Outcome of Children Developing Grade III-IV Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

Acute graft versus host disease (aGvHD) remains one of the major causes of procedure-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Information on the outcome of pediatric patients experiencing this complication is limited. We conducted a retrospective registry-based analysis on children who developed grade III-IV acute GVHD and were reported to the European Blood and Marrow Transplantation (EBMT) registry. Included in the study were children below age of 18 years who were transplanted between 2004 and 2016 (n=28109). Of these children, 1968 experienced grade III-IV acute GvHD: 1370 were had malignancies, while 598 were affected by a non-malignant disorder (NMD). Median year at HSCT was 2009 for patients with malignancies and 2010 for patients with NMD. In this latter group, as expected, the median age at HSCT was lower (5.8 years), in comparison with those affected by malignancies (9 years). The donor was an HLA-identical sibling in 576 cases and an unrelated donor in 895 cases. Umbilical cord blood (UCB) was employed in 282 cases, while a relative other than a compatible sibling in 215 cases. Overall, 1075 patients were given bone marrow (BM), while 598 received peripheral blood stem cells (PBSC). A fully myeloablative conditioning regimen has been employed in 94% of patients with malignancies in comparison with 75% of children with NMD. As a post-transplant pharmacological GvHD prophylaxis, a different strategy of immune suppressive treatment have been used: it consisted in the association of Cyclosporine-A (CSA) and Methotrexate in 40%, CSA alone in 30% and CSA plus Mycophenolate mofetil in 10% of patients. Grade III aGvHD occurred in 1383 patients (70%), while grade IV aGvHD was diagnosed in 585 (30%). Chronic GvHD occurred in 48.2% and 49.3% of patients with malignant and NMD, respectively. It was extensive in 262 (26.8%) patients with malignancies and in 111 (28%) children affected by NMD. Within patients with malignancies, the 2-year Kaplan-Meyer probability of overall survival (OS) was 65.7% (confidence interval 95, 63 - 68.4). In this group, the cumulative incidence of non-relapse mortality (NRM) was 23.1%. Notably, the occurrence of GvHD was responsible of death in 228 patients (CI 14.5%). In the NMD cohort, the 2-year Kaplan-Meyer probability of overall survival (OS) was 67.8% (confidence interval 95, 63.8 - 71.9). Sixty-one patients died to GvHD, being the 2-year cumulative incidence of GvHD-related mortality 19%. These data indicate that the occurrence of grade III-IV aGVHD is associated with a dismal outcome also in pediatric patients. The main cause of fatality is represented by NRM, while leukemia recurrence affected outcome of a lower number of children. Thus, strategies aimed at preventing this immune-mediated complication and at optimizing its treatment are desirable

Management of upper gastrointestinal bleeding in emergency departments, from bleeding symptoms to diagnosis: a prospective, multicenter, observational study.

BACKGROUND: Upper gastrointestinal bleeding (UGB) is common in emergency departments (EDs) and can be caused by many eso-gastro-duodenal lesions. Most available epidemiological data and data on the management of UGB comes from specialized departments (intensive care units or gastroenterology departments), but little is known from the ED perspective. We aimed to determine the distribution of symptoms revealing UGB in EDs and the hemorrhagic lesions identified by endoscopy. We also describe the characteristics of patients consulting for UGB, UGB management in the ED and patients outcomes. METHOD: This was a prospective, observational, multicenter study covering 4 consecutive days in November 2013. Participating EDs were part of the Initiatives de Recherche aux Urgences network coordinated by the French Society of Emergency Medicine. All patients with suspected UGB in these EDs were included. RESULTS: In total, 110 EDs participated, including 194 patients with suspected UGB (median age 66 years [Q1-Q3: 51-81]). Overall, 104 patients (54%) had hematemesis and 75 (39%) melena. Endoscopy revealed lesions in 121 patients, mainly gastroduodenal ulcer or ulcerations (41%) or bleeding lesions due to portal hypertension (20%). The final diagnosis of UGB was reversed by endoscopy in only 3% of cases. Overall, 67 patients (35%) had at least one severity sign. Twenty-one patients died (11%); 40 (21%) were hospitalized in intensive care units and 126 (65%) in medicine departments; 28 (14%) were outpatients. Mortality was higher among patients with clinical and biological severity signs. CONCLUSION: Most of the UGB cases in EDs are revealed by hematemesis. The emergency physician diagnosis of UGB is rarely challenged by the endoscopic findings

Outcomes of Unmanipulated Haploidentical Transplantation Using Post-Transplant Cyclophosphamide (PT-Cy) in Pediatric Patients With Acute Lymphoblastic Leukemia

HLA-haploidentical transplantation (haplo-HCT) using post-transplantation-cyclophosphamide (PT-Cy) is a feasible procedure in children with malignancies. However, large studies on Haplo-HCT with PT-Cy for childhood acute lymphoblastic leukemia (ALL) are lacking. We analyzed haplo-HCT outcomes in 180 children with ALL. Median age was 9 years, and median follow-up was 2.7 years. Disease status was CR1 for 24%, CR2 for 45%, CR+3 for 12%, and active disease for 19%. All patients received PT-Cy day +3 and +4. Bone marrow (BM) was the stem cell source in 115 patients (64%). Cumulative incidence of 42-day engraftment was 88.9%. Cumulative incidence of day-100 acute graft-versus-host disease (GVHD) grade II-IV was 28%, and 2-year chronic GVHD was 21.9%. At 2 years, cumulative incidence of nonrelapse mortality (NRM) was 19.6%. Cumulative incidence was 41.9% for relapse and 25% for patients in CR1. Estimated 2-year leukemia free survival was 65%, 44%, and 18.8% for patients transplanted in CR1, CR2, CR3+ and 3% at 1 year for active disease. In multivariable analysis for patients in CR1 and CR2, disease status (CR2 [hazard ratio {HR} = 2.19; P = .04]), age at HCT older than 13 (HR = 2.07; P = .03) and use of peripheral blood stem cell (PBSC) (HR = 1.98; P = .04) were independent factors associated with decreased overall survival. Use of PBSC was also associated with higher NRM (HR = 3.13; P = .04). Haplo-HCT with PT-Cy is an option for children with ALL, namely those transplanted in CR1 and CR2. Age and disease status remain the most important factors for outcomes. BM cells as a graft source is associated with improved survival

Comorbidities in transplant recipients with acute myeloid leukemia receiving low-intensity conditioning regimens: an ALWP EBMT study

Older age and a high burden of comorbidities often drive the selection of low-intensity conditioning regimens in allogeneic hematopoietic stem cell transplantation recipients. However, the impact of comorbidities in the low-intensity conditioning setting is unclear. We sought to determine the contribution of individual comorbidities and their cumulative burden on the risk of nonrelapse mortality (NRM) among patients receiving low-intensity regimens. In a retrospective analysis of adults (≥18 years) who underwent transplantation for acute myeloid leukemia in the first complete remission between 2008 and 2018, we studied recipients of low-intensity regimens as defined by the transplantation conditioning intensity (TCI) scale. Multivariable Cox models were constructed to study associations of comorbidities with NRM. Comorbidities identified as putative risk factors in the low-TCI setting were included in combined multivariable regression models assessed for overall survival, NRM, and relapse. A total of 1663 patients with a median age of 61 years received low-TCI regimens. Cardiac comorbidity (including arrhythmia/valvular disease) and psychiatric disease were associated with increased NRM risk (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.13-2.09 and HR, 1.69; 95% CI, 1.02-2.82, respectively). Moderate pulmonary dysfunction, though prevalent, was not associated with increased NRM. In a combined model, cardiac, psychiatric, renal, and inflammatory bowel diseases were independently associated with adverse transplantation outcomes. These findings may inform patient and regimen selection and reinforce the need for further investigation of cardioprotective transplantation approaches.</p

Continuously improving outcome over time after second allogeneic stem cell transplantation in relapsed acute myeloid leukemia: an EBMT registry analysis of 1540 patients

Second allogeneic stem cell transplantation (alloSCT2) is among the most effective treatments for acute myeloid leukemia (AML) relapse after first alloSCT (alloSCT1). Long-term EBMT registry data were used to provide large scale, up-to-date outcome results and to identify factors for improved outcome. Among 1540 recipients of alloSCT2, increasing age, better disease control and performance status before alloSCT2, more use of alternative donors and higher conditioning intensity represented important trends over time. Between the first (2000–2004) and last (2015–2019) period, two-year overall and leukemia-free survival (OS/LFS) increased considerably (OS: 22.5–35%, LFS: 14.5–24.5%). Cumulative relapse incidence (RI) decreased from 64% to 50.7%, whereas graft-versus-host disease and non-relapse mortality (NRM) remained unchanged. In multivariable analysis, later period of alloSCT2 was associated with improved OS/LFS (HR = 0.47/0.53) and reduced RI (HR = 0.44). Beyond, remission duration, disease stage and patient performance score were factors for OS, LFS, RI, and NRM. Myeloablative conditioning for alloSCT2 decreased RI without increasing NRM, leading to improved OS/LFS. Haploidentical or unrelated donors and older age were associated with higher NRM and inferior OS. In summary, outcome after alloSCT2 has continuously improved over the last two decades despite increasing patient age. The identified factors provide clues for the optimized implementation of alloSCT2

Post-transplant cyclophosphamide after matched sibling, unrelated and haploidentical donor transplants in patients with acute myeloid leukemia: a comparative study of the ALWP EBMT

BACKGROUND: The use of post-transplant cyclophosphamide (PTCy) is highly effective in preventing graft-versus-host disease (GVHD) in the haploidentical (Haplo) transplant setting and is being increasingly used in matched sibling (MSD) and matched unrelated (MUD) transplants. There is no information on the impact of donor types using homogeneous prophylaxis with PTCy. METHODS: We retrospectively compared outcomes of adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) who received a first allogeneic stem cell transplantation (SCT) with PTCy as GVHD prophylaxis from MSD (n = 215), MUD (n = 235), and Haplo (n = 789) donors registered in the EBMT database between 2010 and 2017. RESULTS: The median follow-up was 2 years. Haplo-SCT carried a significantly increased risk of acute grade II-IV GVHD (HR 1.6; 95% CI 1.1-2.4) and NRM (HR 2.6; 95% CI 1.5-4.5) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9) that translated to no differences in LFS (HR 1.1; 95% CI 0.8-1.4) or GVHD/relapse-free survival (HR 1; 95% CI 0.8-1.3). Interestingly, the use of peripheral blood was associated with an increased risk of acute (HR 1.9; 95% CI 1.4-2.6) and chronic GVHD (HR 1.7; 95% CI 1.2-2.4) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9). CONCLUSIONS: The use of PTCy in patients with AML in CR1 receiving SCT from MSD, MUD, and Haplo is safe and effective. Haplo-SCT had increased risk of acute GVHD and NRM and lower relapse incidence but no significant difference in survival

Hematopoietic stem cell transplantation for DLBCL: a report from the European Society for Blood and Marrow Transplantation on more than 40,000 patients over 32 years

Autologous(auto-) and allogeneic(allo-) hematopoietic stem cell transplantation (HSCT) are key treatments for relapsed/refractory diffuse large B-cell lymphoma (DLBCL), although their roles are challenged by CAR-T-cells and other immunotherapies. We examined the transplantation trends and outcomes for DLBCL patients undergoing auto-/allo-HSCT between 1990 and 2021 reported to EBMT. Over this period, 41,148 patients underwent auto-HSCT, peaking at 1911 cases in 2016, while allo-HSCT saw a maximum of 294 cases in 2018. The recent decline in transplants corresponds to increased CAR-T treatments (1117 cases in 2021). Median age for auto-HSCT rose from 42 (1990-1994) to 58 years (2015-2021), with peripheral blood becoming the primary stem cell source post-1994. Allo-HSCT median age increased from 36 (1990-1994) to 54 (2015-2021) years, with mobilized blood as the primary source post-1998 and reduced intensity conditioning post-2000. Unrelated and mismatched allo-HSCT accounted for 50% and 19% of allo-HSCT in 2015-2021. Three-year overall survival (OS) after auto-HSCT improved from 56% (1990-1994) to 70% (2015-2021), p 40,000 transplants, providing insights for evaluating emerging DLBCL therapies

Allogeneic transplantation in acute myelogenous leukemia: a comprehensive single institution's experience

Debates on the role and timing of allogeneic hemtopoietic stem cell transplantation (HSCT) in acute myelogenous leukemia (AML) have persisted for decades. Time to transplant introduces an immortal time and current treatment algorithm mainly relies on the European LeukemiaNet disease risk classification. Previous studies are also limited to age groups, remission status and other ill-defined parameters. We studied all patients at diagnosis irrespective of age and comorbidities to estimate the cumulative incidence and potential benefit or disadvantage of HSCT in a single center. As a time-dependent covariate, HSCT improved overall survival in intermediate- and poor-risk patients (hazard ratio =0.51; P=0.004). In goodrisk patients only eight were transplanted in first complete remission. Overall, the 4-year cumulative incidence of HSCT was only 21.9% but was higher (52.1%) for patients in the first age quartile (16-57 years old) and 26.4% in older patients (57-70 years old) (P<0.001). It was negligible in patients older than 70 years reflecting our own transplant policy but also barriers to transplantation (comorbidities and remission status). However, HSCT patients need to survive, be considered eligible both by the referring and the HSCT physicians and have a suitable donor to get transplantation. We, thus, comprehensively analyzed the complete decision-making and outcome of all our AML patients from diagnosis to last followup to decipher how patient allocation and therapy inform the value of HSCT. The role of HSCT in AML is shifting with broad access to different donors including haploidentical ones. Thus, it may (or may not) lead to increased numbers of allogeneic HSCT in AML in adults

Matched unrelated donor transplantation versus haploidentical transplantation with post-transplant cyclophosphamide in children with acute myeloid leukemia: a PDWP-EBMT study

In children with acute myeloid leukemia (AML) who lack an HLA identical sibling, the donor can be replaced with an HLA matched unrelated donor (MUD) or a haploidentical donor (haplo). We compared outcomes of patients <18 years with AML in first and second complete remission (CR1 & CR2) undergoing a hematopoietic stem cell transplantation (HCT) either with a MUD with anti-thymocyte globuline (ATG) (n=420) or a haplo HCT with PT-CY (n=96) after a myeloablative conditioning regimen (MAC) between 2011 and 2021, reported to EBMT. A matched pair analysis was performed to adjust for differences among groups. The final analysis was performed on 253 MUD and 95 haplo-HCTs. In the matched cohort, median age at HCT was 11.2 and 10 years and median year of HCT was 2017 and 2018, in MUD and haplo- HCT recipients, respectively. The risk of grade III-IV aGvHD was significantly higher in the haplo group (HR=2.33, 95%CI1.18-4.58, p=0.03). No significant differences were found in 2 years overall survival (OS; 78.4%vs71.5%; HR 1.39, 0.84-2.31, p=0.19), leukemia-free-survival (LFS; 72.7%vs69.5%; HR1.22, 0.76-1.95, p=0.41), CI of relapse (RI; 19.3%vs19.5%; HR=1.14, 0.62-2.08, p=0.68) non-relapse-mortality (NRM; 8%vs11%; HR=1.39, 0.66-2.93, p=0.39) and graft versus host free-relapse free survival (GRFS; 60.7%vs54.5%, HR=1.38, 0.95-2.02, p=0.09) after MUD and haplo-HCT respectively. Our study suggests that haplo-HCT with PT-CY is a suitable option to transplant children with AML lacking a matched related donor

Heckman imputation models for binary or continuous MNAR outcomes and MAR predictors

Abstract Background Multiple imputation by chained equations (MICE) requires specifying a suitable conditional imputation model for each incomplete variable and then iteratively imputes the missing values. In the presence of missing not at random (MNAR) outcomes, valid statistical inference often requires joint models for missing observations and their indicators of missingness. In this study, we derived an imputation model for missing binary data with MNAR mechanism from Heckman’s model using a one-step maximum likelihood estimator. We applied this approach to improve a previously developed approach for MNAR continuous outcomes using Heckman’s model and a two-step estimator. These models allow us to use a MICE process and can thus also handle missing at random (MAR) predictors in the same MICE process. Methods We simulated 1000 datasets of 500 cases. We generated the following missing data mechanisms on 30% of the outcomes: MAR mechanism, weak MNAR mechanism, and strong MNAR mechanism. We then resimulated the first three cases and added an additional 30% of MAR data on a predictor, resulting in 50% of complete cases. We evaluated and compared the performance of the developed approach to that of a complete case approach and classical Heckman’s model estimates. Results With MNAR outcomes, only methods using Heckman’s model were unbiased, and with a MAR predictor, the developed imputation approach outperformed all the other approaches. Conclusions In the presence of MAR predictors, we proposed a simple approach to address MNAR binary or continuous outcomes under a Heckman assumption in a MICE procedure