Tadakazu Kondo

NUP98 rearrangements represent a distinct, high-risk subtype of acute myeloid leukemia (AML), particularly in pediatric patients. However, their prevalence, genetic features, and clinical implications in adult AML remain poorly characterized. Using targeted-capture sequencing, we identified 41 cases with NUP98 rearrangements among 1569 AML cases, representing the majority of 44 NUP98-rearranged cases detected across 4753 myeloid neoplasms. Fifteen distinct fusion partners were detected, with NUP98::NSD1 and NUP98::HOXA9 being the most frequent. Notably, two novel fusions—NUP98::MEOX2 and NUP98::HOXA6—were identified. Co-mutations were relatively infrequent; FLT3-ITD and WT1 mutations were the most common, while NPM1 mutations were exclusive. FLT3-ITD was significantly enriched in NUP98::NSD1 cases, whereas TET2 mutations were more frequent in NUP98::HOXA9 cases. Clonal hierarchy analysis suggested that NUP98 rearrangements occur early in leukemogenesis. NUP98-rearranged AML exhibited higher relapse rates and shorter event-free survival. Specifically, NUP98::NSD1 was associated with a poor induction response, whereas NUP98::HOXA9 and NUP98 fusions with other partners showed higher remission rates but frequent relapse. Allogeneic hematopoietic stem cell transplantation was associated with better survival, underscoring its significance. These findings reveal the genetic and clinical heterogeneity of NUP98-rearranged AML in adults and support its classification as a distinct entity, highlighting the need for fusion partner-specific therapeutic strategies.

Hematopoietic stem cell transplant–associated thrombotic microangiopathy (TA-TMA) is a potentially fatal multisystem complication of hematopoietic cell transplantation for which there is no approved treatment. In a single-arm study (NCT02222545), narsoplimab treatment for TA-TMA demonstrated a median overall survival (OS) of 274 days from date of diagnosis. Here, we compare OS observed in 2 cohorts treated with narsoplimab to OS in a well-matched external control to test survival benefit in patients with high-risk TA-TMA. OS in patients (aged ≥16 years) with high-risk TA-TMA treated with narsoplimab in a single-arm, open-label study (NCT02222545) or in the narsoplimab expanded access program (EAP; NCT04247906) was compared with OS in a control group with high-risk TA-TMA from the Kyoto Stem Cell Transplantation Group (KSCTG) registry. Narsoplimab-treated patients in the single-arm study (N = 28) had a fourfold reduction in risk of mortality compared with patients from the KSCTG registry (N = 111; hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.19, 0.34; P < .0001). Similarly, in high-risk patients treated with narsoplimab in the EAP (N = 49), mortality risk was significantly lower than among high-risk patients from the KSCTG registry (N = 121; HR 0.38; 95% CI 0.28, 0.51; P < .0001). When narsoplimab-treated patients from the single-arm study and the EAP (N = 77) were compared with KSCTG patients, the HR for mortality was 0.28 (95% CI, 0.22, 0.37; P < .0001). In conclusion, in patients with high-risk TA-TMA, narsoplimab treatment significantly reduced mortality relative to a well-matched external control group who did not receive narsoplimab. These results support narsoplimab as a potential therapeutic option for TA-TMA.

Purpose Late-onset non-infectious pulmonary complications (LONIPCs) represent significant sequelae of hematopoietic stem cell transplantation (HSCT), contributing to elevated non-relapse mortality rates. A comprehensive understanding of systemic conditions and prognostic indicators is essential for enhancing supportive care following onset. This study aims to compare respiratory and physical function between patients with LONIPCs and healthy controls, and to identify prognostic factors that influence survival outcomes in patients with LONIPCs. Methods This study included 41 LONIPCs patients admitted to Kyoto University Hospital for lung transplant evaluation. A healthy control group comprised matched living lung transplant donors. Comparisons included respiratory function tests, 6-min walk distance (6MWD), and erector spinae muscle cross-sectional area (ESMA). Multivariate Cox regression analysis was used to identify prognostic factors. Results LONIPCs patients demonstrated significantly reduced respiratory function and 6MWD compared to healthy controls. ESMA was also significantly lower in the patient group. Multivariate Cox regression revealed that decreased knee extensor strength and reduced ESMA were significant predictors of overall survival in patients with LONIPCs. Conclusion Impairments in respiratory and physical function are evident in LONIPCs patients. Modifiable factors such as lower limb muscle strength and skeletal muscle mass, particularly ESMA, are associated with prognosis and should be prioritized in rehabilitation strategies to improve patient outcomes.

Summary: Severe graft‐versus‐host disease (GVHD) remains a major complication of allogeneic haematopoietic stem cell transplantation (allo‐HSCT), necessitating optimal immunosuppressive strategies. This retrospective study used data from the Japanese Transplant Registry Unified Management Program to compare three methotrexate (MTX)‐dosing regimens for GVHD prophylaxis in patients undergoing human leucocyte antigen (HLA)‐matched allo‐HSCT: a low‐dose 3‐day regimen (Ld3:10 mg/m ² on day 1, 7 mg/m ² on days 3 and 6), a low‐dose 4‐day regimen (Ld4: Ld3 with an additional 7 mg/m ² on day 11) and an original‐dose 3‐day regimen (Od3: 15 mg/m ² on day 1, 10 mg/m ² on days 3 and 6). Among 2537 analysed patients, Ld3 was the most commonly used regimen. Multivariate analyses showed no significant differences in the cumulative incidence of grade II–IV acute GVHD among regimens. However, Od3 was associated with an increased risk of grade III–IV acute GVHD, and Ld4 was linked to delayed neutrophil engraftment. This study is the first large‐scale retrospective analysis of the impact of different MTX‐dosing regimens on the outcomes of HLA‐matched allo‐HSCT, providing valuable insights into optimal MTX‐dosing strategies in clinical practice.

NUP98 rearrangements represent a distinct, high-risk subtype of acute myeloid leukemia (AML), particularly in pediatric patients. However, their prevalence, genetic features, and clinical implications in adult AML remain poorly characterized. Using targeted-capture sequencing, we identified 41 cases with NUP98 rearrangements among 1569 AML cases, representing the majority of 44 NUP98 -rearranged cases detected across 4,753 myeloid neoplasms. Fifteen distinct fusion partners were detected, with NUP98::NSD1 and NUP98::HOXA9 being the most frequent. Notably, two novel fusions— NUP98::MEOX2 and NUP98::HOXA6 —were identified. Co-mutations were relatively infrequent; FLT3 -ITD and WT1 mutations were the most common, while NPM1 mutations were exclusive. FLT3 -ITD was significantly enriched in NUP98::NSD1 cases, whereas TET2 mutations were more frequent in NUP98::HOXA9 cases. Clonal hierarchy analysis suggested that NUP98 rearrangements occur early in leukemogenesis. NUP98 -rearranged AML exhibited higher relapse rates and shorter event-free survival. Specifically, NUP98::NSD1 was associated with a poor induction response, whereas NUP98::HOXA9 and NUP98 fusions with other partners showed higher remission rates but frequent relapse. Allogeneic hematopoietic stem cell transplantation was associated with better survival, underscoring its significance. These findings reveal the genetic and clinical heterogeneity of NUP98 -rearranged AML in adults and support its classification as a distinct entity, highlighting the need for fusion partner-specific therapeutic strategies.