Cytokine storm syndromes (CSS) include different entities such as macrophage activation syndrome, primary and secondary hemophagocytic lymphohistiocytosis (HLH), and multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. An effective management strategy is critical in CSS. While biologics have become an essential part of CSS treatment, hematopoietic stem cell transplantation (HSCT) has changed the fate of primary HLH patients. This chapter will focus on the available alternative immunomodulatory therapies in CSS, which include corticosteroids, cyclosporine A, intravenous immunoglobulin, interleukin 18 binding protein, therapeutic plasmapheresis, HSCT, and mesenchymal stromal cell-based therapies.

A new strategy combining anti-thymocyte globulin with post-transplant cyclophosphamide (ATG/PTCy) for graft-versus-host disease (GVHD) prevention was developed. This study aims to perform a systematic review and meta-analysis of studies comparing ATG/PTCy with ATG or PTCy in patients with hematological malignancies undergoing haploidentical hematopoietic stem cell transplantation. Meta-analysis was conducted with Review Manager version 5.4; pooled risk ratios (RRs) and hazard ratios (HRs) were calculated for dichotomous data and time-to-event data, respectively. A fixed-effects model was used if there was no significant heterogeneity. Literature search and study selection identified 14 eligible studies, including both randomized controlled trial and retrospective comparative studies. Different dosage adjustment strategies were applied; the total dose was 2.5-10 mg/kg for ATG and 29-100 mg/kg for PTCy. Meta-analysis results suggest that ATG/PTCy is associated with significantly lower risk of grades II-IV acute GVHD compared with ATG (RR 0.52; 95% CI: 0.41-0.65; P < .00001) and PTCy (RR 0.53; 95% CI: 0.34-0.83; P = .005) without increasing risk of disease relapse. In addition, ATG/PTCy is associated with significantly better overall survival and GVHD-free/relapse-free survival than ATG and PTCy. Future research is required to further establish the benefits of ATG/PTCy and determine the optimal dosage adjustment strategies.
BACKGROUND: Haploidentical stem cell transplantation (haplo-HSCT) is associated with higher incidences of graft-versus-host disease (GVHD). A new strategy combining anti-thymocyte globulin with post-transplant cyclophosphamide (ATG/PTCy) for GVHD prevention has been developed, but its benefits and risks remain unclear.
OBJECTIVE: This study aims to performs a systematic review and meta-analysis of studies comparing ATG/PTCy with ATG or PTCy in patients with hematological malignancies undergoing haplo-HSCT.
METHODS: Literature search was performed in databases including Ovid Medline, Embase, Cochrane Library and China Biology Medicine (CBM). Two investigators independently screened eligible studies and extracted data. Meta-analysis was conducted with Review Manager version 5.4; pooled hazard ratios (HRs) for time-to-event outcomes were obtained using a generic inverse-variance method, and pooled risk ratios (RRs) for dichotomous data were obtained using the Mantel-Haenszel method. A fixed-effects model was adopted if there was no significant heterogeneity. The primary outcome is incidence of acute GVHD.
RESULTS: Literature search and study selection identified 14 eligible studies, including both 1 randomized controlled trial and 13 retrospective comparative studies. Different dosage adjustment strategies were applied; the total dose was 2.5-10 mg/kg for ATG and 29-100 mg/kg for PTCy. Meta-analysis results suggest that ATG/PTCy is associated with significantly lower risk of grades II-IV acute GVHD compared with ATG (RR 0.52; 95% CI: 0.41-0.65; P < .00001) and PTCy (RR 0.53; 95% CI: 0.34-0.83; P = .005) without increasing risk of disease relapse. In addition, ATG/PTCy is associated with significantly lower risk of grades III-IV acute GVHD (RR 0.33; 95% CI: 0.23-0.49; P < .00001) and chronic GVHD (RR 0.65; 95% CI: 0.51-0.81; P = .0002) in comparison with ATG. Further analyses suggest that ATG/PTCy is associated with significantly better overall survival and GVHD-free/relapse-free survival than ATG and PTCy, but the risks of cytomegalovirus (RR 1.42; 95% CI: 1.03-1.95; P = .03) and Epstein Barr Virus (RR 3.17; 95% CI: 1.61-6.23; P = .0008) reactivation are higher when compared with PTCy.
CONCLUSIONS: Our results suggest that the combination of ATG with PTCy for GVHD prevention in haplo-HSCT is associated with improved efficacy but higher risk of infection. Future research is required to further establish the benefits and risks of ATG/PTCy and determine the optimal dosage adjustment strategies.

A mentee\'s perspective of an academic journey on a path paved by a pioneering transplant surgeon-scientist.

The low-dose anti-thymocyte globulin (ATG) plus low-dose post transplantation cyclophosphamide (PTCy) -based (low-dose ATG/PTCy-based) regimen had a promising activity in preventing of graft-versus-host disease (GVHD) in adult patients. However, its efficacy in pediatric patients remain to be defined. Here, we presented the findings from 35 pediatric patients undergoing haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) with the new regimen for GVHD prophylaxis. The cumulative incidences (CIs) of grades II-III and III-IV acute GVHD (aGVHD) were 34% (95% CI, 17-48%) and 11% (95% CI, 0-21%) within 180 days post-transplantation, respectively. The CIs of chronic GVHD (cGVHD) and moderate-to-severe cGVHD within 2 years were 26% (95% CI, 7-41%) and 12% (95% CI, 0-25%), respectively. The 2-year probabilities of overall survival, relapse-free survival, and graft-versus-host disease and relapse-free survival were 89% (95% CI, 78-100%), 82% (95% CI, 68-98%) and 59% (95% CI, 43-80%), respectively. The CIs of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation by day 180 were 37% (95% CI, 19-51%) and 20% (95% CI, 6-32%) respectively. These results strongly advocate for the efficacy of the low-dose ATG/PTCy-based regimen as a robust strategy for GVHD prevention in haplo-PBSCT for pediatric patients.

This retrospective analysis evaluated the use of anti-thymocyte globulin (ATG) with or without post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GvHD) prophylaxis in children with acute leukemia undergoing hematopoietic stem cell transplantation (HSCT). The study included 57 children, with 35 in the ATG-PTCy group and 22 in the ATG group. While overall incidence of acute and chronic GvHD did not differ significantly between groups, the ATG-PTCy group had lower rates of grade II-IV acute GvHD (p = 0.013) and moderate-to-severe chronic GvHD (p = 0.001) compared to the ATG group. Importantly, ATG-PTCy significantly improved GvHD/relapse-free survival (GRFS) compared to ATG (65.71% vs. 36.63%; p = 0.003). There were no differences in engraftment, infection rates, immune reconstitution, overall survival, leukemia-free survival, relapse rate, or non-relapse mortality between the two groups. Combining ATG with PTCy may reduce moderate-to-severe GvHD and improve GRFS in children undergoing HSCT for acute leukemia.

This study aimed to assess the efficacy of dual T-cell suppression using individually tailored doses of antithymocyte globulin (ATG) and attenuated dose of post-transplant cyclophosphamide (PTCy) in haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We conducted a retrospective analysis of 78 adults with acute leukemia or myelodysplastic syndrome who underwent haplo-HSCT using intravenous busulfan and fludarabine conditioning. Thirty-two patients received attenuated ATG/PTCy, while 46 patients received ATG (7.5 mg/kg) as GVHD prophylaxis. The 100-day cumulative incidence of grade III-IV (9.7% vs. 32.4%, P = 0.018) acute GVHD, as well as 2-year moderate-severe chronic GVHD (13.9% vs. 43.9%, P = 0.018) in the ATG/PTCy group were significantly lower than those in the ATG group. The 2-year overall survival was comparable between the two groups. However, 2-year GVHD-free, relapse-free survival in the ATG/PTCy group was significantly higher compared to that in the ATG group (38.9% vs. 21.7%, P = 0.021). Moreover, during post-engraftment period, the ATG/PTCy group exhibited lower incidences of life-threatening bacterial (12.5% vs. 37%, P = 0.033) and viral infection (0% vs. 17.4%, P = 0.035) than the ATG group. In conclusion, the combination of individually tailored ATG and low-dose PTCy appears to be a promising strategy in haplo-HSCT.

Reduced-toxicity conditioning (RIC) regimens are used for allogeneic hematopoietic stem cell transplantation in older patients. However, successful outcomes are hindered by graft-versus-host disease (GVHD), treatment-related mortality, and relapse, particularly after haploidentical donor hematopoietic stem cell transplantation (HID-HSCT). The aim of this study was to evaluate the effectiveness of an RIC conditioning regimen that included a combination of cyclosporin A, methotrexate (on day + 1), mycophenolate, lower doses of post-transplantation PTCy (40 mg/kg on day + 3), and ATG (7.5 mg/kg) as GVHD prophylaxis prior to haplo-stem cell transplantation (haplo-SCT) in older patients.
METHODS: We retrospectively analyzed outcomes in 55 patients ≥ 55 years of age with hematologic malignancies treated with fludarabine, cytarabine, busulfan, and low-dose cyclophosphamide as the conditioning regimen between January 1, 2019, and November 30, 2023.
RESULTS: Neutrophil engraftment was successful in all patients within 28 days, with 54 patients (98.2%) achieving complete donor chimerism. The cumulative incidence of non-relapse mortality was 0% at 30 days, 7.5% at 100 days, and 19% at 1 year. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 25% (95%CI, 15-38%), whereas that of grade III-IV aGVHD was 9.1% (95% CI, 3.3-19%). The cumulative incidence of extensive chronic graft-versus-host disease at 1 year was 3.6% (95%CI, 0.66-11%). The cumulative incidences of relapse, overall survival, and GVHD-free/relapse-free survival at 1 year were 9.0%, 71.6%, and 67.1%, respectively.
CONCLUSIONS: An RIC conditioning regimen, including a combination of lower PTCy/ATG as GVHD prophylaxis, followed by haplo-SCT, might be a promising option for appropriately selected older patients.

Despite notable advancements in immunotherapy in the past decades, allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a promising, potentially curative treatment modality. Only a limited number of studies have performed a direct comparison of two prevalent rabbit anti-thymocyte globulin (r-ATG) formulations-specifically, Thymoglobuline (ATG-T, formerly Genzyme) and Grafalon (ATG-G, formerly Fresenius). The primary objective of our retrospective analysis was to compare the outcomes of adult patients undergoing matched or mismatched unrelated donor (MUD/MMUD) allo-HCT, with a graft-versus-host disease (GvHD) prophylaxis based on either ATG-T or ATG-G. A total of 87 patients who had undergone allo-HCT between 2012 and 2022 were included. We observed no significant differences between ATG-T and ATG-G concerning the occurrence of acute graft-versus-host disease (aGvHD), regardless of its severity. Conversely, chronic graft-versus-host disease (cGvHD) occurred less frequently in the ATG-T group compared to the ATG-G group (7.5% vs. 38.3%, p = 0.001). The negative impact of ATG-G on cGvHD was confirmed by multivariate analysis (HR 8.12, 95% CI 2.06-32.0, p = 0.003). Patients treated with ATG-T manifested a higher incidence of cytomegalovirus (CMV) reactivations (70% vs. 31.9%, p < 0.001), with a shorter time between transplant and CMV (<61 days, 77.8% vs. 33.3%, p = 0.008) and a higher median CMV copy number (1000 vs. 0, p = 0.004). Notably, despite a higher occurrence of CMV reactivations in the ATG-T cohort, most patients were asymptomatic compared to ATG-G (85.7% vs. 43.8%, p = 0.005). By multivariate analysis, only aGvHD had an influence on CMV reactivations (HR 0.18, 95% CI 0.04-0.75, p = 0.019). Finally, we observed no significant differences in terms of 5-year overall survival (OS) and 3-year relapse-free survival (RFS) while comparing ATG-T and ATG-G (32.0% vs. 40.3%, p = 0.423; 66.7% vs. 60.4%, p = 0.544, respectively).

OBJECTIVE: This study aimed to investigate the prognosis of unrelated umbilical cord blood transplantation (UCBT) using low-dose anti-thymocyte globulin (ATG) in children diagnosed with severe aplastic anemia (SAA).
METHODS: This retrospective case series study was conducted involving pediatric SAA patients treated at the Capital Institute of Pediatrics from January 2020 to February 2023. All patients underwent a reduced-intensity conditioning (RIC) regimen alongside low-dose ATG.
RESULTS: The study comprised nine patients (five males) with a median age of 5 years (range: 1.7 to 7 years). The median follow-up duration was 799 days (range: 367 to 1481 days), during which all patients survived. The median time interval from diagnosis to transplantation was 3 months (range: 1 to 9 months). The median dosage of ATG administered was 5 mg/kg (range: 2.5 to 7.5 mg/kg). The median durations for granulocyte and platelet engraftment were 15 days (range: 12 to 23 days) and 26 days (range: 12 to 41 days), respectively. Three patients experienced grade 2-4 acute graft-versus-host disease (aGVHD). Epstein-Barr virus (EBV) reactivation was observed in three patients, while cytomegalovirus (CMV) reactivation occurred in seven patients, with no cases of CMV disease or post-transplant lymphoproliferative disorder (PTLD). One patient experienced recurrence 15 months after transplantation due to influenza A infection.
CONCLUSIONS: These findings indicate that SAA patients may attain a favorable prognosis following UCBT with a RIC regimen combined with low-dose ATG.

暂无摘要。