Data on allogeneic hematopoietic stem cell transplantation (allo-HSCT) for pediatric acute myeloid leukemia, myelodysplasia-related (AML-MR) remain limited. We retrospectively analyzed 732 children and adolescents who underwent first allo-HSCT for AML-MR (n = 252) or AML, defined by differentiation (AML-DD; n = 480) between 2000 and 2018, using Japanese nationwide registry data. The 5-year leukemia-free survival and overall survival (OS) did not differ significantly between AML-MR and AML-DD (44.5% versus 48.2% and 52.6% versus 51.1%, respectively). Within AML-MR, outcomes were heterogeneous: monosomal karyotype (MK) without − 7/del(7q) was associated with inferior OS compared with AML-DD, whereas MK with − 7/del(7q) was not. Among patients with MK, those with − 7/del(7q) had better OS than those without (71.1% versus 31.0%, P = 0.023). A cytogenetics-based three-tier risk model stratified AML-MR outcomes (5-year OS: 63.6%, 51.1%, and 31.8% for low-, intermediate-, and high-risk groups, P < 0.001). Non-remission at HSCT and poor performance status independently predicted inferior survival. Although overall allo-HSCT outcomes in pediatric AML-MR were comparable to AML-DD, subgroup heterogeneity—particularly the adverse impact of MK without − 7/del(7q)—warrants risk-adapted strategies.

Effective risk stratification is vital for donor selection and treatment strategies in allogeneic hematopoietic stem cell transplantation (HSCT). We developed a prediction model for mid- to long-term outcomes after HSCT using a stacked ensemble model (SEM). Using data from the Japanese Transplant Registry Unified Management Program, we analyzed 14,430 patients alive without chronic GVHD (cGVHD) or relapse on day 100 after their first HSCT for hematologic malignancies between 2010 and 2018, predicting 24-month outcomes from pretransplant variables and posttransplant acute GVHD (aGVHD) information, including its treatment, accrued by days 30, 60, and 100. Data were randomly divided into training (80%) and validation (20%) sets, with 14 pretransplant risk factors as input variables. SEM achieved the highest C-index across evaluated endpoints, cGVHD, non-relapse mortality (NRM), and all-cause mortality (ACM), significantly exceeding the weaker learners for all endpoints and, using pretransplant factors, the strongest learner for NRM and ACM as well (both p=0.01), with a smaller, non-significant margin for cGVHD (C-index for cGVHD/NRM/ACM—SEM: 0.574/0.652/0.642, Cox-PH: 0.553/0.635/0.615, Random Survival Forest: 0.564/0.638/0.613, XGBoost: 0.556/0.633/0.627, Dynamic-DeepHit: 0.508/0.607/0.564). The C-index increased as posttransplant aGVHD information accrued (day 30: 0.581/0.655/0.649; day 60: 0.602/0.688/0.656; day 100: 0.606/0.696/0.664). Grade III to IV aGVHD showed predictive contribution to NRM, ultimately impacting ACM. Our SEM-based model offers a useful framework for predicting post-HSCT outcomes and highlights the critical impact of early aGVHD events on long-term prognosis.

Donor selection in allogeneic haematopoietic stem cell transplantation (allo-HSCT) requires balancing donor safety and recipient survival. We aimed to identify dual-association donor factors (DADFs)-donor characteristics associated with both increased serious adverse events (SAEs) and inferior patient survival-using umbilical cord blood (UCB) as a donor-safety benchmark. This nationwide retrospective cohort study analysed Japanese registry data (2013-2022) including 22 892 donors and 29 559 recipients. Logistic regression identified donor SAE risk factors, while patient outcomes were evaluated using inverse probability of treatment weighting (IPTW)-adjusted Cox models with UCB as reference. Propensity score matching (PSM) compared UCB with older donor haploidentical transplantation using post-transplant cyclophosphamide (OD-PTCy-Haplo). Among donors, 93 (0.41%) experienced an SAE. Older donor age and female sex were independent risk factors for SAE. In IPTW-adjusted analyses, allo-HSCT from older haploidentical donors was associated with inferior overall survival (OS) and relapse-free survival (RFS) compared with UCB. In PSM analyses of elderly high-risk recipients, OD-PTCy-Haplo resulted in significantly worse OS and RFS than UCB. Older donor age emerged as a donor characteristic associated with increased donor SAE risk and inferior patient survival, particularly in haploidentical transplantation. UCB may offer a more favourable balance between donor safety and patient outcomes in selected high-risk settings.

The clinical impact of immunosuppression termination (IST) after allogeneic haematopoietic stem cell transplantation (allo-HSCT) remains to be fully elucidated. This study was aimed at assessing the impact of IST within 2 years after transplantation on subsequent clinical outcomes. We analysed data for patients from the Transplant Registry Unified Management Program 2 (TRUMP 2) database who survived without progression for at least 2 years after allo-HSCT. Of the 5061 patients whose median age was 48 (range: 0-79) years, 2320 discontinued immunosuppressive therapy within 2 years (IST group), while 2741 did not (non-IST group). The 4-year overall survival (OS) rate was significantly higher in the IST group than in the non-IST group (95.3% vs. 90.8%; p < 0.01). The 4-year cumulative incidence of non-relapse mortality (NRM) was significantly lower in the IST group than in the non-IST group (3.5% vs. 8.6%; p < 0.01). This reduction in NRM was consistent across major causes, including graft-versus-host disease (GVHD)-related mortality, infection-related mortality and organ failure-related mortality. Immunosuppressive therapy beyond 2 years after allo-HSCT was associated with inferior OS. Our findings suggest that the optimal transplant strategy is necessary to avoid long-term immunosuppression for improving clinical outcomes in allo-HSCT recipients.

Abstract This phase 2 clinical study evaluated the efficacy and safety of post–allogeneic hematopoietic stem cell transplantation maintenance cancer immunotherapy using 2 Wilms tumor 1 (WT1) peptide vaccines, MCI, for pediatric refractory acute leukemias. Each of 17 patients (median age, 8.3 years [range, 2-18]) was intradermally injected with either of the vaccines. The 3-year overall survival (OS) rate (primary end point) was 70.6% (95% confidence interval [CI], 43.1-86.6); this rate was >30%, a historical control benchmark, and was attributable to the fact that 12 clinical responders, who sustained complete remission at year 1 after the initiation of vaccination, had a high 3-year OS rate of 91.7% (95% CI, 53.9-98.7). WT1-specific cytotoxic T-cell (CTL) frequency in peripheral blood (PB) from all 12 clinical responders increased significantly after vaccination, reaching the maximum by week 12 of vaccination (before, 0.25% ± 0.08%; after, 1.07% ± 0.24%; P< .001), whereas WT1-specific CTL frequency in PB from clinical nonresponders remained unchanged after vaccination (before, 0.12% ± 0.2%; after, 0.20% ± 0.25%; P = .424). The estimated 3-year OS rate was significantly higher for 11 immune responders (who showed a ≥1.455-fold increase from the baseline value: 90.9%) than for 5 immune nonresponders (40.0%; P = .027). Elevated WT1-specific CTL frequency in the PB before vaccination predicted the subsequent favorable patient prognosis. No patient discontinued treatment because of MCI. Adverse events including graft-versus-host disease were manageable. MCI was suggested to be very effective and safe for pediatric patients with refractory acute leukemias, indicating its potential to improve their survival through relapse prevention. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry as #UMIN000005319.

ABSTRACT:The TCF3::HLF fusion protein defines a highly aggressive and incurable subtype of B-cell acute lymphoblastic leukemia (B-ALL). Using a newly established mouse model that faithfully recapitulates human TCF3::HLF B-ALL, including osteolytic bone lesions, we identified self-reinforcing interleukin-1β (IL-1β) signaling networks as a central driver of disease progression. TCF3::HLF B-ALL cells displayed marked upregulation of inflammatory cytokines, such as IL1B, IL6, and IFNG. Genetic deletion of IL1B or its receptor IL1R1 suppressed leukemic growth, reduced expression of receptor activator of nuclear factor κB ligand, and ameliorated bone destruction in vivo. Epigenetic profiling revealed a previously unrecognized intronic regulatory element within the IL1B locus bound directly by TCF3::HLF. Importantly, single-cell RNA sequencing of patient samples demonstrated strong IL1B induction at relapse compared with diagnosis, underscoring its clinical relevance. Collectively, these findings establish the TCF3::HLF-IL-1β axis as a critical determinant of leukemic propagation and bone pathology and highlight IL-1β blockade as a potential therapeutic strategy for this otherwise incurable leukemia.

Down syndrome-associated acute lymphoblastic leukaemia (DS-ALL) is associated with inferior outcomes compared with non-DS-ALL; however, data on haematopoietic stem cell transplantation (HSCT) in DS-ALL remain limited. We analysed nationwide data of patients aged <30 years with B-cell precursor ALL who underwent first allogeneic HSCT between 2000 and 2022 in Japan. In total, 56 patients with DS-ALL and 3873 with non-DS-ALL were identified. The incidences of neutrophil engraftment, grade II-IV acute graft-versus-host disease and chronic graft-versus-host disease were comparable between groups. The 4-year event-free survival (EFS) was lower in DS-ALL than in non-DS-ALL (40.3% vs. 55.2%), but was similar when stratified by disease status at HSCT. The 4-year EFS rates in first and second complete remission (CR) were 62.7% and 48.2% in DS-ALL and 69.5% and 56.0% in non-DS-ALL respectively. Relapse, rather than non-relapse mortality (NRM), was the leading cause of treatment failure in DS-ALL. Among patients with DS-ALL undergoing HSCT in CR1/2, myeloablative conditioning (MAC) showed a trend towards superior EFS compared with reduced-intensity conditioning (RIC), which was associated with a higher incidence of NRM. Accordingly, patients in CR1/2 who are unable to tolerate MAC are considered good candidates for emerging novel therapies rather than RIC-HSCT.

IntroductionHemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome caused by excessive cytokine release from activated T cells and macrophages. Primary HLH, or familial HLH (FHL), results from genetic mutations affecting cytotoxic lymphocyte function.Case ReportWe present a case of FHL Type 2 (FHL2) caused by compound heterozygous variants in the PRF1 gene, including one novel missense variant of p.Ala21Val (A21V). A 5-month-old boy presented with persistent fever, pancytopenia, coagulopathy, hepatosplenomegaly, and elevated ferritin, meeting the HLH-2004 diagnostic criteria. Bone marrow revealed hemophagocytosis, and NK cell activity was markedly reduced. Genetic analysis identified compound heterozygous PRF1 variants: A21V and p.Pro16Ser (P16S). Flow cytometric analysis demonstrated markedly reduced PRF1 protein expression in the patient's NK cells. The patient was treated with etoposide, dexamethasone palmitate, and cyclosporine, followed by cord blood transplantation. The patient has been in remission for over a year.DiscussionThe PRF1 A21V variant has not been described in the public database or the literature and is therefore considered a novel pathogenic variant for FHL2 with functional validation. Although the PRF1 P16S variant has been previously reported in the heterozygous state in an adult patient with primary HLH, our findings provide functional and clinical evidence supporting a contributory role of the P16S variant in autosomal recessive early-onset FHL2 when present in trans with the novel A21V variant.ConclusionWe identified a previously unreported PRF1 variant, A21V, and provided the first functional evidence of impaired perforin expression associated with A21V/P16S, highlighting the importance of functional validation of rare PRF1 variants in FHL2.

Purpose:Severe congenital protein C deficiency (SCPCD) is a rare, life-threatening disorder. Plasma-derived protein C concentrate is recommended for the acute and long-term management of SCPCD; however, data in Japanese patients are lacking. In this study, the pharmacokinetics (PK) and safety of protein C concentrate were investigated in a Japanese population. Patients and Methods:This study was an open-label, phase 1/2, nonrandomized, noncontrolled, multicenter clinical trial in Japanese patients with SCPCD (ClinicalTrials.gov: NCT04984889). Patients received a single intravenous dose (80 IU/kg) of human plasma-derived protein C concentrate. The primary endpoints were plasma protein C activity levels and PK parameters. Secondary endpoints for safety included adverse events (AEs). Results:All five enrolled patients (mean age, 15.2 years; mean weight, 34.0 kg) received the predefined dose of protein C concentrate and were included in PK and safety analyses. The geometric mean (coefficient of variation [CV]%) maximum concentration (Cmax) was 1.679 IU/mL (31.7%) and the geometric mean (CV%) area under the curve (AUCinf) was 21.88 IU·h/mL (47.1%). The median (range) half-life for protein C in plasma was 10.7 (7.35-12.4) hours. Cmax and AUCinf tended to be higher in older patients (≥20 years old) than in younger patients (<20 years old), whereas half-life was similar regardless of age. One patient had a mild treatment-related AE of pyrexia. No serious AEs or deaths were reported. Conclusion:PK parameters for protein C concentrate in Japanese patients with SCPCD were determined to be comparable to studies in western populations. A single intravenous 80 IU/kg dose was well tolerated, with no serious treatment-related AEs.

As a second-line treatment for first-line steroid-refractory acute GVHD, ruxolitinib was proven to be significantly more effective than control therapies (nine commonly used therapy options) in a prospective, randomized trial. However, it could sometimes be difficult to administer ruxolitinib for patients with cytopenia or who have difficulty taking it orally regularly. The present retrospective study compared the outcomes of second-line mesenchymal stromal cell (MSC) and antithymocyte globulin (ATG) therapies following first-line steroid therapy for acute GVHD. Clinical data for the total 1120 patients who received MSC (n = 777) and ATG (n = 343) as second-line therapy following first-line steroid therapy for acute GVHD from 2016 to 2022, when both therapies were covered by health insurance in Japan, were extracted from Japanese stem cell transplantation registry data. Overall response rates (ORRs) on day 28 of the MSC and ATG therapies were 62.7% and 51.0%, respectively (multivariate analysis: odds ratio, 1.56; P = 0.001). ORRs for skin, liver, and gastrointestinal tract acute GVHD were 66.3% versus 57.5% (1.43, P = 0.063), 33.1% versus 25.7% (1.18, P = 0.636), and 66.3% versus 49.8% (1.96, P < 0.001), respectively. The incidences of invasive fungal infection and viral infection within the first 100 days after the start of second-line therapy were 3.9% versus 8.2% (Fisher's exact test: P = 0.005) and 13.4% versus 25.1% (P < 0.001), respectively. However, non-relapse mortality, the relapse rate, and overall survival did not differ between MSC and ATG therapies. Furthermore, the propensity score-matched analysis yielded results consistent with the findings described above. In conclusion, this retrospective study demonstrated that the ORR based on whole body assessment and the ORR based on gastrointestinal tract stage assessment were both significantly higher with MSC therapy than with ATG therapy. However, prospective, randomized, controlled trials are necessary for a more accurate comparison.

INTRODUCTION:Ewing sarcoma is a rare malignant tumor that primarily affects children and adolescents, and approximately 20% occur in the chest wall, where achieving local control is challenging due to the need for extensive resection and the proximity to vital organs. Adjuvant radiotherapy improves outcomes but carries a risk of severe complications such as radiation pneumonitis. Radioprotective spacers have been used for abdominal and pelvic tumors, but their use in chest wall tumors is rarely reported. We report a chest wall Ewing sarcoma case in which a radioprotective spacer using expanded polytetrafluoroethylene and a water-inflatable expander was placed to reduce radiation-related organ damage. CASE PRESENTATION:A 15-year-old female presented with a large Ewing sarcoma arising from the left chest wall, measuring 121 × 166 × 93 mm. After diagnosis by wedge biopsy and confirmation of EWSR1::FLI1 fusion, she received neoadjuvant chemotherapy based on the JESS04 protocol. Following significant tumor shrinkage, surgical resection was performed via a 20‑cm thoracotomy. En bloc removal included the tumor, the 5th and 6th ribs, and a portion of the adjacent lung. To reconstruct the chest wall and protect adjacent organs from high‑dose postoperative radiotherapy, a novel radioprotective spacer was inserted. The spacer was constructed by sandwiching a water‑inflatable tissue expander between two expanded polytetrafluoroethylene sheets. This design provided dual functionality: it reinforced the large chest wall defect and physically distanced the left lung from the radiation field. The expander was filled with 70 mL of water to create an adjustable spacer volume and could be deflated if postoperative symptoms occurred. The patient underwent intensity‑modulated radiation therapy with a total dose of 50.4 Gy without respiratory complications. After radiotherapy, the expander was removed, while the expanded polytetrafluoroethylene sheets remained in place to maintain chest wall integrity. At 4 years postoperatively, the patient remains disease‑free and symptom‑free. CONCLUSIONS:This case illustrates the feasibility and safety of combining a radioprotective spacer with structural chest wall reconstruction in pediatric sarcoma. The dual‑purpose design may offer an effective strategy for minimizing radiation‑related toxicity in thoracic tumors requiring multimodal treatment.

Pediatric myelodysplasia syndrome is often characterized by hypoplastic bone marrow morphology and predisposition to infection. Invasive aspergillosis during hematopoietic stem cell transplantation poses a significant threat and often requires voriconazole (VRCZ) therapy. However, difficulties in achieving appropriate VRCZ blood levels due to drug interactions have prompted the exploration of alternative treatments, such as isavuconazole (ISCZ). We present the case of a 4-year-old boy with myelodysplasia syndrome who developed multiple abscesses, including a brain abscess caused by Aspergillus fumigatus, and was successfully treated with ISCZ. Despite initial treatment with liposomal amphotericin B and VRCZ, the patient's condition deteriorated. Transitioning to ISCZ treatment resulted in significant clinical improvement, resolution of the abscesses, and reduced antigen levels. Although ISCZ induced hepatic enzyme elevation, supportive care improved without discontinuation of treatment. This case highlights the potential of ISCZ in cases of pediatric invasive aspergillosis where traditional therapies fail, underscoring the need for further research and formulation development to optimize its use in this population. As more cases accumulate, ISCZ may become a promising option for treating severe invasive aspergillosis in pediatric patients undergoing hematopoietic stem cell transplantation.

We evaluated the impact of center volume on outcomes in patients with B-cell acute lymphoblastic leukemia following their second allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our cohort included 299 patients with relapse and 68 patients with graft failure after their first allo-HSCT between 2003 and 2017. Patients were stratified into low- and high-volume groups based on the number of allo-HSCT performed at each center. The primary endpoint was 5-year overall survival (OS) following the second allo-HSCT. In the relapse cohort, the high-volume group demonstrated significantly better 5-year OS (21.1% vs 13.6%, P = 0.0062) and progression-free survival (16.1% vs 10.6%, P = 0.010). Multivariate analysis showed that high-volume group was a favorable factor for OS (hazard ratio [HR]: 0.72, 95% confidence interval [CI]: 0.56-0.94, P = 0.016). This survival benefit was consistent in both Philadelphia chromosome-negative (HR: 0.71, 95% CI: 0.51-0.99, P = 0.042) and positive (HR: 0.61, 95% CI: 0.39-0.95, P = 0.030) subcohorts. In the graft failure cohort, the high-volume group showed a trend toward better 5-year OS (41.6% vs 24.4%, P = 0.098) and lower 5-year nonrelapse mortality (NRM) (55.9% vs 75.6%, P = 0.067). Multivariate analysis confirmed the protective effect of the high-volume group on NRM (HR: 0.55, 95% CI: 0.30-0.99, P = 0.044). Our findings demonstrate that center volume significantly impacts outcomes after the second allo-HSCT regardless of indication, highlighting the need for inter-center collaboration and standardized management strategies for this high-risk population.