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.

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.

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.

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.

Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients.

PURPOSE: Deficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2. METHODS: We conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS). RESULTS: Thirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2-28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5-16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT. CONCLUSION: HCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency. CLINICAL IMPLICATIONS: HCT is a definitive cure for DADA2 with > 95% survival.

Dynamic mRNA expression of donor-derived activating KIR genes and their significant effects on clinical outcome after haematopoietic stem cell transplantation.

Numerous reports suggest that activating killer immunoglobulin-like receptors (aKIRs) of natural killer (NK) cells, in addition to inhibitory KIRs (iKIRs), play a prognostic role after allogeneic haematopoietic stem cell transplantation (allo-HSCT). We aimed to investigate the association between the dynamic expression of KIRs on NK cells and the outcomes, particularly regarding graft-versus-host disease (GvHD). This study retrospectively enrolled 260 pairs of donors and recipients who had undergone allo-HSCT without in-vitro T cell depletion. The mRNA transcription level of KIRs was determined by quantitative real-time polymerase chain reaction (RT-qPCR). The levels of aKIR transcripts were decreased more than those of iKIRs during the occurrence of GvHD. The transcription levels of KIR2DS2 and KIR2DS4 in the patients developing GvHD, compared with those who were at a tolerance state, showed the most significant decrease in the month at their peak transcription levels (p = 0.03, p = 0.002). Significantly decreased expression of KIR2DS1 (p = 0.02), KIR2DS3 (p = 0.04) and KIR2DS5 (p = 0.04) in the GvHD group was observed when the transcription level reached a maximum. High expression of KIR3DS1 was associated with superior overall survival (OS) (p < 0.001). The expression of KIR2DS4 in the KIR genotype Bx group decreased more during GvHD, particularly at 3M (p = 0.02). These findings suggest that KIR genes are potential post-HSCT biomarkers and dynamic changes in the KIR transcription levels can be detected to better predict the occurrence and evaluate the treatment of GvHD after transplantation.

Pretransplant bone marrow cellularity and blood count recovery are not associated with relapse or survival risk following allogeneic stem cell transplant for AML in CR.

INTRODUCTION: Allogeneic hematopoietic cell transplantation (HCT) can be curative for acute myeloid leukemia (AML). Novel therapies may render patients' bone marrow hypocellularity and lead to prolonged post-therapy pancytopenia. Patients' bone marrow cellularity (BMC) at pretransplant assessment and post-treatment pancytopenia (classification CR-incomplete [CRi]) may manifest AML persistence. METHODOLOGY: We retrospectively examined the impact of BMC and ELN response (ELNr) on a single-center cohort of 337 patients who underwent allogeneic HCT for AML in CR1. RESULTS: Median follow-up was 33 months. Overall survival (OS) for the whole cohort was 55.8% at 2 years, while cumulative incidence of relapse (CIR) was 20.8%, and non-relapse mortality was 27.5%. OS and CIR were not significantly different between BMC groups; and neither was ELNr. ELNr CRi was associated with BMC aplastic and hypocellular marrow states (P < 2.6e-8). Multivariate analysis confirmed neither BMC nor attainment of ELNr CR vs CRi affected OS or relapse. Significant factors for survival included age at transplant, cytogenetic risk, development of acute Gr II-IV GvHD, and moderate-severe chronic GvHD, while cytogenetic risk and chronic GvHD affected relapse. CONCLUSION: Neither ELNr status nor pretransplant BMC influenced relapse post-HCT or OS. Hypocellularity and CRi are not negative prognostic factors for post-HCT outcomes of AML.

Differential Effect of Graft-versus-Host Disease on Survival in Acute Leukemia according to Donor Type.

PURPOSE: The anti-leukemic activity of allogeneic hematopoietic cell transplantation (HCT) depends on both the intensity of conditioning regimen and the strength of the graft-versus-leukemia (GVL) effect. However, it is unclear whether the sensitivity of the GVL effects differs between donor type and graft source. EXPERIMENTAL DESIGN: We retrospectively evaluated the effect of acute and chronic graft-versus-host disease (GVHD) on transplant outcomes for adults with acute leukemia (n = 6,548) between 2007 and 2017 using a Japanese database. In all analyses, we separately evaluated three distinct cohorts based on donor type [(8/8 allele-matched sibling donor, 8/8 allele-matched unrelated donor, and unrelated single-cord blood (UCB)]. RESULTS: The multivariate analysis, in which the development of GVHD was treated as a time-dependent covariate, showed a reductive effect of grade I-II acute GVHD on treatment failure (defined as 1-leukemia-free survival; P < 0.001), overall mortality (OM; P < 0.001), relapse (P < 0.001), and non-relapse mortality (NRM; P < 0.001) in patients receiving from UCB. A reductive effect of limited chronic GVHD on treatment failure (P < 0.001), OM (P < 0.001), and NRM (P < 0.001) was also shown in patients receiving from UCB. However, these effects were not always shown in patients receiving from other donors. The beneficial effects of mild acute and chronic GVHD after UCB transplantation on treatment failure were noted relatively in subgroups of patients with acute myelogenous leukemia and a non-remission status. CONCLUSIONS: These data suggested that the development of mild GVHD could improve survival after UCB transplantation for acute leukemia.

Terminal ileum is the most sensitive site for the histologic diagnosis of grade 4 graft-versus-host disease (GvHD) in the lower GI tract and is a harbinger of poor outcome.

The site of the gastrointestinal (GI) tract where biopsies are most likely to be diagnostic of graft-versus-host disease (GvHD) remains controversial. Recent reports have indicated that biopsies from the rectosigmoid have sufficient sensitivity and specificity for diagnosing GI GvHD and can be obtained via a less invasive flexible sigmoidoscopy procedure. While GvHD histologic grades 1-3 have little correlation with patients' symptoms and overall clinical grade, histologic grade 4 GvHD does correlate with severe clinical presentation and a poor prognosis. We examined cases of lower GI biopsies obtained via a complete colonoscopy with ileal intubation for the evaluation of GvHD within a 2-year period from patients who underwent stem cell transplantation. In our study cohort, grade 4 GvHD was significantly more likely to be identified in a terminal ileum biopsy than in a biopsy from another site in the lower GI tract. Significantly, 5 of 6 patients with histologic grade 4 GvHD diagnosed on ileal biopsies died from complication of severe GI GvHD. Given the poor prognosis of histologic grade 4 GvHD in the terminal ileum, the detection of this finding may serve to inform clinicians that escalation or modification of treatment may need to be considered. Furthermore, our findings suggest that terminal ileal biopsies may help to increase sensitivity for identifying patients at high risk for poor outcome of GvHD.

Combined haploidentical and cord blood transplantation for refractory severe aplastic anaemia and hypoplastic myelodysplastic syndrome.

Umbilical cord blood (UCB) transplantation is a potentially curative treatment for patients with refractory severe aplastic anaemia (SAA), but has historically been associated with delayed engraftment and high graft failure and mortality rates. We conducted a prospective phase 2 trial to assess outcome of an allogeneic transplant regimen that co-infused a single UCB unit with CD34+ -selected cells from a haploidentical relative. Among 29 SAA patients [including 10 evolved to myelodysplastic syndrome (MDS)] who underwent the haplo cord transplantation (median age 20 years), 97% had neutrophil recovery (median 10 days), and 93% had platelet recovery (median 32 days). Early myeloid engraftment was from the haplo donor and was gradually replaced by durable engraftment from UCB in most patients. The cumulative incidences of grade II-IV acute and chronic graft-versus-host disease (GVHD) were 21% and 41%, respectively. With a median follow-up of 7·5 years, overall survival was 83% and GVHD/relapse-free survival was 69%. Patient- and transplant-related factors had no impact on engraftment and survival although transplants with haplo-versus-cord killer-cell immunoglobulin-like receptor (KIR) ligand incompatibility had delayed cord engraftment. Our study shows haplo cord transplantation is associated with excellent engraftment and long-term outcome, providing an alternative option for patients with refractory SAA and hypoplastic MDS who lack human leucocyte antigen (HLA)-matched donors.

The response-guided ATG treatment provides a survival benefit and KPS recovery for patients with steroid refractory acute GVHD: The Nagasaki Transplant Group Experience.

Steroid-refractory acute graft-versus-host disease (SR-aGVHD) is a serious complication that negatively affects the prognosis and quality of life of patients who receive allogeneic hematopoietic stem cell transplantation (allo-HSCT). Antithymocyte globulin (ATG) is one of the second-line treatments for SR-aGVHD. We retrospectively evaluated Karnofsky Performance Status (KPS) recovery and clinical response in 11 patients who received the response-guided low-dose ATG treatment for SR-aGVHD after allo-HSCT using alternative donors. The median dose of ATG per cycle was 1.0 mg/kg (range, 1.0-1.25 mg/kg) and the median number of cycles of ATG was 2 (range, 1-4). The overall response rate was 63.6%, and the estimated overall survival rate at 1 year was 63.6%. Two out of seven patients who survived 1 year after the response-guided ATG treatment had KPS of 80 or higher. The remaining 5 patients had KPS of lower than 80 due to moderate chronic GVHD (cGVHD) and/or ≥grade 3 infectious complications. Based on the poor prognosis of patients with SR-aGVHD, the response-guided ATG treatment represents one therapeutic option. The present results also suggest that chronic GVHD and infectious complications after the response-guided ATG treatment were associated with decreased KPS recovery and impaired social function.

LMP7 polymorphism may modify the presentation and clinical impact of minor histocompatibility antigens in matched related hematopoietic stem cell transplantation.

Differential expression of minor histocompatibility antigens between the recipient and donor determines their disparity and can be modified by immunoproteasomes that regulate their processing and presentation. We examined the impact of HA-1 and HA-8 disparity, and immunoproteasome LMP7 polymorphism in 130 pairs. In multivariate analysis, HA-1 disparity showed a statistically significant association with an increased incidence of acute graft-versus-host disease (aGVHD) II-IV (p = 0.043, HR: 3.71, 95%CI = 1.04-13.26), while LMP7-Q/Q showed a trend toward increased incidence of aGVHD compared to LMP7-Q/K and K/K genotypes (p = 0.087, HR: 2.36, 95%CI = 0.88-6.31). All HA-1 and HA-8 disparate patients who developed aGVHD had the LMP7-Q/Q genotype. No significant association could be detected between HA-1, HA-8, or LMP7 and chronic GVHD, relapse-free survival (RFS), overall survival (OS), or transplant-related mortality (TRM). In conclusion, we suggested an association between the HA-1 disparity and the risk of developing aGVHD with a possible modifying effect of LMP7.

Excellent overall and chronic graft-versus-host-disease-free event-free survival in Fanconi anaemia patients undergoing matched related- and unrelated-donor bone marrow transplantation using alemtuzumab-Flu-Cy: the UK experience.

Haematopoietic stem cell transplantation (HSCT) remains the only curative option in Fanconi anaemia (FA). We analysed the outcome of children transplanted for FA between 1999 and 2018 in the UK. A total of 94 transplants were performed in 82 patients. Among the donors, 51·2% were matched related donors (MRD) while the remainder were alternative donors. Most patients received a fludarabine-cyclophosphamide (Flu-Cy)-based conditioning regimen (86·6%) and in vivo T-cell depletion with alemtuzumab (69·5%). Five-year overall survival (OS) was 85·4% [70·4-93.2] with MRD, 95·7% [72·9-99.4] with matched unrelated donors (MUD), 44·4% [6·6-78.5] with mismatched unrelated donors (MMUD) and 44·4% [13·6-71.9] with mismatched related donors (MMRD) (P < 0·001). Other factors significantly impacting OS were pre-transplant bone marrow status, source of stem cells, cytomegalovirus (CMV) serostatus, preparation with Flu-Cy, use of total body irradiation (TBI) and alemtuzumab as serotherapy. In multivariate analysis, absence of myelodysplastic syndrome (MDS) or leukaemia, bone marrow as source of stem cells, cytomegalovirus (CMV) other than +/- (Recipient/Donor) and Flu-Cy were protective factors for five-year OS. Five-year chronic graft-versus-host-disease (cGVHD)-free event-free survival was 75·4% with the same risk factors except for CMV serostatus. Five-year non-relapse mortality was 13·8% [7·3-22.3]. Only five patients (6·1%) developed grade II-IV acute GVHD and two patients chronic GVHD. These data confirm the excellent outcome of matched related or unrelated HSCT in children with FA.

Interplay Between the Intestinal Microbiota and Acute Graft-Versus-Host Disease: Experimental Evidence and Clinical Significance.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for many hematological disorders and autoimmune diseases, but acute graft-versus-host disease (aGVHD) has remained a major obstacle that limits allo-HSCT and exhibits a daunting mortality rate. The gastrointestinal system is among the most common sites affected by aGVHD. Experimental advances in the field of intestinal microbiota research enhanced our understanding - not only of the quantity and diversity of intestinal microbiota - but also their association with homeostasis of the immune system and disease pathogenesis, including that of aGVHD. Meanwhile, ever-growing clinical evidence suggest that the intestinal microbiota is dysregulated in patients who develop aGVHD and that the imbalance may affect clinical outcomes, indicating a potential predictive role for microbiota dysregulation in aGVHD severity and prognosis. The current animal and human studies investigating the intestinal microbiota in aGVHD and the understanding of the influence and management of the microbiota in the clinic are reviewed herein. Taken together, monitoring and remodeling the intestinal microecology following allo-HSCT may provide us with promising avenues for diagnosing, preventing or treating aGVHD in the clinic.

Allogeneic Hematopoietic Stem Cell Transplantation Mobilized With Pegylated Granulocyte Colony-Stimulating Factor Ameliorates Severe Acute Graft-Versus-Host Disease Through Enrichment of Monocytic Myeloid-Derived Suppressor Cells in the Graft: A Real World Experience.

We compared the effectiveness and safety of pegylated granulocyte colony-stimulating factor (peg-G-CSF) vs. non-peg-G-CSF for hematopoietic stem cell mobilization in allogeneic hematopoietic stem cell transplantation in a real-world setting. We included 136 consecutive healthy donors treated with non-peg-G-CSF (n = 53) or peg-G-CSF (n = 83), and 125 consecutive recipients (n = 42 and 83, respectively) in this study. All harvesting was completed successfully. No significant difference in leukapheresis number and adverse events frequency was observed, nor were there severe adverse events leading to discontinuation of mobilization. The leukapheresis products mobilized by peg-G-CSF had higher total nucleated cells (p < 0.001), monocytic myeloid-derived suppressor cells (p < 0.001), granulocytic myeloid-derived suppressor cells (p = 0.004) and B cells (p = 0.019). CD34+ cells and other lymphocyte subsets (T cells, regulatory T cells, natural killer [NK] cells, etc.) were similar in both apheresis products. Patients who received grafts mobilized by peg-G-CSF exhibited a lower incidence of grade III-IV acute graft-versus-host disease (p = 0.001). The 1-year cumulative incidence of chronic graft-versus-host disease and relapse, 1-year probability of graft-versus-host disease-free relapse-free survival, and overall survival did not differ significantly between subgroups. Our results suggest that collecting allogeneic stem cells after the administration of peg-G-CSF is feasible and safe. Peg-G-CSF mobilized grafts may reduce severe acute graft-versus-host disease compared with non-peg-G-CSF mobilized grafts after allogeneic stem cell transplantation. The beneficial effects of a peg-G-CSF graft might be mediated by increased numbers of monocytic myeloid-derived suppressor cells.