Epidemiology of Diffuse Alveolar Hemorrhage in Pediatric Allogeneic Hematopoietic Cell Transplantation Recipients.

Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary toxicity that can arise after hematopoietic cell transplantation (HCT). Risk factors and outcomes are not well understood owing to a sparsity of cases spread across multiple centers. The objectives of this epidemiologic study were to characterize the incidence, outcomes, transplantation-related risk factors and comorbid critical care diagnoses associated with post-HCT DAH. Retrospective analysis was performed in a multicenter cohort of 6995 patients age ≤21 years who underwent allogeneic HCT between 2008 and 2014 identified through the Center for International Blood and Marrow Transplant Research registry and cross-matched with the Virtual Pediatric Systems database to obtain critical care characteristics. A multivariable Cox proportional hazard model was used to determine risk factors for DAH. Logistic regression models were used to determine critical care diagnoses associated with DAH. Survival outcomes were analyzed using both a landmark approach and Cox regression, with DAH as a time-varying covariate. DAH occurred in 81 patients at a median of 54 days post-HCT (interquartile range, 23 to 160 days), with a 1-year post-transplantation cumulative incidence probability of 1.0% (95% confidence interval [CI], .81% to 1.3%) and was noted in 7.6% of all pediatric intensive care unit patients. Risk factors included receipt of transplantation for nonmalignant hematologic disease (reference: malignant hematologic disease; hazard ratio [HR], 1.98; 95% CI, 1.22 to 3.22; P = .006), use of a calcineurin inhibitor (CNI) plus mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis (referent: CNI plus methotrexate; HR, 1.89; 95% CI, 1.07 to 3.34; P = .029), and grade III-IV acute GVHD (HR, 2.67; 95% CI, 1.53-4.66; P < .001). Critical care admitted patients with DAH had significantly higher rates of systemic hypertension, pulmonary hypertension, pericardial disease, renal failure, and bacterial/viral/fungal infections (P < .05) than those without DAH. From the time of DAH, median survival was 2.2 months, and 1-year overall survival was 26% (95% CI, 17% to 36%). Among all HCT recipients, the development of DAH when considered was associated with a 7-fold increase in unadjusted all-cause post-HCT mortality (HR, 6.96; 95% CI, 5.42 to 8.94; P < .001). In a landmark analysis of patients alive at 2 months post-HCT, patients who developed DAH had a 1-year overall survival of 33% (95% CI, 18% to 49%), compared to 82% (95% CI, 81% to 83%) for patients without DAH (P < .001). Although DAH is rare, it is associated with high mortality in the post-HCT setting. Our data suggest that clinicians should have a heightened index of suspicion of DAH in patients with pulmonary symptoms in the context of nonmalignant hematologic indication for HCT, use of CNI + MMF as GVHD prophylaxis, and severe acute GVHD. Further investigations and validation of modifiable risk factors are warranted given poor outcomes.

Cheng G ，Smith MA ，Phelan R ，Brazauskas R ，Strom J ，Ahn KW ，Hamilton B ，Peterson A ，Savani B ，Schoemans H ，Schoettler M ，Sorror M ，Higham C ，Kharbanda S ，Dvorak CC ，Zinter MS ... -  《-》

Incidence and Impact of Fungal Infections in Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis and Haploidentical Hematopoietic Cell Transplantation: A Center for International Blood and Marrow Transplant Research Analysis.

Fungal infection (FI) after allogeneic hematopoietic cell transplantation (HCT) is associated with increased morbidity and mortality. Neutropenia, HLA mismatch, graft-versus-host disease (GVHD), and viral infections are risk factors for FI. The objectives of this Center for International Blood and Marrow Transplant Research registry study were to compare the incidence and density of FI occurring within 180 days after HCT in matched sibling (Sib) transplants with either calcineurin inhibitor (CNI)-based or post-transplantation cyclophosphamide (PTCy)-based GVHD prophylaxis and related haploidentical transplants receiving PTCy, and to examine the impact of FI by day 180 on transplantation outcomes. Patients who underwent their first HCT between 2012 and 2017 for acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome and received a related haploidentical transplant with PTCy (HaploCy; n = 757) or a Sib transplant with PTCy (SibCy; n = 403) or CNI (SibCNI; n = 1605) were analyzed. The incidence of FI by day 180 post-HCT was calculated as cumulative incidence with death as the competing risk. The associations of FI with overall survival, transplant-related mortality, chronic GVHD, and relapse at 2 years post-HCT were examined in Cox proportional hazards regression models. Factors significantly associated with the outcome variable at a 1% level were kept in the final model. By day 180 post-HCT, 56 (7%) HaploCy, 24 (6%), SibCy, and 59 (4%) SibCNI recipients developed ≥1 FI (P < .001). The cumulative incidence of yeast FI was 5.2% (99% confidence interval [CI], 3.3% to 7.3%) for HaploCy, 2.2% (99% CI, .7% to 4.5%) for SibCy, and 1.9% (99% CI, 1.1% to 2.9%) for SibCNI (P = .001), and that of mold FI was 2.9% (99% CI, 1.5% to 4.7%), 3.7% (99% CI, 91.7% to 6.6%), and 1.7% (99% CI, 1.0% to 2.6%), respectively (P = .040). FI was associated with an increased risk of death, with an adjusted hazard ratio (HR) of 4.06 (99% CI, 2.2 to 7.6) for HaploCy, 4.7 (99% CI, 2.0 to 11.0) for SibCy, and 3.4 (99% CI, 1.8 to 6.4) for SibCNI compared with SibCNI without FI (P < .0001 for all). Similar associations were noted for transplantation-related mortality. FI did not impact rates of relapse or chronic GVHD. Rates of FI by day 180 ranged between 1.9% and 5.2% for yeast FI and from 1.7% to 3.7% for mold FI across the 3 cohorts. The use of PTCy was associated with higher rates of yeast FI only in HaploHCT and with mold FI in both HaploHCT and SibHCT. The presence of FI by day 180 was associated with increased risk for overall mortality and transplant-related mortality at 2 years regardless of donor type or PTCy use. Although rates of FI were low with PTCy, FI is associated with an increased risk of death, underscoring the need for improved management strategies.

Papanicolaou GA ，Chen M ，He N ，Martens MJ ，Kim S ，Batista MV ，Bhatt NS ，Hematti P ，Hill JA ，Liu H ，Nathan S ，Seftel MD ，Sharma A ，Waller EK ，Wingard JR ，Young JH ，Dandoy CE ，Perales MA ，Chemaly RF ，Riches M ，Ustun C ... -  《-》

Venous Thromboembolism Incidence and Risk Factors in Patients Undergoing Hematopoietic Stem Cell Transplantation.

Malignancy is a well-known risk factor for venous thromboembolism (VTE), and the Khorana risk score is effective for screening patients with solid tumors. However, there is a lack of validated screening tools and established risk factors for patients undergoing hematopoietic stem cell transplantation (HCT). Current literature reports a 2.5% to 8.5% incidence of VTE in HCT recipients. Anticoagulation is difficult to manage post-transplantation, given prolonged thrombocytopenia and the likelihood of bleeding. By identifying risk factors, a predictive model may be developed to prospectively test prophylaxis strategies in patients at the highest risk of a thromboembolic event (TE). This retrospective single-center study evaluated the cumulative incidence of TE at 6 months following allogeneic or autologous HCT in adult subjects undergoing transplantation between March 2014 and December 2019. The study also aimed to identify risk factors for developing a TE, evaluate the time from HCT to TE, and compare 1-year survival following HCT between patients with a TE and those without a TE. In evaluating the incidence of TE, ICD-9 and ICD-10 codes were used to determine cancer diagnosis, TE events occurring up 180 days after HCT, and comorbidities of interest. Each subject was reviewed for data accuracy by a manual retrospective chart review. Statistical tests including the cumulative incidence method with competing risks, Gray's test, and univariate and multivariate Cox proportional hazards models were used to analyze the time to first TE, evaluate risk factors, and assess 1-year survival post-HCT in relation to TEs occurring within 180 days of HCT. Variables examined included age, sex, body mass index, transplant type, hospital length of stay (LOS), history of TE prior to transplantation, active infections, graft-versus-host disease (GVHD), veno-occlusive disorder, cytomegalovirus serostatus, and other factors. The study included 636 evaluable patients; the majority were male (57.9%) and white (68.7%) and had undergone autologous HCT (68.4%). Twenty-nine patients (4.6%) experienced a TE within 180 days post-transplantation. TEs were more common in the allogeneic HCT recipients (n = 13/201; 6.5%) compared to the autologous HCT recipients (n = 16/435; 3.7%; P = .122). The cumulative incidence of TE was higher in patients who developed an active infection compared to those who did not (7.6% versus 3.1%; P = .011). Hospital LOS (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.0 to 1.06; P = .036) and active infection (HR, 2.34; 95% CI, 1.1 to 4.95; P = .027) were significantly associated with TE in univariate analysis but were not retained in the final multivariate model. There was no difference in 1-year survival between all patients who experienced a TE and those who did not; however, in the autologous HCT group, 1-year survival rate was significantly lower in patients with a TE compared to those without TE (80.4% versus 95.3%; P = .01) (Figure 3C). None of the examined variables, including a history of TE and GVHD, were associated with TE risk. Although the overall incidence of TE in our study was low, many patients received pharmacologic or mechanical prophylaxis, suggesting that such strategies may be effective in mitigating TE risk. Such factors as infection and hospital LOS may further increase TE risk. Providers should continuously monitor for risk factors and signs and symptoms of TE post-transplantation. It is also imperative to consider chemical prophylaxis if counts are recovered during hospitalization.

Benfield M ，He J ，Arnall J ，Kaizen W ，Jandrisevits E ，Eboli-Lopes K ，Dodd B ，Grunwald MR ，Avalos B ，Copelan E ，Patel JN ... -  《-》

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.

Kiene S ，Albrecht M ，Theurich S ，Scheid C ，Skoetz N ，Holtick U ... -  《Cochrane Database of Systematic Reviews》

Uniform Graft-versus-Host Disease Prophylaxis using Post-Transplantation Cyclophosphamide, Methotrexate, and Cyclosporine following Peripheral Blood Hematopoietic Stem Cell Transplantation from Matched and Haploidentical Donors for Transfusion-Dependent T

Although the survival of patients with transfusion-dependent thalassemia (TD-TM) is reportedly inferior after haploidentical hematopoietic stem cell transplantation (HSCT), the heterogeneity of transplantation approaches in studies suggests the need to assess the effect of conditioning regimen on matched and haploidentical transplantation outcomes. A novel post-transplantation cyclophosphamide (PTCy)-based approach for patients with TD-TM undergoing haploidentical HSCT was reported in our prior study. Here we aimed to retrospectively evaluate the real-world efficacy and safety of graft-versus-host disease (GVHD) prophylaxis in patients with TD-TM after HSCT from matched donors and haploidentical donors (HIDs). In this retrospective multicenter study, among 238 patients with TD-TM who underwent HSCT, 160 underwent peripheral blood HSCT, using uniform GVHD prophylaxis with PTCy, methotrexate, and cyclosporine, at member centers of the Bone Marrow Failure Working Group of Hunan Province between 2019 and 2023. The median age of the cohort at transplantation was 6 years (95% confidence interval [CI], 6 to 7 years). The 160 donors included 99 (61.9%) haploidentical family members, 13 matched sibling donors, and 48 matched or mismatched unrelated donors. The engraftment rate was 98.8% (95% CI, 96.1% to 97.7%). HSCT from HIDs had a lower risk of mixed chimerism (HR, .078; P = .022). Within 100 days after transplantation, 31 patients (19.6%; 95% CI, 14.0% to 26.3%) had grade II-IV acute GVHD (aGVHD), 9 of whom had grade III-IV aGVHD (5.7%; 95% CI, 2.9% to 10.1%). HIDs were significantly associated with a higher risk of grade II-IV aGVHD (HR, 3.973; P = .009). Nineteen patients (11.9%; 95% CI, 7.6% to 17.6%) developed late aGVHD after a median of 516 days (95% CI, 407 to 709 days). Twenty-six patients (16.5%; 95% CI, 11.3% to 22.8%) exhibited any 1 of the diagnostic, distinctive, or atypical features of chronic GVHD (cGVHD) according to the 2014 National Institutes of Health (NIH) criteria after a median of 690 days (95% CI, 496 to 902 days). Among these 26 patients, 7 had NIH-defined cGVHD, 14 had only 1 distinctive sign with no histologic evidence, and 5 had only atypical cGVHD signs. Of the 26 patients, 5 were classified with overlap syndrome. Of 21 patients classified with NIH-defined and potential cGVHD, 3 had moderate cGVHD and 1 had severe cGVHD. Logistic regression analyses identified that grade II-IV aGVHD independently predicted subsequent cGVHD (HR, 3.920; P = .006). The rates of cGVHD were similar in the matched donor and HID groups. Thalassemia-free survival (TFS) and event-free survival (EFS) were 97.5% (95% CI, 94.2% to 99.2%) and 90.6% (95% CI, 85.4% to 94.4%), respectively, after a median of 690 days (95% CI, 496 to 902 days). TFS rates were similar in the matched donor and HID groups (P = .549). The EFS rate was significantly higher in the matched donor group compared to the HID group (P = .033). Our study suggests that when PTCy-based uniform GVHD prophylaxis is administered, HSCT from matched donors and HIDs results in a low incidence of severe GVHD and treatment-related mortality with satisfactory survival.

Gong S ，Tian X ，Yang R ，Yang L ，Wang Z ，Yang K ，Chen K ，He X ，Deng W ，Yang X ，Lei M ，Fu B ... -  《-》