Kimikazu Yakushijin

Background: The incidence of transfusion-transmitted cytomegalovirus (TT-CMV) after hematopoietic stem cell transplantation (HSCT) in the era of universal leukoreduction remains unclear. This study evaluated temporal changes in TT-CMV and clinically significant CMV infection (csCMVi) in Japan. Methods: Data from 5,016 CMV-seronegative HSCT recipients registered between 1999 and 2022 were retrospectively analyzed. TT-CMV was defined as CMV antigenemia and/or CMV disease, and csCMVi as the initiation of pre-emptive therapy or CMV disease. Results: Random donor (RD) blood products were independently associated with TT-CMV (odds ratio 2.35, 95% confidence interval 1.75–3.15, P < 0.001) and csCMVi (subdistribution hazard ratio 2.22, 95% CI 1.67–2.96, P < 0.001). Among allogeneic HSCT recipients receiving RD blood products, TT-CMV decreased from 25.7% in 2007–2020 to 12.7% in 2021–2022, while the 100-day cumulative incidence of csCMVi decreased from 24.7% to 8.3% over the same periods. During 2021–2022, differences between RD and CMV-seronegative donor blood products were not statistically significant. CMV disease incidence did not differ between groups. Conclusions: TT-CMV and csCMVi decreased substantially over time. Although RD blood products remained associated with higher overall risk, the additional benefit of CMV-seronegative blood products may be limited under contemporary transfusion practices.

Background: Although immune checkpoint inhibitors (ICIs) cause grade 3 or higher immune-related adverse events (irAEs), validated biomarkers for identifying patients at risk of these events are lacking. Given the potential contribution of B-cells to irAE development, we evaluated whether early changes in circulating B-cell subsets after nivolumab plus ipilimumab were associated with subsequent severe irAEs. Materials and Methods: This prospective observational study included 12 patients who received nivolumab plus ipilimumab, and an exploratory cohort of five patients who received anti-PD-1 monotherapy. Blood was sampled before treatment, at week 1, and before cycle 2. Flow cytometry quantified CD21low B-cells, CD27+IgD− class-switched B-cells, plasmablasts, and CD19+CD138+ plasma cells. irAEs were assessed for 6 months, and fold changes at week 1 were compared between patients with and without severe irAEs. Paired immunoglobulin G B-cell receptor (BCR) repertoires were analyzed in four patients with grade 3 or higher irAEs. One patient developed myasthenia gravis, and anti-acetylcholine receptor (AChR) antibody was measured in serial serum samples. Results: In the nivolumab plus ipilimumab patients, grade 3 or higher irAEs occurred in five patients. Week-1 increases in all four activated B-cell subsets were significantly greater in these patients, whereas total CD19+ B-cell changes did not differ. Rarefied IgG BCR diversity generally increased in repertoires derived from peripheral blood mononuclear cells, while Gini coefficients decreased in all paired repertoires. In the myasthenia gravis case, anti-AChR antibody exceeded the reference range by Day 11, before symptoms and diagnosis. Conclusion: First-week expansion of activated peripheral B-cell subsets after nivolumab plus ipilimumab was associated with subsequent severe irAEs. These findings support future studies of early B-cell monitoring within integrated multimarker assessments of irAE risk.

Despite recent advances, data on allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients aged ≥70 years remain limited. We identified prognostic factors and developed a risk score to guide transplant eligibility. Using the Japanese Transplant Registry Unified Management Program, we retrospectively analyzed 929 patients aged ≥70 years who underwent their first allo-HSCT for hematologic malignancies between 2000 and 2022. Prognostic factors were identified by multivariate Cox regression to construct a scoring system. The median patient age was 71 years (range, 70-88), with acute myeloid leukemia being the most common disease. The 2-year overall survival (OS) rate was 34.2%. Multivariate analysis identified age ≥75 years, ATL, lymphoma, high disease risk, hematopoietic cell transplant-specific comorbidity index ≥5, and performance status ≥2 as adverse factors. Using the hazard ratio-based scoring system derived from multivariate analysis, patients were stratified into low- (0), intermediate-1- (1), intermediate-2- (2-3), and high-risk (4-5) groups, with 2-year OS rates of 57.1%, 35.0%, 18.3%, and 2.5%, respectively (p < 0.01). We identified prognostic factors and developed a scoring system stratifying survival in patients aged ≥70 years, potentially facilitating the selection of older candidates most likely to benefit from allo-HSCT.

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.

The B-cell receptor (BCR) repertoire serves as a historical record of immunological events. However, deciphering antigen-specific sequences from this vast dataset remains a challenge, particularly for novel pathogens where prior knowledge is absent. While time-course analysis methods such as QASAS have proven effective for tracking immune responses, they rely on existing antibody databases, limiting their applicability to emerging diseases. To overcome this limitation, we introduce LM-QASAS, a reference-free computational framework that integrates antibody language models with repertoire dynamics. By mapping sequences into a high-dimensional semantic embedding space, LM-QASAS identifies functionally convergent clusters of sequences that are semantically similar and exhibit transient expansion upon immune stimulation. In healthy individuals vaccinated with SARS-CoV-2 mRNA vaccines, our method identified spike-specific sequences with over 90% purity, significantly outperforming methods based on simple sequence identity or abundance. Leave-one-out cross-validation demonstrated that LM-QASAS could accurately reconstruct immune dynamics in unseen individuals without external references. Conversely, the method showed limited sensitivity in an influenza vaccine cohort, revealing that the approach is most effective under conditions of robust clonal expansion (high signal-to-noise ratio), such as those induced by mRNA vaccines. LM-QASAS provides a rapid, high-precision platform for monitoring humoral immunity against emerging threats. Significance statement: Antibodies that recognize a pathogen leave traces in a person’s B-cell receptor (BCR) repertoire, but identifying those antigen-specific sequences is difficult, especially for new diseases lacking reference databases. We present LM-QASAS, a reference-free method that combines antibody language models with time-course repertoire data to detect clusters of sequences that expand transiently after immune stimulation. In SARS-CoV-2 mRNA vaccinees, LM-QASAS enriched spike-related sequences with very high precision and enabled reconstruction of immune-response dynamics in unseen individuals using pseudo-reference databases built from other subjects. Analyses of convalescent, post-transplant, and influenza cohorts clarify when the approach works best: strong clonal expansion and a high signal-to-noise ratio. This framework supports rapid monitoring of humoral immunity against emerging threats.