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Summary: The objective of this study was to identify independent prognostic factors of viral encephalitis (VE) after allogeneic haematopoietic stem cell transplantation (allo‐HSCT) and establish a prognostic model to identify post‐transplant VE patients with a greater likelihood of mortality. Among 5380 patients in our centre from 2014 to 2022, 211 patients who developed VE after allo‐HSCT were reviewed in this retrospective study. Prognostic factors were selected, and a prognostic model was constructed using Cox regression analysis. The model was subsequently validated and estimated using the area under the receiver operating characteristic curve (AUC), a calibration plot and decision curve analysis (DCA). Glasgow Coma Scale score <9, lesions >3 lobes on magnetic resonance imaging and severe thrombocytopenia were identified as independent prognostic risk factors for VE patients who underwent allo‐HSCT. The prognostic model GTM (GTM is an abbreviation for a model composed of three risk factors: GCS score <9, severe thrombocytopenia [platelet count <20 000 per microliter], and lesions >3 lobes on MRI) was established according to the regression coefficients. The validated internal AUC was 0.862 (95% confidence interval [CI], 0.773–0.950), and the external AUC was 0.815 (95% CI, 0.708–0.922), indicating strong discriminatory ability. Furthermore, we constructed calibration plots that demonstrated good consistency between the predicted outcomes and the observed outcomes. DCA exhibited high accuracy in this system, leading to potential benefits for patients. [ABSTRACT FROM AUTHOR]

Summary: Reduced‐intensity conditioning regimens are commonly used in allogeneic haematopoietic cell transplantation for non‐Hodgkin lymphoma (NHL); however, the optimal regimen remains unknown. In this study, the outcomes of adult patients with NHL who received fludarabine plus reduced‐dose busulfan (6.4 mg/kg; Flu/Bu2) (n = 286) and fludarabine plus low‐dose melphalan (80 or 100 mg/m2; Flu/Mel80–100) (n = 283) between January 2009 and December 2020 were compared using Japanese registry data. The primary end‐point was the 5‐year overall survival (OS). The 5‐year OS was 53.8% (95% CI, 47.6–59.6) and 42.4% (95% CI, 35.6–49.0) in the Flu/Bu2 and Flu/Mel80–100 groups respectively (p = 0.030). After inverse probability of treatment weighting adjustment, the adjusted HR of Flu/Bu2 compared with Flu/Mel80–100 group for 5‐year OS was 0.77 (95% CI, 0.60–0.99, p = 0.046), 0.97 (95% CI, 0.78–1.21, p = 0.798) for 5‐year progression‐free survival, 0.65 (95% CI, 0.45–0.94, p = 0.022) for 5‐year cumulative risk of non‐relapse mortality and 1.25 (95% CI, 0.95–1.64, p = 0.115) for 5‐year cumulative risk of relapse. In this study, patients with NHL who received Flu/Bu2 were associated with better OS and lower non‐relapse mortality than those who received Flu/Mel80–100. [ABSTRACT FROM AUTHOR]

Summary: The global pandemic has resulted in the common occurrence of SARS‐CoV‐2 infection in the population. In the post‐pandemic era, it is imperative to understand the influence of donor SARS‐CoV‐2 infection on outcomes after allogeneic haematopoietic stem cell transplantation (allo‐HSCT). We retrospectively analysed allo‐HSCTs from donors with mild SARS‐CoV‐2 infection or early recovery stage (ERS) (group 1, n = 65) and late recovery stage (group 2, n = 120). Additionally, we included allo‐HSCT from donors without prior SARS‐CoV‐2 infection as group 0 (n = 194). Transplants from donors with different SARS‐CoV‐2 infection status had comparable primary engraftment and survival rates. However, group 1 had higher incidences of acute graft‐versus‐host disease (aGvHD), grade II–IV (41.5% vs. 28.1% in group 0 [p = 0.014] and 30.6% in group 2 [p = 0.067]) and grade III–IV (22.2% vs. 9.6% [p = 0.004] in group 0 and 12.2% in group 2 [p = 0.049]). Conversely, the risk of aGvHD in group 2 was similar to that in group 0 (p > 0.5). Multivariable analysis identified group 1 associated with grade II–IV (hazard ratio [HR] 2.307, p = 0.010) and grade III–IV (HR 2.962, p = 0.001) aGvHD, which yielded no significant risk factors for survival. In conclusion, we preliminarily demonstrated donors in the active infection state or ERS of mild SARS‐CoV‐2 infection were associated with higher incidences of aGvHD in transplants from related donors. [ABSTRACT FROM AUTHOR]

Cytomegalovirus reactivation (CMVr) and bloodstream infections (BSI) are the most common infectious complications in patients after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Both are associated with great high morbidity whilst the BSI is the leading cause of mortality. This retrospective study evaluated the incidence of CMVr and BSI, identified associated risk factors, assessed their impact on survival in allo-HSCT recipients during the first 100 days after transplantation. The study comprised 500 allo-HSCT recipients who were CMV DNA-negative and CMV IgG-positive before allo-HSCT. Amongst them, 400 developed CMVr and 75 experienced BSI within 100 days after allo-HSCT. Multivariate regression revealed that graft failure and acute graft-versus-host disease were significant risk factors for poor prognosis, whereas CMVr or BSI alone were not. Amongst all 500 patients, 56 (14%) developed both CMVr and BSI in the 100 days after HSCT, showing significantly reduced 6-month overall survival (p = 0.003) and long-term survival (p = 0.002). Specifically, in the initial post-transplant phase (within 60 days), BSI significantly elevate mortality risk, However, patients who survive BSI during this critical period subsequently experience a lower mortality risk. Nevertheless, the presence of CMVr in patients with BSI considerably diminishes their longterm survival prospects. This study provides real-world data on the impact of CMVr and BSI following transplantation on survival, particularly in regions such as China, where the prevalence of CMV IgG-positivity is high. The findings underscore the necessity for devising and executing focused prevention and early management strategies for CMVr and BSI to enhance outcomes for allo-HSCT recipients. [ABSTRACT FROM AUTHOR]

Summary: In this multicentre, real‐world study, we aimed to identify the clinical outcomes and safety of allogeneic haematopoietic stem cell transplantation (allo‐HSCT) in T‐lymphoblastic lymphoma (T‐LBL). A total of 130 Ann Arbor stage III or IV T‐LBL patients (>16 years) treated with allo‐HSCT across five transplant centres were enrolled. The 2‐year cumulative incidence of disease progression, the probabilities of progression‐free survival (PFS), overall survival (OS) and non‐relapse mortality (NRM) after allo‐HSCT were 21.0%, 69.8%, 79.5% and 9.2% respectively. Patients with central nervous system (CNS) involvement had a higher cumulative incidence of disease progression compared with those without CNS involvement (57.1% vs. 18.9%, HR 3.78, p = 0.014). Patients receiving allo‐HSCT in non‐remission (NR) had a poorer PFS compared with those receiving allo‐HSCT in complete remission (CR) or partial remission (49.2% vs. 72.7%, HR 2.21, p = 0.041). Particularly for patients with bone marrow involvement and achieving CR before allo‐HSCT, measurable residual disease (MRD) positivity before allo‐HSCT was associated with a poorer PFS compared with MRD negativity (62.7% vs. 86.8%, HR 1.94, p = 0.036). On multivariate analysis, CNS involvement at diagnosis and receiving allo‐HSCT in NR were associated with disease progression. Thus, our real‐world data suggested that allo‐HSCT appeared to be an effective therapy for adult T‐LBL patients with Ann Arbor stage III or IV disease. [ABSTRACT FROM AUTHOR]

Summary: CD7‐targeted chimeric antigen receptor T‐cell (CAR‐T) therapy has shown promising initial complete remission (CR) rates in patients with refractory or relapsed (r/r) T‐cell acute lymphoblastic leukaemia and lymphoblastic lymphoma (T‐ALL/LBL). To enhance the remission duration, consolidation with allogeneic haematopoietic stem cell transplantation (allo‐HSCT) is considered. Our study delved into the outcomes of 34 patients with r/r T‐ALL/LBL who underwent allo‐HSCT after achieving CR with autologous CD7 CAR‐T therapy. These were compared with 124 consecutive T‐ALL/LBL patients who received allo‐HSCT in CR following chemotherapy. The study revealed that both the CAR‐T and chemotherapy cohorts exhibited comparable 2‐year overall survival (OS) (61.9% [95% CI, 44.1–78.1] vs. 67.6% [95% CI, 57.5–76.9], p = 0.210), leukaemia‐free survival (LFS) (62.3% [95% CI, 44.6–78.4] vs. 62.0% [95% CI, 51.8–71.7], p = 0.548), non‐relapse mortality (NRM) rates (32.0% [95% CI, 19.0–54.0] vs. 25.3% [95% CI, 17.9–35.8], p = 0.288) and relapse incidence rates (8.8% [95% CI, 3.0–26.0] vs. 15.8% [95% CI, 9.8–25.2], p = 0.557). Patients aged ≤14 in the CD7 CAR‐T group achieved high 2‐year OS and LFS rates of 87.5%. Our study indicates that CD7 CAR‐T therapy followed by allo‐HSCT is not only effective and safe for r/r T‐ALL/LBL patients but also on par with the outcomes of those achieving CR through chemotherapy, without increasing NRM. [ABSTRACT FROM AUTHOR]

Human herpes virus 6A and human herpes virus 6B (HHV-6A and HHV-6B) are ubiquitous viruses. The spectrum of clinical manifestations of HHV-6A/B infections is quite wide. The current understanding of the natural history and laboratory diagnosis of HHV-6A and HHV-6B, including their chromosome-integrated form, serves the basis for development of the tools for HHV-6 epidemiological monitoring. This article addresses the epidemiology and diagnosis of infections caused by these viruses, including ones in patients after transplantation of solid organs and allogeneic hematopoietic stem cells.

Background: Most patients with haematological malignancies who undergo allogeneic haematopoietic stem cell transplant (HSCT) receive chemotherapy before the transplant to control the disease. Certain chemotherapy drugs can cause lung toxicity. Conversely, in patients with chronic respiratory conditions, the 6‐min walking test (6MWT) and the desaturation–distance ratio (DDR) have demonstrated prognostic significance. Our objective was to determine whether the 6MWD and DDR, assessed prior to HSCT, have a prognostic impact on survival at 24 months post‐HSCT. Methods: A prospective experimental study was conducted in consecutive patients referred for allogeneic HSCT at Hospital Clinic, Barcelona, Spain. A complete functional respiratory study, including the 6MWT and DDR, was conducted prior to admission. The area under the curve (AUC) and cut‐off points were calculated. Data on patients' characteristics, HSCT details, main events, with a focus on lung complications, and survival at 24 months were analysed. Results: One hundred and seventy‐five patients (39% women) with mean age of 48 ± 13 years old were included. Before HSCT, forced vital capacity and forced expiratory volume in the first second were 96% ± 13% predicted and 92% ± 14% predicted, respectively; corrected diffusing capacity for carbon monoxide 79% ± 15% predicted; 6MWD was 568 ± 83 m and DDR of.27 (.20–.41). The cut‐off points for 6MWD and DDR were 566 m, [.58 95% CI (.51–.64)], p =.024 and.306, [.63 95% CI (.55–.70)], p =.0005, respectively. The survival rate at 24 months was 55%. Conclusion: Our results showed that individuals who exhibit a 6MWD shorter than 566 ms or a decline in DDR beyond.306 experienced reduced survival rates at 24 months after HSCT. [ABSTRACT FROM AUTHOR]

Tracheobronchomalacia (TBM) occurs due to the weakening of cartilaginous part of the trachea, resulting in compromised airway function and leading to symptoms such as dyspnea, cough, and inability to clear secretions. Bronchiolitis obliterans syndrome (BOS) is the most prevalent late noninfectious pulmonary complication in patients who underwent allogeneic haematopoietic stem cell transplantation (HSCT). Therefore, patients experiencing progressive dyspnea and chronic cough after allogenic HSCT, with new obstructive pattern on pulmonary function test, are typically diagnosed with post‐transplant BOS. However, it is important to note that TBM can also manifest as an obstructive defect pattern on pulmonary function test. Tracheomalacia has been reported as a rare complication of allogenic stem cell transplantation. We present two patients who developed TBM following allogeneic HSCT and were initially treated for post‐transplant BOS but did not experience symptom improvement. However, after treatment with continuous positive airway pressure, their symptom subsided. [ABSTRACT FROM AUTHOR]

Summary: Cytomegalovirus (CMV) DNAemia and disease are common complications in patients undergoing allogeneic haematopoietic stem cell transplantation (allo‐HSCT). Few studies have compared the efficacy and safety of the HSCT donor and third‐party CMV‐specific cytotoxic T lymphocytes (CMV‐CTLs) in the treatment of CMV DNAemia and disease. In this study, we retrospectively compared the efficacy and safety of HSCT donor and third‐party CMV‐CTLs in patients with refractory CMV DNAemia or disease after allo‐HSCT at our centre from January 2017 to September 2021. Fifty‐three patients who received CMV‐CTL therapy were enrolled, including 40 in the donor group and 13 in the third‐party group, and they were adults aged 18 years or older. Within 6 weeks of treatment, 26 (65.0%) and 9 (69.2%) patients achieved complete response in the donor and third‐party groups (p = 1.000). The 2‐year overall survival was 59.6% (95% CI 46.1%–77.1%) and 53.8% (32.6%–89.1%) in the donor and third‐party groups (p = 0.860). Four (10.0%) patients in the donor group and two (15.4%) patients in the third‐party group developed acute graft‐versus‐host disease within 3 months after CMV‐CTL infusions. In conclusion, our data suggest that donor and third‐party CMV‐CTLs have comparable efficacy and safety for refractory CMV DNAemia and disease. [ABSTRACT FROM AUTHOR]

Abstract Background Patients with steroid-refractory acute graft-versus-host disease (aGvHD) not tolerating/responding to ruxolitinib (RR-aGvHD) have a dismal prognosis. Methods We retrospectively assessed real-world outcomes of RR-aGvHD treated with the random-donor allogeneic MSC preparation MSC-FFM, available via Hospital Exemption in Germany. MSC-FFM is provided as frozen cell dispersion for administration as i.v. infusion immediately after thawing, at a recommended dose of 1–2 million MSCs/kg body weight in 4 once-weekly doses. 156 patients, 33 thereof children, received MSC-FFM; 5% had Grade II, 40% had Grade III, and 54% had Grade IV aGvHD. Median (range) number of prior therapies was 4 (1–10) in adults and 7 (2–11) in children. Results The safety profile of MSC-FFM was consistent with previous reports for MSC therapies in general and MSC-FFM specifically. The overall response rate at Day 28 was 46% (95% confidence interval [CI] 36–55%) in adults and 64% (45–80%) in children; most responses were durable. Probability of overall survival at 6, 12 and 24 months was 47% (38–56%), 35% (27–44%) and 30% (22–39%) for adults, and 59% (40–74%), 42% (24–58%) and 35% (19–53%) for children, respectively (whole cohort: median OS 5.8 months). Conclusion A recent real-world analysis of outcomes for 64 adult RR-aGvHD patients not treated with MSCs reports survival of 20%, 16% and 10% beyond 6, 12 and 24 months, respectively (median 28 days). Our data thus suggest effectiveness of MSC-FFM in RR-aGvHD.

Summary: This PASS‐ALL study was designed to explore the effect of paediatric‐inspired versus adult chemotherapy regimens on survival of adolescents and young adults (AYA) with high‐risk Philadelphia chromosome‐negative B‐cell acute lymphoblastic leukaemia (HR PH‐ve B‐cell ALL) eligible for allogeneic haematopoietic stem cell transplantation (allo‐HSCT). The PASS‐ALL study is a multicentre, observational cohort study, and 143 patients with HR B‐cell PH‐ve ALL were enrolled from five centres—77 patients allocated in the paediatric‐inspired cohort and 66 in the adult cohort with comparable baseline characteristics. Of the 143 patients, 128 cases underwent allo‐HSCT. Three‐year leukaemia‐free survival (LFS) in the paediatric‐inspired cohort was 72.2% (95% CI 60.8%–83.6%) compared with 44.6% (95% CI 31.9%–57.3%; p = 0.001). Furthermore, time‐to‐positive minimal residual disease (TTP‐MRD) post‐HSCT was marked different, 3‐year cumulative incidence of relapse was 25.9% (95% CI 15.8%–37.2%) in paediatric cohort and 45.4% (95% CI 40.0%–57.9%) in adult cohort (p = 0.026). Finally, the 3‐year OS rate was 75.3% (95% CI 64.9%–85.7%) for the paediatric‐inspired cohort and 64.1% (95% CI 51.8%–76.4%) for the adult cohort (p = 0.074). On a multivariate analysis, paediatric‐inspired regimen is a predictive factor for LFS (HR = 2.540, 95% CI 1.327–4.862, p = 0.005). Collectively, our data suggest that paediatric‐inspired chemotherapy pre‐HSCT results in deeper and durable MRD response reduces relapse post‐HSCT and improves survival in HR B‐cell PH‐ve ALL patients with allo‐HSCT. [ABSTRACT FROM AUTHOR]

Background: Patients with steroid-refractory acute graft-versus-host disease (aGvHD) not tolerating/responding to ruxolitinib (RR-aGvHD) have a dismal prognosis. Methods: We retrospectively assessed real-world outcomes of RR-aGvHD treated with the random-donor allogeneic MSC preparation MSC-FFM, available via Hospital Exemption in Germany. MSC-FFM is provided as frozen cell dispersion for administration as i.v. infusion immediately after thawing, at a recommended dose of 1–2 million MSCs/kg body weight in 4 once-weekly doses. 156 patients, 33 thereof children, received MSC-FFM; 5% had Grade II, 40% had Grade III, and 54% had Grade IV aGvHD. Median (range) number of prior therapies was 4 (1–10) in adults and 7 (2–11) in children. Results: The safety profile of MSC-FFM was consistent with previous reports for MSC therapies in general and MSC-FFM specifically. The overall response rate at Day 28 was 46% (95% confidence interval [CI] 36–55%) in adults and 64% (45–80%) in children; most responses were durable. Probability of overall survival at 6, 12 and 24 months was 47% (38–56%), 35% (27–44%) and 30% (22–39%) for adults, and 59% (40–74%), 42% (24–58%) and 35% (19–53%) for children, respectively (whole cohort: median OS 5.8 months). Conclusion: A recent real-world analysis of outcomes for 64 adult RR-aGvHD patients not treated with MSCs reports survival of 20%, 16% and 10% beyond 6, 12 and 24 months, respectively (median 28 days). Our data thus suggest effectiveness of MSC-FFM in RR-aGvHD. [ABSTRACT FROM AUTHOR]

The immunogenicity of repeated vaccination and hybrid immunity in vulnerable patients remains unclear. We studied the impact of iterative Covid-19 mRNA vaccination and hybrid immunity on antibody levels in immunosuppressed subjects. Patients with liver cirrhosis (n = 38), survivors of allogeneic haematopoietic stem cell transplantation (allo-HSCT) (n = 36) and patients with autoimmune liver disease (n = 14) along with healthy controls (n = 20) were monitored for SARS-CoV-2-S1 IgG after their 1st–3rd vaccine doses, 31 of whom became infected with the Omicron variant after the 2nd dose. Ten uninfected allo-HSCT recipients received an additional 4th vaccine dose. Unexpectedly, immunosuppressed patients achieved antibody levels in parity with controls after the 3rd vaccine dose. In all study cohorts, hybrid immunity (effect of vaccination and natural infection) resulted in approximately 10-fold higher antibody levels than vaccine-induced immunity alone. Three doses of the Covid-19 mRNA vaccine entailed high antibody concentrations even in immunocompromised individuals, and hybrid-immunity resulted further augmented levels than vaccination alone. Clinical trial registration: EudraCT 2021-000349-42 [ABSTRACT FROM AUTHOR]

Relapse after allogeneic haematopoietic stem cell transplantation (HSCT) is one of the key determinants of outcome in myelofibrosis (MF) and remains an important unmet need. In this retrospective single-centre study, we evaluated 35 consecutive patients with MF receiving allogeneic HSCT. At 30 days post-HSCT, full donor chimerism was achieved in 31 patients (88.6%). The median time to neutrophil engraftment was 16.8 (10–42) days and the median time to platelet engraftment was 26 (12–245) days. Four patients (11.4%) experienced primary graft failure. With a median duration of follow-up of 33 (1–223) months, with the 5-year overall survival (OS) and progression-free survival (PFS) were 51.6% and 46.3%, respectively. Relapse after HSCT (P < 0.001), leucocyte count ≥ 18 × 109/L at HSCT (P = 0.003) and accelerated/blast phase disease at HSCT (P < 0.001) were significantly associated with worse OS. Age at HSCT ≥ 54 years (P = 0.01), mutated ETV6 (P = 0.03), leucocyte count ≥ 18 × 109/L (P = 0.02), accelerated/blast phase MF (P = 0.001), and grade 2–3 bone marrow reticulin fibrosis at 12 months post-HSCT (P = 0.002) were significantly associated with worse PFS. JAK2V617F MRD ≥ 0.047 [sensitivity 85.7%; positive predictive value (PPV) 100%; AUC 0.984; P = 0.001] at 6 months and JAK2V617F MRD ≥ 0.009 (sensitivity 100%; PPV 100%; AUC 1.0; P = 0.001) at 12 months were highly predictive of post-HSCT relapse. Inferior OS and PFS were significantly associated with detectable JAK2V617F MRD at 12 months (P = 0.003 and P = 0.0001, respectively). [ABSTRACT FROM AUTHOR]

Background Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is currently the only curative treatment for thalassaemia major (TM). Cord blood (CB) from a sibling has different characteristics from marrow and has potential advantages and disadvantages as a stem cell source.Methods We retrospectively analyzed 68 children with beta-thalassaemia major (β-TM) who underwent fresh cord blood transplantation (F-CBT) from an HLA-matched sibling donor (MSD) between June 2010 and July 2018 in the Department of Pediatrics, Nanfang Hospital and Haematology-Oncology, Shenzhen Children’s Hospital.Results The median infused doses of total nucleated cells (TNCs) and CD34 + cells were 8.51×107/kg and 3.16×105/kg, respectively. The median time to neutrophil and platelet engraftment were, respectively, 27 and 31 days. The cumulative probabilities of acute and chronic graft-versus-host disease (GVHD) were very low after F-CBT (7.8% and 0.0%, respectively). Of the 68 paediatric patients, 67 patients survived during a median follow-up period of 61 months. The estimated 5-year probability of overall survival (OS) and disease-free survival (DFS) were 98.5% and 87.9%, respectively. Three patients experienced graft rejection (GR) (4.5%), and we identified CD34 + cell dose as a significant risk factor for graft failure (p = 0.036) in stratify analysis.Conclusions The above results indicate that patients with β-TM have excellent outcomes after F-CBT from an HLA-MSD.

Summary: We aimed to identify the efficacy of haploidentical related donor (HID) haematopoietic stem cell transplantation (HSCT) in adolescent and young adults (AYAs) with acute myeloid leukaemia (AML) in a large cohort. Consecutive AML AYAs (15–39 years old, n = 599) receiving HID HSCT in complete remission (CR) were included. The 3‐year cumulative incidence of measurable residual disease occurrence, relapse and non‐relapse mortality after HID HSCT was 28.6% (95% CI: 25.0–32.2), 11.6% (95% CI: 9.0–14.2) and 6.7% (95% CI: 4.7–8.7) respectively. The 3‐year probability of event‐free survival, leukaemia‐free survival (LFS) and overall survival (OS) after HID HSCT was 60.7% (95% CI: 56.9–64.8), 81.7% (95% CI: 78.7–84.9) and 85.6% (95% CI: 82.8–88.4) respectively. In multivariable analysis, AML risk category at diagnosis and comorbidity burdens before HID HSCT were independently associated with LFS and OS. Compared to the older adults (≥ 40 years, n = 355) with AML receiving HID HSCT in CR during the same time period, AYAs have a lower incidence of non‐relapse mortality and higher probabilities of LFS and OS. Thus, we firstly confirmed the safety and efficacy of HID HSCT in AYAs with AML‐CR. [ABSTRACT FROM AUTHOR]

Summary: Most events that limit life expectancy after allogeneic haematopoietic stem cell transplantation (allo‐HSCT) occur within the first 2 years; however, treatment outcomes in long‐term survivors who survive for at least 2 years post‐HSCT without relapse are yet to be elucidated. To explore the life expectancy trends and late complications and to assess the main mortality‐related factors, we investigated the characteristics of patients who received allo‐HSCT for haematological malignancies from 2007 to 2019 in our centre and survived in remission for 2 years. A cohort of 831 patients was enrolled; of these, 508 received grafts from haploidentical‐related donors (61.1%). The estimated overall survival rate at 10 years was 91.9% (95% confidence interval [CI], 89.8–93.5), which was affected by prior grade III–IV acute graft‐versus‐host disease (GVHD) (hazard ratio [HR], 2.98; 95% CI, 1.47–6.03; p = 0.002) and severe chronic GVHD (HR, 3.60; 95% CI, 1.93–6.71; p < 0.001). The probability of late relapse and non‐relapse mortality at 10 years was 8.7% (95% CI, 6.9–10.8) and 3.6% (95% CI, 2.5–5.1) respectively. The top cause of late mortality was relapsed (49.0%). Projected long‐term survival in 2‐year disease‐free survivors following allo‐HSCT was excellent. Strategies should be implemented to minimise the late death‐specific hazards in recipients. [ABSTRACT FROM AUTHOR]

Introduction: Chimerism analysis is an important diagnostic tool not only for assessing the risk of relapse after allo-Haematopoietic Stem Cell Transplant (HSCT) in patients with malignant diseases, it is also the predominant method for monitoring post-transplant engraftment status in both haematological malignancies and non malignant haematological disorders. Aim: To show the chimerism data observed in post-HSCT cases of our hospital over last four years and to emphasise on timely and close monitoring of these patients in the laboratory. Materials and Methods: The present study was a retrospective study in which 40 HSCT cases comprising of both haematological malignancies and non malignant haematological disorders were monitored in the molecular laboratory of Army Hospital (Research and Referral), at regular intervals by Short Tandem Repeats-Polymerase Chain Reaction (STR-PCR) for quantification of donor chimerism. The pretransplant workup included Human Leukocyte Antigens (HLA) typing of all recipients and donors, serum Panel Reactive Antibody (PRA) testing and Single Antigen Bead (SAB) assays for detecting donor specific antibodies in all haploidentical transplants. Results: Male patients formed majority, with only nine female cases. After complete HLA matching and preconditioning, 35 patients underwent matched related stem cell transplant, two were Matched Unrelated Donor (MUD) and three haploidentical transplants. Complete donor chimerism at D+90 was reported in 19 patients (73%) of haematologic malignancies with two cases of relapse and five showing evidence of Graft Versus Host Disease (GVHD). Amongst non malignant disorders 10 patients (71.4%) showed complete donor chimerism at D+90 with two cases of GVHD. Conclusions: Post-HSCT, progressive chimerism monitoring is an essential molecular test that predicts engraftment status of the patient by verifying the dynamic relationship between recipient and donor cells. [ABSTRACT FROM AUTHOR]

Summary: Dysbiosis of the gut microbiota has been reported to increase early complications after allogeneic haematopoietic stem cell transplantation (allo‐HSCT). However, it remains unclear whether gut microbial alterations persist during late complications, such as chronic graft‐versus‐host disease (cGVHD) or secondary cancers. Here, we analysed the gut microbiota of 59 patients who survived for 1–21.7 years (median, 6.4 years) after allo‐HSCT. Long‐term survivors showed lower gut microbial diversity than the age‐ and sex‐matched healthy controls. This decreased diversity was reflected in the reduced abundance of the butyrate‐producing bacteria. Patients with a history of grade 3 acute graft‐versus‐host disease (aGVHD) exhibited higher Veillonella abundance than patients with a history of grade 1–2 or non‐aGVHD cases. The abundance of Faecalibacterium showed no decrease only in limited cGVHD cases. Additionally, the microbial structure in the secondary cancer group was significantly different (p < 0.05) from that in the non‐secondary cancer group. This study is the first to show that microbial dysbiosis is present over a 10‐year lifetime after discharge following allo‐HSCT. Our results suggest that these prolonged gut microbial alterations may be associated with the development and exacerbation of late complications in post‐transplant survivors. [ABSTRACT FROM AUTHOR]

Summary: Young adults (YA) represent a minority among recipients of allogeneic haematopoietic stem cell transplantation (HSCT). In order to describe the outcome of YA following HSCT in Germany, 9299 patients who were registered with the German Registry for Stem Cell Transplantation were included in this retrospective analysis of the years 1998–2019. The impact of the variables, such as patient age and sex, sex differences, stem cell source, donor type, conditioning, year of HSCT, the diagnosis, and the achieved remission status were tested in univariable and multivariable analysis for overall, event‐free and relapse‐free survival as well as for the cumulative incidences of non‐relapse and therapy‐related mortality. Altogether, the outcome of YA after HSCT improved over time and was determined by the underlying disease, the age at disease onset, stem cell source, and donor type. Patients were most likely to die from relapse, and survival of HSCT recipients after 10 years was reduced by more than half in comparison to the general population of YA. Deeper understanding of modifiable risk factors may be gained by studies comparing the outcome of YA post‐HSCT with that of children, adolescents and elderly patients. A deliberate and strong patient selection may further improve mortality rates. [ABSTRACT FROM AUTHOR]

This multicentre, phase 2, randomized, controlled study of allogeneic haematopoietic stem cell transplantation (allo-HSCT) recipients compared the immunogenicity of two anti-pneumococcal vaccine regimens: four doses of 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) (3+1+1 experimental group), and three doses of PCV13 followed by PPSV23 (3+0+1 group). Allo-HSCT recipients without active graft-versus-host disease at enrolment were eligible. The primary endpoint was the IgG response rate (≥0.20 mg/mL) for all eight measured serotypes at 5 months after the PPSV23 booster. Seventy-two recipients were randomized, and seventy recipients who received over one PCV13 dose were analysed. The mean ages were 47.2 years (standard deviation, 14.4) in the 3+1+1 group (n = 35) and 49.0 years (standard deviation, 14.3) in the 3+0+1 group (n = 35). There was no significant difference in the overall IgG response rate at 5 months after the PPSV23 booster between the 3+1+1 and 3+0+1 groups (100% (26/26) vs. 93% (27/29), respectively, relative risk (RR): 1.07; 95% confidence interval (CI): 0.97–1.19). This rate was high immediately before the PPSV23 booster in the 3+1+1 group (100% (26/26) compared with 81% (21/26), respectively, RR: 1.24; 95% CI: 1.03–1.49), but this difference disappeared 1 month after the PPSV23 booster (100% (26/26) vs. 97% (28/29), respectively, RR: 1.04; 95% CI; 0.97–1.11). No serious adverse events leading to study dropout occurred. We were not able to determine the efficacy of the experimental arm based on the IgG response rate at 5 months after the PPSV23 booster in allo-HSCT recipients. [ABSTRACT FROM AUTHOR]

Summary: Prolonged isolated thrombocytopenia (PT) is a life‐threatening comorbidity associated with allogeneic haematopoietic stem cell transplantation (allo‐HSCT). Our previous study indicated that dysfunctional bone marrow mesenchymal stromal cells (BM MSCs) played a role in PT pathogenesis and that reactive oxygen species (ROS) accumulation was related to BM MSC senescence and apoptosis. However, the mechanism of the increase in ROS levels in the BM MSCs of PT patients is unknown. In the current case‐control study, we investigated whether nuclear factor erythroid 2‐related factor 2 (NRF2), which is a central regulator of the cellular anti‐oxidant response that can clear ROS in human BM MSCs, was associated with PT after allo‐HSCT. We evaluated whether an NRF2 agonist (tert‐butylhydroquinone, TBHQ) could enhance BM MSCs from PT patients in vitro. We found that BM MSCs from PT patients exhibited increased ROS levels and reduced NRF2 expression. Multivariate analysis showed that low NRF2 expression was an independent risk factor for primary PT [p = 0.032, Odds ratio (OR) 0.868, 95% confidence interval (CI) 0.764–0.988]. In‐vitro treatment with TBHQ improved the quantity and function of BM MSCs from PT patients by downregulating ROS levels and rescued the impaired BM MSC support of megakaryocytopoiesis. In conclusion, these results suggested that NRF2 downregulation in human BM MSCs might be involved in the pathogenesis of PT after allo‐HSCT and that BM MSC impairment could be improved by NRF2 agonist in vitro. Although further validation is needed, our data indicate that NRF2 agonists might be a potential therapeutic approach for PT patients after allo‐HSCT. [ABSTRACT FROM AUTHOR]

Although glucorticosteroids (GCs) are the standard first-line therapy for acute graft-versus-host disease (aGvHD), nearly 50% of aGvHD patients have no response to GCs. The role of T cell metabolism in murine aGvHD was recently reported. However, whether GCs and metabolism regulators could cooperatively suppress T cell alloreactivity and ameliorate aGvHD remains to be elucidated. Increased glycolysis, characterized by elevated 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), and higher rates of glucose consumption and lactate production were found in T cells from aGvHD patients. Genetic upregulation of PFKFB3 induced T cell proliferation and differentiation into proinflammatory cells. In a humanized mouse model, PFKFB3-overexpressing or PFKFB3-silenced T cells aggravated or prevented aGvHD, respectively. Importantly, our integrated data from patient samples in vitro, in a humanized xenogeneic murine model of aGvHD and graft-versus-leukaemia (GVL) demonstrate that GCs combined with a glycolysis inhibitor could cooperatively reduce the alloreactivity of T cells and ameliorate aGvHD without loss of GVL effects. Together, the current study indicated that glycolysis is critical for T cell activation and induction of human aGvHD. Therefore, the regulation of glycolysis offers a potential pathogenesis-oriented therapeutic strategy for aGvHD patients. GCs combined with glycolysis inhibitors promises to be a novel first-line combination therapy for aGvHD patients. [ABSTRACT FROM AUTHOR]

Introduction: A higher CD34+ cell dose in allografts is associated with faster haematopoietic recovery after allogeneic haematopoietic stem cell transplantation (allo‐HSCT). Leukaemia stem cells impair normal bone marrow (BM) niches and induce BM failure during leukemogenesis. However, whether measurable residual disease (MRD), known as the persistence of low‐level leukaemic cells, could influence the effects of CD34+ cell dose on haematopoietic recovery after transplantation in acute lymphoblastic leukaemia (ALL) patients is unknown. Methods: A total of 975 ALL patients were enrolled and classified into pre‐HSCT MRD‐positive and MRD‐negative subgroups. Cox proportional hazard regression models were built for time‐to‐event outcomes. Multivariate analysis was performed to determine independent influencing factors from the univariate analysis. Results: An appropriate CD34+ cell dose was positively associated with faster haematopoietic recovery in the total ALL population. More importantly, in pre‐HSCT MRD‐positive ALL patients, a higher CD34+ cell dose (≥2.76 × 106/kg) was related to faster neutrophil (HR 1.330, 95% CI 1.045–1.692, p = 0.021) and platelet engraftment (HR 1.808, 95% CI 1.412–2.316, p < 0.001) in multivariate analysis. CD34+ cell dose was a crucial factor associated with either engraftment or transplant outcomes, although we did not demonstrate direct correlations of CD34+ cell dose with relapse, TRM, LFS or OS after allo‐HSCT. Conclusion: Our results indicated that no additional CD34+ stem and progenitor cell harvests were needed to ensure successful haematopoietic recovery in pre‐HSCT MRD‐positive patients compared to pre‐HSCT MRD‐negative patients. [ABSTRACT FROM AUTHOR]

Previous studies have reported patients with VEXAS being transplanted in the absence of a prior diagnosis, including one of the patients we report here (P4). Keywords: allogeneic haematopoietic stem cell transplantation; chronic myelomonocytic leukaemia; myelodysplastic syndrome; VEXAS syndrome EN allogeneic haematopoietic stem cell transplantation chronic myelomonocytic leukaemia myelodysplastic syndrome VEXAS syndrome 777 781 5 11/24/22 20221201 NES 221201 Vacuoles, E1-ligase, X-linked, Auto-inflammatory, Somatic (VEXAS) syndrome, is an acquired, progressive systemic auto-inflammatory disorder with overlapping rheumatological and haematological features.1,2 It is caused by myeloid-restricted somatic mutations in ubiquitin-like modifier-activating enzyme 1 ( I UBA1 i ), the gene that encodes E1 ubiquitin ligase. Very few patients had any inflammatory symptoms or disease manifestations classically associated with VEXAS (Table 2).2,5 The MDS features were also different. [Extracted from the article]

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is currently the only curative treatment for thalassaemia major (TM). Cord blood (CB) from a sibling has different characteristics from marrow and has potential advantages and disadvantages as a stem cell source. We retrospectively analyzed 68 children with beta-thalassaemia major (β-TM) who underwent fresh cord blood transplantation (F-CBT) from an HLA-matched sibling donor (MSD) between June 2010 and July 2018 in the Department of Pediatrics, Nanfang Hospital and Haematology-Oncology, Shenzhen Children's Hospital. The median infused doses of total nucleated cells (TNCs) and CD34 + cells were 8.51×107/kg and 3.16×105/kg, respectively. The median time to neutrophil and platelet engraftment were, respectively, 27 and 31 days. The cumulative probabilities of acute and chronic graft-versus-host disease (GVHD) were very low after F-CBT (7.8% and 0.0%, respectively). Of the 68 paediatric patients, 67 patients survived during a median follow-up period of 61 months. The estimated 5-year probability of overall survival (OS) and disease-free survival (DFS) were 98.5% and 87.9%, respectively. Three patients experienced graft rejection (GR) (4.5%), and we identified CD34 + cell dose as a significant risk factor for graft failure (p = 0.036) in stratify analysis. The above results indicate that patients with β-TM have excellent outcomes after F-CBT from an HLA-MSD. [ABSTRACT FROM AUTHOR]

Acute myeloid leukaemia is a rare cancer, with about 3000 cases diagnosed each year in the UK. Diagnosis is based on patient history, blood and bone marrow tests and, in some cases, imaging. Chemotherapy is the mainstay of treatment for acute myeloid leukaemia, with eligible patients also undergoing allogeneic haematopoietic stem cell transplantation, which can be curative. However, patients must be carefully evaluated by the multidisciplinary team before they are put forward for transplant to ensure they are able to tolerate the conditioning therapy required. Improvements in transplant technology have increased donor availability and reduced transplant toxicity. At the same time, greater understanding of the cytogenetics and molecular genetics of acute myeloid leukaemia have helped to ensure that patients receive treatment that gives them the best chance of survival. A recent roundtable discussion considered how current diagnostic and treatment pathways might be adapted or enhanced to leverage good outcomes for the greatest numbers of patients. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome (MDS) with TP53 mutations has a poor prognosis after transplantation, and novel therapeutic means are urgently needed. Decitabine (Dec) monotherapy has demonstrated improved overall response rates in MDS and acute myeloid leukaemia, although these responses were not durable. This study aimed to preliminary evaluate the efficacy of a Dec-containing allogeneic haematopoietic stem cell transplantation (allo-HSCT) preconditioning regimen in TP53-mutant MDS. Nine patients with TP53-mutant myelodysplastic syndromes received the decitabine-containing preconditioning regimen and subsequent myeloablative allo-HCT between April 2013 and September 2021 in different centres. At a median follow-up of 42 months (range, 5 to 61 months), the overall survival (OS) was 89% (8/9), progression-free survival (PFS) was 89% (8/9), and relapse incidence was 11.1%. The incidence of severe acute (grade III-IV) graft-versus-host disease (GVHD) was 22.2% (2/9) and that of chronic moderate-to-severe GVHD was 11.1% (1/9). The 1-year GVHD-free/relapse-free survival (GRFS) was 56% (5/9). In conclusion, we found real-world clinical data that supports the use of a Dec-containing preconditioning regimen before allo-HSCT for possible improved outcomes in TP53-mutant MDS patients; there is therefore an urgent call for an in-depth exploration of the involved mechanism to confirm these preliminary findings. [ABSTRACT FROM AUTHOR]

SUMMARY: Over the last 30 years, allogeneic haematopoietic stem cell transplantation (allo‐HSCT) has been adopted as a therapeutic strategy for many inborn errors of metabolism (IEM), due to the ability of donor‐derived cells to provide life‐long enzyme delivery to deficient tissues and organs. However, (a) the clinical benefit of allo‐HSCT is limited to a small number of IEM, (b) patients are left with a substantial residual disease burden and (c) allo‐HSCT is still associated with significant short‐ and long‐term toxicities and transplant‐related mortality. Haematopoietic stem/progenitor cell gene therapy (HSPC‐GT) was established in the 1990s for the treatment of selected monogenic primary immunodeficiencies and over the past few years, its use has been extended to a number of IEM. HSPC‐GT is particularly attractive in neurodegenerative IEM, as gene corrected haematopoietic progenitors can deliver supra‐physiological enzyme levels to difficult‐to‐reach areas, such as the brain and the skeleton, with potential increased clinical benefit. Moreover, HSPC‐GT is associated with reduced morbidity and mortality compared to allo‐HSCT, although this needs to be balanced against the potential risk of insertional mutagenesis. The number of clinical trials in the IEM field is rapidly increasing and some HSPC‐GT products recently received market approval. This review describes the development of ex vivo HSPC‐GT in a number of IEM, with a focus on recent results from GT clinical trials and risks versus benefits considerations, when compared to established therapeutic strategies, such as allo‐HSCT. [ABSTRACT FROM AUTHOR]

Objectives: Allogeneic haematopoietic stem cell transplantation (allo‐HSCT) is the only currently available curative treatment for sickle cell disease (SCD). Here, we comprehensively evaluated the reconstitution of T‐ and B‐cell compartments in 29 SCD patients treated with allo‐HSCT and how it correlated with the development of acute graft‐versus‐host disease (aGvHD). Methods: T‐cell neogenesis was assessed by quantification of signal‐joint and β‐chain TCR excision circles. B‐cell neogenesis was evaluated by quantification of signal‐joint and coding‐joint K‐chain recombination excision circles. T‐ and B‐cell peripheral subset numbers were assessed by flow cytometry. Results: Before allo‐HSCT (baseline), T‐cell neogenesis was normal in SCD patients compared with age‐, gender‐ and ethnicity‐matched healthy controls. Following allo‐HSCT, T‐cell neogenesis declined but was fully restored to healthy control levels at one year post‐transplantation. Peripheral T‐cell subset counts were fully restored only at 24 months post‐transplantation. Occurrence of acute graft‐versus‐host disease (aGvHD) transiently affected T‐ and B‐cell neogenesis and overall reconstitution of T‐ and B‐cell peripheral subsets. B‐cell neogenesis was significantly higher in SCD patients at baseline than in healthy controls, remaining high throughout the follow‐up after allo‐HSCT. Notably, after transplantation SCD patients showed increased frequencies of IL‐10‐producing B‐regulatory cells and IgM+ memory B‐cell subsets compared with baseline levels and with healthy controls. Conclusion: Our findings revealed that the T‐ and B‐cell compartments were normally reconstituted in SCD patients after allo‐HSCT. In addition, the increase of IL‐10‐producing B‐regulatory cells may contribute to improve immune regulation and homeostasis after transplantation. [ABSTRACT FROM AUTHOR]

Summary: We analysed long‐term outcome of patients receiving haematopoietic allogeneic stem cell transplantation (allo‐HSCT) as a first transplant for high‐risk Hodgkin lymphoma (HL). One hundred and ninety patients were included in this study, 63% of them had previously received brentuximab vedotin and/or checkpoint inhibitors. Seventy patients (37%) received an unrelated donor allo‐HSCT, 99 (51%) had myeloablative conditioning (MAC) and 60% had in vivo T‐cell/depleted grafts (TCD). The 100‐day cumulative incidence (CI) of grade II‐IV acute graft‐versus‐host disease (GVHD) was 25% and the 3‐year CI of chronic GVHD was 38%. The 3‐year CI of non‐relapse mortality (NRM) and relapse rate were 21% and 38% respectively. After a median follow‐up of 58 months, 3‐year overall survival (OS) and progression‐free survival (PFS) were 58% and 41% respectively. Multivariate analysis showed that, in comparison to reduced‐intensity conditioning regimens with or without TCD, MAC using TCD had similar NRM and a lower risk of relapse leading to significantly better OS and PFS. MAC without TCD was associated with higher NRM and worse survival outcomes. These results suggest that in patients with high‐risk HL and candidates of allo‐HSCT, a MAC strategy with TCD might be the best option. [ABSTRACT FROM AUTHOR]

Purpose: This study examines sick leave (SL) and factors associated with full-time SL 1 year after allogeneic haematopoietic stem cell transplantation (allo-HSCT) in patients of working age from 2009 to 2016 (n = 122). Methods: Questionnaire data were collected on admission to the allo-HSCT unit, at 7 months and 1 year after allo-HSCT. Associations between factors and SL were analysed using logistic regression analyses. Results: One year after allo-HSCT, 76% of participants were on SL, with 36% on full-time SL. In univariable analyses, chronic graft-versus-host-disease (cGvHD) (OR 3.07; 95% CI 1.34–7.07; p = 0.01), having symptoms of depression at 7 months (OR 4.81; 95% CI 1.69–13.69; p = 0.00) and low levels of vocational satisfaction at 7 months after treatment (OR 3.27; 95% CI 1.27–8.41; p = 0.01) were associated with full-time SL 1 year after allo-HSCT. cGvHD (OR 3.43; 95% CI 1.35–8.73; p = 0.01) and having symptoms of depression at 7 months after allo-HSCT (OR 3.37; 95% CI 1.2–11.58; p = 0.02) remained significant in multivariable analysis. Conclusion: The majority of allo-HSCT survivors were on SL 1 year after treatment, and cGvHD, low vocational satisfaction and depressive symptoms were associated with full-time SL 1 year after allo-HSCT. Implications for Cancer Survivors: Healthcare professionals need to be observant of and manage the consequences of cGvHD and patients' symptoms of depression in order to support them appropriately in their return-to-work process. [ABSTRACT FROM AUTHOR]

Summary: Adult T‐cell leukaemia/lymphoma (ATL) patients have a poor prognosis. Here, we investigated the impact of TP53 gene mutations on prognosis of ATL treated in different ways. Among 177 patients, we identified 47 single nucleotide variants or insertion‐deletions (SNVs/indels) of the TP53 gene in 37 individuals. TP53 copy number variations (CNVs) were observed in 38 patients. Altogether, 67 of 177 patients harboured TP53 SNVs/indels or TP53 CNVs, and were categorized as having TP53 mutations. In the entire cohort, median survival of patients with and without TP53 mutations was 1·0 and 6·7 years respectively (P < 0·001). After allogeneic haematopoietic stem cell transplantation (HSCT), median survival of patients with (n = 16) and without (n = 29) TP53 mutations was 0·4 years and not reached respectively (P = 0·001). For patients receiving mogamulizumab without allogeneic HSCT, the median survival from the first dose of antibody in patients with TP53 mutations (n = 27) was only 0·9 years, but 5·1 years in those without (n = 42; P < 0·001). Thus, TP53 mutations are associated with unfavourable prognosis of ATL, regardless of treatment strategy. The establishment of alternative modalities to overcome the adverse impact of TP53 mutations in patients with ATL is required. [ABSTRACT FROM AUTHOR]

Abstract Background The significance of very early chimerism assessment before day + 28, which is considered the moment of engraftment, is still unclear. In this retrospective study, we evaluated the clinical impact of very early chimerism on the clinical outcome after allogeneic haematopoietic stem cell transplantation (allo-HSCT) in children with acute lymphoblastic leukaemia (ALL). Methods The study group included 38 boys and 18 girls. Very early chimerism was evaluated on days + 7, + 14, + 21 and + 28 after the transplant. Short tandem repeat polymerase chain reaction (STR PCR) was used to analyse chimerism. Results Overall survival (OS) and event-free survival (EFS) were 84 and 80%, respectively. The OS in the group of 24 patients with complete donor chimerism on day + 14 was 83%, and it did not differ statistically compared to the 32 patients with mixed chimerism on day + 14 (OS was 84%). In our cohort of patients, the matched unrelated donor, male gender of donor, number of transplanted cells above 4.47 × 106 kg and no serotherapy with anti-thymocyte globulin (ATG) were statistically related to a higher level of donor chimerism. The immunophenotypes of disease, age of patient at time HSCT, recipient sex, stem cell source (peripheral blood/bone marrow) and conditioning regimen had no impact on early chimerism. Acute graft versus host disease grades II-IV was diagnosed in 23 patients who presented with donor chimerism levels above 60% on day 7. Conclusions The data presented in this study provide valuable insight into the analysis of very early chimerism in children with ALL treated with HSCT.

Cyclosporin a (CsA) was characterized by a narrow therapeutic window and high interindividual pharmacokinetic variability. In this study, we aimed to identify the association of CYP3A4, ABCB1, ABCC2, ABCG2, NFKB1, POR, and PXR polymorphisms with CsA concentrations in patients with allogeneic haematopoietic cell transplantation (allo-HSCT) based on the route of administration. A total of 40 allo-HSCT recipients receiving CsA were genotyped for CYP3A4, ABCB1, ABCC2, ABCG2, NFKB1, POR, and PXR polymorphisms. The correlation between polymorphisms and CsA concentration was analysed. The CsA dose-adjusted trough concentration (Cssmin/D) of oral or intravenous administration was significantly different (p < 0.001). For CsA Cssmin/D of intravenous administration, CYP3A4 rs2246709 (p = 0.015), ABCC2 rs717620 (p = 0.024), ABCG2 rs2231142 (p = 0.042), PXR rs3732359 (p = 0.008), PXR rs3814058 (p = 0.028) and PXR rs6785049 (p < 0.001) had a significant effect on CsA Cssmin/D. For CsA Cssmin/D of oral administration, ABCC2 rs717620 (p = 0.009) and ABCG2 rs2231142 (p = 0.011) had a significant effect on CsA Cssmin/D. These results illustrated that the CYP3A4, ABCC2, ABCG2, and PXR genotypes were closely correlated with CsA Cssmin/D, suggesting these SNPs were suitable for determining the appropriate dose of CsA. [ABSTRACT FROM AUTHOR]

Sclerodermoid chronic graft-versus-host disease (scGVHD) is a severe complication of allogeneic haema­- topoietic stem cell transplantation. The aim of this study was to investigate the usefulness of high-frequency ultrasound of the skin in assessing the inflammatory patterns and prognosis of patients with scGVHD. A prospective study was carried out with patients who developed scGVHD in the period June 2016 to April 2018. Clinical and ultrasound examinations were performed on the first visit and at 6-month follow-up. A total of 24 patients were included in the study. A 6-month follow-up high-frequency ultrasound of the skin was performed on 20 of the 24 patients. Abnormal B-mode findings in high-frequency ultrasound of the skin consisted of hypoechogenic dermis, hypoechogenicity of septa and hyperechogenicity of lobules in hypodermis. No differences were observed in these basal parameters between treatment progressive/non-responding and inactive/responding scGVHD groups of patients. Basal Doppler showing increased vascular flow with a systolic peak ≥10 cm/s and a vascular resistance index ≥ 0.70 was observed only in those patients who developed progressive/non-responding scGVHD (62.5% vs 0% p = 0.006). In conclusion, Doppler ultrasound is a useful tool to assess the inflammatory activity and outcome of scGVHD. These findings could enhance patient management and help to guide treatment decisions.

Finally, the proportion of patients documented twice with the highest antibody level at SpV2 and SpV2+/SpV3 was similar between V3- and V3+ patients (50% vs. 60%, I P i = 0-55). Vaccine, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) mRNA, coronavirus disease 2019 (COVID-19), allogeneic haematopoietic stem cell transplantation, BNT162b2, third dose Keywords: coronavirus disease 2019 (COVID-19); vaccine; allogeneic haematopoietic stem cell transplantation; BNT162b2; severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) mRNA; third dose EN coronavirus disease 2019 (COVID-19) vaccine allogeneic haematopoietic stem cell transplantation BNT162b2 severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) mRNA third dose e38 e40 3 02/28/22 20220301 NES 220301 The efficacy of two doses of anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) messenger RNA (mRNA) vaccines, successfully demonstrated in healthy populations,1 is progressively reported in recipients of allogeneic haematopoietic stem cell transplant (allo-HSCT) with, surprisingly, high humoral antibody responses of ~80%.1-3 In our own experience based on an observational study of 117 allo-HSCT adult recipients, we found that 83% of them achieved a significant specific humoral response after two doses (V1 and V2) of BNT162b2 anti-SARS-CoV-2 mRNA vaccine (Pfizer BioNTech). [Extracted from the article]

Young donors are associated with a lower cumulative incidence of acute graft‐vs‐host disease (aGVHD) after allogenic haematopoietic stem cell transplantation (allo‐HSCT) than old donors. Although grafts are harvested from healthy donors, it is unclear whether donor age is associated with aGVHD occurrence owing to its effect on cell compositions in grafts. Moreover, the differences in monocyte subsets in grafts between young and old donors and the association between monocyte subsets in bone marrow (BM) grafts and aGVHD remain to be elucidated. In the current study, non‐classical monocytes and the CD4+/CD8+ T cell ratio were remarkably decreased in BM grafts in donors <30 years old. Multivariate analysis further revealed that the level of non‐classical monocytes in BM grafts (≥0.31 × 106/kg) was an independent risk factor for the occurrence of II‐IV aGVHD. In summary, our data indicate that non‐classical monocytes in BM grafts may help identify patients at high risk for aGVHD after allo‐HSCT. Although further validation is required, our results suggest that the low level of non‐classical monocytes and a low ratio of CD4+/CD8+ T cell in BM grafts may be correlated with the lower incidence of aGVHD in young donors. [ABSTRACT FROM AUTHOR]

Antithymocyte globulin (ATG) is widely used for allogeneic haematopoietic stem cell transplantation (allo-HSCT) in severe aplastic anaemia (SAA). Only rabbit-ATG (r-ATG) and porcine-antilymphocyte globulin (p-ALG) are available in China, but the p-ALG-containing conditioning regimen for allo-HSCT in SAA has seldom been reported. In this study, we retrospectively evaluated the outcomes of 41 SAA patients receiving allo-HSCT with a p-ALG-containing conditioning regimen in our transplantation centre. All patients engrafted, and no death during conditioning was observed. The actuarial 3-year overall survival (OS) rates were 95.1 ± 3.4%. The actuarial 3-year disease-free survival (DFS) rates were 85.0 ± 5.7%. Acute graft-versus-host disease (aGVHD) predicted inferior OS (p < 0.05). The interval from diagnosis to transplantation for more than 100 days predicted an inferior DFS rate (p < 0.05) and a higher graft rejection/poor graft function (GR/PGF) rate (p < 0.01). In conclusion, the p-ALG-containing regimen showed satisfactory effects and safety in allo-HSCT for SAA patients. P-ALG could be a potential alternative preparation for r-ATG in SAA allo-HSCT. [ABSTRACT FROM AUTHOR]

Summary: Although chimeric antigen receptor T cells (CAR‐T) targeted at CD19 or CD22 have achieved high complete remission (CR) in refractory/relapsed B‐cell acute lymphoblastic leukaemia (B‐ALL), it is uncertain if allogeneic haematopoietic stem cell transplantation (allo‐HSCT) should be performed after CAR‐T therapy to accomplish a sustainable remission. Fifty‐two cases with relapsed/refractory B‐ALL who underwent allo‐HSCT after CR by CD19 or CD22 CAR‐T were enrolled. The median time from CAR‐T infusion to allo‐HSCT was 50 (34–98) days. Myeloablative reduced‐intensity conditioning (RIC) with total body irradiation/fludarabine‐based or busulfan/fludarabine‐based regimens was used. Incidences of grade II–IV acute graft‐versus‐host disease (aGVHD) and severe aGVHD were 23·1% and 5·8% respectively. Of 48 evaluable cases, 16 developed chronic GVHD (cGVHD) and in three of them the pattern was extensive. With a median follow‐up of 334 (41–479) days, one‐year overall survival and event‐free survival (EFS) were 87·7% and 73·0%. One‐year relapse rate and transplant‐related mortality (TRM) were 24·7% and 2·2% respectively. With quick bridge to allo‐HSCT after CAR‐T therapy, high EFS for refractory/relapsed B‐ALL has been achieved in this relatively large cohort. Our myeloablative RIC regimens have resulted in low incidences of aGVHD, cGVHD, viral reactivation and very low TRM even majority of transplants from haploidentical donors. Long‐term follow‐up is warranted. [ABSTRACT FROM AUTHOR]

CCDC88C-FLT3, myeloid/lymphoid neoplasms with eosinophilia, allogeneic haematopoietic stem cell transplantation, stem and multilineage cells, tyrosine kinase inhibitor CCDC88C-FLT3 gene fusion in CD34-positive haematopoietic stem and multilineage cells in myeloid/lymphoid neoplasm with eosinophilia Her bone marrow aspiration showed hypercellular marrow (>90% cellularity) with increased myeloid cell numbers and abundant eosinophils (10%-20% all nucleated bone marrow cells (Figure S2A)). Keywords: allogeneic haematopoietic stem cell transplantation; CCDC88C-FLT3; myeloid/lymphoid neoplasms with eosinophilia; stem and multilineage cells; tyrosine kinase inhibitor EN allogeneic haematopoietic stem cell transplantation CCDC88C-FLT3 myeloid/lymphoid neoplasms with eosinophilia stem and multilineage cells tyrosine kinase inhibitor 950 952 3 02/07/22 20220201 NES 220201 CONFLICT OF INTEREST The authors declare no competing financial interests. [Extracted from the article]

Introduction: Allogeneic Haematopoietic Stem Cell Transplantation (AHSCT) is a potentially curative therapy for many haematological malignancies. Nearly all patients who undergo AHSCT require frequent transfusion of blood products until Red Blood Cells (RBCs) and platelet engraftment occur. However, blood transfusion has seldom been studied as a risk factor for adverse post-transplant outcome. Aim: To investigate the impact of blood transfusion on posttransplant outcome. Materials and Methods: This single-center retrospective study, analysed the data of 50 adult patients with haematological malignancies who had received AHSCT, regarding the incidence of infection‚ acute and chronic Graft Versus Host Disease (GVHD) and overall survival, for one year after AHSCT. The collected data was divided into two groups according to the amount of transfused RBCs and platelet units; the low transfusion group (10 units, n=20). Results: The incidence of infectious episodes and GVHD development were significantly higher among the high transfusion group than that in low transfusion group (p=0.006) and (p=0.02), respectively. In the low transfusion group, the incidence of acute GVHD was 3.3% and of the chronic GVHD was 3.3% while in high transfusion group, the incidence of acute GVHD was 15% and of chronic GVHD was 20%. The overall survival was significantly lower in the high transfusion group 25% than that in the low transfusion group, 46.7% (p=0.02) during the first year post-transplant. Conclusion: Data from the present study indicate that higher transfusion history was associated with increased risk of infection, development of GVHD and worse overall survival in patients who received AHSCT. Thus, new rational for improving transfusion practice based on symptoms driven criteria for such patients is highly warranted.

Graft-versus-host disease (GVHD) remains a major complication following allogeneic haematopoietic stem cell transplantation (allo-HSCT) leading to high transplant-related mortality. Natural killer (NK) cells have been found to mitigate GVHD without attenuating the graft-versus-tumour (GVT) activity in the murine model of haematopoietic stem cell transplantation. Sphingosine-1-phosphate receptor 5 (S1PR5) is a very important chemokine receptor on NK cells that governs NK cell distribution in vivo and trafficking at lesion sites. Our preliminary studies showed that the incidence of GVHD was negatively correlated with S1PR5 expression in the NK cells of patients after allo-HSCT. In the present study, we found that S1PR5 deficiency in murine NK cells blocked the migration of NK cells from the bone marrow to the GVHD target organs and attenuated the inhibitory effects on the alloreactive T cells, especially CD3+ CD8+ T cells, which may be the reason why the loss of S1PR5 in NK cells could aggravate GVHD in recipient mice. Furthermore, we also demonstrated that the absence of S1PR5 expression in NK cells did not interfere with the antitumour effects of NK cells and T cells in vivo. Taken together, our data indicate that S1PR5 plays an essential role in balancing GVHD and GVT activity. [ABSTRACT FROM AUTHOR]

Allogeneic haematopoietic stem cell transplantation (allo‐HSCT) is the only curative method in treating haematologic malignant diseases. Graft‐versus‐host disease (GVHD) is a common complication post–allo‐HSCT, which can be life‐threatening. Mesenchymal stem cells (MSCs) as an adult stem cell with immunoregulatory function have demonstrated efficacy in steroid resistant acute GVHD (aGVHD). However, the outcome of aGVHD treated with MSCs in clinical trials varied and its underlying mechanism is still unclear. TGF‐β1 is a potent cytokine, which plays a key role in immunoregulation. In the present study, we firstly transduced the lentivirus vector containing TGF‐β1 gene with mouse bone marrow‐derived MSCs. Then, we investigated the immunosuppressive effect of TGF‐β1 gene‐modified MSCs on lymphocytes in vitro and its preventive and therapeutical effects on murine aGVHD model in vivo. Murine MSC was successfully isolated and identified. TGF‐β1 was efficiently transduced into mouse MSCs, and high level TGF‐β1 was detected. MSC‐TGF‐β1 shared the same morphology and immunotypic features of normal MSC. In vitro, MSC‐TGF‐β1 showed enhanced immunosuppressive function on lymphocyte proliferation. In vivo, MSC‐TGF‐β1 showed enhanced amelioration on the severity of aGVHD both in prophylactic and therapeutic murine models. Finally, the macrophages (MØs) derived from MSC‐TGF‐β1–treated mice showed a remarkably increasing of anti‐inflammatory M2‐like phenotype. Furthermore, the differentiation of CD4+ CD25+ Foxp3+ Treg cells was significantly increased in MSC‐TGF‐β1–treated group. Taken together, we proved that MSC‐TGF‐β1 showed enhanced alleviation of aGVHD severity in mice by skewing macrophages into a M2 like phenotype or increasing the proportion of Treg cells, which opens a new frontier in the treatment of aGVHD. [ABSTRACT FROM AUTHOR]

The mammalian target of rapamycin (mTOR) inhibitor, DNA damage inducible transcript 4 (DDIT4), has inducible expression in response to various cellular stresses. In multiple malignancies, studies have shown that DDIT4 participates in tumorigenesis and impacts patient survival. We aimed to study the prognostic value of DDIT4 in acute myeloid leukaemia (AML), which is currently unclear. Firstly, The Cancer Genome Atlas was screened for AML patients with complete clinical characteristics and DDIT4 expression data. A total of 155 patients were included and stratified according to the treatment modality and the median DDIT4 expression levels. High DDIT4 expressers had shorter overall survival (OS) and event‐free survival (EFS) than the low expressers among the chemotherapy‐only group (all P <.001); EFS and OS were similar in the high and low DDIT4 expressers of the allogeneic haematopoietic stem cell transplantation (allo‐HSCT) group. Furthermore, in the DDIT4high group, patients treated with allo‐HSCT had longer EFS and OS than those who received chemotherapy alone (all P <.01). In the DDIT4low group, OS and EFS were similar in different treatment groups. Secondly, we analysed two other cytogenetically normal AML (CN‐AML) cohorts derived from the Gene Expression Omnibus database, which confirmed that high DDIT4 expression was associated with poorer survival. Gene Ontology (GO) enrichment analysis showed that the genes related to DDIT4 expression were mainly concentrated in the acute and chronic myeloid leukaemia signalling pathways. Collectively, our study indicates that high DDIT4 expression may serve as a poor prognostic factor for AML, but its prognostic effects could be outweighed by allo‐HSCT. [ABSTRACT FROM AUTHOR]