Makoto Onizuka

Summary: Unrelated cord blood transplantation (CBT) is an important alternative donor option for adult patients with myelodysplastic syndrome (MDS); however, the prognostic significance of cord blood unit characteristics following CBT remains unclear and may vary according to disease risk. We conducted a nationwide retrospective study of 1767 adult patients with MDS who underwent first single‐unit CBT between 1999 and 2023, including 529 patients with low‐risk and 1238 with high‐risk disease at transplantation. Cord blood unit characteristics were not significantly associated with disease‐free survival (DFS) in patients with low‐risk MDS. In contrast, in patients with high‐risk MDS, higher cryopreserved cluster of differentiation (CD)34 ⁺ cell dose and higher colony‐forming unit–granulocyte/macrophage dose were associated with improved DFS, whereas human leucocyte antigen (HLA) serological one‐locus mismatch and female‐to‐male donor–recipient sex mismatch were independently associated with inferior DFS. Restricted cubic spline Cox regression demonstrated a significant non‐linear association between CD34 ⁺ cell dose and DFS, as well as relapse, in high‐risk MDS. These findings demonstrate that the prognostic impact of cord blood unit characteristics after single‐unit CBT differs according to MDS risk status and support a risk‐adapted approach to cord blood unit selection, particularly for patients with high‐risk MDS.

Donor polymorphisms in killer-cell immunoglobulin-like receptor (KIR) and HLA shape natural killer (NK) cell activity, which may influence relapse risk after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, association studies have been limited by insufficient allele-level KIR genotyping. Using high-resolution, long-read genotyping of 15 KIR genes, we performed an unbiased discovery analysis in 219 patients with T-cell leukemia/lymphoma (ATL) who underwent allo-HSCT to identify relapse-associated donor KIR/HLA polymorphisms. We comprehensively tested associations between donor KIR/HLA amino acid–level combinations and relapse risk, accounting for linkage disequilibrium across KIR haplotypes, and validated the findings in independent cohorts. In ATL, KIR3DL1∗005 or KIR3DS1∗013 with glutamic acid at position 62 in the HLA-B α2 domain (HLA-B-D2-62E) and KIR3DL1∗001/∗007/∗015/∗020 with HLA-B-D2-62V (valine) were high-risk (H) combinations. Meanwhile, KIR3DL1∗015 with isoleucine at position 80 in the HLA-B α1 domain (HLA-B-D1-80I) and KIR3DL1∗001/∗005/∗007/∗020 with HLA-B-D1-80T (threonine) were low-risk (L) combinations. Compared with L-/H+ donors (n = 119), L+/H-, L-/H-, and L+/H+ donors (n = 80) showed reduced relapse (adjusted hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.19-0.65; P = 7.5 × 10-4) and improved overall survival (adjusted HR, 0.67; 95% CI, 0.45-0.98; P = .038). Those donors were associated with reduced relapse in other T-cell malignancies (n = 145; adjusted HR, 0.37; 95% CI, 0.16-0.89; P = .026) but not in acute myeloid leukemia (n = 965; P = .77), suggesting disease specificity. Low-risk combinations increased CD107a degranulation of KIR3DL1+ NK cells against HLA class I–deficient targets, consistent with enhanced NK cell education. These findings support KIR/HLA-based donor selection and underscore the role of antitumor NK cell immunity.

Summary: CD34 ⁺ cell dose is believed to impact the outcomes of allogeneic peripheral blood stem cell transplantation (PBSCT), yet the optimal dose remains unclear. We retrospectively reviewed 2407 adult patients with acute myeloid leukaemia who underwent their first related PBSCT between 2000 and 2019. The median infused CD34 ⁺ cell dose was 3.67 × 10 ⁶ /kg. Patients were divided into three groups based on infused CD34 ⁺ cell dose: low (1.0–2.0 × 10 ⁶ /kg), intermediate (2.0–4.0 × 10 ⁶ /kg) and high (4.0–10.0 × 10 ⁶ /kg) groups. The 5‐year overall survival rates were 37.2%, 40.2% and 37.4% in the low, intermediate and high groups respectively ( p = 0.176). Although the high‐group patients experienced faster neutrophil engraftment, cumulative incidences of infection and primary engraftment failure were comparable across groups. Platelet engraftment was significantly delayed in the low group, with 21.7% failing to engraft at day 100, compared to 14.6% and 13.4% in the intermediate and high groups ( p < 0.001). Furthermore, the incidence of secondary graft failure was significantly higher in the low group. In conclusion, a CD34 ⁺ cell dose >2.0 × 10 ⁶ /kg improves platelet engraftment and reduces the risk of secondary graft failure but does not confer additional long‐term benefits.

Post-transplant cyclophosphamide (PTCy) is now being increasingly applied to HLA-matched donor (MD) transplantation. Prior studies in Western countries have demonstrated that allogeneic hematopoietic cell transplantation (allo-HCT) employing PTCy yields better outcomes with HLA-matched donors (MDs) than with haploidentical donors (HIDs). However, the effect of HLA mismatch may differ among racial groups. We retrospectively analyzed adult patients with hematological malignancies who underwent their first allo-HCT with PTCy from MDs or HIDs registered to the Japanese registry database between 2013 and 2021. Among 63 (related, n = 33; unrelated, n = 30) and 1261 patients who received MD and HID allo-HCT with PTCy, 50 (related, n = 30; unrelated, n = 20) and 100 patients were assigned to MD and HID groups by 1:2 propensity score matching (PSM). The results showed that MD recipients had better neutrophil recovery (hazard ratio [HR], 1.48; 95% confidence interval [CI], 1.04–2.10; P = 0.031) and lower risk of non-relapse mortality (NRM) (HR, 0.19; 95% CI, 0.05–0.81; P = 0.024) than HID recipients. Multivariable analyses in the entire cohort before PSM confirmed these findings. Fatal infection was the primary cause of NRM in the HID group. This study is the first to demonstrate that, within a homogeneous Asian cohort, MD may have an advantage over HID in PTCy-based allo-HCT in facilitating neutrophil engraftment and reducing the risk of NRM.

In this registry-based study, we evaluated the efficacy of different antiviral therapies for adult patients who developed human herpesvirus-6B (HHV-6B) encephalitis after their first cord blood transplantation (CBT). Among 3,862 CBT recipients registered in Japan between January 2019 and December 2023, HHV-6B encephalitis occurred in 289 patients within 100 days post-transplant (7.5%). Antiviral treatments included foscarnet (FCN) monotherapy (n = 190), ganciclovir (GCV) monotherapy (n = 12), and FCN/GCV combination therapy (n = 74). The FCN/GCV group was associated with a potential improvement in 1-year survival compared with the FCN and GCV groups (63.2% vs. 52.5% vs. 41.7%, p = 0.38). Moreover, FCN/GCV therapy was identified as an independent predictor of improved survival compared with FCN monotherapy (HR, 0.60; 95% CI, 0.38–0.95; p = 0.031). Furthermore, the combination FCN/GCV therapy showed better survival than FCN monotherapy in the patients after neutrophil engraftment (1-year survival 68.1% vs. 51.6%), but worse survival in patients before engraftment (1-year survival 34.1% vs. 54.6%). Together, these findings provide real-world evidence linking antiviral regimen selection to post-transplant outcomes in HHV-6B encephalitis and suggest that FCN/GCV combination therapy may offer a survival advantage over FCN monotherapy in selected CBT patients, with treatment strategies potentially tailored according to hematologic recovery.