Chronic Graft-versus-host Disease Research Articles

Outcomes of Hematopoietic Stem Cell Transplantation in Patients With Thalassemia Major: How Do Anti-HLA Antibodies Impact?: The Impact of Anti-HLA Antibodies on Transplantation Outcomes in Thalassemia Major.

To investigate the effects of anti-human Leucocyte Antigen (HLA) antibody positivity on early hematopoietic stem cell transplantation (HSCT) results in patients with thalassemia major (TM). One hundred and twenty-four HLA-matched HSCTs were performed in patients with TM between 2015 and 2022. Ninety-one patients were screened for anti-HLA antibodies by testing panel reactive antigens (PRA). Demographic and transplantation characteristics of patients were recorded. The presence of PRA was tested with the Antibody Testing Assay (Luminex LIFECODES HLA Antibody Identification System). The number of PRA-positive patients was 54. There was no relationship between acute graft versus host disease (GVHD), chronic GVHD, grade of GVHD, and viral reactivation of the patients. However, platelet engraftment took around 3 days longer in the PRA-positive group (p = 0.05). The median number of erythrocyte transfusions was significantly higher in PRA-positive patients in the post-transplant period (p = 0.003), as was the median number of platelet transfusions (p = 0.003). Treosulfan conditioning increased the stable mixed chimerism (MC) rate by 3.8-fold (p = 0.011). In contrast, reduced rates of MC were found in patients who received matched unrelated donor cells or peripherally derived stem cells (p = 0.011 and p = 0.039, respectively) in the posttransplantation period in TM patients. PRA-positivity did not affect MC (p = 0.478). However, 80% of patients who had primary graft failure (n = 5; p = 0.59) and 75% of patients who died (n = 4) were PRA positive (p = 0.64), but these results were statistically insignificant due to the low number of patients. Anti-HLA antibodies primarily delayed platelet engraftment in TM patients and increased the erythrocyte and thrombocyte transfusion requirements. Although PRA positivity was more common in patients with primary graft failure or who died, there was no statistically significant impact of PRA positivity on chimerism, acute or chronic GVHD, viral activation, or mortality rates.

The prophylactic application of low-dose rabbit antithymocyte globulin in matched siblings HSCT with high-risk factors for graft-versus-host disease

Relapse and graft-versus-host disease (GVHD) are currently the predominant causes of mortality post allogeneic hematopoietic stem cell transplantation (allo-HSCT). The contentious use of antithymocyte globulin (ATG) for preventing GVHD in matched sibling HSCT scenarios has been a topic of significant debate. A retrospective analysis was conducted on matched sibling HSCT cases with high-risk factors for GVHD in our center from January 2018 to June 2023. Our assessment revealed that the group administered with ATG exhibited a 30 % incidence of acute GVHD (aGVHD), in contrast to 81.8 % in the non-ATG cohort (P = 0.037) among matched sibling HSCT cases with high GVHD risk factors. Furthermore, chronic GVHD (cGVHD) occurred in 20 % of the ATG group and 72.7 % of the non-ATG group (P = 0.03). Notably, the administration of ATG did not significantly impact disease relapse (p = 0.149), infection rates (p = 0.64), granulocyte recovery time (p = 0.15), platelet recovery time (p = 0.12), overall survival (p = 0.889), or disease-free survival time (p = 0.787). The use of rabbit antithymocyte globulin (r-ATG) at a 5 mg/kg dosage demonstrated a notable reduction in aGVHD and cGVHD incidences within sibling matched HSCT cases with high-risk factors for GVHD, without increasing rates of disease recurrence or infections. These findings highlight the potential benefit of using low-dose r-ATG in high-risk of GVHD sibling matched allogeneic HSCTs, although further validation with a larger cohort is necessary.

Post-transplant relapse in pediatric acute lymphoblastic leukemia in the era of CAR-T cell therapy. A multicenter analysis of Grupo Español de Trasplante Hematopoyetico y Terapia Celular (GETH-TC) Pediatric Committee.

BackgroundThe management of relapsed acute lymphoblastic leukemia (ALL) after hematopoietic stem cell transplantation (HSCT) has evolved significantly. Initially, treatment options were limited to palliative care, salvage chemotherapy, and second HSCT. Currently, the focus has shifted to innovative immunotherapies, particularly CAR T-cell therapy. ObjectivesThis study aims to: 1. Analyze outcomes after relapse following HSCT and identify prognostic factors associated with prolonged survival. 2. To evaluate and compare treatment strategies, including immunotherapy (e.g., CAR T-cell therapy) and second HSCT after achieving a new remission, or both treatments in high-risk cases. Study designThis retrospective, multicenter study will evaluate the outcomes of HSCT relapse in pediatric ALL patients. Key endpoints include disease-free survival (DFS), relapse rate, and NRM. We enrolled 73 children with ALL who relapsed after HSCT in 10 hospitals of the Pediatric Committee of the Spanish Group of Transplantation (GETH-TC) between 2013 and 2021. Among them, 56 patients (77%) had B-cell ALL and 17 (23%) had T-cell ALL. ResultsThe median time to relapse was 6 months after the first HSCT. CAR-T cell therapy was administered to 31 patients, all of whom achieved complete remission with negative MRD. However, two patients died prematurely due to cytokine release syndrome (CRS), resulting in a NRM of 7±4%. Sixteen patients relapsed after CAR-T therapy with a cumulative incidence (CI) of 65±11%. Seven of these patients subsequently underwent a second HSCT. The only significant prognostic factor for DFS was the MRD level prior to CAR-T therapy: DFS was 20±8% with MRD ≥3% compared to 100% with MRD <3% (p=0.002). At a median follow-up of 17 months after CAR-T therapy, DFS was 28±10% and overall survival (OS) was 40±10%. Second allogeneic HSCT was performed in 23 patients, including 7 who had previously received CAR-T therapy. Three patients died from NRM (CI: 19±10%). Eight patients relapsed after the second HSCT (CI: 52±13%), of which 2 were successfully treated with CAR-T therapy. At a median follow-up of 33 months after the second HSCT, DFS was 29±11% and OS was 32±10%. Of 17 patients with T-cell ALL, only 2 survived after a second HSCT with a DFS of 12±9%. Of the 73 patients, 20 are alive with a median follow-up of 4 years (DFS: 20±5%). Time to relapse after HSCT was the strongest predictor of outcome; no patient who relapsed within 6 months after the first HSCT survived. There was a trend towards worse DFS in patients who developed chronic GVHD during the first transplant, with 8 out of 9 relapsing despite rescue therapy (p<0.07). ConclusionsChildren with relapsed ALL after HSCT have a substantial chance of long-term survival if relapse occurs more than 6 months after the first transplant and if chronic GVHD was not present. The treatment paradigm has shifted to immunotherapy, including monoclonal antibodies and CAR-T therapy. The role of bridging to a second allogeneic HSCT after CAR-T therapy to improve long-term survival remains a subject of ongoing debate.

COMPARABLE OUTCOMES AFTER BUSULFAN- OR TREOSULFAN-BASED CONDITIONING FOR ALLO-HSCT IN CHILDREN WITH ALL – RESULTS OF FORUM

The superiority of TBI-based versus chemotherapy-conditioning for allo-HSCT in children with ALL has been established in the international, prospective phase-III FORUM study (#NCT01949129), randomizing 417 patients ≤ 18 years at diagnosis (4-21 years at HSCT) in CR, transplanted from HLA-matched sibling or unrelated donors. Due to the unavailability of TBI in some regions and to accommodate individual contraindications, this study reports the pre-specified comparison of outcomes of patients receiving busulfan-based (BU) or treosulfan-based (TREO) regimens from 2013 to 2018. 180 and 128 patients (median age 9.9 years) received BU/THIO/FLU or TREO/THIO/FLU, respectively. Data were analysed as of 02/2023, with a median follow-up of 4.2 years (range 0.3-9.1). Three-year overall survival was 0.71 (0.64-0.77) (BU/THIO/FLU) and 0.72 (0.63-0.79) (TREO/THIO/FLU), event-free survival was 0.60 (0.53-0.67) (BU/THIO/FLU) and 0.55 (0.46-0.63) (TREO/THIO/FLU), with both p = NS. The 3-year cumulative incidence of relapse (0.31 (0.25-0.38) BU, 0.36 (0.27-0.44) TREO, p = 0.779) and non-relapse mortality (0.08 (0.05-0.13) BU, 0.09 (0.05-0.15) TREO, p = 0.831) were comparable (p = NS). One case of fatal veno-occlusive disease occurred in each group. No significant differences in acute and chronic GvHD or GvHD-free and relapse-free survival (0.48 (0.41-0.55) BU, 0.45 (0.37-0.54) TREO, p = 0.89) were recorded. Outcomes for CR1 or CR2 patients were similar irrespective of the regimen used. In conclusion, BU/THIO/FLU or TREO/THIO/FLU regimens can be an alternative to TBI for ALL patients > 4 years with contraindications or lack of access to TBI.

A contemporary downtrend in chronic GVHD?

A contemporary downtrend in chronic GVHD?

PTCy-based graft-versus-host disease prophylaxis for matched sibling donor allogeneic hematopoietic cell transplantation

AbstractPosttransplant cyclophosphamide (PTCy) is a promising graft-versus-host disease (GVHD) prophylaxis in haploidentical and matched unrelated donor hematopoietic stem cell transplantation (HSCT), but its role in matched sibling donor (MSD) transplants remains unclear. We conducted a retrospective study of 413 MSD-HSCT patients receiving peripheral blood stem cell (PBSC) grafts from January 2010 to January 2023. Patients were categorized into 4 groups: group I (calcineurin inhibitor [CNI] + methotrexate [MTX] or mycophenolate mofetil [MMF]), group II (CNI + MTX or MMF + antithymocyte globulin [ATG]), group III (PTCy + ATG + CNI), and group IV (PTCy + CNI + MMF). PTCy was associated with a significant reduction in grade 2 to 4 (hazard ratio [HR], 0.6; P = .01) and grade 3 to 4 acute GVHD (HR, 0.2; P = .001) and all-grade (HR, 0.5; P = .007) and moderate-to-severe chronic GVHD (HR, 0.4; P = .001) compared with CNI + MTX (or MMF)–containing regimens. PTCy did not increase relapse risk; PTCy reduced nonrelapse mortality (NRM; HR, 0.3; P < .002), leading to improved GVHD-free/relapse-free survival (GRFS; HR, 0.4; P < .001). PTCy was also associated with improved overall survival (HR, 0.56; P = .01). Bloodstream infections are increased with PTCy (HR, 1.5; P = .001). The addition of ATG to PTCy did not further improve GRFS and was associated with a higher incidence of clinically significant cytomegalovirus (csCMV; HR, 2.16; P = .002) and Epstein-Barr virus (csEBV) reactivation (HR, 9.5; P < .001) and a numerical increase in NRM (HR, 1.7; P = .2). PTCy significantly appeared to improve GRFS in the MSD setting using PBSC grafts. The addition of ATG to PTCy increases csCMV and csEBV reactivation without further improving GRFS. Prospective trials and PTCy dose optimization are warranted.

Different impacts of granulocyte colony-stimulating factor administration on allogeneic hematopoietic cell transplant outcomes for adult acute myeloid leukemia according to graft type.

We retrospectively evaluated the impacts of using granulocyte colony-stimulating factor (G-CSF) and its timing on posttransplant outcomes for 9766 adults with acute myeloid leukemia (AML) between 2013 and 2022 using a Japanese database. We separately evaluated three distinct cohorts based on graft type: 3248 received bone marrow transplantation (BMT), 3066 received peripheral blood stem cell transplantation (PBSCT), and 3452 received single-unit cord blood transplantation (CBT). Multivariate analysis showed that G-CSF administration significantly accelerated neutrophil recovery after BMT, PBSCT, and CBT. However, it was associated with a higher risk of grades II-IV acute graft-versus-host disease (GVHD) across all graft types. Moreover, an increased incidence of overall chronic GVHD was observed with G-CSF administration in BMT and CBT patients, but not in PBSCT patients. G-CSF administration significantly improved overall survival (OS) and leukemia-free survival (LFS) only following CBT. Regarding the timing of G-CSF, in comparison with late initiation of G-CSF (Days 5-10), early initiation (Days 0-4) did not provide benefits for hematopoietic recovery regardless of graft type. In contrast, late initiation was significantly associated with a lower risk of grades II-IV acute GVHD and better OS and LFS in CBT patients. These data demonstrated that G-CSF administration accelerated neutrophil recovery and increased the risk of grades II-IV acute GVHD across all graft types, but significantly improved survival outcomes but only following CBT. Therefore, routine use of G-CSF should be considered for CBT in adult patients with AML.

GVHD after CAR T-cell therapy post allogeneic hematopoietic cell transplantation - successfully treated by extracorporeal photopheresis.

CAR T-cell therapy is highly effective, but also associated with unique toxicities. Because of the origin of T cells in patients who previously underwent allogeneic hematopoietic cell transplantation (alloHCT), graft-versus-host disease (GVHD) in the post-CAR T-cell setting poses a relevant concern but is only scarcely studied. Potential risk factors and mitigation strategies (from CAR T-cell modifications to clinical management) are yet to be determined. Sharing our retrospective experience and a mini-review of the literature, our aim is to better understand the frequency and risk of the potential occurrence of GVHD after CAR T cells, which are most likely underestimated. Here, we present a cohort of 11 patients with symptoms suggestive of GVHD out of 25 allografted patients treated with CAR T cells, of whom 3 patients (12%) had GVHD most likely triggered by the preceding CAR T-cell treatment. Severe chronic pulmonary GVHD occurred in a patient after CD19-directed CAR T-cell therapy. Extracorporeal photopheresis (ECP) mediated successful long-term control of GVHD without causing relapse of the underlying disease. In conclusion, CD19-directed CAR T-cell therapy seems to be feasible in patients after alloHCT but might comprise the potential risk of triggering GVHD, most likely depending on the T-cell source, donor compatibility, and the specific CAR construct used.

A Phase II, Open-Label Study of Lenalidomide and Dexamethasone Followed by Donor Lymphocyte Infusions in Relapsed Multiple Myeloma Following Upfront Allogeneic Stem Cell Transplant.

To date, the only potential curative treatment for multiple myeloma (MM) remains allogeneic (allo) hematopoietic cell transplant (HCT), although, most patients will eventually relapse. In relapsed patients, donor lymphocyte infusions (DLIs) have been reported to control disease, but the optimal strategy prior to and doses of DLIs remain unclear. With this study (NCT03413800), we aimed to investigate the efficacy and toxicity of lenalidomide and dexamethasome (Len/Dex) followed by escalating pre-determined doses of DLIs in MM patients who relapsed after allo HCT. Patients aged 18-65 years with relapsed MM following upfront tandem autologous (auto)/allo HCT were eligible. Treatment consisted of six cycles of Len/Dex followed by three standardized doses of DLIs: 5 × 106 CD3+/kg, 1 × 107/kg and 5 × 107/kg every 6 weeks. Bone marrow minimal measurable disease (MRD) using flow cytometry (10-5) was performed at enrolment, then every 3 months for 2 years or until disease progression, in a subset of patients. The primary endpoint was efficacy as measured by progression-free survival (PFS) at 2 years following Len/Dex/DLIs. Secondary objectives were safety including GVHD, response including MRD status and overall survival (OS). A total of 22 patients participated in this study, including 62% with high-risk cytogenetics. With a median follow-up of 5.3 years (range: 4.1-6.1), PFS and OS were 26.5% (95% CI: 10.4-45.9%) and 69.2% (95% CI: 43.3-85.1%), respectively. Overall, the best responses achieved post-Len/Dex + DLIs were complete remission in 9.1%, very good partial response in 50%, and progressive disease in 40.9%. Among the nine patients tested for MRD, only two achieved a negative status after receiving DLIs. Six patients died, all due to disease progression. No acute GVHD was observed after DLIs. We report a very low incidence of moderate/severe chronic GVHD of 18.2% with no need for systemic immunosuppressants one year after diagnosis. No unexpected adverse events were observed. Interestingly, a positive correlation between response to Len/Dex re-induction and response to DLIs was found (p = 0.0032). Our findings suggest that Len/Dex/DLIs in second line treatment after upfront tandem auto/allo HCT in relapsed MM patients remains feasible and safe. With a potential correlation between induction chemotherapy and DLI responses, more potent induction regimens together with higher doses of DLIs should be considered in the future.

Association between early anti-cytomegalovirus therapy and the incidence of chronic graft-versus-host disease.

Ganciclovir and foscarnet are two representative anti-cytomegalovirus (CMV) agents. A previous regional study revealed a lower risk of chronic graft-versus-host disease (GVHD) in patients who received pre-emptive foscarnet. We conducted a retrospective nationwide study to confirm the results. A total of 8890 patients aged 16 or older with hematological malignancies who received foscarnet (n = 1555) or ganciclovir (n = 7335) during their first hematopoietic stem cell transplantation (HSCT) were included. The risks of chronic GVHD (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.13-1.40; P < 0.001) and extensive chronic GVHD (HR, 1.16; 95% CI, 1.01-1.33; P = 0.033) were higher with ganciclovir. Among male patients with a female donor, the incidence of extensive chronic GVHD 3years after HSCT was clearly lower with foscarnet (13%; 95% CI, 9-16%) than with ganciclovir (27%; 95% CI, 25-29%; P < 0.001). In male patients who received HSCT from female donors, foscarnet recipients showed significantly lower incidence of extensive chronic GVHD than ganciclovir recipients, regardless of donor source or previous acute GVHD. While caution is necessary, these results indicate that foscarnet affects alloimmunization and might reduce the incidence of chronic GVHD.

Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Fanconi Anemia: Results of a Single Center with a Fludarabine-Based Conditioning Regimen

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) remains the only curative treatment for bone marrow failure (BMF) and hematologic complications of Fanconi anemia (FA). The evolution remains affected by the toxicity, the risk of graft failure, and clonal evolution. This study aimed to identify factors affecting outcomes in FA patients after allo-HSCT. We included FA patients who underwent allo-HSCT between January 2006 and December 2021. The conditioning regimen was cyclophosphamide/fludarabine (Cy/Flu) ± rabbit anti-thymocyte globulin (ATG). Bone marrow was the stem cell source from HLA-matched related donors in all transplants. Twenty-three patients, 19 with BMF and 4 with MDS/clonal evolution, were included. The median age was 11 years (5-39 years). Five patients (22%) received serotherapy with the conditioning regimen. Engraftment occurred in all patients without severe regimen-related toxicity. The 100-day cumulative incidence (CI) of grade II-IV acute GvHD (a GVHD) and 5-year CI of chronic GvHD (cGVHD) were 17% and 32%, respectively. The 5-year CI of late secondary graft failure was 10.5%. Two patients developed clonal evolution (AML; n = 2) and one patient developed nephrotic syndrome (n = 1). The 10-year overall survival (OS) and event-free survival (EFS) were 80% and 75%, respectively. There was a trend toward a better EFS in patients aged &lt;10 years compared to patients aged ≥10 years (100% versus 61%; p = 0.06). At the last follow-up, 18 patients were alive, and 4 expired. Causes of death were infections with refractory GVHD (n = 1), graft failure (n = 2), and renal failure (n = 1). Despite the small patient population, we show excellent outcomes, particularly for those transplanted in the first decade.

Contemporary Updates in the Prevention and Treatment of Graft-Versus-Host Disease.

Graft-versus-host disease (GVHD) is a serious complication after allogeneic HCT. Recently, several pivotal studies have been conducted demonstrating significant improvements in the management of GVHD. Here, we review important trials pertaining to GVHD prevention, acute GVHD treatment, and treatment of steroid refractory acute and chronic GVHD. Clinical trials in preventing GVHD demonstrate lower rates of severe acute GVHD and chronic GVHD with post-transplant cyclophosphamide. For acute GVHD, lower risk acute GVHD appears amenable to steroid-sparing therapies, such as sirolimus and itacitinib. Combinations with novel agents such as itolizumab appear promising for high risk acute GVHD. For steroid-refractory acute GVHD, ruxolitinib should be considered first line therapy. For chronic GVHD requiring therapy beyond steroids, ruxolitinib, belumosudil, and ibrutinib are now available and should be considered. Increasingly, GVHD has become a manageable complication after allogeneic HCT potentially translating to greater success with allogeneic HCT in the future.

Mismatched unrelated donors allogeneic hematopoietic stem cell transplantation with antithymocyte globulin for hematological malignancies: a multicenter retrospective study in China.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) utilizing mismatched unrelated donors (MMUD) present a vital option for patients with hematologic malignancies without human leukocyte antigen (HLA)-matched donors. This multicenter retrospective study encompassed 211 adults with hematological malignancies receiving allo-HSCT with antithymocyte globulin (ATG) from ≥1 HLA locus MMUD. The findings revealed cumulative incidences of II-IV acute graft-versus-host disease (GVHD) at 180 days at 26.5%, and III-IV acute GVHD at 12.3%, with 3-year cumulative incidences for total and moderate-severe chronic GVHD at 37.0% and 21.0%. The 3-year non-relapse mortality (NRM) and relapse rates were 19.7% and 25.8%. The study reported a 3-year overall survival (OS) rate of 63.1%, a disease-free survival (DFS) rate of 54.5%, and a GVHD-free, relapse-free survival (GRFS) rate of 40.8%. Administration of a lower-dose ATG-Genzyme (ATG-G, ≤ 6 mg/kg) correlated with improved engraftment without significantly affecting survival, relapse, or viral reactivation rates. The quantity of HLA mismatches did not impact engraftment, GVHD, viral reactivation, OS, DFS, GRFS, relapse, or NRM. In conclusion, MMUD allo-HSCT with ATG demonstrates favorable outcomes for patients with hematological malignancies, with no evident correlation between the degree of mismatch and post-transplantation results. Utilizing a lower dose of ATG-G ( ≤ 6 mg/kg) proved efficacious, delivering comparable clinical advantage.

Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an established treatment option for many malignant and non-malignant haematological disorders. Peripheral blood stem cells represent the main stem cell source in malignant diseases due to faster engraftment and practicability issues compared with bone marrow stem cells. Since the early 2000s, there have been many developments in the clinical field. Allo-HSCT using haploidentical family donors (haplo-HSCT) has emerged as an alternative for people who do not have human leukocyte antigen (HLA)-matched siblings or unrelated donors. In addition, the introduction of new methods and strategies in allo-HSCT, such as the use of post-transplant cyclophosphamide (PT-Cy), better donor selection, the more frequent administration of anti-thymocyte globulins (ATGs), but also improved management of side effects such as graft-versus-host disease (GvHD) and infection, have impacted outcomes after allo-HSCT. In addition, as transplant indications and strategies continue to adapt in line with novel research findings, the effect of the stem cell source on post-transplant outcomes is unclear. For our analysis, we considered peripheral blood stem cells as the standard graft source for adults with haematological malignancies. This is an update of a review first published in 2014. To assess the effect of bone marrow transplantation versus peripheral blood stem cell transplantation in adults with haematological malignancies with regard to overall survival, disease-free survival, incidence of non-relapse or transplant-related mortality, incidence of extensive chronic graft-versus-host disease (GvHD), incidence of acute GvHD grades III to IV, incidence of overall chronic GvHD, and quality of life. For this update we searched CENTRAL, MEDLINE, Embase, and two trials registries on 2 November 2022 with no language restrictions. We included randomised controlled trials (RCTs) comparing bone marrow transplantation (BMT) with peripheral blood stem cell transplantation (PBSCT) in adults (aged ≥ 18 years) with haematological malignancies. Two review authors independently selected studies and extracted data. We evaluated risk of bias using the original Cochrane risk of bias tool (RoB 1), and we evaluated the certainty of the evidence using the GRADE approach. The updated search identified no new studies for inclusion. We found two additional reports relating to a previously included study; they provided new data on quality of life and infection rates after transplantation. As these are clinically relevant outcomes, quality of life was added to the summary of findings table (replacing acute GvHD II to IV), and rate of infection was added to our list of secondary outcomes. We included nine RCTs with a total of 1521 participants. Overall, the risk of bias in the included studies was low. Median participant age across studies ranged from 21 to 45 years, and studies took place in Canada, the USA, New Zealand, Brazil, Australia, Egypt, and across Europe. Bone marrow transplantation (BMT) compared with peripheral blood stem cell transplantation (PBSCT) likely results in little to no difference in overall survival (hazard ratio (HR) for all-cause death 1.07, 95% CI 0.91 to 1.25; 6 studies, 1330 participants; moderate-certainty evidence). There may be little to no difference between BMT and PBSCT in terms of disease-free survival (HR for disease recurrence or all-cause death 1.04, 95% CI 0.89 to 1.21; 6 studies, 1225 participants; low-certainty evidence) and non-relapse or transplant-related mortality (HR 0.98, 95% CI 0.76 to 1.28; 3 studies, 758 participants; low-certainty evidence). BMT compared with PBSCT likely results in lower rates of extensive chronic GvHD (HR 0.69, 95% CI 0.54 to 0.90; 4 studies, 765 participants; moderate-certainty evidence) and overall chronic GvHD (HR 0.72, 95% CI 0.61 to 0.85; 4 studies, 1121 participants; moderate-certainty evidence). BMT compared with PBSCT may reduce the incidence of acute GvHD grades III to IV, although the 95% CI of the HR is also compatible with no effect (HR 0.75, 95% CI 0.55 to 1.02; 3 studies, 925 participants; moderate-certainty evidence). Evidence from two trials that used different quality of life assessment instruments suggests that BMT compared with PBSCT may be associated with higher quality of life five years after transplantation. Moderate-certainty evidence suggests little to no difference in overall survival following allo-HSCT using bone marrow versus peripheral blood stem cells (the current clinical standard stem cell source). Low-certainty evidence suggests little to no difference between the stem cell sources in terms of disease-free survival and non-relapse or transplant-related survival. BMT likely reduces the risk of extensive chronic GvHD and overall chronic GvHD compared with PBSCT. Evidence from two RCTs suggests that BMT compared with PBSCT may result in higher long-term quality of life, possibly due to the lower chronic GvHD incidence. With this update, we aimed to supply the most recent data on the choice of stem cell source for allo-HSCT in adults by including new evidence published up to November 2022. We identified no new ongoing studies and no new RCTs with published results. Further research in this field is warranted.

Sociodemographic Determinants of Allogeneic Hematopoietic Stem Cell Transplant Outcomes

Background: Allogeneic hematopoietic stem cell transplant (allo-HCT) is a curative therapy for several high-risk hematologic disorders. While clinical factors significantly impact post-transplant outcomes, socio-demographic determinants such as age, gender, and ethnicity play a crucial role in the success of allo-HCT. Furthermore, performance status and comorbidities also affect the outcomes. We aimed to investigate the influence of socio-demographic determinants on allo-HCT outcomes. Methods: For this retrospective single-center study, we included all patients undergoing matched unrelated donor (MUD) and haploidentical (haplo) allo-SCT at the University of Kanas Medical Center from August 2016 to July 2021. Cox regression analysis compared overall survival (OS) and disease-free survival (DFS). Hazard ratios (HR) with 95% confidence intervals (CI) were calculated. Logistic regression was performed to compare relapse, non-relapse mortality (NRM), acute and chronic graft versus host disease (GVHD), and GVHD-free Relapse-free survival (GRFS). Odds ratios (0R) with 95% CI were calculated. Linear regression was performed to compare platelet and neutrophil engraftment, and the correlation coefficient (R) was calculated. Multivariate analyses were performed for recipient age, gender, ethnicity, Karnofsky's performance status (KPS), and Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI). SPSS version 28 and R version 4.16 were used for data analysis. Statistical significance was considered at p&amp;lt;0.05. Results: A total of 452 patients were included, of which 276 had MUD allo-HCT while 176 had haplo allo-HCT. The median age of the recipients was 57 years (18-77), of which 61% were male (n=277). Ethnicity was Caucasians (n=381, 84%), Hispanics (n=28, 6%), African Americans (n=20, 5%), and others (n=23, 5%). KPS was 60-80% in 67% (n=304) patients and 90% or higher in 33% (n=148) of patients. Fifty-six percent of patients (n=251) had an HCT-CI score of 3 and above. Myeloablative and reduced-intensity conditioning were performed in 169 (37%) and 283 (63%) recipients. The graft source was bone marrow in 224 (49.6%) and 228 (50.4%) had peripheral blood stem cell grafts. The median graft cell dose was 4 million CD34 cells/kg. GVHD prophylaxis included tacrolimus/methotrexate (n=241, 53%) and post-transplant cyclophosphamide-based (n=211, 47%). Hematologic diagnoses included myeloid (n=322, 71%), lymphoid (n=101, 22%), and others (n=29, 7%). In univariate analyses for recipient age, gender, ethnicity, KPS, and HCT-CI, predictors include OS: age (years, HR 1.03, 95% CI 1.01-1.04, p&amp;lt;0.001), HCT-CI (≥3 vs 0-1: HR 1.40, 95% CI 1.03-1.91, p=0.030), and KPS (60-80% vs ≥90%: HR 1.61, 95% CI 1.14-2.26, p=0.006); DFS: age (years, HR 1.02, 95% CI 1.01-1.03, p&amp;lt;0.001) and KPS (60-80% vs ≥90%: HR 1.41, 95% CI 1.04-1.90, p=0.028); GRFS: None; Relapse: None; NRM: age (years, HR 1.02, 95% CI 1.01-1.04, p=0.001); acute GVHD: gender (male vs female, HR 0.59, 95% CI 0.40-0.87, p=0.007); chronic GVHD: KPS (60-80% vs ≥90%: HR 0.64, 95% CI 0.43-0.96, p=0.029); engraftment: None. Multivariate models were adjusted for all significant predictors identified in the univariate analyses. After adjusting for confounders, higher recipient age significantly predicted inferior OS (HR 1.10, 95% CI 1.01-1.04, p=0.0084), inferior DFS (HR 1.02, 95% CI 1.01-1.03, p=0.0012), and higher NRM (OR 1.03, 95% CI 1.01-1.04, p=0.005). Male gender significantly predicted lower risk of acute GVHD ((OR 0.59, 95% CI 0.40-0.86, p=0.007). African American ethnicity compared to Caucasians significantly predicted inferior OS (HR 1.90, 95% CI 1.01-3.58, p=0.046). KPS was a significant predictor of a higher risk of chronic GVHD (HR 0.62, 95% CI 0.40-0.95, p=0.028). HCT-CI did not predict any of the outcomes. No other significant associations were observed between these factors and post-transplant outcomes. Conclusion: In this single-center study, recipient age significantly affected OS, DFS, and NRM. The recipient's gender had a notable impact on acute GVHD, while ethnicity influenced OS. KPS was associated with chronic GVHD; interestingly, HCT-CI had no impact on post-transplant outcomes. Our findings suggest the need for larger studies to explore and mitigate the sociodemographic determinants of transplant outcomes.

Impact of Donor Age and Gender on Allogeneic Hematopoietic Stem Cell Transplantation

Background: Allogeneic hematopoietic stem cell transplant (allo-SCT) is critical in managing hematologic disorders. Donor age and gender are essential factors for post-transplant outcomes, and younger male donors have been associated with improved outcomes. We aimed to investigate the impact of donor age and gender on outcomes in patients undergoing matched unrelated donor (MUD) and haploidentical (haplo) allo-SCT. Methods: For this retrospective single-center study, we included allo-SCT recipients who received a MUD (n=276) or haplo (n=176) SCT at the University of Kanas Medical Center from August 2016 to July 2021. Cox regression analysis compared overall survival (OS) and disease-free survival (DFS). Hazard ratios (HR) with 95% confidence intervals (CI) were calculated. Logistic regression was performed to compare relapse, non-relapse mortality (NRM), acute and chronic graft versus host disease (GVHD), and GVHD-free Relapse-free survival (GRFS). Odds ratios (0R) with 95% CI were calculated. Linear regression was performed to compare platelet and neutrophil engraftment, and the correlation coefficient (R) was calculated. Multivariate analyses were performed for donor age as a continuous and categorical variable (&amp;lt;30 years vs 30 years and above). SPSS version 28 and R version 4.16 were used for data analysis. Statistical significance was considered at p&amp;lt;0.05. Results: We included 452 Allo-SCT recipients who received a MUD (n=276) or Haplo (n=176) SCT. The median recipient age was 57 (18-77) years and 277 (61%) were male. The median age of the donor was 28 (10-65) years, with 57% of donors being younger than 30 years. Seventy-one percent (n=331) of donors were male. Myeloablative and reduced-intensity conditioning were performed in 169 (37%) and 283 (63%) recipients. The graft source was bone marrow in 224 (49.6%), and 228 (50.4%) had peripheral blood stem cell grafts. The median graft cell dose was 4 million CD34 cells/kg. GVHD prophylaxis included tacrolimus/methotrexate (n=241, 53%) and post-transplant cyclophosphamide-based (n=211, 47%). Hematologic diagnoses included myeloid (n=322, 71%), lymphoid (n=101, 22%), and others (n=29, 7%). After adjusting for significant variables in the multivariate regression models, OS was not affected by the donor age (HR 1.005, 95% CI 0.991-1.021, p=0.476) and donor age &amp;lt;30 years (HR 0.923, 95% CI 0.681-1.252, p=0.608). Donor age had a marginal association with relapse (donor age: OR 0.974, 95% CI 0.950-0.997, p=0.032; donor age &amp;lt;30 years: OR 1.760, 95% CI 1.131-2.775, p=0.013) and NRM (donor age: OR 1.025, 95% CI 1.001-1.048, p=0.034; donor age &amp;lt;30 years: OR 0.656, 95% CI 0.417-1.031, p=0.067). The donor's age did not affect GRFS, DFS, acute and chronic GVHD, and engraftment. Allo-SCT with male donors had superior OS (HR 0.626, 95% CI 0.452-0.868, p=0.0049) compared to female donors. Faster platelet engraftment was observed using male donors (R -4.212, -7.90 to -0.517, p=0.0250). GRFS, Relapse, DFS, NRM, acute and chronic GVHD, and neutrophil engraftment were not affected by donor gender. Conclusion: The use of male donors was associated with superior overall survival and faster platelet engraftment, while donor age did not significantly impact post-transplant outcomes. Our findings suggest improved survival with the use of male donors regardless of donor age, and these findings should be validated in a larger contemporary cohort.

Therapeutic Targeting of the Inflammasome to Mitigate Murine Sclerodermatous Chronic Graft Versus Host Disease

Therapeutic Targeting of the Inflammasome to Mitigate Murine Sclerodermatous Chronic Graft Versus Host Disease

Sativex Oromucosal Spray in Patients with Chronic Graft Versus Host Disease: Effect on Sclerodermal Features and Refractory Muscle Cramps

Sativex Oromucosal Spray in Patients with Chronic Graft Versus Host Disease: Effect on Sclerodermal Features and Refractory Muscle Cramps

Real-World Efficacy of Belumosudil in Treating Fibrotic Symptom Burden in Chronic Gvhd: Modified Lee Symptom Score Assessment after Multiple Treatment Failures

Real-World Efficacy of Belumosudil in Treating Fibrotic Symptom Burden in Chronic Gvhd: Modified Lee Symptom Score Assessment after Multiple Treatment Failures

Impact of Systemic Antibiotics Use on Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Post-transplant complications lead to significant morbidity and mortality in the management of patients undergoing allogeneic hematopoietic stem cell transplant (allo-HCT). Broad-spectrum systemic antimicrobials and better prophylaxis strategies have reduced infection-related morbidity and mortality in allo-HCT patients. However, broad-spectrum antibiotic use disrupts the microbiome and immunome, which may result in poor post-transplant outcomes. We aimed to evaluate the impact of systemic antibiotics on allo-HCT outcomes. Methods: A retrospective multicenter analysis was conducted, including allo-HCT patients in the publicly available Center for International Blood and Marrow Transplant (CIBMTR) registry from 2013 to 2018 using P5646 data by Ramathan et al. Chi-square and t-tests were used to compare categorical and continuous baseline demographics. Multivariate Cox regression analyses were used to calculate hazard ratios (HR) with 95% confidence intervals (CI) for overall survival (OS), disease-free survival (DFS), relapse, non-relapse mortality (NRM), acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD), engraftment, and infection-related mortality between the two groups. Statistical analysis was conducted using R version 4.16, with statistical significance defined as p &amp;lt;0.05. Results: Among 7524 allo-HCT patients, 5779 were administered broad-spectrum systemic antibiotics (SA) while 1745 were not given systemic antibiotics (NSA). The median age was 58.58 years (range: 2.03-82.67) in the SA group and 56.18 years (range: 2.00 - 77.86) in the NSA group, and 58% were men in both groups. Ethnicities were Caucasian (76%), Hispanic (8%), African American (6%), and others (10%). The primary disorders included acute myeloid leukemia (47%), myelodysplastic syndrome (35%), and acute lymphoblastic leukemia (18%). Myeloablative conditioning was used in 53% of patients. Donor types were matched unrelated (49.5%), matched related (34%), and cord blood (16%). Graft sources were bone marrow (15%), peripheral blood stem cells (68%), and cord blood (16%). GVHD prophylaxis regimens included Tacrolimus and Cyclosporine-based (77%), post-transplant Cyclophosphamide-based (9%), Ex vivo T-cell depletion or CD34 selection (3%), and others (11%). In the multivariate regression analyses, systemic antibiotics independently predicted poor OS (55% SA vs 57% NSA; HR 1.13, 95% CI 1.01-1.22, p=0.026). Higher incidence of NRM (19% SA vs 15% NSA; HR 1.32, 95% CI 1.12-1.55, p=0.001), grade 2-4 aGVHD (41% SA vs 34% NSA; HR 1.24, 95% CI 1.12-1.38, p&amp;lt;0.001), and cGVHD (40% SA vs 39% NSA; HR 1.12, 95% CI 1.01-1.24, p=0.040) were observed with SA use. The two groups had no significant difference in DFS, relapse, infection-related mortality, and engraftment rates. The outcomes analyses were adjusted for the significant predictors identified in the univariate analyses. Conclusion: Systemic antibiotics use in allo-HCT patients is associated with higher morbidity and mortality. Judicious use and de-escalation of systemic antibiotics when safe may help to improve post-transplant outcomes. Future research exploring microbiome restoration could result in better post-transplant outcomes.