Factors influencing overall survival and GvHD development after allogeneic hematopoietic stem cell transplantation - single centre experience.

BACKGROUNDS: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a substantial therapeutic procedure for the treatment of a wide spectrum of severe diseases. Despite advancements in treatment and supportive care, alloHSCT still carries a considerable mortality risk, primarily caused by graft-versus-host disease (GvHD). Our retrospective analysis aimed to identify the factors influencing overall survival and GvHD development in HLA-identical sibling alloHSCT. We have analyzed patients' and donors' age, AB0 compatibility, recipient-donor gender match, stem cell source, time from the diagnosis to alloHSCT, conditioning regimen type, GvHD prophylaxis, and relapse. PATIENTS AND METHODS: Our study included 96 patients (54 male, 42 female) who underwent HLA-identical sibling alloHSCT. The median follow-up was 64.5 months (range 1-218 months), and the median age of both recipients and donors was 34 years. Malignant hematological diseases were the most common indications for alloHSCT. RESULTS: GvHD and its complications accounted for the highest number of deaths (N = 24; 46.2%), followed by relapse (N = 18; 34.6%). Acute GvHD developed in 30 patients (31.3%), while chronic GvHD occurred in 25 patients (26.0%), resulting in a total of 45 patients (46.9%) experiencing GvHD. Male recipients with female donors had significantly worse overall survival compared to other patients (P = 0.01; HR = 2.33). Overall survival was better in patients transplanted within 1 year from the diagnosis compared to those transplanted after 1 year (P = 0.03; HR = 1.93). No factor reached statistical significance regarding the impact on acute GvHD, chronic GvHD, or overall GvHD. CONCLUSION: We confirmed that sex mismatch, specifically in the case of a female donor and a male recipient, significantly negatively affects overall survival after alloHSCT. Additionally, overall survival is significantly shorter when the interval between the diagnosis and alloHSCT exceeds one year.

High CD34-positive cell dose in matched unrelated donor allogeneic hematopoietic stem cell transplant is not associated with graft-versus-host disease or mortality.

BACKGROUND: CD34+ stem cells serve as the primary graft source for allogeneic transplants, with a minimum of 2-4 × 106 cells/kg needed for engraftment. There are conflicting data on outcomes at high stem cell doses, with studies limited by few patients receiving doses far above the minimum target. STUDY DESIGN AND METHODS: In this retrospective, single-center study of patients with hematologic malignancies who underwent matched unrelated donor transplants, we assessed outcomes for engraftment, survival, relapse, and graft-versus-host disease (GVHD) for the highest CD34+ dose quintile (>13 × 106 cells/kg, n = 36) compared to the remaining patients (n = 139). Similar analysis was performed correlating T cell dose and outcomes. RESULTS: There was no difference between the groups in neutrophil engraftment, with a trend toward faster platelet engraftment. There was no significant difference in mortality (adjusted risk ratio [aRR] = 1.02, 95% confidence interval [CI] = 0.85-1.22), relapse (aRR = 1.10, 95% CI = 0.85-1.42), or overall survival by Kaplan-Meier analysis (p = .44). High CD34+ dose was not associated with higher incidence of acute GVHD (aRR = 0.99 grades II-IV, aRR = 1.18 grades III-IV) or chronic GVHD (aRR = 0.87 overall, RR = 1.21 severe). There was limited correlation between CD34+ and T cell dose (R2 = .073), and there was no significant difference in survival, relapse, or GVHD in the highest T cell dose quintile (n = 33) compared to the remaining quintiles (n = 132). DISCUSSION: We found no difference in survival, relapse, or GVHD incidence or severity in patients receiving CD34+ doses above prior cutoffs reported in the literature. These data do not support the routine use of graft CD34+ dose reduction.

Single vs double umbilical cord blood transplantation in acute leukemia: Systematic review and meta-analysis.

BACKGROUND AND AIMS: Umbilical cord blood transplantation (UCBT) has emerged as a promising treatment option for patients with acute leukemia needing hematopoietic stem cell transplantation. Both single (sUCBT) and double cord blood units (dUCBT) demonstrate potential benefits, but studies comparing their effectiveness have shown mixed results. This meta-analysis aimed to determine the comparative safety and efficacy of sUCBT versus dUCBT in acute leukemia patients. METHODS: Electronic databases were systematically examined to identify relevant studies comparing single vs double UCBT published until November 2023. Nine studies involving 3864 acute leukemia patients undergoing UCBT were included. Outcomes analyzed were acute graft-versus-host disease (GVHD), chronic GVHD, relapse, non-relapse mortality, leukemia-free survival and overall survival. Pooled risk ratios (RR) with 95% confidence intervals (CI) were calculated using a random effects model. RESULTS: The risk of Grade II-IV acute GVHD (RR 1.55, 95% CI 1.19-2.03) and Grade III-IV acute GVHD (RR 1.25, 95% CI 1.07-1.46) were significantly higher with dUCBT. Relapse risk was lower with dUCBT (RR 0.57, 95% CI 0.38-0.88) while overall survival favored sUCBT (RR 1.25, 95% CI 1.06-1.46). No significant differences were observed for chronic GVHD, non-relapse mortality or leukemia-free survival. CONCLUSION: Both single and double UCBT have potential as effective treatments for acute leukemia. The choice of treatment should consider various factors, including the risk of GVHD, relapse, and mortality. More research, especially randomized trials, is needed to provide definitive guidance on the optimal use of single and double unit UCBT in patients with acute leukemia.

[Analysis of efficacy and prognosis of allogeneic hematopoietic stem cell transplantation for the treatment of combined immunodeficiency].

Objective: To evaluate the efficacy of allogeneic hematopoietic stem cell transplantation for the treatment of combined immunodeficiency (CID) and explore prognostic risk factors. Methods: In this retrospective cohort study, clinical characteristics, laboratory tests and prognosis of 73 CID children who underwent allogeneic hematopoietic stem cell transplantation from February 2014 to April 2022 in the Children's Hospital of Fudan University were analyzed. Based on the subtypes of diseases, all patients were divided into severe combined immunodeficiency disease (SCID) group and other CID group. Based on the types of donors, all patients were divided into matched sibling donor group, matched unrelated donor group, unrelated cord blood group, and haploidentical donor group. Kaplan-Meier method and Log-Rank test were used to analyze the survival data. Cox regression was used to analyze prognostic factors. Results: Among the 73 patients, there were 61 (84%) males and 12 (16%) females. Fifty-five (75%) patients were SCID, and 18 (25%) patients were other CID. Donor source included 2 (3%) matched sibling donors (MSD), 3 (4%) matched unrelated donors (MUD), 64 (88%) unrelated cord blood (UCB), and 4 (5%) haploidentical donors. The age at transplant was 10.7 (5.9, 27.5) months, and the follow-up time was 36.2 (2.5, 62.9) months. The 3-year overall survival rate of 73 patients with CID was (67±6) %. No significant difference was found in the 3-year overall survival rates between patients with SCID (55 cases) and other CID (18 cases) ((64±7) % vs. (78±10) %, χ2=1.31, P=0.252). And no significant difference was found in the 3-year overall survival rates among patients who received MSD or MUD (5 cases), UCB (64 cases), and haploidentical donor (4 cases) transplant (100% vs. (66±6)% vs. (50±25) %, χ2=2.30, P=0.317). Cox regression analysis showed that the medical history of sepsis (HR=2.55, 95%CI 1.05-6.20, P=0.039) and hypoalbuminemia at transplant (HR=2.96, 95%CI 1.14-7.68, P=0.026) were independent risk factors for the prognosis of allogeneic hematopoietic stem cell transplantation in pediatric patients with CID. Conclusions: Allogeneic hematopoietic stem cell transplantation is an effective treatment for CID. The medical history of sepsis and hypoalbuminemia at transplant were risk factors for prognosis. Enhancing infection prevention and nutritional intervention before transplant can improve patient prognosis.

Amphiregulin, ST2, and REG3α biomarker risk algorithms as predictors of nonrelapse mortality in patients with acute GVHD.

ABSTRACT: Graft-versus-host disease (GVHD) is a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Algorithms containing either the gastrointestinal (GI) GVHD biomarker amphiregulin (AREG) or a combination of 2 GI GVHD biomarkers (suppressor of tumorigenicity-2 [ST2] + regenerating family member 3 alpha [REG3α]) when measured at GVHD diagnosis are validated predictors of NRM risk but have never been assessed in the same patients using identical statistical methods. We measured the serum concentrations of ST2, REG3α, and AREG by enzyme-linked immunosorbent assay at the time of GVHD diagnosis in 715 patients divided by the date of transplantation into training (2004-2015) and validation (2015-2017) cohorts. The training cohort (n = 341) was used to develop algorithms for predicting the probability of 12-month NRM that contained all possible combinations of 1 to 3 biomarkers and a threshold corresponding to the concordance probability was used to stratify patients for the risk of NRM. Algorithms were compared with each other based on several metrics, including the area under the receiver operating characteristics curve, proportion of patients correctly classified, sensitivity, and specificity using only the validation cohort (n = 374). All algorithms were strong discriminators of 12-month NRM, whether or not patients were systemically treated (n = 321). An algorithm containing only ST2 + REG3α had the highest area under the receiver operating characteristics curve (0.757), correctly classified the most patients (75%), and more accurately risk-stratified those who developed Minnesota standard-risk GVHD and for patients who received posttransplant cyclophosphamide-based prophylaxis. An algorithm containing only AREG more accurately risk-stratified patients with Minnesota high-risk GVHD. Combining ST2, REG3α, and AREG into a single algorithm did not improve performance.

Treatment-Sensitive and Treatment-Dependent Chronic Graft-versus-Host Disease Yield Superior Failure-Free and Overall Survival Compared to Treatment-Resistant Chronic Graft-versus-Host Disease.

Response to treatment of chronic graft-versus-host disease (cGVHD) may help predict prognosis and outcomes. We hypothesized that the response of cGVHD to treatment and the ability to taper immunosuppression define distinct treatment response categories that differ in terms of risk factors and prognosis. Our aim was to determine specific clinical characteristics and outcomes associated with 3 distinct cGVHD treatment response groups based on the response to and duration of immunosuppressive therapy (IST) as treatment-sensitive (TS), treatment-resistant (TR), and treatment-dependent (TD) cGVHD. This retrospective single-institution cohort study included 1142 consecutive adult and pediatric recipients of allogeneic hematopoietic cell transplantation (HCT) performed for malignant and nonmalignant disorders at the University of Minnesota between 2008 and 2016. All donor, graft, conditioning regimen, and GVHD prophylaxis strategies were included, but only patients who commenced systemic treatment within 30 days of cGVHD diagnosis were included. A total of 185 patients who developed cGVHD necessitating IST within 30 days of cGVHD diagnosis were included in this analysis. At 1 year after cGVHD onset, 13% of the patients were TS, 27% were TD, and 60% were TR (including 14% deceased), whereas at 2 years after cGVHD onset, 29% were TS, 5% were TD, and 66% were TR (including 22% deceased). In a landmark analysis starting at 1 year after cGVHD onset, 5-year failure-free survival (FFS) and overall survival (OS) were lowest in the TR group (FFS, 38%; OS, 70%), with comparable outcomes in the TD (74% and 82%, respectively) and TS (79% for both) groups. Compared to no cGVHD, TR cGVHD was associated with worse OS at 5 years after cGVHD (hazard ratio, 2.09 versus no cGVHD; 95% confidence interval, 1.3 to 3.3; P < .01). Our findings suggest that refining cGVHD classification into 3 treatment response states defines important predictors of early and late clinical outcomes and identifies patients needing more effective treatment.

RhD mismatch does not affect haematopoietic recovery, graft-versus-host disease and survival in allogeneic haematopoietic cell transplantation: A Japanese registry-based study.

BACKGROUND AND OBJECTIVES: ABO blood group mismatch between the donor and the recipient can affect the success of the transplant as well as problems with the red blood cells during allogeneic haematopoietic cell transplantation (HCT). However, the impact of the Rhesus (Rh) D mismatch on transplant outcomes in allogeneic HCT has been poorly elucidated. MATERIALS AND METHODS: We retrospectively evaluated the impact of the RhD mismatch on post-transplant outcomes in 64,923 patients who underwent allogeneic HCT between 2000 and 2021 using a Japanese registry database. RESULTS: Out of the whole group, 64,293, 322, 270 and 38 HCTs were done when the recipient or donor was RhD-mismatched with (+/+), (-/+), (+/-) or (-/-) combinations. The difference in RhD between recipient/donor (-/+), (+/-) and (-/-) did not affect haematopoietic recovery, acute and chronic graft-versus-host disease (GVHD), overall survival (OS), non-relapse mortality (NRM) or relapse when RhD (+/+) was used as the reference group in multivariate analysis. CONCLUSION: Our registry-based study demonstrated that RhD mismatch between recipient and donor did not significantly impact haematopoietic recovery, GVHD, OS, NRM or relapse after allogeneic HCT. These data suggest that RhD mismatches may not need to be avoided for recipient and donor combinations in allogeneic HCT.

Long term outcomes of nonmyeloablative allogeneic stem cell transplantation with TSEB TLI and ATG for Mycosis Fungoides and Sezary Syndrome.

Advanced stage (IIB-IVB) Mycosis Fungoides (MF) and Sezary Syndrome (SS) have a poor prognosis with median survival <5 years. We report long-term outcomes of a non-myeloablative allogeneic stem cell transplantation regimen consisting of total skin electron beam therapy, total lymphoid irradiation and antithymocyte globulin. Our prospective cohort consisted of 41 patients with a higher proportion of MF (34MF, 7SS). Acute GVHD Grade 2 to 4 was seen in 31.7% and chronic GVHD Grade 2 to 4 in 24%. The cumulative incidence of non-relapse mortality was 9.8% at 1 year and 12.6% at 2 years. At Day +90 post-transplant 66% of patients had a complete response (CR). With a median post-transplant follow up of 5.27 years, the 5-year overall survival rate was 37.7% (MF 36.7%, SS 57.1%). The 5-year cumulative incidence of progressive disease or relapse was 52.7% in all patients but only 20.8% in those with CR at transplant compared to 70.6% in those not in CR at transplant (p = 0.006). Long term survival is possible in advanced MF and SS with non-myeloablative transplantation and outcomes are improved in patients with CR at transplant.

Increased donor inhibitory KIR are associated with reduced GVHD and improved survival following HLA-matched unrelated donor HCT in paediatric acute leukaemia.

Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer cell-mediated effects after haematopoietic stem cell transplantation (HCT). Previous work has shown that accounting for known KIR-KIRL interactions may identify donors with optimal NK cell-mediated alloreactivity in the adult transplant setting. Paediatric acute leukaemia patients were retrospectively analysed, and KIR-KIRL combinations and maximal inhibitory KIR ligand (IM-KIR) scores were determined. Clinical outcomes were examined using a series of graphs depicting clinical events and endpoints. The graph methodology demonstrated that prognostic variables significant in the occurrence of specific clinical endpoints remained significant for relevant downstream events. KIR-KIRL combinations were significantly predictive for reduced grade 3-4 aGVHD likelihood, in patients transplanted with increased inhibitory KIR gene content and IM-KIR = 5 scores. Improvements were also observed in associated outcomes for both ALL and AML patients, including relapse-free survival, GRFS and overall survival. This study demonstrates that NK cell KIR HLA interactions may be relevant to the paediatric acute leukaemia transplant setting. Reduction in aGVHD suggests KIR effects may extend beyond NK cells. Moving forward clinical trials utilizing donors with a higher iKIR should be considered for URD HCT in paediatric recipients with acute leukaemia to optimize clinical outcomes.

Peripheral blood stem cell transplantation using HLA-haploidentical donor with post-transplant cyclophosphamide versus HLA-matched sibling donor for lymphoma.

Data comparing HLA-haploidentical donors and HLA-matched sibling donors (MSDs) in peripheral blood stem cell transplantation (PBSCT) for lymphoma are scarce. We retrospectively analyzed 465 patients with lymphoma aged 16 years or older who underwent PBSCT using haploidentical donors with post-transplant cyclophosphamide (PTCy-haplo) (n = 166) or MSDs with calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis (n = 299). Two-year overall survival (OS), progression-free survival (PFS), and GVHD-free, relapse-free survival (GRFS) in the PTCy-haplo and MSD groups were 49.2% versus 51.9% (P = 0.64), 38.0% versus 39.9% (P = 0.97), and 27.7% versus 18.5% (P = 0.006), respectively. In multivariable analyses, PTCy-haplo recipients had slower neutrophil recovery (hazard ratio [HR], 0.62; P < 0.001) and platelet recovery (HR, 0.54; P < 0.001), lower risk of chronic GVHD (HR, 0.64; P = 0.038) and extensive chronic GVHD (HR, 0.45; P = 0.008), and better GRFS (HR, 0.66; P = 0.003) than MSD transplant recipients. OS, PFS, relapse or progression, and non-relapse mortality were similar between the groups. The difference might be mainly due to PTCy use rather than donor type; however, the results suggested that PTCy-haplo could be a possible option as an alternative to conventional MSD transplantation for lymphoma in PBSCT.

Overlap chronic GVHD is associated with adverse survival outcomes compared to classic chronic GVHD.

Chronic graft-versus-host-disease (cGVHD) is divided into two subtypes: classic (absence of acute GVHD features) and overlap cGVHD ('ocGVHD'), in which both chronic and acute GVHD clinical features are present simultaneously. While worse outcomes with ocGVHD have been reported, there are few recent analyses. We performed a secondary analysis of data from the ABA2 trial (N = 185), in which detailed GVHD data were collected prospectively and systematically adjudicated. Analyses included cumulative incidence of classic versus ocGVHD, their specific organ manifestations, global disease severity scores, non-relapse mortality (NRM), disease-free survival (DFS) and overall survival (OS) in these two cGVHD subtypes. Of 92 patients who developed cGVHD, 35 were classified as ocGVHD. The 1-year cumulative incidence, organ involvement, and global severity of classic and ocGVHD were similar between ABA2 patients receiving CNI/MTX+placebo and CNI/MTX+abatacept; thus, cohorts were combined for ocGVHD evaluation. This analysis identified ocGVHD as having significantly higher severity at presentation and at maximum global severity compared to classic cGVHD. OS and DFS were significantly lower for ocGVHD versus classic cGVHD. OcGVHD is associated with increased cGVHD severity scores, and is associated with decreased OS and DFS compared to classic cGVHD, underscoring the high risks with this cGVHD subtype.

Low Rate of Infectious Enterocolitis in Allogeneic Stem Cell Transplant Recipients with Acute Diarrhea: A Prospective Study by the GETH-TC.

Acute diarrhea is a common and debilitating complication in recipients of allogeneic hematopoietic stem cell transplantation (HCT). In this prospective, observational, and multicenter study we examined all episodes occurring in the first 6 months of 142 consecutive adult patients who underwent a reduced-intensity conditioning HCT in 10 Spanish tertiary university hospitals. Fifty-four patients (38%) developed a total of 75 acute diarrhea episodes. The median time from HCT to the first episode was 38 days (4-157). The main cause of enterocolitis was lower GI-aGVHD (38%), followed by infections (21%) and drug-related toxicity (8%). Causative infectious causes were identified in only 16/75 episodes (21%). C. difficile-related infection was the most common infectious agent with an incidence and recurrence of 13% and 2%, respectively. With a median follow-up for survivors of 32 months, the non-relapse mortality (NRM) and the overall survival (OS) at 1 year, were 20% (95% C.I.: 14-28%) and 69% (95% C.I.: 61-77%), respectively. Development of enterocolitis was not associated with higher NRM (p = 0.37) or worse OS (p = 0.9). This real-life study confirms that the diagnosis and management of acute diarrhea in the early stages after HCT is challenging. Nosocomial infections seem to be relatively uncommon, probably due to more rational use of antibiotics.

High cutaneous amphiregulin expression predicts fatal acute graft-versus-host disease.

BACKGROUND: Amphiregulin (AREG) is increased in circulation in acute graft-versus-host disease (aGVHD) and is associated with poor steroid response and lower survival. The expression of AREG in aGVHD target organs and its association with clinical outcomes are unknown. METHODS: We performed AREG immunohistochemical staining on skin specimens from 67 patients with aGVHD between the years 2010 and 2015. Two blinded reviewers assessed AREG expression and scored specimens with a semiquantitative scale ranging from 0 (absent) to 4 (most intense). RESULTS: Median AREG score of aGVHD cases was 3. Sixteen of 67 (23.9%) aGVHD cases had an AREG >3. High skin AREG expression (>3 vs. ≤3) was associated with increased overall clinical grade of aGVHD (52.9% vs. 33.4% clinical grade III-IV, p = 0.02), reduced 3-year overall survival (OS; 13% vs. 61%, p < 0.01), and increased 3-year non-relapse mortality (NRM; 56% vs. 20%, p = 0.05). CONCLUSION: High skin AREG immunohistochemical expression is associated with high clinical grade aGVHD, poor OS, and increased NRM.

Randomized Phase III BMT CTN Trial of Calcineurin Inhibitor-Free Chronic Graft-Versus-Host Disease Interventions in Myeloablative Hematopoietic Cell Transplantation for Hematologic Malignancies.

PURPOSE: Calcineurin inhibitors (CNI) are standard components of graft-versus-host disease (GVHD) prophylaxis after hematopoietic cell transplantation (HCT). Prior data suggested that CNI-free approaches using donor T-cell depletion, either by ex vivo CD34 selection or in vivo post-transplant cyclophosphamide (PTCy) as a single agent, are associated with lower rates of chronic GVHD (cGVHD). METHODS: This multicenter phase III trial randomly assigned patients with acute leukemia or myelodysplasia and an HLA-matched donor to receive CD34-selected peripheral blood stem cell, PTCy after a bone marrow (BM) graft, or tacrolimus and methotrexate after BM graft (control). The primary end point was cGVHD (moderate or severe) or relapse-free survival (CRFS). RESULTS: Among 346 patients enrolled, 327 received HCT, 300 per protocol. Intent-to-treat rates of 2-year CRFS were 50.6% for CD34 selection (hazard ratio [HR] compared with control, 0.80; 95% CI, 0.56 to 1.15; P = .24), 48.1% for PTCy (HR, 0.86; 0.61 to 1.23; P = .41), and 41.0% for control. Corresponding rates of overall survival were 60.1% (HR, 1.74; 1.09 to 2.80; P = .02), 76.2% (HR, 1.02; 0.60 to 1.72; P = .95), and 76.1%. CD34 selection was associated with lower moderate to severe cGVHD (HR, 0.25; 0.12 to 0.52; P = .02) but higher transplant-related mortality (HR, 2.76; 1.26 to 6.06; P = .01). PTCy was associated with comparable cGVHD and survival outcomes to control, and a trend toward lower disease relapse (HR, 0.52; 0.28 to 0.96; P = .037). CONCLUSION: CNI-free interventions as performed herein did not result in superior CRFS compared with tacrolimus and methotrexate with BM. Lower rates of moderate and severe cGVHD did not translate into improved survival.

Poor survival and prediction of prolonged isolated thrombocytopenia post umbilical cord blood transplantation in patients with hematological malignancies.

Prolonged isolated thrombocytopenia (PIT) is a common complication after umbilical cord blood transplantation (UCBT). However, data on PIT prediction and impacts on transplantation outcomes for UCBT patients are rare. We retrospectively analyzed 244 patients with hematological malignancies who received single-unit UCBT at the First Affiliated Hospital of USTC between August 2018 and December 2019. Among them, PIT occurred in 49 recipients, with a crude incidence of 20.1%. In the PIT patients, the 2-year cumulative incidence of transplant-related mortality (TRM) was significantly higher, and the probabilities of 2-year overall survival, leukemia-free survival and graft-versus-host disease (GVHD)-free relapse-free survival were significantly poorer (57.1% vs. 88.6%; 53.1% vs. 81.9%; 22.4% vs. 59.8%; p < 0.001), without remarkable increases in the cumulative incidence of relapse or chronic GVHD. Importantly, the multivariate analysis revealed that lower high-resolution HLA compatibility (≤6/10), lower infused CD34+ cell count (≤1.78 × 105 /kg), grade II-IV acute GVHD preplatelet engraftment, a lower pretransplantation platelet count (≤100 × 109 /L), and a longer neutrophil engraftment time (≥17 days) were independent risk factors for PIT after UCBT. These results demonstrate that PIT is common after UCBT, predicting inferior survival and the need for more monitoring during the early phase.

A phase II study of post-transplant cyclophosphamide combined with tacrolimus for GVHD prophylaxis after HLA-matched related/unrelated allogeneic hematopoietic stem cell transplantation.

A combination of three post-transplant drugs, cyclophosphamide (PTCy), a calcineurin inhibitor, and mycophenolate mofetil, has long been used for prophylaxis of graft-versus-host-disease (GVHD) after HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT). Recently, this combination has been used following HLA-matched allo-HCT as well, but the optimal combination of drugs for GVHD prophylaxis in an HLA-matched setting remains unclear. This prospective phase II study evaluated the safety and efficacy of PTCy plus tacrolimus (TAC) for GVHD prophylaxis after allo-HCT from HLA-matched related donors (MRD) or HLA-matched unrelated donors (MUD). The cumulative incidences of grades II-IV and III-IV acute GVHD at 100 days post-transplantation were 18% and 5.9%, respectively, in the MRD group, and 18% and 9.1%, respectively, in the MUD group. The cumulative incidences of moderate to severe chronic GVHD at 1 year were 12% and 9.1% in the MRD and MUD groups, respectively. The 1-year overall survival rates in the MRD and MUD groups were 88% and 64%, respectively, and the 1-year GVHD-free, relapse free survival rates were 59% and 50%, respectively. These results suggest that GVHD prophylaxis with a less intensive double drug combination (PT/Cy and TAC) might be feasible after HLA-matched allo-HCT.Clinical Trial Notation This trial was a prospective single-center trial registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; identification number: UMIN000023890) and the Japan Registry of Clinical Trials (jRCTs051180143).

T-Cell Epitopes Shared Between Immunizing HLA and Donor HLA Associate With Graft Failure After Kidney Transplantation.

CD4+ T-helper cells play an important role in alloimmune reactions following transplantation by stimulating humoral as well as cellular responses, which might lead to failure of the allograft. CD4+ memory T-helper cells from a previous immunizing event can potentially be reactivated by exposure to HLA mismatches that share T-cell epitopes with the initial immunizing HLA. Consequently, reactivity of CD4+ memory T-helper cells toward T-cell epitopes that are shared between immunizing HLA and donor HLA could increase the risk of alloimmunity following transplantation, thus affecting transplant outcome. In this study, the amount of T-cell epitopes shared between immunizing and donor HLA was used as a surrogate marker to evaluate the effect of donor-reactive CD4+ memory T-helper cells on the 10-year risk of death-censored kidney graft failure in 190 donor/recipient combinations using the PIRCHE-II algorithm. The T-cell epitopes of the initial theoretical immunizing HLA and the donor HLA were estimated and the number of shared PIRCHE-II epitopes was calculated. We show that the natural logarithm-transformed PIRCHE-II overlap score, or Shared T-cell EPitopes (STEP) score, significantly associates with the 10-year risk of death-censored kidney graft failure, suggesting that the presence of pre-transplant donor-reactive CD4+ memory T-helper cells might be a strong indicator for the risk of graft failure following kidney transplantation.

Low Soluble Programmed Cell Death Protein 1 Levels After Allogeneic Stem Cell Transplantation Predict Moderate or Severe Chronic GvHD and Inferior Overall Survival.

Programmed cell death protein-1 (PD-1) is an inhibitory co-receptor required for regulating immune responsiveness and maintaining immune homeostasis. As PD-1 can be released as bioactive soluble molecule, we investigated the clinical significance of soluble PD-1 (sPD-1) after allogeneic hematopoietic stem cell transplantation (HSCT) regarding graft-versus-host disease (GvHD), relapse, and overall survival (OS) in a mono-centric cohort of 82 patients. Compared to pre-HSCT and to healthy controls, post-HSCT sPD-1 plasma levels were significantly increased during an observation time of three months. Univariate analysis revealed that low sPD-1 plasma levels at month one, two or three post HSCT were associated with acute GvHD grade III-IV, the onset of moderate/severe chronic GvHD (cGvHD) and inferior OS, DFS, and TRM, respectively. No relationship was detected to relapse rates. sPD-1 plasma levels were significantly increased in ATG-treated patients compared to ATG-untreated patients. Multivariate analysis revealed that a low sPD-1 plasma levels status at one or two month(s) after HSCT is an independent indicator for inferior OS, DFS, or TRM. A low sPD-1 plasma levels status at month three post HSCT is predictive for the onset of moderate/severe cGvHD. Thus, our study pinpoints the soluble inhibitory co-receptor PD-1 as a promising candidate molecule for the prediction of clinical HSCT outcome.

Diverting Enterostomy Improves Overall Survival of Patients With Severe Steroid-refractory Gastrointestinal Acute Graft-Versus-Host Disease.

OBJECTIVE: The aim of this study was to evaluate the benefit of diverting enterostomy (DE) in patients with severe steroid-refractory (SR) gastrointestinal acute graft-versus-host-disease (GI-aGVHD) following allogeneic hematopoietic stem-cell transplantation (ASCT). SUMMARY AND BACKGROUND DATA: Severe GI-aGVHD refractory to the first-line steroid therapy is a rare but dramatic life-threatening complication. Second lines of immunosuppressors have limited effects and increase the risk of sepsis. Data suggest that limiting GI bacterial translocation by DE could restrain severe GI-aGVHD. METHODS: From 2004 to 2018, we retrospectively reviewed all consecutive patients undergoing ASCT for hematologic malignancies who developed severe SR GI-aGVHD. We compared patients in whom a proximal DE was performed (Enterostomy group) with those not subjected to DE (Medical group). The primary endpoint was the 1-year overall survival (OS) measured from the onset of GI-aGVHD. Secondary endpoints were the 2-year OS and causes of death. RESULTS: Of the 1295 patients who underwent ASCT, 51 patients with severe SR GI-aGVHD were analyzed (13 in Enterostomy group and 38 in Medical group). Characteristics of patients, transplantation modalities, and aGVHD severity were similar in both groups. The 1-year OS was better after DE (54% vs 5%, P = 0.0004). The 2-year OS was also better in "Enterostomy group" (31% vs 2.5%; P = 0.0015), with a trend to lower death by sepsis (30.8% vs 57.9%; P = 0.091). CONCLUSION: DE should be considered for severe GI-aGVHD as soon as resistance to the corticosteroid is identified.

Ruxolitinib resistance or intolerance in steroid-refractory acute graft-versus-host disease - a real-world outcomes analysis.

Ruxolitinib for steroid-refractory acute graft-versus-host disease (SR-aGVHD) results in resistance or intolerance in 1/5 of patients. Outcomes of such patients are undefined. We identified these patients in a multicentre review and reported outcomes. Ruxolitinib-resistant aGVHD was identified in 48/307 patients. Among patients receiving additional therapy, the overall response rate to next therapy was 36%. Median survival was 21 days. Ruxolitinib intolerance led to treatment discontinuation in 16/307 patients. Ten intolerant patients received additional therapy with 50% experiencing continued improvement of aGVHD. Median survival was 50 days in these patients. These data serve as a baseline for future SR-aGVHD studies.