Ryu Yanagisawa

Graft-versus-leukemia (GVL) effect is mainly mediated by alloreactive T and NK cells through human leukocyte antigen (HLA). Although most HLA genes are located on the short arm of chromosome 6, the clinical significance of deletion of the short arm of chromosome 6 (del6p) which could attenuate the GVL effect has not been elucidated. We investigated impact of del6p at the diagnosis of hematological malignancies on allogeneic cell transplantation, using a Japanese registry database. Del6p was highly associated with additional chromosomal abnormalities. In the univariate analysis, the del6p group showed a higher incidence of relapse at 2 years among the entire cohort (2y-relapse 48.3% vs 25.7%, P <0.001). Multivariate analysis confirmed that del6p was significantly associated with an increased risk of relapse (HR 1.30 [95% CI: 1.02-1.65], P = 0.036). The del6p group also tended to be associated with relapse, when focusing on patients with complex karyotype (HR 1.25 [95% CI: 0.97-1.60], P = 0.079). Additionally, the impact of del6p on relapse was more evident in the HLA-mismatched than in the HLA-matched cohort. These results suggest that del6p at diagnosis might attenuate the GVL effect through HLA status.

Summary: 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.

Comparative data on alternative donor platforms in adolescent and young adult (AYA) allogeneic hematopoietic cell transplantation (HCT) are limited. We conducted a nationwide retrospective registry study in Japan comparing unrelated umbilical cord blood transplantation (UCBT), haploidentical transplantation without post-transplant cyclophosphamide (non-PTCy-haplo), and PTCy-based haploidentical transplantation (PTCy-haplo). The study included 458 patients aged 16-25 years (UCBT, n = 101; non-PTCy-haplo, n = 132; PTCy-haplo, n = 225). The main endpoints were overall survival (OS) and relapse-free survival (RFS); relapse, non-relapse mortality (NRM), graft-versus-host disease (GVHD), and engraftment were also evaluated. UCBT showed the most favorable survival. In multivariable analyses, non-PTCy-haplo was associated with inferior OS and RFS, higher NRM, and a higher incidence of grade II-IV acute GVHD than UCBT. PTCy-haplo was associated with inferior OS versus UCBT but showed no significant differences in RFS, relapse, NRM, acute GVHD, or chronic GVHD. Both haploidentical platforms showed faster neutrophil engraftment than UCBT, and PTCy-haplo also showed faster platelet engraftment. Sensitivity analyses restricted to malignant disease and stratified by conditioning intensity supported these findings. In this AYA cohort, UCBT was associated with the most favorable survival, non-PTCy-haplo showed consistently inferior outcomes, and PTCy-haplo remained a practical alternative when rapid donor availability and early hematopoietic recovery are prioritized.

Poor venous flow during leukapheresis may compromise cell collection; however, reliable predictors remain limited. We retrospectively analyzed 146 leukapheresis procedures involving patients with hematologic malignancies ( n = 79) and healthy donors ( n = 67) at two institutions, with continuous monitoring of peripheral blood flow using laser Doppler flowmetry (LDF). Poor venous flow, defined in this study as persistent low inlet pressure requiring a > 10% reduction in the draw rate to continue leukapheresis, occurred in 29.1% of patients and 26.9% of donors. In patients, multiple myeloma, lower baseline blood flow, and higher pulse amplitude were independently associated with poor venous flow, whereas in donors, older age was an independent predictor. Peripheral blood flow decreased at the onset of poor venous flow without concomitant changes in blood pressure or LDF‐derived pulse rate. These findings suggest that LDF may help predict poor venous flow during leukapheresis and support pre‐procedural risk stratification.

Introduction: Epstein–Barr virus‐associated hemophagocytic lymphohistiocytosis (EBV‐HLH) is highly prevalent in Asia. This study evaluated the safety and efficacy of a risk‐stratified treatment guided by dexamethasone (DEX) response and plasma EBV‐DNA levels. Our goal was to optimize etoposide dosing and establish a safer EBV‐HLH treatment. Methods: We conducted a single‐arm, multicenter, risk‐stratified Phase II clinical trial, EBV‐HLH15, for EBV‐HLH. Patients were classified into three groups based on age, DEX response, and plasma EBV‐DNA load. In the low‐risk (LR) group, etoposide was eliminated from the treatment regimen. In the intermediate‐risk and high‐risk group (IR/HR group), etoposide dosing was reduced by up to 60% compared with the HLH‐2004 study to attenuate treatment intensity, whereas rituximab was added in the HR group to maintain it. Results: Of 56 patients suspected of EBV‐HLH enrolled, 26 (14 in LR, eight in IR, and four in HR group) were eligible for EBV‐HLH15. The median age was 3.5 years (range: 1.0–8.0). The 1‐year overall survival of the LR and IR/HR groups was 100% and 81.5% (95% confidence interval [CI] = 43.5–95.1), respectively. The event‐free survival of the LR and IR/HR groups was 78.6% (95% CI = 47.2–92.5) and 58.3% (95% CI = 27.0–80.1), respectively. Most events (9/10, mainly deterioration or recurrence of HLH) occurred within 3 weeks of treatment initiation. No patients received rituximab as scheduled in Weeks 5 and 6. Conclusion: Risk‐stratified treatment for EBV‐HLH guided by DEX response and plasma EBV‐DNA levels after 2 weeks of treatment was safe and effective.

Background Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory condition triggered by a combination of genetic predispositions and environmental factors. Reports of previous outcomes from the HLH-2004 protocol in Japan revealed patients with idiopathic HLH who had poor prognoses. This study aimed to reevaluate the genetic background of such patients to identify potential novel genetic variants. Methods Whole-genome sequencing was performed on residual samples from HLH patients enrolled in a study of the HLH-2004 protocol in Japan, excluding those associated with Epstein–Barr virus infection. Sequence variants were interpreted based on the American College of Medical Genetics and Genomics standards and guidelines. Results Nineteen patients were analyzed, including seven diagnosed with familial HLH (FHL) and twelve with unknown causes. Among patients with FHL, five had variants in PRF1 and two in UNC13D, consistent with the original diagnoses. Genetic variants (all UNC13D) were identified in three of the 12 previously undiagnosed patients. One patient had an unknown outcome and the others died of HLH. Conclusion Failure to establish a genetic diagnosis during initial evaluation may have negatively impacted the prognosis of patients with HLH. Comprehensive genetic studies and the development of early screening methods may improve treatment outcomes for HLH.

Although the hematopoietic cell transplantation (HCT)‐comorbidity index (HCT‐CI) score is associated with an increased risk of mortality after allogeneic HCT, it remains unclear how pre‐HCT liver dysfunction affects clinical outcomes. We retrospectively compared clinical HCT outcomes among four groups stratified according to the presence of HCT‐CI liver and other organ scores, using a Japan transplant registry database between 2010 and 2020. Of the 14235 recipients, 1527 tested positive for an HCT‐CI liver score including HBV or HCV hepatitis (n = 503). The 5‐year overall survival (OS) was significantly lower in the HCT‐CI liver(+) other(+) and HCT‐CI liver(−) other(+) groups compared to the HCT‐CI liver(+) other(−) and HCT‐CI liver(−) other(−) groups [49.9% vs. 59% vs. 66.5% vs. 68.3%, p < 0.001]. A multivariate analysis showed that both the HCT‐CI liver(+) other(+) [HR 1.62, p < 0.001] and HCT‐CI liver(−) other(+) groups [HR 1.21, p < 0.001] were significantly associated with inferior OS. Similarly, both the HCT‐CI liver(+) other(+) [HR 1.89, p < 0.001] and liver(−) other(+) groups [HR 1.26, p < 0.001] were significantly associated with an increased risk of NRM. On the other hand, the HCT‐CI liver(+) other(−) group was not associated with either OS or NRM. Separately analyzing the subcohorts with or without HCT‐CI other scores, the presence of an HCT‐CI liver score alone did not affect survival, while the co‐presence of pretransplant liver dysfunction seemed to synergistically increase the adverse impact on OS and NRM among recipients with other organ comorbidities. Further studies will be needed to identify optimal strategies for recipients with pretransplant liver dysfunction.