of Grade II to IV acute GVHD (9.1% versus 27.3%) and moderate/severe chronic GVHD (0% versus 27.3%) in PTCy recipients. Patients who developed GVHD had decreased MDSC-mediated T-cell suppression, as well as higher levels of IL-10, a cytokine closely linked to GVHD biology. Overall, these findings provide support for the role of MDSCs in mediating GVHD protection after PTCy-based haploHCT. © 2022 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Unrelated cord blood transplantation with myeloablative conditioning for pediatric acute lymphoblastic leukemia in remission: prognostic factors.

The number of individuals undergoing unrelated cord blood transplantation (UCBT) has increased in recent years; however, information on prognostic factors is limited. We retrospectively analyzed data from 475 children and adolescents receiving UCBT with myeloablative conditioning for acute lymphoblastic leukemia (ALL) in complete remission (CR), based on a nationwide registry. In the total patient cohort, 5-year leukemia-free survival (LFS) and overall survival (OS) rates after UCBT were 61.1% and 67.7%, respectively. UCBT at first CR and UCBT after 2007 were associated with good survival, while grade II-IV acute graft-versus-host disease (GVHD) was associated with low relapse rate but did not affect survival. Analysis according to human leukocyte antigen (HLA) disparity revealed that tacrolimus-based GVHD prophylaxis resulted in higher OS and lower relapse rate and nonrelapse mortality (NRM) than cyclosporine-based GVHD prophylaxis in patients transplanted with 6/6 and ≤4/6 HLA-matched umbilical cord blood. Furthermore, grade II-IV acute GVHD was associated with good LFS and low relapse rate, without high NRM, in patients receiving 5/6 HLA-matched UCBT. These data indicate that prognostic factors for ALL differ depending on HLA disparity in UCBT.

Is immunological recovery clinically relevant at 100 days after allogeneic transplantation?

Background/AimsImmune reconstitution following allogeneic hematopoietic stem cell transplantation (HSCT) is affected by multiple variables during the transplantation.MethodsWe assessed the clinical factors contributing to immune function reconstitution at 100 days post-allogeneic HSCT in 114 patients receiving fludarabine-based conditioning. Immunophenotypic analysis using flow cytometry was performed to evaluate the percentage and the absolute numbers of T-cell subsets, natural killer cells, and B-cells as clinical outcomes.ResultsTacrolimus-based graft-versus-host disease (GVHD) prophylaxis, T-cell depletion, and acute GVHD were significantly associated with delayed immune reconstitution of T-cell subsets. The incidence of chronic GVHD was significantly increased in the normal recovery group compared to the abnormal group (p = 0.01). Epstein-Barr virus reactivation was more frequently observed in the abnormal group of T-cell subsets (p = 0.045). All viral reactivation events including cytomegalovirus reactivation appeared to be more frequent in the abnormal group of T-cell subsets.ConclusionsThe immune recovery status post-allogeneic HSCT was affected by GVHD prophylactic regimens, especially in cases receiving tacrolimus-based GVHD prophylaxis, T-cell depletion, and possibly those manifesting acute GVHD. Delayed immune reconstitution might increase the morbidity due to viral reactivation. Treatment strategies are needed to prevent infectious complications and enhance immune reconstitution based on the immune recovery status following allogeneic HSCT with fludarabine-based conditioning.

Donor Clonal Hematopoiesis Increases Risk of Acute Graft Versus Host Disease after Matched Related Transplantation in AML and MDS Patients

Oran: AROG pharmaceuticals: Research Funding; Astex pharmaceuticals: Research Funding. Champlin:Sanofi-Genzyme: Research Funding; Actinium: Consultancy; Johnson and Johnson: Consultancy. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Kantarjian:Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; BMS: Research Funding; Jazz Pharma: Research Funding; Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Popat:Jazz: Consultancy; Incyte: Research Funding; Bayer: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy.

«Graft-Versus-Host» Disease after Haploidentical Hematopoietic Stem Cell Transplantation from Relative Donors in Children with Cancer, Prophylaxis Regimens and Correlation with «Graft-Versus-Tumor» Effect: a Retrospective Cohort Study

Background. «Graft-versus-host» disease (GVHD) is a major complication of allogeneic Hematopoietic Stem Cell Transplantation (HSCT), the main cause of non-relapse mortality. The actual problems of alternative donors HSCTs are GVHD prophylaxis and its distinction from «graft-versus-tumor» (GVT) effect. Objective. Assessment of incidence and severity of GVHD in children with very high-risk cancer after non-T-depleted haplo-HSCT; searching some correlation between controlled chronic GVHD (chGVHD) and GVT effect after HSCT, compare cyclosporine (CSA) and tacrolimus based GVHD prophylaxis. Methods. We provided the GVHD assessment in 74 recipients of haplo-HSCs from relatives since 2001 till 2018 in retrospective cohort study. Effect of chGVHD on the HSCT results was assessed in 23 patients with acute myeloid leukemia (AML) and 15 patients with solid tumors. We analyzed the incidence of severe acute and chronic GVHD in patients who received CSA or tacrolimus-based prophylaxis. Results. The incidence of severe aGHVD in our study was 15%, chGVHD — 12%. Switch CSA to tacrolimus resulted in reduction of severe aGVHD from 21% to 9% and full elimination of severe extensive chGVHD. Controlled chGVHD after haplo-HSCT was associated with relapse reduction from 48.7% to 30% and improvement of overall survival (OS) from 46.5% to 80.8% in patients with AML. We haven’t seen any clinically significant antitumor effect of graft in patients with solid tumors. Conclusion. In our study the incidence of severe GVHD corresponds to world data after HSCTs from alternative donors, it went down after switch from CSA to tacrolimus. We found some correlation between controlled chGVHD development and HSCT results improvement in patients with AML. The GVT effect of haplo-graft in solid tumors is almost absent.

Impact of CYP3A5, POR, and CYP2C19 Polymorphisms on Trough Concentration to Dose Ratio of Tacrolimus in Allogeneic Hematopoietic Stem Cell Transplantation.

Single nucleotide polymorphisms in drug-metabolizing genes may affect tacrolimus pharmacokinetics. Here, we investigated the influence of genotypes of CYP3A5, CYP2C19, and POR on the concentration/dose (C/D) ratio of tacrolimus and episodes of acute graft-versus-host disease (GVHD) in Japanese recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Thirty-six patients receiving the first HSCT using tacrolimus-based GVHD prophylaxis were enrolled with written informed consent. During continuous intravenous infusion, HSCT recipients carrying the CYP3A5*1 allele, particularly those with at least one POR*28 allele, had a significantly lower tacrolimus C/D ratio throughout all three post-HSCT weeks compared to that in recipients with POR*1/*1 (p < 0.05). The CYP3A5*3/*3 genotype and the concomitant use of voriconazole were independent predictors of an increased tacrolimus C/D ratio during the switch from continuous intravenous infusion to oral administration (p < 0.05). In recipients receiving concomitant administration of voriconazole, our results suggest an impact of not only CYP3A5 and CYP2C19 genotypes, but also plasma voriconazole concentration. Although switching from intravenous to oral administration at a ratio of 1:5 was seemingly appropriate in recipients with CYP3A5*1, a lower conversion ratio (1:2–3) was appropriate in recipients with CYP3A5*3/*3. Our results suggest that CYP3A5, POR, and CYP2C19 polymorphisms are useful biomarkers for individualized dosage adjustment of tacrolimus in HSCT recipients.

Outcomes of Patients with Recurrent and Refractory Lymphoma Undergoing Allogeneic Hematopoietic Cell Transplantation with BEAM Conditioning and Sirolimus- and Tacrolimus-Based GVHD Prophylaxis

The current standard of care for patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) is high-dose conditioning followed by autologous stem cell transplantation (ASCT). For some patients (ie, those with highest-risk disease, insufficient stem cell numbers after mobilization, or bone marrow involvement) allogeneic hematopoietic cell transplantation (alloHCT) offers the potential for cure. However, the majority of patients undergoing alloHCT receive reduced-intensity conditioning as a preparative regimen, and studies assessing outcomes of patients after alloHCT with myeloablative conditioning are limited. In this retrospective study, we reviewed outcomes of 22 patients with recurrent and refractory NHL who underwent alloHCT with myeloablative BEAM conditioning and received tacrolimus/sirolimus as graft-versus-host disease (GVHD) prophylaxis at City of Hope between 2005 and 2018. With a median follow-up of 2.6 years (range, 1.0 to 11.2 years), the probabilities of 2-year overall survival and event-free survival were 58.3% (95% confidence interval [CI], 35.0% to 75.8%) and 45.5% (95% CI, 24.4% to 64.3%), respectively. The cumulative incidence of grade II to IV acute GVHD was 45.5% (95% CI, 23.8% to 64.9%), with only 1 patient developing grade IV acute GVHD. However, chronic GVHD was seen in 55% of the patients (n = 12). Of the 22 eligible patients, 2 had undergone previous ASCT and 2 had undergone previous alloHCT. Both patients with previous ASCT developed severe regimen-related toxicity. Patients who underwent alloHCT with chemorefractory disease had lower survival rates, with 1-year OS and EFS of 44.4% and 33.0%, respectively. In conclusion, alloHCT with a BEAM preparative regimen and tacrolimus/sirolimus-based GVHD should be considered as an alternative option for patients with highest-risk lymphoma whose outcomes are expectedly poor after ASCT.

Graft-versus-host disease-free, and relapse-free survival in Japanese patients with hematological malignancies

Graft-versus-host disease (GVHD) -free, relapse-free survival (GRFS) is an important, composite endpoint for clinical trials, which provides a patient-centered measure of transplant success. This review discusses the results of the Japanese Transplant Registry study. This large-scale study examined 23,302 patients with hematological malignancy and characterized GRFS according to a variety of graft sources. The GRFS rate at 1 year was 41% in all patients. GRFS was superior in patients undergoing bone marrow transplantation compared to peripheral blood stem cell transplantation, owing to lower risk of developing grades III-IV acute and chronic GVHD. The best GRFS rates were observed in patients that received HLA-matched related bone marrow transplants; however, this was not the case in HLA-mismatched donors. GRFS after single-cord blood transplantation was almost comparable with HLA-matched unrelated bone marrow transplantation, possibly due to the low risk of chronic GVHD. Other factors associated with increased GRFS rates included female patients; use of anti-thymocyte globulin prophylaxis for standard-risk disease; recent transplantations; gender combinations other than from a female donor to a male patient; absence of prior autologous transplantation; myeloablative conditioning; negative cytomegalovirus serostatus; and use of tacrolimus-based GVHD prophylaxis. These results provide valuable information for deciding the best choice of graft sources and type of GVHD prophylaxis to be used.

Graft-versus-host Disease–free, Relapse-free Survival After HLA-identical Sibling Peripheral Blood Stem Cell Transplantation With Tacrolimus-based Graft-versus-host Disease Prophylaxis in Japanese Patients

The ideal post-allogeneic hematopoietic cell transplantation recovery is not just the cure of hematologic malignancies but also freedom from ongoing morbidity. Recent studies have revealed that HLA-identical sibling peripheral blood stem cell transplantation (PBSCT) had been providing impaired graft-versus-host disease (GVHD)–free relapse-free survival (GRFS) due to a higher risk of GVHD. Study on GVHD prophylaxis bears clinical reliance when focused on Japanese population because risk of GVHD differs among races. We identified 15 consecutive Japanese patients who received tacrolimus-based GVHD prophylaxis after myeloablative HLA-identical sibling PBSCT. No episode of grade ≥ II acute GVHD and only one episode of grade III toxicity were documented, with the control of mean weekly blood tacrolimus concentrations during the first 4 weeks at 13 to 17 ng/mL. An estimated 46.7% (95% CI: 21.4% to 71.9%) of the patients enjoyed their GRFS at 3 years after transplantation, and failure in the treatment of chronic GVHD was not reported during the median follow-up period of 1059 days (range, 784 to 1778 days) after the development of chronic GVHD. The results suggest that the application of tacrolimus with the optimization of its blood concentrations may effectively prevent ongoing morbidities after HLA-identical sibling PBSCT.

Doses of Total Nucleated Cells and Activated T-Cells Transplanted Influence Survival and Graft Versus Host Disease Among AML and MDS Recipients of Reduced-Intensity Mobilized Peripheral Blood Allografts

Background: Patients undergoing allogeneic hematopoietic stem cell transplant with reduced-intensity conditioning (RIC-alloSCT) rely primarily on the graft-versus-tumor (GVT) effect to prevent relapse. Although relapse remains high in this setting, previous data suggest modifications of allograft composition could produce enhanced GVT effect and improve outcomes. Prior retrospective studies suggested higher total nucleated cell (TNC) and CD8 dose correlate with improved overall survival (OS) and a reduction in relapse among all patients undergoing RIC-alloSCT. The aim of our study was to further investigate this association by comparing transplant outcomes with detailed graft immunophenotyping data including T-cell and NK-cell activation and maturation status and CD34 cell doses in patients with AML and MDS undergoing RIC-alloSCT.Methods: We performed a retrospective analysis using data from consecutive patients with AML and MDS who underwent RIC-alloSCT at a single center from 2010-2015 who had graft immunophenotyping data available. We compared transplant outcomes with TNC per kilogram (kg) and dose of CD3, CD4, CD8, CD34, and NK cells along with selected activation and maturation subsets. A competing risk regression analysis was conducted to examine the association between cell dose/kg and risk of relapse and graft versus host disease (GVHD). Overall survival and relapse free survival (RFS) were assessed utilizing the Cox proportional hazard model. Estimates of survival probability were determined by the Kaplan-Meier survival function. The log-rank test was used to compare OS and RFS among patients. Univariable and multivariable regression analyses were performed. Disease Risk Index (DRI) was used to stratify risk among patients. To identify optimal cutoffs (OC) of continuous variables for a specific outcome, a Classification and Regression Tree (CART) algorithm was utilized.Results: Our study included 142 patients who underwent RIC-alloHSCT for AML (n=97, 68%) and MDS (n=45, 32%). The vast majority of patients (98%) received fludarabine and busulfan conditioning with 65% receiving anti-thymocyte globulin. All patients received tacrolimus-based GVHD prophylaxis. Overall relapse rate was 37% at 3 years. Overall survival was 49% with median follow-up of 3.2 years.Total Nucleated Cell Dose: In multivariable analysis controlling for disease, comorbidity index, and performance status, a high infused TNC dose (10.6 - 16.8 x 108 cells/kg) correlated with improved overall survival (HR 0.27, 95% CI [0.12 - 0.59], p=0.001) and relapse free survival (HR 0.31, 95% CI [0.15 - 0.64], p=0.002). However, a very high TNC dose (OC >16.8 x 108 cells/kg) correlated with significantly worse OS (HR 2.84, 95% CI [1.16 - 6.98], p=0.023) and trended toward worse RFS (HR 2.09, 95% CI [0.88 - 4.93], p=0.093). Higher TNC doses were also correlated with an increased risk of chronic GVHD (HR 2.16, 95% CI [1.28 - 3.67], p=0.004, OC 9.8 x 108 cells/kg).Cell Subsets: Very low CD3 cell doses (OC <1.06 x 108 cells/kg) correlated with worse OS (HR 3.30, 95% CI [1.23 - 8.85], p=0.017) and worse RFS (HR 2.64, 95% CI [1.01 - 6.88], p=0.047). High CD3 doses were correlated with an increase in acute GVHD (all grades) (HR 2.41, 95% CI [1.36 - 4.25], p=0.002, OC 4.1 x 108 cells/kg). NK, CD4, CD8, and CD34 cell dose was not associated with relapse, OS, or RFS in multivariable analysis. Utilizing a previously published (Reshef et al, JCO, 2015) cutoff of 7.2 x 108 cells/kg, there was a trend toward a reduction in relapse with higher CD8 cell dose, but this did not reach statistical significance (HR 0.67, 95% CI [0.39 - 1.16], p=0.15). A high dose of late activated T-cells (CD3+/HLA-DR+) correlated with increased risk of acute GVHD (HR 2.31, 95% CI [1.26 - 4.20], p=0.006, OC 2.01 x 107 cells/kg) and chronic GVHD (HR 1.85, 95% CI [1.12 - 3.07], p=0.016, OC 6.6 x 106 cells/kg).Conclusion: Among AML and MDS patients following RIC-alloSCT, higher infused TNC/kg was associated with improved RFS and overall survival, confirming findings from a recent study (Martin et al, Haematologica, 2016). However, very high TNC doses may be deleterious. T-cell activation state influences risk of GVHD. Further research needs to be pursued to corroborate these findings and potentially optimize TNC and T-cell doses. We were unable to identify a significant correlation between CD8 cell dose and relapse or overall survival. [Display omitted] [Display omitted] DisclosuresLozanski:Genentech: Research Funding; Boehringer Ingelheim: Research Funding; Stemline Therapeutics Inc.: Research Funding; Beckman Coulter: Research Funding. Andritsos:Hairy Cell Leukemia Foundation: Research Funding.

Outcomes of Grades II-IV Acute Graft-Versus-Host Disease Post-Allogeneic Hematopoietic Stem Cell Transplantation: How Much Progress Was Achieved?

Despite recent reduction in mortality following hematopoietic cell transplant (HCT), graft versus host disease (GVHD) remains a major causes of failure. It is unclear if advances in antiviral, antifungal and antibacterial prophylaxis/treatment, and immunosuppression, have led to better survivals following the onset of acute GVHD (aGVHD). We therefore analyzed within the CIBMTR database outcomes over time of allogeneic HCT recipients who developed grade II-IV aGVHD. The objectives were to determine the change in overall survival (OS), disease-free survival (DFS), treatment-related mortality (TRM) and to identify risk factors.Methods: Between 1999 and 2012, 7295 patients with AML (57%), ALL (29%) or MDS (14%) received sibling (35%) or unrelated donor (65%) blood (65%) or marrow (35%) HCT (1216 for 1999-2001, 2329 for 2002-2005, 3750 for 2006-2010), and 3312 (45%) developed grades II-IV aGVHD. Median follow-up was 141 (3-174), 96 (3-144) and 49 (3-95) months for 1999-2001, 2002-2005, and 2006-2010 periods respectively. Multivariate models were built using the Cox's proportional hazards model. Clinical variables were tested for the affirmation of the proportional hazards assumption. Factors violating the proportional hazards assumption were adjusted through stratification. Stepwise model building procedure was used in developing models for each outcome with a threshold of 0.05 for both entry and stay in the model. Interactions between the main variable, (i.e. year of transplant) and the adjusted covariates were tested.Results: Univariate analyses showed a decrease in the incidence of grades III-IV aGVHD: 56 % (52-60), 47 %(44-50), and 38% (36-40) for 1999-2001, 2002-2005, and 2006-2010, respectively (p= <0.001). Multivariate analyses showed that age of recipient, organ affected by aGVHD, treatment of aGVHD (steroids vs. other), disease status at transplant and KPS influenced OS; while age of recipient, organ affected by aGVHD, treatment of aGVHD (steroids vs. other), CMV serostatus matching, disease status at transplant, unrelated donor age and KPS affected OS and TRM. After adjusting for these factors, recipients of tacrolimus-based GVHD prophylaxis who developed grade II aGVHD had better OS after 2006 (HR 0.78, p=0.02), while a trend for lower TRM (HR 0.79, p=0.056) and better OS (HR 0.83, p=0.08) were observed for those with grades III-IV aGVHD.Conclusions: Incidence of grades III-IV aGVHD has overall decreased and OS and TRM have improved over time for recipients of tacrolimus-based GVHD prophylaxis who developed grades II-IV aGVHD. DisclosuresAlousi:Therakos, Inc: Research Funding.

Prophylactic and therapeutic treatment of graft-versus-host disease in Japan.

Allogeneic hematopoietic stem cell transplantation in Japan is very different from that in Western countries in terms of the homogeneous genetic background, the preference for bone marrow to peripheral blood stem cells, use of a single unit in cord blood transplantation, and frequent use of non-myeloablative preconditioning due to a large number of elderly patients. Therefore, conclusions obtained from well-designed prospective and/or comparative studies of treatment of graft-versus-host disease (GVHD) performed in the United States or Europe may not fit Japanese transplant patients. This article reviews the studies of prophylactic and therapeutic treatment of acute and chronic GVHD that have been conducted in Japan. A randomized study demonstrated a lower incidence of acute GVHD in tacrolimus-based prophylaxis than in cyclosporine A-based prophylaxis. Retrospective and non-randomized prospective studies suggest that cyclosporine A-based and tacrolimus-based GVHD prophylaxis regimens are well researched and nearly optimized for Japanese patients, including infusion methods and target blood concentration. However, most other studies were performed in a single institute including a small number of patients, resulting in biased conclusions. There is no conclusive report on steroid-refractory acute and chronic GVHD. This review provides a baseline for starting prospective studies to create new evidence for GVHD treatment from Japan.

Severe Gut Acute Graft Versus host Disease (GVHD) Influence Thrombotic Microangiopathy in 86 Allogeneic Hematopoietic Stem Cell Recipients Who Received Tacrolimus-Based Regimen for GVHD Prophylaxis

AbstractAbstract 1955 Background and aims:Transplantation-associated thrombotic microangiopathy (TA-TMA) is a significant complication of allogeneic stem cell transplantation (HSCT). Although endothelial injury represents the final common pathway of disease, the exact pathophysiology of TA-TMA remains unclear. A variety of potential risk factors have been proposed such as different conditioning regimens, the development of acute graft versus host disease (GVHD), concomitant infection, or the use of calcineurin inhibitor (cyclosporine, tacrolimus) and sirolimus. The recent use of both tacrolimus and sirolimus for GVHD prophylaxis suggest increasing the risk of TA-TMA, especially in patients receiving busulfan and cyclophosphamide. However, there are little studies in which tacrolimus/sirolimus GVHD prophylaxis was compared with other tacrolimus-based regimens in order to determine the really increased incidence of TA-TMA.The purpose of this study was to determine the incidence and risk factors of TA-TMA in 86 allogeneic-HSCT recipients who received tacrolimus-based regimens (with sirolimus or with methotrexate) for GVHD prophylaxis. Patients and Methods:We conducted a retrospective cohort study of 86 consecutive allogeneic-HSCT recipients (aged over 18 years) transplanted in our unit between September 2007 and July 2012; GVHD prophylaxis consisted on tacrolimus and methotrexate (N = 19) or tacrolimus and sirolimus (N= 64); 3 patients received tacrolimus and sirolimus for acute GVHD treatment. Median age was 51 years (range 20–68) and 59.3% male. 40.7% of patients were diagnosed of acute leukemia, 23.3% myelodisplastic syndrome, 23.2% lymphoproliferative disorders, 7% multiple myeloma, 5.9% other hematological malignancies. The EBMT status at the moment of HSCT was intermediate/advanced in 63% of patients. The source of stem cells was peripheral blood in 87.2% and bone marrow in 12.8%. 57% of patients receiving an unrelated donor transplant. Nineteen patients (22.1%) received a HLA-mismatch graft. Reduced intensity conditioning was administered in 74.4%. 67.4% developed acute GVHD, 58.1% grade II-IV acute GVHD. Median follow-up was 248 days (range 16–1357).The diagnosis of TA-TMA was considered according to probable TMA criteria as defined by validation study by Cho et al. Results:TA-TMA occurred in 9/86 patients (10,5%): 2/19 patients in the tacrolimus-methotrexate regimen group (10.5%) and 7/67 in the tacrolimus/sirolimus regimen group (10.4%). Median time until diagnosis of TA-TMA was 67 days (range, 37 – 405 days), and 8/9 patients were diagnosed before the day +110 post-HSCT; none of them developed chronic GVHD previously to the diagnosed of TA-TMA. Several variables have been analyzed but only acute GVHD (p=0.026) and acute gut GVHD (p=0.007) were significantly associated with TA-TMA in the univariate analysis. Of note, in the tacrolimus/sirolimus group, only acute gut GVHD (p=0.04) but not acute GVHD, was associated with TA-TMA. In the multivariate analysis, only grade ≥2 acute gut GVHD retained their association with TA-TMA development (OR = 13.33, 95% CI = 1.51 – 117.38). Conclusions:In contrast to previously published evidence, these data support that the use of tacrolimus/sirolimus GVHD prophylaxis does not increase the risk of TA-TMA compared to tacrolimus/methotrexate regimen. However, none of the patients included in our study have received busulfan-cyclophosphamide conditioning.On the other hand, the most important risk factor for TA-TMA in allogeneic-HSCT recipients who received tacrolimus-based GVHD prophylaxis regimens was grade ≥2 acute gut GVHD. Consequently we propose especially close monitoring for TA-TMA in these patients. Disclosures:No relevant conflicts of interest to declare.

Acute Graft-Versus-Host Disease Following Umbilical Cord Blood Transplantation: Retrospective Survey Involving 2015 Japanese Patients.

BACKGROUND Limited information is available on incidences and clinical features of acute graft-versus host disease (GVHD) after cord blood transplantation and large-sized researches have been awaited.METHODS We investigated the incidences and clinical features of acute GVHD in 2,015 patients reported to the Japan Cord Blood Bank Network, who underwent cord blood transplantation between June 1997 and August 2006.RESULTS Of 2,015 patients, 1481 patients (73%) achieved neutrophil engraftment at a median of day 22 (range, 6–81). Cumulative incidence of neutrophil recovery at day 100 was 0.74 (95%CI, 0.73–0.76). Of 2015 patients, 708 patients developed grade II-IV acute GVHD: grade II (n=423), grade III (n=237), and grade IV (n=48). The median onset was day 19 (range, 4–190). The cumulative incidences of grade II-IV and III-IV acute GVHD at day 100 were 0.35 (95% CI, 0.33–0.37) and 0.14 (95% CI, 0.12–0.15), respectively. Skin and gastrointestinal acute GVHD was documented in 1,006 and 405 patients, respectively, whereas liver GVHD was diagnosed in 149 patients. Multivariate analysis identified the following predictors of grade II-IV acute GVHD: the number of infused nucleated cells, transplantation from female donors to female recipients, TBI-containing preparative regimens, methotrexate-containing GVHD prophylaxis, and tacrolimus-based GVHD prophylaxis. Overall survival rates at three years of patients with grade 0-I, II and III-IV GVHD who survived 100 days or longer were 0.58 (95%CI, 0.53–0.63), 0.61 (95% CI, 0.54–0.67) and 0.40 (95%CI, 0.31–0.49), respectively.CONCLUSIONS Acute GVHD following cord blood transplantation is mild and has graft-versus malignancy effects. [Display omitted]