Long-term follow-up of haploidentical haematopoietic stem cell transplantation in paediatric patients with high-risk acute myeloid leukaemia: Report from a single centre.

Data from 200 children with high-risk acute myeloid leukaemia who underwent their first haploidentical haematopoietic stem cell transplantation (haplo-HSCT) between 2015 and 2021 at our institution were analysed. The 4-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) were 71.9%, 62.3% and 32.4% respectively. The 100-day cumulative incidences of grade II-IV and III-IV acute graft-versus-host disease (aGVHD) were 41.1% and 9.5% respectively. The 4-year cumulative incidence of chronic GVHD (cGVHD) was 56.1%, and that of moderate-to-severe cGVHD was 27.3%. Minimal residual disease (MRD)-positive (MRD+) status pre-HSCT was significantly associated with lower survival and a higher risk of relapse. The 4-year OS, EFS and CIR differed significantly between patients with MRD+ pre-HSCT (n = 97; 63.4%, 51.4% and 41.0% respectively) and those with MRD-negative (MRD-) pre-HSCT (n = 103; 80.5%, 73.3% and 23.8% respectively). Multivariate analysis also revealed that acute megakaryoblastic leukaemia without Down syndrome (non-DS-AMKL) was associated with extremely poor outcomes (hazard ratios and 95% CIs for OS, EFS and CIR: 3.110 (1.430-6.763), 3.145 (1.628-6.074) and 3.250 (1.529-6.910) respectively; p-values were 0.004, 0.001 and 0.002 respectively). Thus, haplo-HSCT can be a therapy option for these patients, and MRD status pre-HSCT significantly affects the outcomes. As patients with non-DS-AMKL have extremely poor outcomes, even with haplo-HSCT, a combination of novel therapies is urgently needed.

Mega-dose decitabine conditioning and prophylactic donor lymphocyte infusion for patients with relapsed/refractory AML with active disease at the time of allogeneic haematopoietic cell transplantation: A multicenter prospective phase II study.

Patients with relapsed/refractory acute myeloid leukaemia (R/R AML), especially those who failed in novel target agents are related to dismal survival. We developed a multi-institutional, single-arm, prospective phase II trial, to investigate intensified conditioning with 'Mega-Dose' decitabine (MegaDAC) following allogeneic haematopoietic cell transplantation (allo-HCT) for R/R AML. From 2019 to 2023, 70 heavily treated R/R AML patients in active disease were consecutively enrolled. Significantly, every patient (n = 18) harbouring specific mutations exhibited no response to their best available target agents (BATs). Moreover, 74.3% of the enrolled patients did not reach remission following venetoclax-based regimens. All patients underwent intravenous decitabine (400 mg/m2) along with busulfan and cyclophosphamide. Median follow-up was 26 months (8-65) after HCT. All engrafted patients achieved MRD negativity post-HCT, with a median 3.3-log reduction in recurrent genetic abnormalities. The regimen was well tolerated, without irreversible grades III-IV toxicity peri-engraftment. The estimated 2-year CIR was 29.6% (18.4%-41.7%) and the est-2-year NRM was 15.5% (7.8%-25.5%). The est-2-year LFS, OS, and GRFS were 55.0% (43.5%-69.4%), 58.6% (47.0%-73.0%), and 42.9% (31.9%-57.6%), respectively. Multivariate analysis showed that pre-HCT drug exposures had no significant impact on primary outcomes. MegaDAC is highlighted as an effective and safe option for R/R AML in the new era of targeted therapies.

A phase II study of belumosudil for chronic graft-versus-host disease in patients who failed at least one line of systemic therapy in China.

BACKGROUND: Chronic graft-versus-host disease (cGVHD) is an immune-related disorder that is the most common complication post-allogenic hematopoietic stem cell transplant. Corticosteroids with or without calcineurin inhibitors (CNIs) remain the mainstay of cGVHD treatment for first-line therapy. However, for many patients, cGVHD symptoms cannot be effectively managed and thus require second-line therapy. Currently, there is no approved treatment for second-line cGVHD treatment in China. In this study, belumosudil, a highly selective and potent rho-associated coiled-coil-containing protein kinase-2 inhibitor demonstrated to be effective for cGVHD in the United States and other Western countries, is investigated in patients with cGVHD in China for its overall benefit-risk balance. METHODS: This multicenter, open-label phase II study evaluated the safety, efficacy, and pharmacokinetics of oral belumosudil 200 mg once daily in cGVHD patients who had been treated with at least one line of systemic therapy in China. The primary endpoint was overall response rate (ORR); each individual patient's response was assessed by the investigator using the 2014 National Institutes of Health consensus criteria. Secondary endpoints were duration of response (DOR), time to response (TTR), changes in Lee Symptom Scale (LSS) score, organ response rate, corticosteroid dose change, CNI dose change, failure-free survival, time-to-next-treatment, overall survival, and safety. RESULTS: Thirty patients were enrolled in the study with a median follow-up time of 12.9 months. ORR was 73.3% (95% confidence interval: 54.1-87.7%) and all responders achieved partial response. Median DOR among responders was not reached and median TTR was 4.3 weeks (range: 3.9-48.1). Fifteen patients (50.0%) achieved clinically meaningful response in terms of reduction in LSS score by ≥ 7 points from baseline. Corticosteroid and CNI dose reductions were reported in 56.7% (17/30) and 35.0% (7/20) of patients, respectively. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity, with 11 patients (36.7%) experiencing grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAE was pneumonia (n = 5, 16.7%). CONCLUSIONS: Belumosudil treatment demonstrated a favorable benefit-risk balance in treating cGVHD patients who previously have had standard corticosteroid therapy in China where approved second-line setting is absent. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04930562.

Mini-dose methotrexate combined with methylprednisolone for the initial treatment of acute GVHD: a multicentre, randomized trial.

BACKGROUND: There is an urgent unmet need for effective initial treatment for acute graft-versus-host disease (aGVHD) adding to the standard first-line therapy with corticosteroids after allogeneic haematopoietic stem cell transplantation (allo-HSCT). METHODS: We performed a multicentre, open-label, randomized, phase 3 study. Eligible patients (aged 15 years or older, had received allo-HSCT for a haematological malignancy, developed aGVHD, and received no previous therapies for aGVHD) were randomly assigned (1:1) to receive either 5 mg/m2 MTX on Days 1, 3, or 8 and then combined with corticosteroids or corticosteroids alone weekly. RESULTS: The primary endpoint was the overall response rate (ORR) on Day 10. A total of 157 patients were randomly assigned to receive either MTX plus corticosteroids (n = 78; MTX group) or corticosteroids alone (n = 79; control group). The Day 10 ORR was 97% for the MTX group and 81% for the control group (p = .005). Among patients with mild aGVHD, the Day 10 ORR was 100% for the MTX group and 86% for the control group (p = .001). The 1-year estimated failure-free survival was 69% for the MTX group and 41% for the control group (p = .002). There were no differences in treatment-related adverse events between the two groups. CONCLUSIONS: In conclusion, mini-dose MTX combined with corticosteroids can significantly improve the ORR in patients with aGVHD and is well tolerated, although it did not achieve the prespecified 20% improvement with the addition of MTX. TRIAL REGISTRATION: The trial was registered with clinicaltrials.gov (NCT04960644).

Mesenchymal stromal cells plus basiliximab improve the response of steroid-refractory acute graft-versus-host disease as a second-line therapy: a multicentre, randomized, controlled trial.

BACKGROUND: For patients with steroid-refractory acute graft-versus-host disease (SR-aGVHD), effective second-line regimens are urgently needed. Mesenchymal stromal cells (MSCs) have been used as salvage regimens for SR-aGVHD in the past. However, clinical trials and an overall understanding of the molecular mechanisms of MSCs combined with basiliximab for SR-aGVHD are limited, especially in haploidentical haemopoietic stem cell transplantation (HID HSCT). METHODS: The primary endpoint of this multicentre, randomized, controlled trial was the 4-week complete response (CR) rate of SR-aGVHD. A total of 130 patients with SR-aGVHD were assigned in a 1:1 randomization schedule to the MSC group (receiving basiliximab plus MSCs) or control group (receiving basiliximab alone) (NCT04738981). RESULTS: Most enrolled patients (96.2%) received HID HSCT. The 4-week CR rate of SR-aGVHD in the MSC group was obviously better than that in the control group (83.1% vs. 55.4%, P = 0.001). However, for the overall response rates at week 4, the two groups were comparable. More patients in the control group used ≥ 6 doses of basiliximab (4.6% vs. 20%, P = 0.008). We collected blood samples from 19 consecutive patients and evaluated MSC-derived immunosuppressive cytokines, including HO1, GAL1, GAL9, TNFIA6, PGE2, PDL1, TGF-ß and HGF. Compared to the levels before MSC infusion, the HO1 (P = 0.0072) and TGF-ß (P = 0.0243) levels increased significantly 1 day after MSC infusion. At 7 days after MSC infusion, the levels of HO1, GAL1, TNFIA6 and TGF-ß tended to increase; however, the differences were not statistically significant. Although the 52-week cumulative incidence of cGVHD in the MSC group was comparable to that in the control group, fewer patients in the MSC group developed cGVHD involving ≥3 organs (14.3% vs. 43.6%, P = 0.006). MSCs were well tolerated, no infusion-related adverse events (AEs) occurred and other AEs were also comparable between the two groups. However, patients with malignant haematological diseases in the MSC group had a higher 52-week disease-free survival rate than those in the control group (84.8% vs. 65.9%, P = 0.031). CONCLUSIONS: For SR-aGVHD after allo-HSCT, especially HID HSCT, the combination of MSCs and basiliximab as the second-line therapy led to significantly better 4-week CR rates than basiliximab alone. The addition of MSCs not only did not increase toxicity but also provided a survival benefit.

Targeting TFH cells is a novel approach for donor-specific antibody desensitization of allograft candidates: an in vitro and in vivo study.

The presence of donor-specific antibodies (DSA) are associated with graft failure either following human leukocyte antigen (HLA)-mismatched allogeneic stem cell transplantation or after organ transplantation. Although targeting B cells and plasma cells have been used for desensitization, there have been reports of failure. T-follicular helper (Tfh) cells assist B cells in differentiating into antibody-secreting plasma cells. We used haploidentical allograft as a platform to investigate the possibility of targeting Tfh cells to desensitize DSA. The quantities of circulating Tfh (cTfh) cell subsets in allograft candidates were abnormal, and these cells, including the cTfh2 and cTfhem cell subsets, were positively related to the production of anti-HLA antibodies. Ex vivo experiments showed that the cTfh cells of anti-HLA antibody-positive allograft candidates could induce B cells to differentiate into DSA-producing plasmablasts. The immune synapse could be involved in the assistance of cTfh cells to B cells in antibody production. In vitro experiments and in vivo clinical pilot studies indicated that targeting cTfh cells with sirolimus can inhibit their auxiliary function in assisting B cells. Ex vivo and in vivo studies demonstrated the effect of sirolimus and rituximab on DSA desensitization compared with either sirolimus or rituximab alone (60%, 43.75%, and 30%, respectively). Our findings provide new insight into the role of Tfh cells in the pathogenesis of DSA production in HLA-mismatched transplant candidates. Our data also indicate that targeting Tfh cells is a novel strategy for DSA desensitization and combination of sirolimus and rituximab might be a potential therapy. The prospective cohort of this study is registered at http://www.chictr.org.cn as #ChiCTR-OPC-15006672.

Clinical characteristics and outcomes of allogeneic hematopoietic stem cell transplantation recipients with coronavirus disease 2019 caused by the Omicron variant: a prospective, observational cohort study.

We aimed to describe the clinical characteristics, particularly the occurrence and risk factors of severe/critical illness, in allogeneic hematopoietic stem cell (allo-HSCT) recipients infected with coronavirus disease 2019 (COVID-19) caused by Omicron variant in an observational prospective study (n = 311). The median time from allo-HSCT to COVID-19 diagnosis was 8.5 months (range 0.8-106.1) months. Four patients (1.3%) were reported to be asymptomatic during Omicron variant infection, and 135 (43.4%) patients showed lower respiratory tract disease. Thirty-four (10.9%) patients were categorized into serious infection (severe illness n = 25; critical illness n = 9) and the median duration from COVID-19 diagnosis to serious infections was 6 days (range, 0-29) days. Thirteen (4.2%) and 6 (1.9%) patients required intensive care unit care and invasive mechanical ventilation, respectively. Receiving more than 1 type of immunosuppressive therapies at COVID-19 diagnosis was associated with severity and persistence of infection. Six patients (1.9%) died after diagnosis of COVID-19 infection. The 4-week probability of overall survival after COVID-19 diagnosis was 98.7%, which was 100% and 88.2% for non-serious and serious infection group (P < 0.001), respectively. Thus, we observed a relatively low serious infection and mortality rate in allo-HSCT recipients infected with COVID-19 caused by Omicron variant.

Photoinduced Asymmetric Alkene Aminohetarylation with Chiral Sulfoximine Reagents.

Given the pivotal role of ß-(het)arylethylamine moiety in bioactive molecules, the direct amino(het)arylation of alkenes occupies a privileged position in the construction of (het)arylethylamine derivatives. Herein we devise chiral sulfoximines as novel bifunctional reagents which exhibit remarkable efficiency in the challenging asymmetric alkene aminohetarylation reaction, particularly in terms of reactivity and stereo-control. The chiral reagents can be conveniently accessed in gram scale, and efficiently generate N-centered radicals under mild photochemical conditions. The transformation proceeds through enantioselective 1,4-hetaryl migration, ensuring precise chirality transfer from sulfur- to carbon-centers, rendering wide applicability to both aromatic and aliphatic alkenes. Furthermore, the method is straightforward to operate and does not require transition metals or photosensitizers, making it an attractive and practical option.

Mutation of the TP53 gene in acute lymphoblastic leukemia does not affect survival outcomes after haploidentical hematopoietic stem cell transplantation.

Previous studies have demonstrated that TP53 mutation is correlated with insufficient therapy response and unfavorable prognosis in acute lymphoblastic leukemia (ALL). Few studies have investigated the impact of TP53 mutation in ALL patients after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We completed a retrospective study of 65 ALL patients with available TP53 status who underwent haplo-HSCT. They were divided into a TP53 mutation group (TP53mut ) and a TP53 wild-type (TP53wt ) group. TP53mut showed comparable 2-year cumulative incidence of relapse (CIR) rates (13.1% vs 12.5%, P = .96) and 2-year leukemia-free survival (LFS) (74.2% vs 77.4%, P = .80) with TP53wt . No significant differences in 2-year overall survival (OS) rates (82.9% vs 87.3%, P = .61) or 2-year NRM rates (12.7% vs 10.2%, P = .69) were observed in TP53mut and TP53wt patients. Multivariate analysis suggested that white blood cell (WBC) count at initial diagnosis (>50 × 109 /L: hazard ratio [HR] = 3.860, P = .016) and age (>40 years old: HR = 4.120, P = .012) are independent risk factors for 2-year LFS. Our study showed that TP53 mutations may not be related to the unfavorable impact on survival in ALL patients after treatment with haplo-HSCT. The present results suggested that haplo-HSCT may eliminate the poor prognosis effect of TP53 mutation in ALL.

Haploidentical haematopoietic stem cell transplantation for TP53-mutated acute myeloid leukaemia.

Acute myeloid leukaemia (AML) patients with tumour protein p53 (TP53) mutations are often resistant to chemotherapy and have worse clinical outcomes than patients without TP53 mutations. In this study, we compared clinical outcomes of patients with AML with and without TP53 mutations who underwent haploidentical haematopoietic stem cell transplantation (haplo-HSCT). For the TP53-mutation group and TP53 wild-type group, the 2-year cumulative incidence of relapse (CIR) was (39.0% vs. 21.2% respectively, p = 0.088), the 2-year non-relapse mortality (NRM) rate was (3.2% vs. 8.4% respectively, p = 0.370), the 2-year leukaemia-free survival (LFS) was (57.7% vs. 71.3% respectively, p = 0.205), the 2-year overall survival (OS) rate was (69.9% vs. 81.3% respectively, p = 0.317), the 100-day cumulative incidence of Grade II-IV acute graft-versus-host disease (GvHD) was (6.5% vs. 20.7% respectively, p = 0.074), the 2-year cumulative incidence of chronic GvHD was (52.3% vs. 53.1% respectively, p = 0.493) and the 2-year GvHD-free/relapse-free survival (GRFS) was (57.7% vs. 69.6% respectively, p = 0.347). Our data showed that there were no significant differences in 2-year clinical outcomes between the two groups. Multivariable analysis showed TP53 mutations had no significant impact on CIR, NRM, OS, GvHD, LFS or GRFS. Our findings suggest that patients with AML with TP53 mutations may at least partially benefit from haplo-HSCT. Haplo-HSCT might be the recommended treatment for such patients.

COVID-19 infection in patients with haematological malignancies: A single-centre survey in the latest Omicron wave in China.

As the COVID-19 variant Omicron surge in Beijing, China, a better understanding of risk factors for adverse outcomes may improve clinical management in patients with haematological malignancies (HM) diagnosed with COVID-19. The study sample includes 412 cases, mainly represented by acute leukaemia, chronic myeloid leukaemia (CML), plasma cell disorders and lymphoma and chronic lymphocytic leukaemia. COVID-19 pneumonia was observed in 10.4% (43/412) of patients, and severe/critical illness was observed in 5.3% (22/412). Among the 86 cases with advanced malignancies, 17.6% (12/86) of patients developed severe/critical COVID-19, which was significantly higher than reported in patients with stable malignancies (9/326, 2.70%, p < 0.001). Similarly, the advanced malignancy cohort had a higher mortality rate (9/86, 10.5% vs. 0/326, 0%, p < 0.001) and a poor 30-day overall survival (OS) compared with the stable malignancy cohort (74.2% vs. 100.0%, p < 0.0001). Overall, nine patients (2.2%) died. The primary cause of death was progressive HM in four patients and a combination of both COVID-19 and HM in five patients. In the multivariable analysis, over 65 years of age, comorbidities and advanced malignancy were correlated with severe/critical COVID-19 in HM patients. This study sheds light on the poor outcomes among COVID-19 HM patients with the leading cause of advanced malignancy.

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.

Time-dependent analysis of the impact on early cytomegalovirus reactivation of HLA mismatch and acute graft-versus-host disease after allogeneic hematopoietic cell transplantation from related donors in acquired aplastic anemia.

Cytomegalovirus (CMV) reactivation is an important issue in allogeneic hematopoietic cell transplantation (HCT). The incidence of early CMV reactivation is notably high in HLA-mismatched HCT. However, the interactions between HLA mismatch and acute graft-versus-host disease (aGvHD), a time-dependent event, make it methodologically challenging to evaluate the independent impact on CMV reactivation of the two variables. We retrospectively analyzed 355 patients with acquired aplastic anemia who received related donor transplants using a unified antithymocyte globulin-based platform. Patients were divided into group 1 (6/6 HLA match), group 2 (1-2/6 HLA allelic mismatch), and group 3 (3/6 HLA allelic mismatch). The impact of covariates was analyzed through two models: (1) time-dependent Cox and (2) dynamic landmarking analysis. The time-dependent Cox model showed that the HLA mismatch of 3/6 alleles (hazard ratio (HR) =1.852, P = .004) and aGvHD (HR = 1.009, P = .019) were independent risk factors for CMV reactivation. With the dynamic landmarking analysis, a higher HLA disparity correlated to increased early CMV reactivation (HR = 1.606, P = .001) at all time points. Developing aGvHD following HCT was generally associated with a higher incidence of CMV reactivation (HR = 1.623, P = .013), though its impact decreased with successive later landmark time points. In conclusion, our data suggest that the higher HLA disparity and aGvHD increases susceptibility to early CMV reactivation. In particular, the dynamic landmarking analysis demonstrated the time-varying effect of aGvHD on CMV reactivation, and HLA mismatch showed a profound impact over time following HCT.

Development and validation of a mortality predicting scoring system for severe aplastic anaemia patients receiving haploidentical allogeneic transplantation.

Haploidentical allogeneic haematopoietic stem cell transplantation (haplo-HSCT) is a significant alternative treatment for severe aplastic anaemia (SAA). To improve this process by modifying the risk stratification system, we conducted a retrospective study using our database. 432 SAA patients who received haplo-HSCT between 2006 and 2020 were enrolled. These patients were divided into a training (n = 288) and a validation (n = 144) subset randomly. In the training cohort, longer time from diagnosis to transplantation, poorer Eastern Cooperative Oncology Group (ECOG) status and higher haematopoietic cell transplantation-specific comorbidity index (HCT-CI) score were independent risk factors for worse treatment-related mortality (TRM) in the final multivariable model. The haplo-HSCT scoring system was developed by these three parameters. Three-year TRM after haplo-HSCT were 6% [95% confidence interval (CI), 1-21%], 21% (95% CI, 7-40%), and 47% (95% CI, 20-70%) for the low-, intermediate-, and high-risk group, respectively (P < 0·0001). In the validation cohort, the haplo-HSCT scoring system also separated patients into three risk groups with increasing risk of TRM: intermediate-risk [hazard ratio (HR) 2·45, 95% CI, 0·92-6·53] and high-risk (HR 11·74, 95% CI, 3·07-44·89) compared with the low-risk group (P = 0·001). In conclusion, the haplo-HSCT scoring system could effectively predict TRM after transplantation.

CMV infection combined with acute GVHD associated with poor CD8+ T-cell immune reconstitution and poor prognosis post-HLA-matched allo-HSCT.

Cytomegalovirus (CMV) infection and acute graft-versus-host disease (aGVHD) are two major complications that contribute to a poor prognosis after hematopoietic stem cell transplantation (HSCT). Superior early immune reconstitution (IR) is associated with improved survival after HSCT. However, when all three factors, CMV infection, aGVHD, and IR, are concomitantly considered, the effects of the triple events on HSCT are still unknown and should be studied further. Thus we enrolled 185 patients who were diagnosed as hematological malignancies and treated with HLA-matched sibling transplantation (MST) between January 2010 and December 2014, of whom 83 were positive for CMV infection and 82 had aGVHD. Results showed that patients with both aGVHD and CMV infection had significantly higher non-relapse mortality (NRM), lower overall survival (OS), and delayed CD8+ T-cell IR. Multivariate analyses showed that both aGVHD combined with CMV infection and delayed CD8+ T-cell IR were independent risk factors for prognosis post-MST. Recurrent CMV infections are associated with poor CD8+ T-cell reconstitution. However, superior IR could protect against the negative effects of aGVHD and CMV infection on the transplant outcomes.

Monitoring of post-transplant MLL-PTD as minimal residual disease can predict relapse after allogeneic HSCT in patients with acute myeloid leukemia and myelodysplastic syndrome.

BACKGROUND: The mixed-lineage leukemia (MLL) gene is located on chromosome 11q23. The MLL gene can be rearranged to generate partial tandem duplications (MLL-PTD), which occurs in about 5-10% of acute myeloid leukemia (AML) with a normal karyotype and in 5-6% of myelodysplastic syndrome (MDS) patients. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently one of the curative therapies available for AML and MDS with excess blasts (MDS-EB). However, how the prognosis of patients with high levels of MLL-PTD after allo-HSCT, and whether MLL-PTD could be used as a reliable indicator for minimal residual disease (MRD) monitoring in transplant patients remains unknown. Our study purposed to analyze the dynamic changes of MLL-PTD peri-transplantation and the best threshold for predicting relapse after transplantation. METHODS: We retrospectively collected the clinical data of 48 patients with MLL-PTD AML or MDS-EB who underwent allo-HSCT in Peking University People's Hospital. The MLL-PTD was examined by real-time quantitative polymerase chain reaction (RQ-PCR) at the diagnosis, before transplantation and the fixed time points after transplantation. Detectable MLL-PTD/ABL > 0.08% was defined as MLL-PTD positive in this study. RESULTS: The 48 patients included 33 AML patients and 15 MDS-EB patients. The median follow-up time was 26(0.7-56) months after HSCT. In AML patients, 7 patients (21.2%) died of treatment-related mortality (TRM), 6 patients (18.2%) underwent hematological relapse and died ultimately. Of the 15 patients with MDS-EB, 2 patients (13.3%) died of infection. The 3-year cumulative incidence of relapse (CIR), overall survival (OS), disease-free survival (DFS) and TRM were 13.7 ± 5.2, 67.8 ± 6.9, 68.1 ± 6.8 and 20.3% ± 6.1%, respectively. ROC curve showed that post-transplant MLL-PTD ≥ 1.0% was the optimal cut-off value for predicting hematological relapse after allo-HSCT. There was statistical difference between post-transplant MLL-PTD ≥ 1.0% and MLL-PTD < 1.0% groups (3-year CIR: 75% ± 15.3% vs. 0%, P < 0.001; 3-year OS: 25.0 ± 15.3% vs. 80.7% ± 6.6%, P < 0.001; 3-year DFS: 25.0 ± 15.3% vs. 80.7 ± 6.6%, P < 0.001; 3-year TRM: 0 vs. 19.3 ± 6.6%, P = 0.277). However, whether MLL-PTD ≥ 1% or MLL-PTD < 1% before transplantation has no significant difference on the prognosis. CONCLUSIONS: Our study indicated that MLL-PTD had a certain stability and could effectively reflect the change of tumor burden. The expression level of MLL-PTD after transplantation can serve as an effective indicator for predicting relapse.

Comparable clinical outcomes of haploidentical hematopoietic stem cell transplantation in patients with hepatitis-associated aplastic anemia and non-hepatitis-associated aplastic anemia.

Hepatitis-associated aplastic anemia (HAAA), a rare subtype of aplastic anemia (AA), is defined as bone marrow failure occurring after acute hepatitis. Severe HAAA requires immunosuppressive therapy (IST) or hematopoietic stem cell transplantation (HSCT) as lifesaving treatment. The outcomes of HAAA patients who underwent haploidentical hematopoietic stem cell transplantation (haplo-HSCT) have not been systematically evaluated. We retrospectively compared the characteristics of 15 patients with HAAA and 60 non-hepatitis-associated aplastic anemia (non-HAAA) patients, all 75 of whom underwent haplo-HSCT in our hospital between January 2006 and October 2021. The median ages of the patients were 18 years old (range, 3-36) for HAAA patients and 13 years (range, 2-45) for non-HAAA patients (p = 0.693). The median time for neutrophil engraftment was 14 days (range, 11-22) in the HAAA group and 12 days (range, 10-21) in the non-HAAA group (p = 0.363). At the time of analysis, 15 HAAA patients and 58 non-HAAA patients were alive, and their median follow-up times were 37 (range, 3-87) months and 31 (range, 2-110) months (p = 0.347), respectively. There were no significant differences in the three-year overall survival (OS) rates (100% vs. 96.7 ± 0.33%, P = 0.638) or liver event-free survival (LEFS) (80.0 ± 0.17% vs. 76.7 ± 0.19%, P = 0.747) between the two groups. Despite the small number of HAAA patients due to the rarity of the disease, these results, such as the similar incidence rates of 3-year OS and fewer liver events than expected, suggest that haplo-HSCT is a feasible treatment for HAAA a when there are no human leukocyte antigen (HLA)-matched donors available and has a low risk of transplant-related mortality and complications.

The impact of pretransplant serum ferritin on haploidentical hematopoietic stem cell transplant for acquired severe aplastic anemia in children and adolescents.

Haploidentical hematopoietic stem cell transplant (haplo-HSCT) provides an important alternative for children and adolescents with acquired severe aplastic anemia (SAA) lacking matched donors. To test whether pretransplant serum ferritin (SF) represents a candidate predictor for survival and a potential biomarker for graft-versus-host disease (GvHD) in pediatric haplo-HSCT, we retrospectively evaluated 147 eligible patients with SAA who underwent haplo-HSCT. The patients were divided into the low-SF group (< 1000 ng/mL) and the high-SF group (≥ 1000 ng/mL). We found that SF ≥1000 ng/mL independently increased the risk of grade II-IV aGvHD (HR = 2.596; 95% CI, 1.304-5.167, P = 0.007) and grade III-IV aGvHD (HR = 3.350; 95% CI, 1.162-9.658, P = 0.025). Similar probabilities of transplant-related mortality at 100 days were observed in the two groups (6.19 ± 2.45% vs 8.00 ± 3.84%, P = 0.168). The two-year overall survival (85.29 ± 3.89% vs 92.00% ± 3.84%, P = 0.746) and failure-free survival (83.23% ± 4.08% vs 83.37% ± 6.27%, P = 0.915) were comparable. GvHD-/failure-free survival were 60.06 ± 5.10% and 75.56 ± 6.87%, respectively (P = 0.056). In conclusion, elevated pretransplant SF level is associated with higher incidences of grade II-IV aGvHD and grade III-IV aGvHD. However, it is not associated with worse survival after haplo-HSCT for children and adolescent patients with SAA.

Recipient and donor PTX3 rs2305619 polymorphisms increase the susceptibility to invasive fungal disease following haploidentical stem cell transplantation: a prospective study.

BACKGROUND: Invasive fungal disease (IFD) is a severe complication after haploidentical stem cell transplantation (haplo-HSCT) and has a poor prognosis. It has been shown that genetic polymorphism may be one possible reason for the increased risk of IFD. This study aimed to assess the role of genetic polymorphism in the level of susceptibility to IFD after haplo-HSCT. METHODS: In this study, we prospectively enrolled 251 patients who received haplo-HSCT at the Peking University Institute of Hematology from 2016 to 2018. Forty-three single nucleotide polymorphisms (SNPs) of the genomic DNA were genotyped in blood samples from both recipient and donor. RESULTS: Twenty-two patients (8.8%) were diagnosed with proven or probable IFD. The independent risk factors for IFD were grades 3-4 acute graft-versus-host disease, cytomegalovirus reactivation, and recipient and donor rs2305619 (PTX3) (P < 0.05) in multivariate analysis. Meanwhile, we combined the variables to develop the IFD risk scoring system and stratified patients into low- (0-2) and high-risk (3-4) groups. The 30-day and 100-day cumulative incidence of IFD in the low- and high-risk groups were 2.1% and 10.2%, 4.2% and 20.3%, respectively (P = 0.015). CONCLUSIONS: PTX3 rs2305619 polymorphism increase the susceptibility of IFD after haplo-HSCT in the Chinese Han population, and the IFD scoring system could be useful in risk stratification for IFD after HSCT.

Haploidentical hematopoietic stem cell transplantation for patients with myeloid sarcoma: a single center retrospective study.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been regarded as a potential strategy for myeloid sarcoma (MS). The previous reports focused mainly on matched sibling donor (MSD) or matched unrelated donor (MUD) transplantation. There are no reports on haploidentical HSCT (haplo-HSCT) in MS. We retrospectively reviewed 14 MS patients who underwent haplo-HSCT. All patients achieved complete donor engraftment. The median time for neutrophil engraftment and platelet engraftment were 10 (12-21) days and 18 (8-31) days. The 100-day cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) and 3-year cumulative incidence of chronic GVHD were 37.7% (95%CI, 23.2-52.1%) and 35.7% (95%CI, 22.2-49.2%). Cytomegalovirus (CMV) reactivation was documented in 86% patients, and only one patient developed CMV pneumonia. Treatment-related mortality occurred in one (7%) patient. The 1- and 3-year cumulative incidence of relapse was 21.4% (95%CI, 11.8-31.1%) and 35.7% (95%CI, 22.4-49.0%). The probability of overall survival at 1 and 3 years was 71.4% (95%CI, 51.3-99.5%) and 64.3% (95%CI, 43.5-95.0%), respectively. The probability of disease-free survival at 1 and 3 years was 71.4% (95%CI, 51.3-99.5%) and 57.1% (95%CI, 36.3-89.9%), respectively. In conclusion, haplo-HSCT is a feasible method for patients with MS who have no MSD or MUD.