III-IV aGVHD Research Articles

Optimized Double-Unit Cord Blood Transplantation Mitigates Transplant-Related Mortality Resulting in High Progression-Free Survival in Adults with Hematologic Malignancies

Background : Double-unit cord blood transplantation (dCBT) with intermediate intensity conditioning (Cy50/ Flu150/ Thio10/ TBI400cGy) and cyclosporine-A (CSA)/ mycophenolate mofetil (MMF) graft-versus-host disease (GVHD) prophylaxis has been associated with high progression-free survival (PFS) in adult patients (pts) with hematologic malignancies ( Barker JN et al, Blood Advances 2020). Now, our Center has investigated multiple refinements to further mitigate transplant-related mortality (TRM). Herein, we have analyzed transplant outcomes in these adult dCBT pts to establish an optimized dCBT platform. Methods : Consecutive adult first allograft pts with high-risk hematologic malignancies who underwent first allografts with intermediate intensity dCBT between 3/2018-8/2022 were analyzed. Optimizations involved further refined unit selection placing highest priority on unit quality (i.e. optimized banking practices) & CD34+ cell dose over HLA-match, ensuring therapeutic (CSA) levels (> 250 ng/mL) by day 0, prompt treatment of pre-engraftment syndrome (PES) & letermovir prophylaxis in CMV seropositive pts from day +7. Also, we have investigated 2 strategies to mitigate acute graft-versus-host disease (aGVHD): pts early in the study period received CSA, MMF & tocilizumab (8 mg/kg on day -1) prophylaxis ( Toci Group), whereas recent pts ( Recent Group) received CSA/ MMF with prompt therapy of clinically diagnosed aGVHD. Results : Of 74 patients (Table), 49 were in the Toci Group, & 25 in the Recent Group. Most pts were transplanted for acute leukemia (n = 55, 74%) & over half (n = 39, 53%) had non-European ancestry. Distribution of diagnoses, CMV serostatus, HCT-CI & graft characteristics were similar between the groups but Recent Group pts tended to be younger (38 vs. 47 years, p = 0.071). Toci Group pts had delayed neutrophil recovery [engraftment incidence 94% (95%CI: 87-99) at a median of 25 days (range 16-40), one graft failure], but low rates of PES (n = 19, 39%). The day-100 incidence of grade II-IV & III-IV aGVHD were 69% (95%CI: 56-82) & 10% (95%CI: 2-19), respectively. One pt (false negative CMV-serostatus) who did not receive letermovir had CMV infection. One-year TRM was 16% (95%CI: 6-27) with a 1-year relapse rate of 6% (95%CI: 3-13). TRM was due to infection (n = 3), aGVHD (n = 3, 1 with concurrent COVID-19 infection), multiorgan failure (n = 2) & graft failure (n = 1). With a median follow-up of 47 months (range 28-62), the 1-year OS was 84% (95%CI: 73-94) & 1-year PFS was 78% (95%CI: 66-89). By contrast, the engraftment incidence in Recent Group pts was 100% with a faster median neutrophil recovery of 19 days (range 11-36, p = 0.002) & all engrafted platelets at a median of 36 days (range 24-92). However, most Recent group pts developed PES [n = 20 (80%), p < 0.001] although this responded promptly to short course corticosteroids. Day 100 grade II-IV aGVHD was also higher [92% (95%CI: 81-99), p = 0.009], although grade III-IV aGVHD was low [8% (95%CI: <1-19)] & similar to tocilizumab pts. Day 100 incidence of CMV was 0%. With a median follow-up of 17 months (range 6-50), the 1-year TRM in Recent Group pts is 0% with a 1-year relapse incidence of 13% (95%CI: 7-27). Consequently, the 1-year OS & PFS are high at 96% (95%: 89-99) & 87% (95%CI: 74-99), respectively (Figure). Conclusions: Optimized dCBT with intermediate intensity conditioning, graft selection that prioritizes unit quality & CD34+ dose, CSA/ MMF prophylaxis with prompt therapy of PES & aGVHD, & letermovir CMV prophylaxis mitigates TRM in young & middle-aged adults. Thus, combined with relatively low relapse rates, the PFS & OS are high. Tocilizumab has been abandoned due to its notable association with delayed neutrophil engraftment & lack of survival advantage. Letermovir is highly effective completely preventing CMV infections & may contribute to the reduced aGVHD-related mortality recently (as compared to the pre-tocilizumab era), since avoidance of CMV antiviral therapy toxicities greatly facilitates aGVHD prevention & therapy. Given the rapid availability of cryopreserved unmanipulated CB grafts & frequent limitations of URD availability for minority populations, optimized dCBT is a highly attractive curative therapy for acute leukemias & other high-risk myeloid malignancies warranting prospective multi-center investigation.

Low-Dose Decitabine Plus Venetoclax As Post-Transplant Maintenance for High-Risk Myeloid Malignancies

Background: Allogeneic stem cell transplantation (allo-SCT) is potentially curative for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, post-SCT relapse remains a major cause of treatment failure for these patients and strategies to prevent post-transplant relapse are urgently needed. The combination of venetoclax (VEN) with either azacitidine (AZA) or decitabine (DEC) has shown promising results in older or unfit patients with AML and is now being investigated in younger patients as well. Herein, we report our experience of administering low-dose DEC and VEN as post-transplant maintenance in patients with high-risk myeloid malignancies. Methods: A retrospective chart review was performed to evaluate outcomes of patients with AML and MDS that received post-SCT maintenance with DEC and VEN at the University of Alabama at Birmingham. DEC was administered at 10mg/m 2 on days 1-3 per cycle and VEN was given at a target dose of 200mg on days 1-28 for AML and days 1-14 for MDS. The dose of VEN was reduced to 20mg when administered with voriconazole or posaconazole or 100mg when administered with fluconazole or isavuconazium. The cycle length was 4 weeks. Results: We identified 19 patients between March 2021 and May 2023 that received post-SCT DEC/VEN for AML and MDS (Table 1). The median follow-up was 10m (range 3-26m). The median age was 60y (range 34-69y). There were 10 (53%) females and 13 (68%) non-Hispanic whites (NHWs). Fourteen patients had AML and 5 had MDS. For patients with AML, 10 had poor-risk and 4 had intermediate-risk disease per ELN 2017. At the time of transplant, 11 patients with AML were in CR1 (CR1=6, CRi1=5), 2 were in CR2 (CR2=1, CRi2=1) and 1 was in CR3. Three patients with AML had MRD+ at the time of transplant (CRi1=2, CR3=1). For patients with MDS, 2 had very-high and 2 had high-risk disease per R-IPSS. One patient had therapy-related MDS. Two patients with MDS had CR, 2 had stable disease and 1 had hematological-improvement at the time of transplant. Overall, 6 patients (32%) had a TP53 mutation. Donor type was matched-related in 5 patients, matched-unrelated in 12 patients and haploidentical in 2 patients. Seventeen patients received reduced-intensity conditioning (RIC). GVHD prevention consisted of tacrolimus and methotrexate in 14 patients and post-transplant cyclophosphamide-based in 5 patients. The median time to initiating maintenance therapy was 69d (range 54-200d) post-SCT. The median number of cycles administered was 6 (range 2-24). Grade III-IV neutropenia, anemia and thrombocytopenia occurred in 5, 1 and 2 patients, respectively. Two patients had febrile neutropenia and one patient had candida esophagitis. Five patients required a reduction or interruption in the dose due to adverse events. In all cases, the VEN duration was shortened by 1 week. The cumulative incidence (CI) of day 100 grade II-IV and III-IV aGVHD was 13% and 5%, respectively. There were no grade IV cases. The 1y CI of moderate-severe cGVHD was 26%. To date, one patient who received a RIC haplo-SCT for poor-risk AML in CR2 relapsed 14m after SCT. The 1y non-relapse mortality was 11%. The 1y OS for the entire cohort was 84% (Figure 1). Conclusion: Our preliminary data suggests that the combination of low-dose DEC plus VEN is a safe and potentially effective strategy to reduce the risk of post-SCT relapse. Adverse effects mainly included manageable cytopenias with no increase in risk of GVHD. The efficacy of the combination appears to be promising but needs longer follow-up as well as confirmation in large, randomized studies.

Effectiveness and Safety of Rabbit Anti-Thymocyte Globulin Versus Non-Anti-Thymocyte Globulin Regimens for Graft-Versus-Host Disease Prophylaxis: A Systematic Review and Meta-Analysis

Introduction:Graft-versus-host disease (GVHD) is a serious complication after allogeneic hematopoietic stem cell transplant (HSCT), limiting its success. Meta-analyses have confirmed clinical efficacy and safety of several types of anti-thymocyte globulins (ATGs) in GVHD prophylaxis; however, there are no meta-analyses assessing the efficacy of rabbit anti-thymocyte globulin (rATG; Thymoglobulin ®) in particular. This study assessed the effectiveness and safety of rATG relative to non-ATG prophylaxis regimens for acute GVHD (aGVHD) or chronic GVHD (cGVHD) based on randomized controlled trials (RCTs) and observational studies. Methods:A literature search was conducted in MEDLINE, Embase, Cochrane Central, and the Web of Science using the PICOS framework to identify studies published until June 2022 focusing on the prophylaxis use of rATG in GVHD. The United States and European Union clinical trial registry databases were also searched to identify unpublished data from studies. Efficacy outcomes included incidences of aGVHD (Grade II-IV and Grade III-IV), cGVHD (mild to severe and moderate to severe) and overall survival. Safety outcomes included the incidence of relapse, cytomegalovirus (CMV) infection, and Epstein-Barr virus (EBV) reactivation. Pre-specified subgroups of interest included donor type, and stem cell source (an unrelated peripheral blood [PB]/bone marrow [BM] transplant, a related PB/BM transplant, or a mixed unrelated and related PB/BM transplant). All analyses present the overall effect, the effect by subgroups, and the percentage contributing to the overall effect. Results: Overall, 4295 records were retrieved from the databases and hand searching (1000 from PubMed, 1700 from Embase, 1419 from the Web of Science, 155 from the Cochrane Central, 20 from the clinical trial registry databases and 1 from hand searching). After screening, 45 studies (6 RCTs, 35 retrospective studies and 4 prospective observational studies) published between 2001 and June 2022 were included in this review. Among the 45 studies, 39 reported aGVHD Grade II-IV, 33 reported aGVHD Grade III-IV, 33 reported mild to severe cGVHD, 31 reported moderate to severe cGVHD, and 41 reported overall survival ( Table). Use of rATG for GVHD prophylaxis resulted in a significant 24% reduction in Grade II-IV aGVHD (RR=0.76; 95% CI: 0.68-0.85) and a significant 43% reduction in Grade III-IV aGVHD (RR=0.57; 95% CI: 0.49-0.65) compared with non-ATG arm across all donor types. Similarly, a 35% reduction was observed in mild to severe cGVHD (RR=0.65; 95%CI: 0.57-0.74) and a significant 48% reduction (RR=0.52; 95% CI: 0.45-0.60) was observed in moderate to severe cGVHD across all donor types. Use of rATG decreased overall mortality by 9% (RR=0.91; 95% CI: 0.85-0.99). Among the subgroups, the decrease in mortality was statistically significant in unrelated PB/BM transplant donors. The incidence of relapse was reported in 36 studies, with an overall 18% increase (RR=1.18; 95% CI: 1.08-1.30) for patients treated with rATG. However, among the subgroups, the incidence of relapse was comparable between rATG and non-ATG prophylaxis arms for all types of donors. rATG and non-ATG prophylaxis regimens were comparable in terms of CMV infection (RR=1.00; 95% CI: 0.88-1.15). The incidence of EBV infection was significantly higher in the rATG arm (RR=2.53; 95% CI: 1.54-4.17) than that in the non-ATG arm. Conclusions: This meta-analysis provides useful information to support patients and health-care providers in making treatment decisions for the prevention of aGVHD or cGVHD after allogeneic HSCT. rATG demonstrated significant reductions in the incidence of both aGVHD and cGVHD and increased the overall survival across donor types and stem cell sources despite slightly increased risk of relapse in rATG arm versus non-ATG arm.

Phase I/II Study of Reduced Dosing of Post-Transplantation Cyclophosphamide (PTCy) after HLA-Identical Peripheral Blood Hematopoietic Stem Cell Transplantation

Introduction Post-transplant cyclophosphamide (PTCy)-based prophylaxis for acute graft versus host disease (aGvHD) has become a standard protocol in HLA haploidentical bone marrow transplantation. Preliminary evidence indicates that compared to the standard dosage (50 mg/kg on days +3 and +4 post-transplantation), a regimen of half the typical cyclophosphamide dosage is both feasible and effective. However, the optimal dosage and timing of PTCy for aGvHD prophylaxis in a HLA identical setting, using peripheral stem cells as the graft, remain unknown. This study aims to investigate the efficacy and safety of a reduced PTCy dosage regimen in patients undergoing peripheral blood stem cell transplants (PBSCT) with HLA indentical donors. Methods This prospective, single-center phase I/II study enrolled patients scheduled for PBSCT with HLA identical donors. The aGVHD prophylaxis regimen comprised PTCy on days +3 and +4, followed by cyclosporine initiation from day 5 post-transplant. In the phase I stage, an initial cohort of five patients received PTCy at a dosage of 50 mg/kg/day on days +3 and +4 (designated as dose level 1, DL1). This was followed by a 3+3 dose de-escalation design with subsequent dose levels as follows: DL2, 50 mg/kg on day +3 and 25 mg/kg on day +4; and DL3, 25 mg/kg on both day +3 and +4. The dose-limiting toxicity for this de-escalation was defined as the occurrence of grade III-IV aGVHD within the first 100 days post-transplantation. The phase II stage comprised an expansion cohort, which was based on the optimal dose identified during phase I. aGvHD classification was established using the Mount Sinai Acute GVHD International Consortium (MAGIC) criteria, while chronic GvHD (cGvHD) was assessed per the latest National Institutes of Health Consensus on cGvHD. Patients were closely followed-up at +1, +2, +3, +4, +6, +9, +12, +18, and +24 months post-transplant. Results In the first stage, a total of 11 patients (5 in DL1, 3 in DL2, and 3 in DL3) were included, and no patient developed grade III-IV aGVHD. Based on this, DL3 was selected as the PTCy dose for phase II, which comprised 18 patients. Overall, 29 patients (17 females, 12 males) with a median age of 39 years (range 17-65) were included, and the median follow-up duration was 12.7 months (range 2.2-22.1). Patient and disease characteristics are summarized in Table 1. By day +30 post-ASCT, all patients achieved complete remission (CR) and minimal residual disease (MRD) clearance. No patient developed grade III-IV aGVHD within 100 days post-transplantation. There was no significant difference in the neutrophil and platelet engraftment interval among the three groups (Figure 1A, B). Among the 21 patients who received the DL3 dose of PTCy, the estimated cumulative incidence of grade II to IV aGVHD at day +100 was recorded at 28.6%, and the incidence of aGVHD at day +100 presented no difference among the three DL groups (Figure 1C). In addition, 1 patient in DL3 developed grade IV intestinal aGVHD on day +141 and died one month later. The estimated 1-year cumulative incidence of hemorrhagic cystitis (HC) and cytomegalovirus (CMV) reactivation was 19.3% and 19%, respectively (Figure 1D). Five patients (all in DL3) experienced relapse, with a median interval of 6.7 months and an estimated 1-year cumulative incidence of 10.6%. A total of 5 fatalities occurred during our study (1 in DL1, and 4 in DL3), 1 due to relapse, 2 from COVID-19-associated pulmonary aspergillosis, 1 from severe septicemia and 1 due to grade IV aGVHD as mentioned above. The estimated 6-month cumulative incidence of NRM was 9.5%, presenting no difference among the three DL groups (Figure 1E). Among the 20 evaluable patients, the estimated 1-year cumulative incidence of chronic GVHD (cGVHD) and moderate cGVHD was 37.3% and 16% (Figure 1F), respectively, with no severe cGVHD observed. No cases of patient relapse were reported. The estimated 1-year progression-free survival (PFS) and overall survival (OS) were 61.2% and 80.4%, respectively (Figure 1G). Conclusion The findings of this study substantiate that a two-day regimen of PTCy at 25 mg/kg/day serves as an effective and safe prophylactic measure against aGVHD, comparable to the standard dosing protocol. However, to definitively establish whether the de-escalated PTCy dosage provides superior outcomes to the standard regimen, longer-term follow-up and comparative studies are warranted.

Effectiveness of In Vivo T-Cell Depleted Regimen Containing Porcine Antilymphocyte Globulin and Rabbit Antithymocyte Globulin in Preventing Acute Gvhd after Haploid Hematopoietic Stem Cell Transplantation

Objective To compare the clinical efficacy of porcine antilymphocyte globulin (p-ALG) and rabbit antithymocyte globulin (r-ATG) in the treatment of hematologic malignancies using haploid hematopoietic stem cell transplantation (haplo- HSCT), this study was conducted. Methods This was a single center retrospective analysis of 178 subjects who received haplo-HSCT with p-ALG or r-ATG from January 2020 to December 2022. The patients were divided into three groups according to the doses of p-ALG or r-ATG used in the conditioning regimens. The study evaluated and compared the occurrence of early fever, graft versus host disease (GVHD), infection, and survival among the three groups of patients. Results A total of 178 patients were enrolled in the study with a median age of 30 (14-61) years, including 95 men and 83 women. The median follow-up time post-transplantation was 20.1 (1.7-36.9) months. The study included 57 patients in the p-ALG 75mg/kg group, 49 patients in the p-ALG 90mg/kg group, and 72 patients in the r-ATG 7.5mg/kg group, respectively. The incidences of neutrophil and platelet engraftment, respectively, were 100%,93.5%, and 91.3% (p=0.133); 100%, 93.6%, 90.3% (p=0.033) in P-ALG 75mg/kg, P-ALG 90mg/kg and r-ATG 7.5mg/kg. The median time to neutrophil engraftment was 11 days for the P-ALG 75mg/kg group, 12 days for the P-ALG 90mg/kg group, and 12 days for the r-ATG 7.5mg/kg group (p=0.133). The median time to platelet engraftment was 12 days for the P-ALG 75mg/kg group, 14 days for the P-ALG 90mg/kg group, and 13 days for the r-ATG 7.5mg/kg group (p=0.033). In the p-ALG 75mg/kg, p-ALG 90mg/kg, and r-ATG 7.5mg/kg groups, 16 patients (28.1%), 24 patients (49.0%) and 35 patients (48.6%) developed fever within 14 days after transplantation, respectively. Cytokine release syndrome was found to be the most common cause of fever. The incidence of grades Ⅱ-Ⅳ acute GVHD (aGVHD) and grades Ⅲ-Ⅳ aGVHD, respectively, were 15.8%, 12.2%, and 12.5% (p=0.853); 5.3%, 2.0%, and 5.6% (p=0.523) in P-ALG 75mg/kg, P-ALG 90mg/kg and r-ATG 7.5mg/kg. The cumulative incidence of chronic GVHD at 1 year was 14.0%, 10.2%, and 15.3% (p=0.731) in the three groups. 43.9%, 71.4%, and 61.1% of patients in the p-ALG 75mg/kg, p-ALG 90mg/kg and r-ATG 7.5mg/kg groups, respectively, experienced at least one infection within 1 year after haplo-HSCT (p=0.0.13). Notably, the CMV infection rate in the p-ALG 75mg/kg group was significantly lower than in the p-ALG 90mg/kg and r-ATG 7.5mg/kg groups. The 2-year overall survival (OS) rates of p-ALG 75mg/kg, p-ALG 90mg/kg and r-ATG 7.5mg/kg groups were 78.2%, 70.6%, and 72.3% (p=0.491). The cumulative incidence of 2-year relapse were 33.0%, 29.8%, and 30.0% (p=0.834). ConclusionsCompared with r-ATG group, the p-ALG 75mg/kg group showed a lower incidence of infection. However, there were no significant differences between the two groups in terms of the incidence of grades Ⅱ-Ⅳ aGVHD, 2-year overall survival (OS), and 2-year cumulative incidence of relapse. p-ALG (75mg/kg) has a comparable effect on the prevention of GVHD after haplo-HSCT with a lower incidence of infection. Keywords: Porcine antilymphocyte globulin; Rabbit antithymocyte Globulin; Haploidentical hematopoietic cell transplantation; Graft versus host disease; Infection

Glycolysis-Driven IFN-γ Expression in T-Cell Via Histone Lactylation Promotes Acute Graft-Versus-Host Disease

Background Cell metabolism is a highly regulated process essential for sustaining life and driving evolution. Cellular metabolites and metabolic flux intricately govern post-translational modifications of proteins. In the context of acute graft-versus-host disease (aGVHD), T cells undergo enhanced glycolysis, resulting in increased lactate production. Consequently, lactate may act as a substrate for lysine lactylation (Kla), influencing gene expression by modulating histone biology. This study aims to assess T cell glucose metabolism during aGVHD, investigate the role of histone lactylation, and explore its impact on T cell functionality. Methods We conducted a comparative analysis of histone lactylation between aGVHD patients and individuals undergoing allo hematopoietic stem cell transplantation (control). Subsequently, we established a murine bone marrow transplant model and isolated T cells for analysis. Glucose metabolism status was assessed using extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) assays, along with the 2-NBDG glucose uptake assay. To comprehensively investigate histone lactylation in T cells, we employed the cleavage under targets and tagmentation (CUT&Tag) technique to explore its regulatory effects on gene expression. To investigate the impact of lactatylation on aGVHD pathology, we constructed an aGVHD model by applying T cells with a specific deletion of LDHA. Results By analyzing the serum lactate at the onset of aGVHD, we found that patients with grade III-IV aGVHD had significantly higher lactate levels compared to those with grade I-II aGVHD ( Figure 1A). In light of this finding, we further examined the histone lactylation levels in T cells from aGVHD patients. The results demonstrated an enhanced histone lactylation in these T cells compared to controls ( Figure 1B). In the aGVHD mice, the ECAR of T cells exhibited a significant increase ( Figure 1C). Intriguingly, the OCR were also significantly higher in the aGVHD mice compared to the bone marrow T cell-depleted (BM-TCD) mice ( Figure 1D). Additionally, the 2-NBDG revealed a significantly higher fluorescence intensity in aGVHD mice ( Figure 1E). Through analysis of T cell RNA-seq data, we discovered upregulation of most glycolytic enzymes in aGVHD mice similar to human data ( Figure 1F). Notably, LDHA, glucose transporter 1 ( Slc2a1), and monocarboxylate transporter 4 ( Slc16a3) were highly upregulated ( Figure 1G). The upregulation of LDHA in T cells from aGVHD mice prompted us to investigate the presence of histone lactylation. The results revealed that histone in T cells from aGVHD mice exhibited a higher level of lactylation ( Figure 1H). Because lactylation was particularly prominent at the H4K12 site, we conducted CUT&Tag experiments. We found promoters of key regulatory genes of the Th1 subset, such as Tbx21 and Ifng, along with several genes associated with IFN-γ production, including Stim2, Crtam, Il18rap, Fasl, and Phf11a, Cxcr3 were all lactylated ( Figure 1I). Specifically, the Call Peak analysis confirmed the elevated H4K12la levels on the promoters Tbx21 and Ifng ( Figure 1J). The expression of IFN-γ and CXCR3 in CD4 + and CD8 + T cells of aGVHD mice was significantly higher than in BM-TCD mice ( Figure 1K). To confirm the role of histone lactylation in IFN-γ generation, we intervened with T cells using the p300 lactylation writer inhibitor (A485). The results demonstrated a significant reduction in histone lactylation upon A485 treatment, which was effectively restored by the addition of neutral lactate sodium (Nala) ( Figure 1L). Notably, A485 treatment led to a decrease in IFN-γ + T cells, while Nala administration resulted in a substantial recovery of IFN-γ expression ( Figure 1M). Additionally, the infusion of Cd4creLdhafl/fl T cells into recipient mice improved the survival of aGVHD mice ( Figure 1N). Conclusion This study represents the first global investigation of T cell histone lactylation in aGVHD. Importantly, we have uncovered a novel link between histone lactylation and the regulation of IFN-γ-related gene expression in the context of aGVHD. Considering the heightened glycolysis and the pivotal role of IFN-γ in aGVHD pathology, it is plausible to postulate that T cell-produced lactate induces histone lactylation, thereby promoting the transcription of IFN-γ-related genes and contributing to the development of aGVHD.

Herombopag, a Second Generation Thrombopoietin-Receptor Agonist, Stimulates Platelet Engraftment after Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: The delayed platelet engraftment is a common complication in allogeneic hematopoietic stem cell transplantation (allo-HSCT), which elevates treatment-related mortality and impairs quality of life. Although some studies reported that platelet engraftment after allo-HSCT was promoted by thrombopoietin-receptor agonists (TPO-RAs), the recommended detailed TPO-RA administration is still lacking. This prospective, single-center, investigator-initiated pilot study aims to explore the efficacy and safety of herombopag, a second-generation TPO-RA, to stimulate platelet engraftment in haploidentical allo-HSCT (haplo-HSCT). Methods: A total of 36 patients (median age 38; range 15-59 years) with anaplastic anemia, myelodysplastic syndrome, acute leukemia, granulocytic sarcoma, or primary hemophagocytic lymphohistiocytosis were enrolled between November 2021 and June 2023. All patients received haplo-HSCT and post-transplant cyclophosphamide for acute graft-versus-host disease (aGVHD) prophylaxis. Patients received herombopag from day+5 post-HSCT until platelet>100,000/µL, disease progression, intolerable toxicity, or withdrawal of informed consent. The dose of herombopag was 5 mg/day initially and reduced to 2.5 mg/day when platelet>75,000/µL. Complete platelet engraftment (CPE) was defined as a platelet count exceeding 50,000/μl for seven consecutive days without transfusion. Partial platelet engraftment (PPE) was defined as a platelet count exceeding 20,000/μl for seven consecutive days without transfusion. The objective response included both CPE and PPE. The primary endpoint was the 21-day cumulative incidence and 28-day cumulative incidence of CPE and objective response after haplo-HSCT. The secondary endpoints were time to CPE, time to objective response, platelet transfusion units, aGVHD, relapse, non-relapse mortality, and safety. Results: The patients received herombopag treatment for a median of 15 days. The 21-day cumulative incidence of CPE was 55.6%, and that of objective response was 77.8%. The 28-day cumulative incidence of CPE was 69.4%, and that of objective response was 80.6%. The median time to objective response was 20.5 (95%CI 17-27) days. The median time to CPE was 23 (95%CI 10-33) days. The mean units of platelet transfusions required within 30 days after HSCT was 6.7. The median follow-up time was 12.1 months. The one-year overall survival rate was 85.3% (95%CI 72.8%-99.8%). Two patients died of aGVHD and two patients died of lung infection. Four Patients (11.1%) experienced molecular relapse. The cumulative incidence of grade III-IV aGVHD was 16.7%. Furthermore, cytomegalovirus reactivation occurred in 13 patients (36.1%). The most common herombopag-related adverse events were hypomagnesemia (61.1%), increased GGT (52.8%), increased ALT (38.9%), and increased bilirubin (19.4%). No grade III/IV adverse events were observed. Conclusion: Herombopag significantly stimulates platelet engraftment in haplo-HSCT patients and has a favorable safety profile. Further research with a larger sample size and longer follow-up period is required to confirm its optimal use.

Efficacy of venetoclax combined with decitabine conditioning regimen for allogeneic hematopoietic stem cell transplantation in high-risk and elderly patients with myeloid neoplasms.

This prospective clinical investigation focused on the addition of venetoclax and decitabine to myeloablative conditioning regimens, targeting high-risk and elderly individuals undergoing allogeneic hematopoietic stem cell transplantation. In total, 19 patients were enrolled in the trial between December 2021 and February 2023, and their progress was monitored for a median follow-up period of 258 days, ranging from 35 to 544 days. In the initial regimen (n=11), venetoclax was administered at a dosage of 400 mg per day from day -14 to day -1, while in the modified regimen (n=8), it was administered from day -14 to day -5. Decitabine was orally administered at a dosage of 20mg/m2/day from day -7 to day -3. Grade 3/4 adverse events observed included hematological events, hypertension, infections, allergy, and increased amylase. In the entire cohort, the overall survival (OS) and relapse-free survival (RFS) rates at 6 months were 63% (95% CI, 45-89) and 63% (95% CI, 45-89), respectively. The non-relapse mortality (NRM) rate at 6 months was 37% (95% CI, 16-58), while the cumulative incidence of relapse (CIR) was 0. However, the incidence of grade II-IV acute graft-versus-host disease (aGVHD) and grade III-IV aGVHD within 100 days was found to be 31% (95% CI, 12-53) and 26% (95% CI, 9-47), respectively. These rates indicate a relatively high occurrence, making it less suitable to administer the regimen to elderly patients. Therefore, further high-quality studies are required to enhance the conditioning regimen specifically for high-risk and elderly patients diagnosed with myeloid neoplasms. Clinical trial registration: ChiCTR2100050272.

Thiotepa-busulfan-fludarabine Compared to Treosulfan-based Conditioning for Haploidentical Transplant With Posttransplant Cyclophosphamide in Patients With Acute Myeloid Leukemia in Remission: A Study From the Acute Leukemia Working Party of the EBMT.

We conducted a registry analysis including adult acute myeloid leukemia (AML) patients in remission who had received thiotepa, busulfan, and fludarabine (TBF) or treosulfan-based (Treo) conditioning for haplo-hematopoietic stem cell transplant (HSCT) with posttransplant cyclophosphamide (PTCy) between 2010 and 2020. A total of 1123 patients met the inclusion criteria (968 received TBF and 155 received Treo). A 1:1 matched-pair analysis was performed on 142 TBF and 142 Treo patients. In the Treo group, 68% of patients received treosulfan at a dose ≥36 g/m2 and 54% of patients received a second alkylator (thiotepa or melphalan). We observed a trend toward increased incidence of grade II-IV acute (a) graft-versus-host disease (GVHD) at 180 days in the TBF group compared with Treo (29% versus 20%; P = 0.08), while incidence of grade III-IV aGVHD was not statistically different. Similarly, the incidence of chronic (c) GVHD was not statistically different in the 2 groups. Incidence of nonrelapse mortality at 2 years was 19% in TBF and 14% in Treo (P = 0.4). Relapse incidence at 2 years was not statistically different in the 2 groups (16% and 18% in TBF and Treo, respectively; P = 0.9). Leukemia-free survival, overall survival, and GVHD-free, relapse-free survival was 65% versus 68% (P = 0.6), 73% versus 76% (P = 0.5), and 54% versus 53% (P = 0.8) in TBF versus Treo, respectively. In conclusion, we did not find a significant difference between the 2 conditioning in the present study; Treo and TBF represent 2 valid alternative regimens for haplo-HSCT with PTCy for AML in remission.

Impact of Donor Statin Treatment on Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation

Some retrospective studies have suggested that long-term donor statin use may protect against graft-versus-host disease (GVHD) in patients receiving cyclosporine (CSP)-based immunosuppression after allogeneic hematopoietic cell transplantation (HCT), but prospective studies of short-term treatment of donors with statin have shown conflicting results. We conducted 2 consecutive prospective clinical trials to assess whether donor statin treatment was associated with protection against severe acute GVHD (aGVHD). In a single-arm phase II trial (study 1), we evaluated whether short-term statin treatment of HLA-matched related donors for 14 days before HCT prevented grade III-IV aGVHD. In a prospective observational cohort study (study 2), we evaluated whether longer-term (>14 days) donor statin use was required for GVHD-protective effects. Study 1 was terminated after 6 of the 35 recipients (17%) developed grade III-IV GVHD. For study 2, we identified 135 patients whose unrelated donors had received long-term treatment with statins up to the time of HCT and 4942 patients whose donors had not received long-term statin treatment. The adjusted odds ratio for grade III-IV aGVHD (statin versus no statin) was .83 (95% confidence interval [CI], .46 to 1.50; P=.54). Multivariable analysis showed no statistically significant differences between the 2 groups in the risk of grade II-IV aGVHD, chronic GVHD, nonrelapse mortality, recurrent malignancy, or overall mortality. Among patients receiving CSP-based immunosuppression, including 35 with donors receiving long-term statin treatment and 973 with donors who did not receive statins, the adjusted odds ratio of grade III-IV aGVHD was .30 (95% CI, .07 to 1.35; P=.12). In study 1, short-term statin treatment of donors was ineffective in preventing grade III-IV GVHD. In study 2, in the prespecified subgroup of recipients given CSP-based immunosuppression, nondefinitive evidence suggested that donor statin use was associated with a reduced risk of severe aGVHD.

Treosulfan-Based Conditioning Regimen In Pediatric Hematopoietic Stem Cell Transplantation: A Retrospective Analysis on Behalf of the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC)

Data on treosulfan-based conditioning regimens are little by little increasing, and the benefits of this approach are consistent, particularly regarding acute toxicity. This study aims to describe the results of treosulfan-based conditioning regimens in children, focusing on toxicity and outcomes when used to treat both malignant and non-malignant diseases. Retrospective observational study on pediatric patients treated in Spain with treosulfan-based conditioning regimens before hematopoietic stem cell transplantation (HSCT), based on data collection from electronic clinical records. One hundred and sixty treosulfan-based conditioning HSCTs to treat non-malignant diseases (n=117) or malignant diseases (n=43) in 158 children and adolescents are reported. Median age at HSCT was 5.1 years (IQR: 2-10). The most frequent diagnoses were primary immunodeficiency (n=42; 36%) and sickle cell disease (n=42; 36%) in the non-malignant cohort and acute lymphoblastic leukemia (n=15; 35%) in the malignant cohort. Engraftment occurred in 97% of the patients. There was a longer median time to neutrophil engraftment (17 vs. 14 days; p=0.008) and platelet engraftment (20 vs. 15 days; p=0.002) in the non-malignant cohort. The 1-year cumulative incidence of VOD was 7.98 (95%CI [4.6-13.6]), with no significant differences between cohorts. The 1-year cumulative incidence of grade III-IV aGvHD was higher in the malignant cohort (18% vs. 3.2%; p=0.011). Overall, cGvHD was more frequently observed in the malignant cohort for both total incidence (9 vs. 3%; p<0.001) and 2-year cumulative incidence of total cGvHD (16 vs. 1.9%; p<0.001). The 2-year cumulative TRM was 15%, with no differences between cohorts. 5-year Overall Survival was 80% (95%CI [72-86]) and was higher in the non-malignant cohort (87 vs. 61%; p=0.01). The 2-year cumulative incidence of relapse in the malignant cohort was 25%. 5-year cumulative GRFS rate was 60% (95%CI [51-70]) and was higher in the non-malignant cohort (72 vs. 22%; p<0.001). The treosulfan-based radiation-free conditioning regimen is feasible, achieving a high engraftment rate and 5-year overall survival. A treosulfan-based conditioning regimen is an emerging option for the first HSCT in non-malignant diseases.

Efficacy and safety of TBI+rATG-based conditioning regimen for haploidentical allogeneic hematopoietic stem cell transplantation in 11 cases of chemotherapy-resistant advanced peripheral T-cell lymphoma

Objective: To evaluate the clinical outcomes and safety of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) using a conditioning regimen based on total body irradiation (TBI) and rabbit anti-human thymocyte globulin (rATG) in the management of chemotherapy-resistant advanced peripheral T-cell lymphoma (PTCL) . Methods: Clinical data of 11 patients with chemotherapy-resistant advanced PTCL who underwent haplo-HSCT with a TBI+rATG-based conditioning regimen at the Department of Hematology, Shanghai Liquan Hospital and Shanghai Zhaxin Integrated Traditional Chinese and Western Medicine Hospital, from September 2019 to December 2022 were retrospectively analyzed. Results: ①Among the 11 patients (six males and five females), with a median age of 40 years (range: 22-58 years), there were six cases of PTCL, not otherwise specified (PTCL-NOS), three cases of angioimmunoblastic T-cell lymphoma (AITL), one case of large-cell transformation of mycosis fungoides (MF-LCT), and one case of T-cell large granular lymphocytic leukemia (T-LGLL). According to the Lugano staging system, all patients were in stage Ⅲ or Ⅳ, and eight patients had B symptoms. Before transplantation, the median number of prior lines of chemotherapy was 4 (range: 2-10), and all patients had progressive disease (PD). The median time from diagnosis to transplantation was 17 months (range: 6-36 months). ②The conditioning regimen consisted of a TBI dose of 10 Gy, administered at 2 Gy on day -8 and 4 Gy from day -7 to day -6, rATG was administered at a daily dose of 2.5 mg/kg from day -5 to day -2. Etoposide (VP-16) was given at a dose of 15 mg/kg/d from day -5 to day -4, while cyclophosphamide (CTX) was administered at a dose of 50 mg/kg/d from day -3 to day -2. In patients with central nervous system involvement, etoposide and cyclophosphamide were replaced with thiotepa (TT) at a dose of 5 mg/kg/d from day -5 to day -4. Additionally, cytarabine (Ara-C) was added at a dose of 2.0 g/m(2) twice a day from day -3 to day -2 into the conditioning. ③Successful engraftment was achieved in all patients, with a median time to neutrophil engraftment of 14.5 d (range: 11-16 d) and a median time to platelet engraftment of 13 days (range: 8-18 days). Acute graft-versus-host disease (aGVHD) occurred in one patient (grade Ⅰ-Ⅱ), and another patient experienced grade Ⅲ-Ⅳ aGVHD. Among the eight survivors, four developed chronic GVHD (cGVHD). ④Post-transplantation, nine patients achieved complete response (CR). ⑤Hematopoietic suppression occurred in all patients after conditioning, with three experiencing diarrhea, four developing mucositis, three exhibiting elevated transaminase/bilirubin levels, and seven developing infectious complications. These non-hematologic adverse events were effectively managed. ⑥At one year post-transplantation, the non-relapse mortality (NRM) was (22.5±14.0) %, the cumulative incidence of relapse (CIR) was (20.2±12.7) %, and overall survival (OS) rate was (72.7±13.4) %, and disease-free survival (DFS) rate was (63.6±14.5) % . Conclusion: TBI+rATG-based conditioning regimen for haplo-HSCT is an effective and safe treatment approach for patients with chemotherapy-resistant advanced PTCL.

Comparison of outcomes for patients with acute myeloid leukemia undergoing haploidentical stem cell transplantation in first and second complete remission.

There was no consensus on whether prognostic advantages existed when transplant conducted at first complete remission (CR1) stage than at second complete remission (CR2) stage for patients with AML who received haploidentical hematological stem cell transplantation (haplo-HSCT). In 768 consecutive AML patients who received haplo-HSCT from January 2014 to December 2017, a 1:2 ratio matched-pair analysis was performed, 69 patients who in CR2 group and 138 CR1 patients were enrolled. Hematopoietic recovery, graft versus host disease (GVHD), relapse, transplant related mortality (TRM), disease-free survival (DFS) and overall survival (OS) were compared in two groups, and further evaluated in low-, intermediate-, and high-risk subgroups. The cumulative incidences of 30-day myeloid recovery and 90-day platelet recovery were comparable in CR1 and CR2 groups. The cumulative incidences of grade II-IV and grade III-IV aGVHD were not significantly different. The cumulative incidences of relapse at 3-year and 5-year in these two groups were 12.4% versus 11.6% (P = 0.880) and 12.4% versus 17.5% (P = 0.322). The cumulative incidences of TRM at 3-year and 5-year were both 10.9% versus 23.2% (P = 0.019). The probability of DFS at 3-year and 5-year were 76.7% versus 65.2% (P = 0.029) and 76.7% versus 59.3% (P = 0.009). The probability of OS at 3-year and 5-year were 81.8% versus 68.1% (P = 0.026) and 76.7% versus 59.3% (P = 0.026). In the intermediate-risk group, TRM was lower in CR1 group, DFS and OS of CR1 group were superior to CR2 group. In conclusion, haplo-HSCT at CR1 stage was of better prognosis for intermediate-risk AML patients than at CR2 stage.

CD3+TCRαβ/CD19+-Depleted Mismatched Family or Unrelated Donor Salvage Stem Cell Transplantation for Graft Dysfunction in Inborn Errors of Immunity

A minority of children experience significant graft dysfunction after an allogeneic hematopoietic stem cell transplant (HSCT) for inborn errors of immunity (IEI). The optimal approach to salvage HSCT is unclear with respect to conditioning regimen and stem cell source. This single-centre retrospective case series reports the outcomes of salvage CD3+TCRαβ/CD19 depleted mismatched family or unrelated donor stem cell transplantation (TCRαβ-SCT) between 2013 - 2022 for graft dysfunction in 12 children with IEI. Outcomes of interest were overall survival (OS), event free survival (EFS), graft-versus-host disease (GvHD)-free and event-free survival (GEFS), toxicities, GvHD, viremia and long-term graft function. A retrospective audit of patients who underwent second CD3+TCRαβ/CD19 depleted mismatched donor graft using Treosulfan-based reduced toxicity myeloablative conditioning. Median age at first HSCT was 8.76 months (range, 2.5 months - 6 years) and at second TCRαβ-SCT was 3.6 years (1.2 - 11 years). Median interval between first and second HSCT was 1.7 years (3 months - 9 years). The primary diagnoses were: severe combined immunodeficiency (SCID) (n=5) and non-SCID IEI (n=7). The indications for second HSCT were: primary aplasia (n=1), secondary autologous reconstitution (n=6), refractory aGVHD (n=3) and secondary leukemia (n=1). Donors were either haploidentical parental donors (n=10) or mismatched unrelated donors (n=2). All received TCRαβ/CD19-depleted-PBSC with a median CD34+ cell dose of 9.3 × 106/kg (2.8-32.3 × 106/kg) and a median TCRαβ+ cell dose of 4 × 104/kg (1.3-19.2 × 104/kg). All engrafted with median days to neutrophil and platelet recovery of 15 (12-24) and 12 (9-19). One developed secondary aplasia and one had secondary autologous reconstitution, but both underwent a successful third HSCT. Four (33%) had grade II aGvHD and none had grade III-IV aGvHD. None had cGvHD but one developed extensive cutaneous cGVHD after third HSCT using PBSC and ATG. Nine (75%) were noted to have at least one episode of blood viremia with HHV6 (n=6, 50%), adenovirus (n=6, 50%), EBV (n=3, 25%) or CMV (n=3; 25%). Median duration of follow-up was 2.3 years (range: 0.5 - 10 years) and the 2-year OS, EFS and GEFS were 100% (95% confidence interval, 0-100%), 73% (37-90%) and 73% (37%-90%) respectively. TCRαβ-SCT from mismatched family or unrelated donors, using a chemotherapy only regimen, is a safe alternative donor salvage transplant strategy for second HSCT in patients without a suitably matched donor.

Phase II, Open-Label Clinical Trial of Urinary-Derived Human Chorionic Gonadotropin/Epidermal Growth Factor for Life-Threatening Acute Graft-versus-Host Disease

Treatments that aid inflammation resolution, immune tolerance, and epithelial repair may improve outcomes beyond high-dose corticosteroids and other broad immunosuppressants for life-threatening acute graft-versus-host disease (aGVHD). We studied the addition of urinary-derived human chorionic gonadotropin/epidermal growth factor (uhCG/EGF; Pregnyl; Organon, Jersey City, NJ) to standard aGVHD therapy in a prospective Phase II clinical trial (ClinicalTrials.gov identifier NCT02525029). Twenty-two patients with Minnesota (MN) high-risk aGVHD received methylprednisolone 48 mg/m2/day plus 2000 units/m2 of uhCG/EGF s.c. every other day for 1 week. Patients requiring second-line aGVHD therapy received uhCG/EGF 2000 to 5000 units/m2 s.c. every other day for 2 weeks plus standard of care immunosuppression (physician's choice). Responding patients were eligible to receive maintenance doses twice weekly for 5 weeks. Immune cell subsets in peripheral blood were evaluated by mass cytometry and correlated with plasma amphiregulin (AREG) level and response to therapy. Most patients had stage 3-4 lower gastrointestinal tract GVHD (52%) and overall grade III-IV aGVHD (75%) at time of enrollment. The overall proportion of patients with a response at day 28 (primary endpoint) was 68% (57% with complete response, 11% with partial response). Nonresponders had higher baseline counts of KLRG1+ CD8 cells and T cell subsets expressing TIM-3. Plasma AREG levels remained persistently elevated in nonresponders and correlated with AREG expression on peripheral blood T cells and plasmablasts. The addition of uhCG/EGF to standard therapy is a feasible supportive care measure for patients with life-threatening aGVHD. As a commercially available, safe, and inexpensive drug, uhCG/EGF added to standard therapy may reduce morbidity and mortality from severe aGVHD and merits further study.

Survival analysis of transplant-associated thrombotic microangiopathy under different diagnostic criteria and the efficacy of plasma exchange.

BACKGROUND Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication of hematopoietic stem cell transplantation (HSCT). The efficacy and survival of plasma exchange (PE) for TA-TM have not been fully clarified. In addition, there is a lack of consensus on diagnostic criteria for TA-TMA. MATERIAL AND METHODS We retrospectively analyzed32 patients diagnosed with TA-TMA by different diagnostic criteria from January 2018 to February 2022 at the First Medical Center of the PLA General Hospital. RESULTS (1) The patients with TA-TMA treated with PE in this study had a remission rate of 42.8%, a 100-day OS of 47.6%, and a 6-month OS of 38.1%. The only factor affecting the response to PE treatment was the number of PE sessions (P = 0.047). (2) III-IV aGVHD prior to TA-TMA diagnosis (P = 0.002), renal or neurological dysfunction (P = 0.021), and the time to onset of TA-TMA (P = 0.002) were independent risk factors for overall survival with TA- TMA. (3) Probable TA-TMA had the highest survival rate, but the Jodele criteria are expected to diagnose earlier and provide the greatest benefit to patients. CONCLUSIONS PE is an effective treatment for TA-TMA especially in cases where complement blockers are not available. In addition, probable TA-TMA improved prognostic survival through early detection of patients with TA-TMA. There is a need for further large prospective trials to identify the population more suitable for PE treatment of TA-TMA and more valid diagnostic criteria.

Low-dose post-transplant cyclophosphamide with G-CSF/ATG based haploidentical protocol provides favorable outcomes for SAA patients.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT), as one of the life-saving treatments for severe aplastic anemia (SAA), is widely used because of its great donor availability. Over decades, granulocyte colony-stimulating factor (G-CSF)/antithymocyte globulin (ATG)-based protocol (the so-called Beijing Protocol) has achieved favorable engraftment and survival outcomes. In this study, we modified the conventional Beijing Protocol: the full-dose Cyclophosphamide (Cy) (200 mg/kg in total) was divided into 42.75 mg/kg Cy on day -5 to day -2 and Low dose post-transplant Cy (PTCy) (14.5 mg/kg on days +3 and +4), hoping to reduce the incidence of severe acute graft-versus-host disease (aGVHD) and to guarantee successful and stable engraftment. Here we retrospectively reported and analyzed the data of first 17 patients with SAA who had received haplo-HSCT using this novel regimen between August 2020 and August 2022. The median follow-up was 522 days (range, 138-859 days). No patient developed primary graft failure. Four (23.5%) patients developed grade II bladder toxicity, two (11.8%) patients developed grade II cardiotoxicity. All patients achieved neutrophil and platelet engraftment at median times of 12 days (range, 11-20 days) and14 days (range, 8-36 days). During our follow-up, no patients developed grade III-IV aGVHD. The cumulative incidence of grade II and grade I aGVHD at 100 days was 23.5% (95% CI, 6.8%-49.9%) and 47.1% (95% CI, 23.0%-72.2%). Three patients (17.6%) developed chronic GVHD of skin, mouth, and eyes and all of which were mild. All patients are alive by the end of the follow-up, with a failure-free survival of 100%, which was defined as survival without treatment failures, such as death, graft failure, or relapse rate. The rate of cytomegalovirus (CMV) reactivation was 82.4% (95% CI, 64.3%-100%). The rate of Epstein-Barr virus (EBV) reactivation was 17.6% (95% CI, 3.8%-43.4%). No CMV disease and post-transplantation lymphoproliferative disorder (PTLD) occurred among these patients. In conclusion, the encouraging results of prolonged survival outcomes and reduced incidence of GVHD suggest promising effect of this novel regimen in haplo-HSCT for patients with SAA. Larger-sample prospective clinical trials are needed to confirm the effectiveness of this regimen.

Impact of Iron Overload and Iron Chelation with Deferasirox on Outcomes of Patients with Severe Aplastic Anemia after Allogeneic Hematopoietic Stem Cell Transplantation

Patients suffering from severe aplastic anemia (SAA) need frequent blood transfusions during allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, these transfusions can result in an excess of iron in the body tissues, which can negatively impact the success of transplantation. This study aimed to examine the impact of pretransplantation iron overload (IO) on the outcomes of allo-HSCT in patients with SAA. It also investigated whether iron chelation (IC) therapy is necessary to enhance transplantation outcomes in SAA patients by providing guidelines for determining when excess iron should be chelated. The study consisted of 2 parts. In cohort 1, which was retrospective and conducted from April 2012 to December 2018, SAA patients receiving their first allo-HSCT were divided into 2 groups based on their pretransplantation serum ferritin (SF) level: the IO group (SF >1000 ng/mL; n=17) and the non-IO group (SF ≤1000 ng/mL; n=48). Cohort 2, a prospective clinical trial conducted from January 2019 to July 2020, included SAA patients diagnosed with IO who were treated with IC therapy using deferasirox at a dose of 10 to 30 mg/kg. Patients were separated into 2 groups based on their pretransplantation SF level: the IC success (ICsuccess) group (SF ≤1000 ng/mL; n=18) and the IC failure (ICfailure) group (SF >1000 ng/mL; n=28). All participants were evaluated for the correlation between pretransplantation SF level and transplantation outcomes. A P value <.05 was considered statistically significant. There was no significant difference in the speed of engraftment among the 3 cell lineages or in the incidence of 100-day grade II-IV acute graft-versus-host disease (aGVHD), grade III-IV aGVHD, or 3-year chronic GVHD between the 2 groups in both cohorts. Of note, however, in cohort 1, both 1-year overall survival (OS) (41.2% versus 83.3%; P < .001) and 3-year OS (35.3% versus 83.3%; P < .001) were significantly worse in the IO group. Furthermore, 180-day transplantation related mortality (TRM) (47.1% versus 14.6%; P=.005) and 1-year TRM (52.9% versus 16.7%; P=.002) were significantly higher in the IO group. The IO group was significantly associated with inferior 3-year OS in both univariate and multivariate analyses. In cohort 2, 1-year OS (88.9% versus 42.9%; P=.003) and 3-year OS (83.3% versus 42.9%; P=.007) were significantly better in the ICsuccess group, whereas 180-day TRM (11.1% versus 39.3%; P=.040) and 1-year TRM (11.1% versus 57.1%; P=.003) were significantly lower in the ICsuccess group. These differences were confirmed in both univariate and multivariate analyses. This study involving 2 cohorts shows that pre-HSCT IO has a negative impact on transplantation outcomes in SAA patients. Chelating excess iron with an SF level <1000 ng/mL was found to be necessary and could potentially improve the outcomes.

Efficacy and Safety of Allogeneic Hematopoietic Stem Cell Transplantation with Decitabine-containing Regimen in Myelodysplastic Syndromes and Myelodysplastic Syndromes Transformed Acute Myeloid Leukemia

To evaluate the efficacy and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with decitabine (Dec)-conditioning regimen in the treatment of myelodysplastic syndrome (MDS) and MDS transformed acute myeloid leukemia (MDS-AML). The characteristics and efficacy data of 93 patients with MDS and MDS-AML who received allo-HSCT in our center from April 2013 to November 2021 were retrospectively analyzed. All patients were administered by myeloablative conditioning regimen containing Dec (25 mg/m2 /d×3 d). Among the 93 patients, 63 males and 30 females, were diagnosed as MDS（n ＝77）, MDS-AML（n ＝16）. The incidence of I/II grade regimen-related toxicity (RRT) was 39.8%, and III grade RRT was only found in 1 patient (1%). Neutrophil engraftment was successful in 91 (97.8%) patients after a median neutrophil engraftment time of 14 (9-27) days; Successful platelet engraftment was achieved in 87 (93.5%) patients, with a median engraftment time of 18 (9-290) days. The incidence of acute graft versus host disease（aGVHD） and grade III-IV aGVHD was 44.2% and 16.2%, respectively. The incidence of chronic graft versus host disease（cGVHD） and moderate-to-severe cGVHD was 59.5% and 37.1%, respectively. Of the 93 patients, 54 (58%) developed posttransplant infections, among which lung infection (32.3%) and bloodstream infection (12.9%) were the most common. The median follow-up after transplantation was 45 (0.1-108) months. The 5-year overall survival (OS) rate, disease-free survival (DFS) rate, treatment-related mortality, and cumulative incidence of relapse were 72.7%, 68.4%, 25.1%, and 6.5%, respectively. And the 1-year graft-versus-host disease/relapse-free survival rate was 49.3%. The patients in different group of relative high-risk prognostic scoring or low-risk prognostic scoring, with or without poor-risk mutation(s), with mutations number ≥3 or <3 had similar 5-year OS rate (more than 70%). Multivariate analysis showed that the incidence of grade III-IV aGVHD was the independent risk factor affecting OS（P =0.008）and DFS (P =0.019). Allo-HSCT with Dec-conditioning regimen is feasible and effective in the treatment of patients with MDS and MDS-AML, especially those in high prognostic risk and with poor-risk mutations.

The Characteristics of T Lymphocyte Reconstitution after Haploid Hematopoietic Stem Cell Transplantation in SAA and Its Relationship with aGVHD

To investigate the recovery characteristics of T cell subsets in patients with severe aplastic anemia (SAA) who received haploid hematopoietic stem cell transplantation(HSCT) and its relationship with acute graft-versus-host disease(aGVHD). The clinical data of 29 SAA patients who received haploid hematopoietic stem cell transplantation in the department of hematology, Shanxi Bethune Hospital from June 2018 to January 2022 were retrospectively analyzed. The absolute counts of CD3+T, CD4+T, CD8+T lymphocytes and the ratio of CD4+T/CD8+T lymphocytes in all patients before transplantation, 14, 21, 30, 60, 90 and 120 days after transplantation were analyzed. The proportion of T lymphocytes was compared in the non-aGVHD group, the grade Ⅰ-Ⅱ aGVHD group and the grade III-IV aGVHD group. The counts of all T cells in 27 patients were far below the normal level at 14 and 21 days after transplantation, but there was obvious heterogeneity. There was a certain relationship between T cell immune reconstitution and conditioning regimen, age, and immunosuppressive treatment before transplantation. CD3+T cells showed a steady upward trend at 30, 60, 90, and 120 days after transplantation, and returned to the normal levels at 120 days after transplantation; faster recovery of CD4+T cells was closely related to aGVHD, which was at 30, 60, 90, 120 days after transplantation showed a slow upward trend, and which was still far below the normal level of 120 days after transplantation. CD8+T cell counts began to recover at 14 and 21 days after transplantation, and the recovery was earlier than the CD4+T cells, and its recovery speed was rapid 30 and 60 days after transptantation, which showed an upward trend and exceeded the normal levels 90 days after transplantation. Since CD8+ T cells reconstituted quickly, while the CD4+ T cells reconstitution was slowly, which made the long-term CD4+T/CD8+T cell ratio after transplantation was inverted . Compared with the non-aGVHD group, the absolute counts of CD3+T, CD4+T, and CD8+T cells in the aGVHD group were significantly higher than those in the non-aGVHD group at each time period after transplantation. In the aGVHD group, grade Ⅲ-Ⅳ aGVHD occurred more frequently in the early post-transplantation period (within 14-21 days), the grade Ⅰ-Ⅱ aGVHD group mostly occurred within 30-90 days after transplantation, and CD3+T, CD4+T, CD8+T cell counts in the grade Ⅲ-Ⅳ aGVHD group were significantly higher than those in the grade Ⅰ-Ⅱ aGVHD group; and the greater the proportion of CD4+T, the more severe the degree of aGVHD. The speed of T cell immune reconstitution after SAA haploid transplantation is different, which is related to the conditioning regimen, age, and immunosuppressive therapy before transplantation. The rapid recovery of CD4+ T cells is closely related to the occurrence of aGVHD.