Background: Patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) with FLT3-Internal Tandem Duplication (ITD) mutation have a poor prognosis and high risk of relapse, even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Prevention of disease relapse remains a challenge.Objective: To investigate the efficacy and tolerability of gilteritinib maintenance therapy in R/R AML patients with FLT3-ITD mutation.Methods: We retrospectively analyzed 96 AML patients who received allo-HSCT between 2017 and 2022. Patients were divided into two groups based on whether they received gilteritinib maintenance therapy or not. To minimize selection bias, we implemented propensity score matching and selected 80 propensity score-matched patients for comparison, 40 in each group. The therapeutic process and clinical outcomes were retrospectively analyzed.Results: All patient baseline and transplant characteristics were similar between the gilteritinib and the control group. Gilteritinib therapy conferred significant survival advantages (P = 0.013 for OS and P = 0.026 for RFS). Relapse remained the main reason of treatment failure with 3-year incidence of 25.0% (95%CI 12.8-39.2%) and 55.0% (95%CI 38.1-69.0%) for the gilteritinib group and the control group(P = 0.010). In multivariate Cox regression analysis, gilteritinib maintenance was the only factor associated with improved OS (HR = 0.395, P = 0.040) and RFS (HR = 0.447, P = 0.030).Conclusions: Our results indicated that gilteritinib maintenance therapy reduced the risk of relapse for FLT3-ITD mutated R/R AML. Compared with patients without maintenance therapy, gilteritinib treatment showed a similar incidence of NRM and GVHD, leading to significant survival advantages in this high-risk cohort of patients.

Our study includes 278 patients aged between 40 and 50 years from 29 centers who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) from matched sibling donors (MSDs) (n = 106) and haploidentical donors (HIDs) (n = 172) over the last decade. Univariate analysis revealed that HID recipients was associated with more serious disease severity, a delayed allo-HSCT after diagnosis, a higher pretransplant transfusion burden and poor performance status pre-transplant than MSD recipients in clinical settings. After these pretransplant clinical factors were well balanced following propensity score-matching (PSM), 80 matched pairs were selected for further analysis. Following PSM, the cumulative incidences of neutrophil were comparable between two matched groups (P = 0.14), while the 100-day engraftment rates of platelet were significant lower in HID-HCT (P < 0.001); The HID cohort showed higher cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) compared with MSD group (P = 0.04). In contrast, the incidence of severe (grade III-IV) acute GVHD and chronic GVHD were not statistically significant (severe acute GVHD P = 0.10; chronic GVHD P = 0.28). Our study observed comparable overall survival (OS) (P = 0.14); failure free survival (FFS) (P = 0.23); GVHD-free/relapse-free survival (GRFS) (P = 0.26) between matched HID and MSD recipients. In conclusion, our data indicates that allo-HSCT from an HID could be considered for SAA patients between 40 and 50 years old who do not have an MSD.

Chronic graft-versus-host disease (cGVHD) is a leading long-term complication following allogeneic hematopoietic stem-cell transplantation (Allo-HSCT). However, its impact on outcomes in critically ill Allo-HSCT recipients has little been evaluated.

We conducted a post hoc analysis of a multicenter cohort study involving Allo-HSCT recipients admitted to 14 French intensive care units (ICUs) between January 1, 2015, and December 31, 2020. The primary endpoint was 90-day mortality after admission.

The prevalence of cGVHD was 10% (114/1164), with a severe form of the disease in half the patients. The most common manifestation was skin involvement (94%), followed by gastrointestinal tract (56%), liver (28%), and lungs (19%). The primary reason for ICU admission was acute respiratory failure (43%), with 65% of patients presenting with multi-organ dysfunction. Overall survival was 61% at 90 days and 40% at 3 years. The Sequential Organ Failure Assessment score at ICU admission was the only independent predictor of 90-day mortality (HR/point 1.32 [95% CI 1.21-1.46]; p < 0.01). cGVHD severity did not significantly influence survival. Patients with cGVHD had comparable survival rates to those with controlled acute GVHD or without GVHD (90-day: 61% vs. 55% and 66%; 3-year: 40% vs. 32% and 47%).

In critically ill Allo-HSCT recipients, the presence or severity of cGVHD is not associated with survival and should not influence the decision to admit or not the patient to the ICU. However, careful discussions about the goals of care should be undertaken in patients with severe hepatic or pulmonary involvement.

Retrospectively registered.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) use in refractory/relapsed B-cell non-Hodgkin lymphoma (R/R B-NHL) has been reduced due to the efficacy of CAR-T-cell therapy as salvage treatment. However, there remains a need for data regarding the long-term outcomes following allo-HSCT, to fully characterize this procedure as benchmark to design further studies on the role of allogeneic stem cell transplantation OBJECTIVE: To assess long-term outcomes of R/R B-NHL patients after allo-HSCT, in a multicenter study among six Italian hematology centers STUDY DESIGN: Data were collected from 285 allo-HSCT procedures performed among 281 R/R B-NHL patients, in 2000-2020. All patients signed informed consent for sharing data with the GITMO/EBMT Registry, the study was approved by the Institutional Review Board of the coordinating center. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), cumulative incidence function (CIF) of disease-related death and non-relapse mortality (NRM). The median age at transplant was 50 years (19-70), with 94 (33%) female patients. Histological subsets included indolent lymphoma (123 patients; 43.3%), aggressive lymphoma (124; 43.7%), and mantle-cell lymphoma (MCL; 37; 13%). At allo-HSCT, 135 patients (47.7%) exhibited complete remission (CR), 63 (22.3%) partial response, 30 (10.6%) stable disease, and 55 (19.4%) progressing disease. Myeloablative regimens were employed in 86 procedures (30.2%). The median follow-up for surviving patients was 8.7 years (0.3-22).

Three-year PFS was 43.7% (95% CI 37.9-49.4), 9-year PFS 39.3% (33.4- 45.1), 3-year OS 50.4% (44.5-56.1), and 9-year OS 46.6% (40.5-52.5). Positive predictors of 3-year PFS included indolent lymphoma (55.3%) vs. aggressive (37.9 %) and MCL (27.0%); and CR at allo-HSCT (51.9%) vs non-CR (30.9-38.9%). Similar associations were observed for OS. Among patients in CR, outcomes did not significantly differ among histological subtypes. Among patients not in CR, outcomes were significantly better for indolent lymphoma (3-year PFS: 56.6%), compared to aggressive (26.4%), and MCL (0%). Regarding transplant-procedures, the subgroup receiving post-transplant cyclophosphamide-based program for GVHD prophylaxis had a significantly improved outcome. Overall, 56 patients (19.6%) died from lymphoma progression, with 1-year and 3-year CIF of disease-related death of 15.9% (95% CI 11.9-20.5) and 18.5 (14.2-23.2), respectively. The latest disease recurrence occurred at 5.4 years post-allo-HSCT. Early NRM occurred in 75 patients (12-month CIF 26.1%), and late NRM in 25 patients (5-year CIF 31.2%; 25.9-36.7). At present, 95 patients (33.3%) are long survivors in continuous CR at 5-22 years since transplant.

Despite pronounced toxicity, allo-HSCT is effective in high-risk, R/R B-NHL, with 5-year PFS expectancy of ∼40%, and approximately one-third of long survivors in CR. Patients undergoing allo-HSCT in CR exhibited the best results. Among patients not in CR, the greatest benefits were obtained in indolent lymphoma. Allo-HSCT remains a potentially curative option for R/R B-NHL patients and further investigations are warranted to define its possible use in patients unable to undergo or failing CAR-T-cell therapy and/or bispecific monoclonal antibodies.

Unrelated donor hematopoietic stem cell transplantation (URD-HSCT) is a curative option for severe aplastic anemia (SAA), but the optimal conditioning regimen remains unclear. This retrospective study compares Busulfan/Cyclophosphamide/Anti-thymocyte globulin (Bu/Cy/ATG) and Fludarabine/Cyclophosphamide/Anti-thymocyte globulin (Flu/Cy/ATG) protocols to identify the best regimen for SAA patients. We retrospectively analyzed the clinical outcomes of 107 SAA patients who underwent URD-HSCT with Flu/Cy/ATG (n=63) or Bu/Cy/ATG (n=44) between November 2012 and December 2022. No significant differences were observed in the cumulative incidence of neutrophil/platelet engraftment, graft failure, graft-versus-host disease (GVHD), or CMV viremia. Overall survival (OS) at 7 years was 95.5% (95% CI: 89.5-100) with Bu/Cy/ATG vs. 85.5% (95% CI: 77.1-94.7) with Flu/Cy/ATG, and failure-free survival (FFS) at 7 years was 95.5% (95% CI: 89.5-100) versus 83.9% (95% CI: 75.2-93.6). Multivariate analysis identified Bu/Cy/ATG protocol as favorable for OS (Hazard ratio, HR 0.122, 95% CI: 0.021-0.715, P = 0.020) and FFS (HR 0.090, 95% CI: 0.015-0.538, P = 0.008). Moreover, multivariate analysis confirmed that the Bu/Cy/ATG regimen significantly reduced the risk of EBV viremia (Relative risk, RR 0.175, 95% CI: 0.026-0.717, P = 0.032) and post-transplant lymphoproliferative disorder (RR 0.031, 95% CI: 0-0.536, P = 0.012). Subgroup analysis through multivariate modeling further demonstrated that the Bu/Cy/ATG regimen demonstrated superior OS, FFS and EBV infection outcomes in patients older than 30 years. The Bu/Cy/ATG regimen, compared to Flu/Cy/ATG protocol, offers superior outcomes, including improved OS/FFS and reduced EBV infection, suggesting it may be the preferred choice for SAA patients undergoing URD-HSCT, especially for patients older than 30 years. Larger cohorts and prospective trials are needed to validate these findings.

The aim of this open-label, multicenter, randomized controlled trial was to determine the efficacy and safety of sequential umbilical cord-derived mesenchymal stem cell (UC-MSC) infusion for graft-versus-host disease (GVHD) prevention within 3 months of haploidentical hematopoietic stem cell transplantation (haplo-HSCT).

This open-label study evaluated UC-MSC infusion (administer 1 × 106/kg 4 hours before the commencement of day 0, once weekly for the first month after transplantation, once every 2 weeks for the second month, and once during the third month, totaling eight doses). The primary end point was the 2-year cumulative incidence of severe chronic GVHD (cGVHD).

In the primary analysis, 192 qualified participants between age 18 and 60 years with haplo-HSCT in three transplant centers in China were enrolled and randomly assigned to the MSC and control groups. In the primary analysis, the estimated 2-year cumulative incidence of severe cGVHD and all grades of cGVHD was lower in the MSC group than in the control group (P = .033 and P = .022). The cumulative incidence of grade 1 to 4, 2 to 4, and 3 to 4 acute GVHD (aGVHD) in patients in the MSC group significantly decreased (all P < .001). The 3-year GVHD-free and relapse-free survival (GRFS) rate in the MSC group was 62.4%, which was significantly higher than that in the control group (32.0%, hazard ratio [HR], 0.34, P < .001). MSC infusion did not influence the cumulative incidence of relapse (P = .34) and nonrelapse mortality (P = .45).

Our findings suggest that sequential infusion of MSCs within 3 months after haplo-HSCT significantly reduced both the incidence and severity of cGVHD and aGVHD, manifesting as a better GRFS rate for patients.

Allogeneic hematopoietic stem cell transplantation is recommended for TP53-mutant acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) despite a high relapse rate and poor survival. To understand TP53 alterations on a molecular level and define stratified prognostic outcomes following transplantation, we performed targeted next-generation sequencing on 63 patients who underwent transplantation for TP53-mutant AML/MDS and profiled their molecular spectrum. Sixty-eight TP53 mutations were detected, with a median variant allele frequency of 46.8%. Copy number alterations at the TP53 locus were present in 19 patients (30%). Complex karyotype was detected in 48 patients (76%) and was significantly associated with larger TP53 clone size, bi-allelic status, and the absence of concurrent mutations, reflecting the high TP53 mutational burden. Specifically, 51 patients (81%) with the dominant TP53 clone greatly overlapped with those with the complex karyotype. Multivariable overall survival (OS) analysis identified AML (hazard ratio [HR], 2.51; P = 0.03) and TP53 clonal dominance (HR, 5.30; P = 0.002) as prognostic factors. One-year OS was worse in AML with the dominant TP53 clone than in others (13% vs 61%; P < 0.001). Our results underscore the utility of mutational profile-guided risk stratification in patients with TP53-mutant AML/MDS, and could aid in transplantation-related decision-making.

Deficits in motor performance and functional abilities represent a severe complication for individuals with steroid refractory chronic graft versus host disease (cGVHD) and is associated with decreased survival and high morbidity. The objective of this study was to characterize the impact of pomalidomide on motor and functional outcomes in patients with cGVHD. Thirty-four adult patients with cGVHD were enrolled in a randomized and unblinded trial. Pomalidomide was administered orally at two dose levels: low (0.5 mg/d) or high (initial 0.5 mg/d, escalating 0.5 mg/d every 2 weeks to a maximum 2 mg/d). Efficacy was assessed primarily by the Activity Card Sort (ACS), 2 Minute Walk Test (2MWT), Medical Outcomes Study Short Form 36 (SF-36), Active Range of Motion (AROM), Disabilities of the Arm, Shoulder, and Hand (DASH), and Manual Abilities Measure 36 (MAM). Compared to baseline, the pooled sample of study participants at 6 months showed improvement in hand skills (MAM, P = .01), upper extremity (UE) function (DASH, P = .01), and health related quality of life (SF-36 Physical Component Summary score (PCS), P = .02). Though no statistically meaningful differences between the two dose groups were found, the low-dose group had greater improvements in AROM, walk distance, UE and hand function, and in the high-demand physical leisure and social subdomains of the ACS as compared to the high-dose group. Responders to pomalidomide performed better than nonresponders on most measures at the 6-month endpoint. The study suggests pomalidomide, at both dose levels, may improve several aspects of motor and functional abilities. However, further study is warranted to determine if the trends found in this study, are sustained over time in larger, and in more diverse cGVHD populations. The findings highlight the potential utility of administering functional and motor tests, such as the ACS, DASH, and MAM, to patients with cGVHD, to fully elucidate the efficacy of treatment options for persons with steroid refractory cGVHD.

Graft-versus-host disease (GVHD) is a major complication of hematopoietic stem cell transplantation (HSCT). Histologic diagnostic criteria and several grading systems have been described for colonic GVHD; however, for esophageal GVHD (eGVHD) limited reports exist to date. In this study, a total of 130 patients with esophageal biopsies of HSCT were included, with a median age of 44 years (2-77 years) and a male predominance (54.6%). Of these, 82 (63%) had a clinical diagnosis of eGVHD. Cases were divided into 2 groups: those without apoptotic bodies, dyskeratotic cells, or ulceration (group 1, no histologic evidence of eGVHD) (42%) and those with at least one of those features (group 2) (58%). Group 2 cases were associated with extragastrointestinal tract GVHD (P = .024), a clinical diagnosis of eGVHD (P = .001), older age (P < .001), stem cells derived from peripheral blood (P < .001), higher number of intraepithelial lymphocytes (P = .002), presence of acute inflammation (P < .001), and basal cell hyperplasia (P = 0.016). Apoptotic bodies were seen in 65 (89%), dyskeratotic cells in 27 (37%) and an ulcer in 28 (37%) of the group 2 cases. The sensitivity (Sn), specificity (Sp), and accuracy (acc) of the group 2 cases for a clinical diagnosis of eGVHD was 68.3%, 60.4%, and 65.4%, respectively. Apoptotic bodies (P = .012) and dyskeratotic cells (P < .001) but not ulceration (P = .881), were associated with a clinical diagnosis of eGVHD. The Sn, Sp, and acc for apoptotic bodies, dyskeratotic cells, and ulcer were 59.3%, 63.8% and 60.9%; 30.9%, 95.7%, and 54.7%; and 21.9%, 79.2%, and 43.1%, respectively. Cases with only apoptotic bodies or ulceration were considered as possible GVHD, and those with dyskeratotic cells as likely GVHD, which were associated with GVHD-specific survival (P = .030). This study provides a comprehensive characterization of the esophageal histologic findings in patients with HSCT. Further studies are needed to corroborate these findings in other patient populations.

Antithymocyte globulin (ATG) has been used to prevent the incidence of graft-versus-host disease (GVHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Low-dose ATG can suppress GVHD without increasing the risk of infectious complications. However, the relationship between ATG exposure and transplant outcomes in low-dose settings remains unclear, particularly in terms of the effect of absolute lymphocyte count (ALC) on its pharmacokinetics. This study aimed to explore the relationship between ATG exposure and transplant outcomes, with a focus on immune reconstitution and GVHD prevention, and to examine whether the pre-ATG ALC could predict ATG exposure in the low-dose setting.

This prospective, multicenter, observational study included 71 patients with hematologic malignancies who underwent peripheral blood stem cell transplantation at six centers between May 2019 and March 2023. The serum concentration of ATG was measured over time. The area under the curve (AUC) was determined, and the correlations with the incidence of GVHD, post-transplant immune recovery, and survival were examined.

Fifty-three of the 71 patients received ATG; the remaining 18 did not. Three distinct patterns of ATG administration were observed: standard (total 2.5 mg/kg: 1.25 mg/kg administered on days-2 and -1), early standard (total 2.5 mg/kg administered before day-2), and early reduced (total 1.25 mg/kg: single dose administered before day-2). Successful immune reconstitution (CD4 ≥ 120/μL at day 60) exhibited correlations with improved relapse-free survival (78.9% vs 47.7%, P = 0.034) and lower relapse rates (4.9% vs 37.2%, P = 0.003). Lower post-transplant AUC (≤ 250 μg/mL/day) exhibited an independent association with successful immune reconstitution (OR = 6.59 [95% CI, 1.23-35.40], P = 0.028). The post-transplant ATG exposure in the early reduced group was lower than those in the standard (P < 0.001) and early standard groups (P = 0.004). The ATG/ALC ratio was strongly correlated with the post-transplant AUC in the early administration groups (Spearman's correlation coefficient = 0.71, P < 0.001). The incidences of grade II-IV acute GVHD (17.1% vs. 39.4%, P = 0.013) and moderate-to-severe chronic GVHD (19.6% vs. 49.4%, P = 0.029) were significantly lower in the ATG group compared to the non-ATG group. The administration methods and ATG exposure levels had no effect on the incidence of GVHD in the ATG group.

Early administration of reduced-dose ATG prevents the incidence of GVHD; furthermore, it potentially optimizes immune reconstitution by lowering post-transplant ATG exposure. The strong correlation between pre-ATG ALC and ATG exposure indicates that ALC-based dosing strategies may be beneficial even in low-dose settings. The ATG/ALC ratio is a practical tool for individualizing ATG dosing during early administration.

The objective of this longitudinal cohort study was to identify predictors of progression to ocular graft-versus-host disease in allogeneic hematopoietic stem cell transplant recipients.

Patients (n = 49) were examined before hematopoietic stem cell transplantation (HSCT) and 3, 6, 12, 24, and 36 months after HSCT. Outcome measures included ocular surface disease index questionnaire, Schirmer I test, corneal fluorescein staining, tear break-up time, and tear cytokine concentration. Diagnosis of ocular GVHD (oGVHD) was made in accordance with the International Consensus Criteria for chronic oGVHD. A group of healthy controls (n = 20) without dry eye disease was recruited for comparison.

At baseline, the intended HSCT group had a lower Schirmer test value, a higher corneal fluorescein staining score, and a lower tear film break-up time compared with the control group. There was no significant difference in ocular surface disease index score. The intended HSCT group had significantly higher tear interleukin (IL)-1, IL-6, IL-8, IL-10, interferon gamma-induced protein (IP)-10, and TNF-α concentrations at baseline. When considering an increase of at least 2 points of the International Consensus Criteria for chronic oGVHD score after HSCT to exclude preexisting dry eye disease, only 19% (n = 7) developed either probable (11%, n = 4) or definite (8%, n = 3) oGVHD. In a longitudinal analysis, a significant association between progression to oGVHD and tear IL-6, IL-8, IL-17A, and IP-10 concentration was detected.

This study highlights the added value of performing a baseline ophthalmological examination in intended HSCT recipients. Posttransplant oGVHD rates may be overestimated if pretransplant ocular surface disease is not considered. Longitudinal tear cytokine analysis in our cohort suggests that IL-6, IL-8, IL-17A, and IP-10 may be useful as biomarkers for oGVHD.

Antithymocyte globulin (ATG) is used in pediatric allogeneic hematopoietic cell transplantation (HCT) to prevent graft-versus-host disease (GVHD) and graft failure (GF). Poor T-cell recovery, associated with increased mortality, is the main toxicity of ATG. Model-based precision dosing of ATG (MBD-ATG) minimizes toxicity while maintaining efficacy. We report updated results of the single-arm phase 2 PARACHUTE trial investigating MBD-ATG, combined with real-world experience using identical MBD-ATG. Consecutive patients receiving a first T-cell-replete HCT for any indication were evaluated. Results were compared with historical patients receiving conventional fixed ATG dosing (FIX-ATG). Primary outcome was overall survival (OS). The MBD-ATG group consisted of 214 patients (58 trial patients; 156 real-world patients); 100 patients received FIX-ATG. MBD-ATG led to superior OS compared with FIX-ATG (hazard ratio [HR] for death, 0.56; 95% confidence interval [CI], 0.34-0.93; P = .026), and lower treatment-related mortality (TRM; HR, 0.51; 95% CI, 0.29-0.92; P = .025). Successful T-cell reconstitution (>0.05 × 109/L CD4+ T cells twice within 100 after HCT) was improved in MBD-ATG vs FIX-ATG (87% ± 2% vs 47% ± 5%; P < .0001). The improved T-cell reconstitution led to lower TRM (HR, 0.19; 95% CI, 0.09-0.36; P < .0001). Incidence of grade 2-4 acute GVHD was comparable, whereas chronic GVHD (HR, 0.35; 95% CI, 0.17-0.72; P = .004) and GF (HR, 0.36; 95% CI, 0.13-0.97; P = .044) were both less frequent in MBD-ATG compared with FIX-ATG. MBD-ATG results in improved OS and reduced TRM, while reducing chronic GVHD and GF. This easy-to-implement approach improves outcomes after pediatric HCT, confirmatory studies are needed. The PARACHUTE trial is registered with the Dutch Trial Register as #NL4836.

Therapeutic drug monitoring of busulfan (Bu) used as conditioning for allogeneic stem cell transplantation (allo-HSCT) is recommended as pharmacokinetics (PK) display variability. Since 2019, we give Bu 1x/d (Bu-Q24) instead of 4x/d (Bu-Q6) for practical convenience, despite limited studies evaluating the best way of application. Our aim was to analyze the correlation between Bu administration (Bu-Q6 versus Bu-Q24), Bu-PK and clinical outcome in 256 adult patients receiving Bu as conditioning regimen for allo-HSCT. This is a retrospective study of adult patients receiving a myeloablative chemotherapeutic regimen containing Bu to treat hematological malignancies. The population was separated into 2 groups according to Bu administration, namely Bu-Q6 and Bu-Q24. A total of 133 patients received Bu-Q6 and 123 Bu-Q24. Bu-Q6 patients were more commonly treated with cyclophosphamide and Bu-Q24 with fludarabin. Bu-Q6 showed lower cumulative area-under-the-curve values than Bu-Q24 (63.78 mg/h/L in Bu-Q6 and 70.12 mg/h/L in Bu-Q24, P = .06). Only 44% of the patients fell within the 1st AUC FDA target range in Bu-Q6 versus 62% in Bu-Q24 (P < .01). Overall, Bu-Q24 appeared to be superior to Bu-Q6 for most outcomes, showing lower incidence of toxicity grade≥II (78% versus 90%, P = .02), with less uro-renal (14% in Bu-Q24 versus 26% in Bu-Q6; P = .02), pulmonary (2% versus 8%, P = .05) and gastro-intestinal toxicities (10% versus 17%, P < .01). Patient receiving Bu-Q24 had fewer infections (51% versus 65%; P = .04), particularly bacterial (33% versus 47%, P = .03) and fungal infections (10% versus 20%; P = .03). At 2 yr, Bu-Q24 tended to have lower treatment-related mortality (5% versus 10%, P = .13), relapse rate (37% versus 42%, P = .55) and incidence of acute and chronic graft-versus-host-disease (24% versus 28%; 32% versus 36%, respectively). The overall survival was 81% (95% CI 74% to 89%) in Bu-Q24 and 69% (95% CI 62% to 77%, P = .03) in Bu-Q6, without impact on the relapse rate or incidence of acute and chronic graft-versus-host-disease. The only benefit of Bu-Q6 was mucositis grade≥III, with an incidence of 36% versus 60% in Bu-Q24 (P < .01). At 2 yr, patients with a cumulative AUC < 59.11 mg/h/L had the lowest TRM, without impact on the OS. Bu clearance was largely influenced by BMI and age > 60 yr. Bu administered once a day shows benefit both in the short and long term compared to Bu administered 4 times a day, but data are heterogeneus, Bu-Q24 being more commonly associated with use of fludarabine, Bu-Q6 with use of cyclophosphamide in this study.

Ocular graft versus host disease (oGVHD) is a common complication of allogeneic hematopoietic stem cell transplantation and may be associated with dry eye disease and chronic inflammation and fibrosis. Immune dysregulation, particularly the Th1/Th2 imbalance, plays a key role in the progression of oGVHD. This case study presents two oGVHD patients (a 20-year-old with acute oGVHD and a 59-year-old with chronic oGVHD), analyzing clinical dry eye parameters (Schirmer test I, tear film break-up time, Ocular Surface Disease Index (OSDI), and kerato-conjunctival staining) alongside tear biomarkers. A 27-plex tear cytokine analysis was performed using the Luminex200 platform, assessing various biomarkers against a control group-defined normal range. Key biomarkers included beta2-microglobulin (β2-MG), complement components, chemokines, growth factors, and both pro-inflammatory and anti-inflammatory cytokines, as well a series of soluble ligand and receptors. The study identified distinct biomarker progression patterns during topical corticosteroid treatment in the acute oGHVD patient, suggesting potential shifts in Th1/Th2 responses as the disease progressed. Notably, the soluble CD27, TNF-related apoptosis-inducing ligand (TRAIL) receptor 2 (TRAIL-R2), chemokine ligand 2 (CCL2), and IL-1β, initially elevated, normalized during treatment, while tear-soluble Fas remained highly elevated (>400-fold). Conversely, soluble TRAIL, which was initially at very low levels (100-fold lower), increased during treatment and reached normal tear levels, coinciding with improvements in the clinical ocular inflammation symptoms and OSDI score. This case study also highlights potential differences between acute and chronic oGVHD, particularly in the distinct patterns of novel tear biomarkers such as CD27, TRAIL/TRAIL-R2, and CCL2. Enhancing our understanding of biomarker dynamics may improve disease monitoring and pave the way for personalized management strategies to improve patient outcomes.

Acute graft versus host disease (aGVHD) is a major complication of hematopoietic stem cell transplantation; it results from donor-derived immune response against host tissues and typically involves the liver, skin and the GI tract. The incidence of acute GVHD is declining due to the advances in HLA typing, reduced intensity conditioning and GVHD prophylaxis. However, corticosteroids remain the mainstay frontline treatment of aGVHD for many decades and as the number of allogeneic transplants continues to increase, there remains a large unmet need to improve frontline treatment for aGVHD. In this review, we outline risk factors, epidemiology and pathogenesis of aGVHD. We discuss the evolving risk stratification, beginning from the initial Gluckesberg system to more recent biomarker-based strategies. We summarize the completed trials that underpin current frontline management and outline future directions.

Although the hematopoietic cell transplantation (HCT)-comorbidity index (HCT-CI) score is associated with an increased risk of mortality after allogeneic HCT, it remains unclear how pre-HCT liver dysfunction affects clinical outcomes. We retrospectively compared clinical HCT outcomes among four groups stratified according to the presence of HCT-CI liver and other organ scores, using a Japan transplant registry database between 2010 and 2020. Of the 14235 recipients, 1527 tested positive for an HCT-CI liver score including HBV or HCV hepatitis (n = 503). The 5-year overall survival (OS) was significantly lower in the HCT-CI liver(+) other(+) and HCT-CI liver(-) other(+) groups compared to the HCT-CI liver(+) other(-) and HCT-CI liver(-) other(-) groups [49.9% vs. 59% vs. 66.5% vs. 68.3%, p < 0.001]. A multivariate analysis showed that both the HCT-CI liver(+) other(+) [HR 1.62, p < 0.001] and HCT-CI liver(-) other(+) groups [HR 1.21, p < 0.001] were significantly associated with inferior OS. Similarly, both the HCT-CI liver(+) other(+) [HR 1.89, p < 0.001] and liver(-) other(+) groups [HR 1.26, p < 0.001] were significantly associated with an increased risk of NRM. On the other hand, the HCT-CI liver(+) other(-) group was not associated with either OS or NRM. Separately analyzing the subcohorts with or without HCT-CI other scores, the presence of an HCT-CI liver score alone did not affect survival, while the co-presence of pretransplant liver dysfunction seemed to synergistically increase the adverse impact on OS and NRM among recipients with other organ comorbidities. Further studies will be needed to identify optimal strategies for recipients with pretransplant liver dysfunction.

Chronic graft-versus-host disease (cGVHD) is a major serious complication after allogeneic stem-cell transplantation (allo-HSCT), and often mimics autoimmune diseases. Central nervous system (CNS) symptoms are rare manifestations of cGVHD, and are difficult to diagnose. CNS manifestations of cGVHD were discussed in the 2020 National Institutes of Health cGVHD Consensus Project as one of the "atypical cGVHD manifestations" with involvement of various organ systems other than classical cGVHD organs. We experienced a case of myelitis after allo-HSCT diagnosed as cGVHD of the CNS. The neurological symptoms progressed after corticosteroid pulse therapy, resulting in severe paralysis and paresthesia of the lower extremities. The clinical course and magnetic resonance imaging findings showed some similarities with multiple sclerosis. We decided to use rituximab after the patient became refractory to corticosteroids because rituximab has been reported to be effective in multiple sclerosis by suppressing B cells on both sides of the blood-brain barrier. Rituximab was effective for the neurologic symptoms in our case. In atypical cGVHD, treatments used in corresponding autoimmune diseases may be reasonable and effective.

Chronic graft-versus-host disease (cGVHD) is the most common cause of late non-relapse mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Rho-associated coiled-coiled kinases (ROCK) inhibitors have been shown to balance the pro-inflammatory and regulatory T-cell subsets in addition to reducing fibrosis in cGVHD, resulting in the development of multiple ROCK2 inhibitors including belumosudil.

We describe the pathophysiology of cGVHD and the role of ROCK2 in cGVHD. This includes a review of the current and ongoing clinical data with belumosudil, and an overview of current ROCK2 inhibitors in development for cGVHD, including rovadicitinib, zelasudil, and GV-101.

Many of the recent novel agents with unique mechanisms such as ROCK2 inhibitors (i.e. belumosudil) provide high response rates but rarely yield complete responses in cGVHD. The future of management of cGVHD will rely on investigating combination therapy upfront that may achieve deeper complete responses, developing newer preventative therapies, and advancements in biomarker detection/risk stratification for cGVHD.

Recto-colic graft-versus-host disease (GVHD) is a frequent and serious complication of hematopoietic stem cell allogeneic transplantation, which is sometimes difficult to diagnose. The aim of our study was to identify histological diagnostic and prognostic criteria for recto-colic GVH.

Patients allografted at Amiens university hospital from 2012 to 2017 were retrieved. Those who had a recto-colic biopsy were included and divided into two groups (final diagnosis of GVH and non-GVH), then biopsies were reviewed by 2 pathologists.

One hundred and nineteen patients were included. Sixty-seven were allocated to the GVH group and 52 to the non-GVH group. In the GVH group, we observed a significantly greater number of apoptotic bodies (AB) on standard HES staining and with the anti-Caspase 3 immunohistochemistry, cryptolytic AB abscesses, atrophy, regenerative glands and glands lined with eosinophilic cells (P<0.001). Anti-Caspase 3 immunohistochemistry revealed more AB than standard HES staining (P<0.005). But to differentiate GVH cases from non-GVH cases, we obtained a threshold value of 3.5 AB per 10 contiguous crypts on standard HE staining and with the anti-Caspase 3 immunohistochemistry. From 4 AB per 10 contiguous crypts, on HES staining and anti-Caspase 3 immunostaining, the diagnosis of GVH became consistent. No non-GVH case had more than 6 AB per 10 contiguous crypts. GVH patients with more than 8 AB per 10 contiguous crypts had a worse prognosis (P<0.001).

We confirm the value of AB and their counting in the diagnosis of GVH, with a diagnostic threshold of 4 AB and a prognostic threshold of 8 AB. Glands lined with eosinophilic cells could be an additional diagnostic criterion in favor of GVH to be confirmed by further studies.

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established curative treatment option for acute myeloid leukemia (AML) in second complete remission (CR2). However, whether the addition of consolidation chemotherapy after achieving CR2 can improve transplant outcomes remains controversial. Methods: In this single-center retrospective study, we analyzed consecutive AML patients who underwent their first HSCT in CR2 at our institution between January 2015 and December 2019. Results: For the consolidation (n = 72) and no consolidation groups (n = 63), the 5-year cumulative incidence of relapse (CIR) was (17.6% vs. 19.9%; p = 0.54), the 5-year non-relapse mortality rate (NRM) was (9.7% vs. 17.5%; p = 0.20), the 5-year leukemia-free survival (LFS) was (72.7% vs. 62.7%; p = 0.15), and the 5-year overall survival (OS) was (81.9% vs. 68.3%; p = 0.08). Additional consolidation therapy to achieve negative measurable residual disease (MRD) did not result in significantly improved outcomes compared to immediate HSCT in MRD positive status, with similar LFS (76.9% vs. 67.0%, p = 0.2) and OS (88.3% vs. 75.0%, p = 0.14). Multivariable analysis indicated that consolidation chemotherapy did not significantly affect CIR, NRM, LFS, or OS. Conclusions: Our findings suggest no significant differences in clinical outcomes between the groups, indicating that AML patients in CR2 might proceed to HSCT without delay.

Despite clinical benefit with the use of chimeric antigen receptor (CAR) T cells, the need to manufacture patient-specific products limits its clinical utility. To overcome this barrier, we developed an allogeneic "off-the-shelf" CAR T-cell product using Epstein-Barr virus (EBV)-specific T cells (EBV-VSTs) genetically modified with a CD19-specific CAR (19-28z). Patients with relapsed/refractory (R/R) B-cell malignancies were stratified into 3 treatment cohorts: cohort 1 (n = 8; disease recurrence after allogeneic or autologous hematopoietic cell transplantation [HCT]), cohort 2 (n = 6; consolidative therapy after autologous HCT), or cohort 3 (n = 2; consolidative therapy after allogeneic HCT). The primary objective of this trial was to determine the safety of multiple CAR EBV-VST infusions. Most patients (n = 12/16) received multiple doses (overall median, 2.5 [range, 1-3]) with 3 × 106 T cells per kg determined to be the optimal dose enabling multiple treatments per manufactured cell line. Severe cytokine release syndrome or neurotoxicity did not occur after infusion, and no dose-limiting toxicity was observed in the trial. Median follow-up was 48 months (range, 4-135) with 4 deaths due to disease progression. Overall survival of all patients was 81% at 12 months and 75% at 36 months. Postinfusion expansion and persistence were limited, and CAR EBV-VSTs demonstrated a unique T-cell phenotype compared with autologous 19-28z CAR T cells. Our study demonstrates the feasibility and safety of an allogeneic "off-the-shelf" CAR EBV-VST product with favorable outcomes for patients with CD19+ R/R B-cell malignancies. This trial was registered at www.ClinicalTrials.gov as #NCT01430390.

Whether patients with acute myeloid leukemia (AML) harboring nucleophosmin mutations (NPM1mut) and measurable residual disease (MRD) should undergo allogeneic stem cell transplantation (allo-SCT) in complete remission (CR) remains debatable. This study assessed whether bone marrow (BM) NPM1mut MRD, detected via quantitative reverse transcription polymerase chain reaction (qRT-PCR) with 10-5 sensitivity, influences allo-SCT benefit. Data from 4 German transplantation centers included 174 patients with AML NPM1mut who underwent first allo-SCT between 2011 and 2022. Among 122 patients transplanted in CR, pre-allo-SCT MRD was positive in 54%. After allo-SCT, BM MRD negativity increased from 65% (day +30) to 73% (day +100), with FMS-like tyrosine kinase 3-internal tandem duplication and ELN risk profile affecting MRD conversion at day +30. No significant difference in leukemia-free survival (LFS) or overall survival (OS) was observed based on pretransplant MRD (3-year LFS MRD positive [MRD+], 60% vs MRD negative [MRD-], 74%; hazard ratio [HR], 1.5; P = .28; 3-year OS MRD+, 68% vs MRD-, 78%; HR, 1.42; P = .39). MRD persistence and molecular relapse outcomes did not differ (P = .8). Adverse molecular risk (HR, 4.69; P = .003) and relapsed/refractory disease (HR, 2.83/3.59; P = .005/0.001) predicted poor prognosis, while posttransplant maintenance improved survival (HR, 0.48; P = .06). Our findings suggest that in patients with NPM1mut AML MRD positivity at transplant, as assessed by qRT-PCR do not experience worse posttransplant outcomes.

To determine the prevalence of ocular graft-versus-host disease after allogeneic hematopoietic stem cell transplantation and to characterize the risk factors associated with its development in a pediatric population.

This retrospective chart review included 105 patients during a five-year period (2013-2017) from the Pediatric Oncology Institute (GRAACC-UNIFESP). The diagnosis of graft-versus-host disease was performed by the treating hematologist in conjunction with an ophthalmologist in accordance to National Institutes of Health (NIH) consensus criteria.

Systemic graft-versus-host disease occurred in 44 of 105 (41.9%) patients, predominantly in males (54.5%) whereas ocular disease was diagnosed in seven (6.7%) of the patients. All the analyzed risk factors including diagnosis, type of conditioning regimen, use of radiotherapy in conditioning, donor sex, type and source of graft, human leukocyte antigen mismatch, and sex mismatch were not statistically significantly associated with the development of ocular disease, except for age. Ocular graft-versus-host disease patients presented a higher mean age compared to patients without ocular disease (p-value = 0.015).

Although less prevalent than in adults, ocular morbidity remains a concern in pediatric patients following allogeneic transplantation. Early diagnosis and regular ophthalmic follow-ups are recommended after the transplantation regardless of systemic graft-versus-host disease status.

Rapid tapering of cyclosporine (CsA) in the early phase after allogeneic transplantation may induce a potent graft-versus-leukemia/lymphoma (GVL) effect. We retrospectively reviewed the outcomes of patients with high-risk hematological malignancies who underwent their first transplantation at our institution. The blood CsA concentration was maintained at around 300 ng/ml. Our planned schedule for tapering CsA in patients without graft-versus-host disease (GVHD) or with limited GVHD was to reduce the dose by 10% per week starting from day 30 for related HSCT or from day 50 for unrelated HSCT. In total, we began tapering CsA in 36, and classified them into 2 an "On-schedule group" or "Delayed group" based on the timing of starting tapering. The cumulative incidences of grade II-IV acute GVHD overall were 33.8% and 39.4% (P = 0.746) in the On-schedule and Delayed groups. The On-schedule group showed no significant difference in non-relapse mortality, but showed a trend toward a higher relapse rate, resulting in significantly worse overall survival (55.6% vs 72.2% at 1y, P = 0.025) and worse disease-free survival (38.9% vs 66.7% at 1y, P = 0.059). These findings suggest that early CsA tapering after HSCT in high-risk patients was not effective.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative approach for many hematologic disorders, and donor cell leukemia (DCL) remains a complication rarely observed after HSCT. The number of reported cases of DCL slightly exceeds 100, with acute myeloid leukemia (AML) being the most common type. To date, only a few cases of chronic lymphocytic leukemia (CLL) emerging from donor cells have been described in the literature. Here, we report two cases of CLL of donor origin, which emerged in patients after HSCT for AML. In the reported cases, patients maintained complete remission of AML after HSCT. Both donors were free of CLL before transplantation. Several years after HSCT (9 and 3 years, respectively), lymphocytosis with proven B-cell clonality was detected in recipients prompting a detailed blood analysis to be performed also in donors. CLL population was demonstrated in both cases. The first donor-recipient pair did not meet criteria for CLL treatment and eventually died from causes not related to underlying hematologic malignancy. The second couple received Bruton's tyrosine kinase inhibitors with good disease control. The presented cases raise the question of possible clonal evolution of B-lymphocytes in donor-origin cells. Prospective screening of potential donors for pre-malignant alterations remains a matter of discussion.

Haploidentical stem cell transplantation (haplo-HSCT) has demonstrated promising results in patients without severe comorbidities. There is also an increasing need for haplo-HSCT in patients with severe comorbidities. However, the high risk of treatment-related mortality (TRM) hindered its extensive application. We aimed to investigate a novel conditioning regimen (Bu/Flu/Cy/ATG) followed by haplo-HSCT in patients with severe comorbidities.

This prospective, single-arm clinical trial was performed at Peking University Institute of Hematology, China. Patients were enrolled if they were (1) diagnosed with acute leukemia, myelodysplastic syndrome (MDS), or chronic myelomonocytic leukemia (CMML); (2) patients with no HLA-matched sibling donor or matched unrelated donor available but with a haplo-HSCT donor; (3) patients with hematopoietic cell transplantation comorbidity index (HCT-CI) scores ≥3. The primary endpoint was 2-year TRM.

From June 2018 to November 2022, a total of 72 patients were enrolled. All patients achieved neutrophil engraftment. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) at day 100 was 20.8%. The cumulative incidences of cytomegalovirus (CMV) viremia and Epstein‒Barr (EB) viremia at day 100 were 72.2% and 31.9%, respectively. The cumulative incidence of 2-year TRM was 25.1%. The cumulative incidence of 2-year relapse was 8.6%. The probabilities of 2-year overall survival and leukemia-free survival were 71.9% and 65.6%, respectively.

This study suggested that a novel conditioning regimen followed by haploidentical HSCT might be a promising option for patients with severe comorbidities. The study was registered as a clinical trial (NCT03412409).

Allogeneic stem cell transplantation (alloSCT) represents a curative option for patients with relapsed/refractory (r/r) aggressive lymphomas. We compared outcomes of alloSCT in r/r PTCL and r/r DLBCL pts (n = 150) who underwent identical myeloablative conditioning chemotherapy, GvHD prophylaxis, and relapse management. 5-year PFS and OS were significantly superior in PTCL compared to DLBCL (56% vs. 24%; 56% vs. 28%; p ≤ 0.005). A landmark analysis (day≥ +100 post-alloSCT) markedly favored outcomes in PTCL vs. DLBCL: 5-year PFS and OS of 76% vs. 30% and 76% and 35%, respectively (p ≤ 0.003). Non-relapse mortality was comparable (35% PTCL vs. 34% DLBCL, p = 0.894), whereas post-alloSCT relapse mortality was significantly higher in DLBCL (36% vs. 10%, p = 0.0007). The occurence of limited chronic GvHD did not improve outcomes in DLBCL, whereas extensive chronic GvHD was a negative risk factor for both (HR 2.09 and 2.80, p ≤ 0.006). In conclusion, we gained evidence for strong graft-versus-lymphoma activity against PTCL but not DLBCL.