Published papers

Pre-engraftment syndrome (PES) is a unique complication of cord blood transplantation (CBT) whose risk factors and impact on transplant outcomes remain controversial. Using a nationwide database in Japan, we analyzed a total of 3734 patients who underwent single-unit CBT. PES occurred in 18.3% of patients, and risk factors for PES included a higher hematopoietic cell transplantation-specific comorbidity index, first transplantation, myeloablative conditioning (MAC), lower total nucleated cell (TNC) dose, and graft-versus-host disease (GVHD) prophylaxis regimens excluding tacrolimus with methotrexate. Patients who developed PES had significantly higher incidences of grade II–IV acute GVHD (53.1% vs. 31.3%, p < 0.001) and chronic GVHD (27.2% vs. 21.7%, p = 0.002) compared to those without PES. Landmark analysis with multivariable adjustment revealed that PES was independently associated with increased non-relapse mortality (NRM, hazard ratio [HR] 1.46; 95% CI 1.22–1.75; p < 0.001), reduced relapse incidence (HR 0.78; 95% CI 0.63–0.96; p = 0.020), and a trend toward inferior overall survival (OS, HR 1.13; 95% CI 0.98–1.30; p = 0.088). Moreover, patients who experienced both PES and acute GVHD had the highest 2-year NRM (31.7%; 95% CI 26.0%–37.6%) and the lowest 2-year OS (55.9%; 95% CI 50.0%–62.4%), compared with those who experienced either PES (NRM 20.7%; OS 65.0%) or acute GVHD (NRM 19.5%; OS 62.8%) (p < 0.001), highlighting the combined effects of these complications. This study, the largest to date on PES, demonstrates its clinical significance as an early complication with lasting effects on transplant outcomes.

Cytokine release syndrome (CRS) is the most common adverse event of chimeric antigen receptor T (CAR-T) cell therapy and is usually characterized by systemic symptoms such as fever, hypotension, and hypoxia. However, there have been several recent reports of local CRS characterized by cervical swelling. This localized syndrome can cause life-threatening laryngeal edema and requires early diagnostic treatment. Here we report 3 cases of local CRS where bilateral salivary gland swelling emerged following anti-CD19 CAR-T cell therapy for relapsed or refractory diffuse large B-cell lymphoma. Following tocilizumab treatment for systemic CRS, all patients exhibited cervical swelling. Physical examinations revealed significant swelling of the bilateral submandibular glands, and computed tomography scans showed substantial enlargement of the bilateral parotid and submandibular glands. Immediate treatment with dexamethasone effectively managed the potentially life-threatening laryngeal or pharyngeal edema, thereby preventing severe airway obstruction. This study has demonstrated, for the first time to our knowledge, that salivary gland enlargement is a common finding in local CRS. This observation suggests that physicians should continue to closely monitor the risk of developing cervical edema leading to life-threatening airway obstruction after systemic CRS, even in patients treated with tocilizumab. If salivary gland swelling is observed, it would be better to consider prompt evaluation and dexamethasone administration.

The impact of absolute neutrophil count (ANC) before allogenic hematopoietic stem cell transplantation (HSCT) on the outcomes for patients with aplastic anemia (AA) remains unclear. We retrospectively evaluated the relationship between ANC before transplantation and patient outcomes, involving 883 adult Japanese patients with AA who underwent allogeneic HSCT as their first transplantation between 2008 and 2020. Patients were divided into three groups based on ANC: 0/µL (n = 116); 1–199 (n = 210); and ≥ 200 (n = 557). In the low ANC groups (ANC < 200), patient age was higher, previous anti-thymocyte globulin (ATG) treatments were infrequent, duration from diagnosis to transplantation was shorter, hematopoietic cell transplantation-comorbidity index (HCT-CI) was higher, ATG-based conditioning was used infrequently, and peripheral blood stem cell from related donor and cord blood were used frequently. In multivariate analysis, patient age, previous ATG treatment, HCT-CI, stem cell source, and ANC before transplantation were significantly associated with 5-year overall survival (OS) (“ANC ≥ 200”: 80.3% vs. “ANC 1–199”: 71.7% vs. “ANC 0”: 64.4%). The cumulative incidence of bacterial infection, invasive fungal disease, and early death before engraftment were significantly higher in the low ANC groups. Among patients with ANC of zero before transplantation, younger patient age, shorter duration from diagnosis to transplantation, HCT-CI of 0, and bone marrow from related donor as stem cell source were significantly associated with better OS. Consequently, ANC before allogeneic HSCT was found to be a significant prognostic factor in adult patients with AA. Physicians should pay attention to ANC before transplantation.

Phlegmonous gastritis (PG) is a rare, life-threatening bacterial infection characterized by thickening of the gastric wall. We report a case of PG in a 17-year-old male following allogeneic hematopoietic stem cell transplantation for severe aplastic anemia. Seven months after transplantation, the patient presented with severe abdominal pain, fever, and significant gastric wall thickening on CT. Initial antibiotic therapy was initiated immediately. The patient developed multiple organ failure; however, his condition rapidly improved with intensive care. After two weeks, the patient improved and was successfully discharged. This is the first report of PG after transplantation, highlighting the need for an early diagnosis and treatment.

Paroxysmal nocturnal hemoglobinuria (PNH) is a lifelong, clonal hematologic disease posing life-threatening risks if untreated. The prognosis for PNH has improved with the advent of C5 inhibitors, which are now the standard of care where available. As treatment options continue to expand, healthcare providers can better address both PNH management and the impact of treatment on patients' daily lives. To investigate the burden of disease and key factors taken into consideration when patients with PNH choose their preferred treatment, we conducted an in-depth patient interview survey. Of survey participants (N = 30), 70.0% were receiving intravenous C5 inhibitors. Notably, 56.7% of all patients reported needing ≥ 1 hospital visit per month, and 46.7% required a day off from work or school for visits (33.3% among those receiving intravenous C5 inhibitors). A frequently reported burden of PNH treatment was financial concern, including the cost of treatment, hospital visits, and the negative impact on income. Additionally, burden related to waiting times and distance from the hospital and the overall time spent on outpatient PNH care were identified with similar results for patients receiving intravenous C5 inhibitors. These results suggest that the time and effort to get to treatment centers and the time required to receive treatment for PNH were critical unmet needs in PNH care. Our study indicates that persistent burdens associated with current PNH care should be taken into account alongside therapeutic effectiveness when making treatment decisions. Further analysis with a larger sample size is required to confirm these findings.

Post-transplant relapse remains a major cause of treatment failure in adult B-cell acute lymphoblastic leukemia (ALL). The introduction of inotuzumab ozogamicin (InO) and blinatumomab (Blina) has expanded salvage options; however, their impact on outcomes and safety in patients relapsing after allogeneic stem cell transplantation has not been fully defined. To evaluate the impact of the availability of InO and Blina on clinical outcomes in adult B-cell ALL patients with post-transplant relapse, and to assess the safety of these agents in the post-transplant setting. We retrospectively analyzed 150 adult patients with B-cell ALL who relapsed after the first allogeneic stem cell transplantation. Patients were divided according to the time of their post-transplant relapse based on the approvals of InO and Blina in Japan: the pre-InO/Blina group (n = 95) and the post-InO/Blina group (n = 55). Outcomes were analyzed separately for Philadelphia chromosome (Ph)-negative and Ph-positive ALL. Overall survival (OS) after post-transplant relapse, complete remission (CR) rates as the best response before a second transplantation or last follow-up, and outcomes after a second transplantation were compared between groups. Adverse events associated with post-transplant use of InO and Blina were also evaluated. Among 95 patients with Ph-negative ALL, outcomes were significantly better in the post-InO/Blina group than in the pre-InO/Blina group, with the 2-year OS after post-transplant relapse improving from 19% to 51% (P = .003) and, among 88 treated patients, the CR rate increasing from 36% to 77% (P < .001). Multivariable analyses identified the time of post-transplant relapse and disease status at the first transplantation as independent prognostic factors for OS. Among 43 patients who underwent a second transplantation, the 2-year OS after second transplantation improved from 27% in the pre-InO/Blina group to 55% in the post-InO/Blina group (P = .029). In contrast, among 55 patients with Ph-positive ALL, OS after post-transplant relapse did not differ between groups. Among 32 patients treated with InO after post-transplant relapse, no patient developed veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) during InO therapy; however, 5 of 17 patients (29%) who subsequently underwent the second transplantation developed VOD/SOS. An interval of <2.5 months between InO and the second transplantation was associated with a higher VOD/SOS risk (56% versus 0%, P = .029). Among 30 patients treated with Blina, cytokine release syndrome occurred in 53% (grade 3 to 4, 7%) and immune effector cell-associated neurotoxicity syndrome in 13% (grade 3, 3%), with no fatal events. The prognosis of adult Ph-negative B-cell ALL after post-transplant relapse improved substantially in the post-InO/Blina era, including improved survival after a second transplantation. Overall, the safety profiles of InO and Blina in the post-transplant setting were acceptable, although VOD/SOS remains an important concern in patients proceeding to a second transplantation after InO.

The optimal bridge strategy at the decision for allogeneic hematopoietic stem cell transplantation (HSCT) in patients with myelodysplastic syndrome (MDS) is unclear. We performed a prospective observational study in which 110 patients with MDS who were decided to undergo HSCT were enrolled. Among these 110 patients, 77 patients were enrolled in this study within 1 month from the decision for HSCT. Among these 77 patients, 13 patients had a human leukocyte antigen (HLA)-matched sibling, 54 patients started an unrelated donor search, and the other 10 patients directly selected cord blood (CB) at the decision for HSCT, and 13 (100%), 38 (70.4%), and 9 (90%) patients actually underwent HSCT within 1 year, respectively. The overall survival (OS) at 1 year from their enrollment was 70.9%, and the selection of azacitidine use at the decision for HSCT was not associated with OS. Among 60 of the 77 patients who actually underwent HSCT within a year from their enrollment, a lower relapse rate after HSCT was observed in those who selected CB at the decision to undergo HSCT. However, this preferable effect of CB selection disappeared when patients who were enrolled in this study in > 1 month from the decision for HSCT were additionally included in the analyses. In conclusion, the selection of bridge strategy at the decision for HSCT did not affect outcomes in patients with MDS. The immediate performance of HSCT may be associated with better outcomes.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) offers a curative potential for myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN). We examined survival trends using a nationwide database of 7175 patients who underwent their first allo-HSCT between 1998 and 2022. Overall mortality decreased over time in patients with early MDS (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.65–0.97, p = 0.026 in 2013–2017; HR 0.54, 95% CI 0.42–0.70, p < 0.001 in 2018–2022), advanced MDS (HR 0.80, 95% CI 0.71–0.90, p < 0.001 in 2013–2017; HR 0.74, 95% CI 0.65–0.85, p < 0.001 in 2018–2022), chronic myelomonocytic leukaemia (HR 0.45, 95% CI 0.32–0.64, p < 0.001 in 2013–2017; HR 0.53, 95% CI 0.37–0.74, p < 0.001 in 2018–2022) and atypical chronic myeloid leukaemia (HR 0.32, 95% CI 0.13–0.80, p = 0.016 in 2013–2017; HR 0.26, 95% CI 0.10–0.68, p = 0.006 in 2018–2022). These decreases in overall mortality were mainly attributable to reductions in non-relapse mortality. Meanwhile, no significant difference in overall mortality was observed in patients with MDS/MPN-unclassified and therapy-related myeloid neoplasm. Across all disease subtypes, relapse incidence did not significantly decrease over time, highlighting persistent challenges in reducing the risk of post-transplant relapse.

Objective: Patients with relapsed or refractory (r/r) indolent non-Hodgkin lymphoma (iNHL) live with incurable disease for a long-term, experiencing multiple relapses and treatments that impair their health-related quality of life (HRQOL). We aimed to better understand the unmet needs and HRQOL of patients with r/r iNHL. Methods: This convergent mixed-methods study evaluated patients with r/r iNHL who received treatment. Unmet needs and HRQOL were assessed quantitatively using self-administered questionnaires and analyzed statistically. Qualitative data were collected through face-to-face semi-structured interviews for reflexive thematic analysis. Quantitative and qualitative findings were integrated through narrative discussion and joint display. Results: Questionnaire respondents (50 participants, mean age: 72.42 years) reported unmet needs in the health system and information and psychological domains and a negative association between unmet needs and HRQOL. Interviews (20 participants, mean age: 72.75 years) identified four themes: “unremarkable symptoms,” “anxiety of progression in the near future,” “make the best of life,” and “means to live with uncertainty.” Integration revealed that participants accepted their low HRQOL and attempted to make the best of life, influencing their perception of unmet needs. Conclusions: Throughout the long course of r/r and repeated treatment, patients with iNHL accepted their low HRQOL, valued their current situations, and endeavored to make the best of life. In this situation, support in the psychological and health system and information domains is crucial. Support for the unmet needs of patients with r/r iNHL is essential as they strive to live their best lives while maintaining a favorable HRQOL.

Chronic myelomonocytic leukaemia (CMML) is a haematological malignancy with a poor prognosis. Allogeneic haematopoietic stem cell transplantation remains the only curative approach. Without human leucocyte antigen-matched related sibling donors, the optimal alternative donor has yet to be established. Although unrelated bone marrow transplantation (UBMT) has been extensively studied, cord blood transplantation (CBT) for CMML remains largely unexplored. This nationwide retrospective study compared the outcomes of UBMT and single-unit umbilical CBT in patients with CMML. This study included 118 patients who underwent their first allo-HSCT during 2013–2021. Of these, 50 received BMT (UBMT group), while 68 underwent CBT (CBT group). The primary endpoint was the 3-year overall survival (OS). There were comparable 3-year OS rates between the UBMT (51.0%, 95% confidence interval [CI]: 34.1–65.5%) and CBT (46.2%, 95% CI: 33.2–58.1%; P = 0.60) groups. In the inverse probability of treatment weighting analysis, CBT did not show significantly improved outcomes compared with UBMT regarding the 3-year OS rate (hazard ratio 0.97 [95% CI: 0.57–1.66], P = 0.91). Thus, CBT may serve as an alternative to UBMT for patients with CMML. Further research is necessary to optimise transplantation strategies and enhance outcomes in patients with CMML undergoing CBT.

Hepatitis B virus (HBV) reactivation is a well-recognized complication in patients with resolved HBV infection undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Although HBV DNA-guided preemptive nucleos(t)ide analog therapy prevents HBV-related hepatitis, strategies to prevent HBV reactivation itself remain limited. Hepatitis B vaccination after allo-HCT has been suggested as a potential preventive strategy, but prospective randomized evidence is lacking. To evaluate whether hepatitis B (HepB) vaccination reduces HBV reactivation after allo-HCT and to examine the association between vaccination-induced anti-hepatitis B surface antibody (anti-HBs) response and protection against HBV reactivation. In this multicenter randomized controlled trial (UMIN000034113), adults who were hepatitis B surface antigen-negative and anti-hepatitis B core antigen-positive and underwent first allo-HCT were prospectively enrolled. At 140 days post-HCT, patients without HBV reactivation were randomized to receive HepB vaccination or no vaccination. HBV DNA levels and anti-HBs titers were centrally monitored for 2 years after transplantation. The primary endpoint was HBV reactivation, defined as HBV DNA ≥ 1.3 log IU/mL. Vaccine response was defined as anti-HBs response, requiring both an increase in anti-HBs from baseline and a post-vaccination anti-HBs ≥ 10 mIU/mL. Among 109 enrolled patients, 64 were randomized. With a median HBV DNA follow-up of 19.4 months, HBV reactivation occurred in 6 of 33 patients in the vaccination group, including 2 who experienced reactivation before receiving the first vaccine dose, and 9 of 31 patients in the control group. Probabilities of HBV reactivation were 19.8% and 37.9% in the HepB vaccination and control groups, respectively, at 18 months after randomization (P = .205). Baseline anti-HBs <10 mIU/mL was a significant risk factor for HBV reactivation. No HBV-related hepatitis was observed. Vaccine responses were achieved in 9 of 29 patients after the initial series and in 5 of 10 after the additional series. Importantly, HBV reactivation did not occur after patients achieved anti-HBs response, although several reactivation events occurred before vaccination or before anti-HBs response was achieved. No severe vaccine-related adverse events were observed. Although HepB vaccination did not significantly reduce HBV reactivation, it was feasible and induced anti-HBs response in a subset of patients. Achieving vaccine-induced anti-HBs response may provide protective immunity against HBV reactivation after allo-HCT.

Although cytomegalovirus (CMV) remains a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT), the incidence of CMV retinitis is considered to be lower than the incidence of CMV infection in other organs following allogeneic HSCT. In this study, the incidence and characteristics of CMV retinitis were retrospectively evaluated in recipients of allogeneic HSCT. Ophthalmological screening was performed at the development of ocular symptoms or positive CMV infection using peripheral blood evaluated by pp65 antigenemia or polymerase chain reaction. Of the 514 patients, 13 patients developed CMV retinitis. The median onset of CMV retinitis was day 34 (range, 21–118) post transplant, and the cumulative incidence was 2.5% (95% CI, 1.6–4.2) at 6 months after transplantation. Five patients presented ocular symptoms at the onset. In the remaining eight asymptomatic patients, the diagnosis of CMV retinitis was made by the screening guided by positive CMV infection. All evaluable patients responded to antiviral treatment but three showed incomplete improvement with ocular sequela. Our results suggest that the incidence of CMV retinitis after allogeneic HSCT is not negligible and active ophthalmological screening based not only on symptoms but also positive CMV infection monitoring contributes to the early diagnosis of CMV retinitis.

Persistence of leukemic stem cells (LSCs) results in the recurrence of chronic myeloid leukemia (CML) after the administration of tyrosine kinase inhibitors (TKIs). Thus, the detection of minimal residual disease (MRD) with LSC potential can improve prognosis. Here, we analyzed 115 CML patients and found that CD25 was preferentially expressed on the phenotypic stem and progenitor cells (SPCs), and TKI therapy decreased the number of CD25-positive cells in the SPC fraction. To detect MRD harboring BCR-ABL1 fusion DNA, we developed a highly-sensitive method using patient-specific primers and next-generation sequencing. By using this method, we identified that in patients who achieved molecular remission, almost all residual CD25-positive SPCs were BCR-ABL1-negative. Moreover, in some patients BCR-ABL1 was detectable in peripheral B cells but not in SPCs. We conclude that CD25 marks LSCs at diagnosis but does not mark MRD following TKI treatment and that analysis of peripheral B cells can allow sensitive detection of MRD.

The majority of adults are seropositive for human herpesvirus 6 (HHV-6). HHV-6 reactivation can occur after allogeneic hematopoietic stem cell transplantation (HSCT) and lead to life-threatening central nervous system disorders. In this prospective study, we evaluated the relationship between HHV-6 reactivation and anti-HHV-6 IgG antibody levels in recipients of allogeneic HSCT. The HHV-6 viral load in the plasma was quantitatively measured weekly after allogeneic HSCT by real-time polymerase chain reaction. The level of anti-HHV-6 IgG antibody was measured by enzyme‐linked immunosorbent assay before and serially after transplantation. In 28 of the 56 evaluated patients (50%), HHV-6 reactivation was detected after transplantation. In a multivariate analysis, cord blood as the stem cell source was the only significant factor associated with HHV-6 reactivation (odds ratio, 8.6; 95% confidence interval, 2.3 to 32.6; P < .01). When evaluated in the recipients of cord blood transplantation (CBT), the anti-HHV-6 antibody level before transplantation was significantly lower in the patients with HHV-6 reactivation compared with those without (sample positivity index: median, 2.04 [range, 0.95 to 5.98] versus 4.15 [range, 3.93 to 5.65]; P < .05). The anti-HHV-6 antibody level was significantly decreased at 3 months post-transplantation compared with before transplantation (P < .01). Such differences were not observed in other stem cell sources. Our results demonstrate that the low anti-HHV-6 antibody level before transplantation was associated with the reactivation of HHV-6 after CBT, and that the anti-HHV-6 antibody level was significantly decreased specifically after CBT. These results suggest that HHV-6-specific humoral immunity plays a role in HHV-6 reactivation after CBT.

Haematopoietic stem cells (HSCs) are a rare cell type that reconstitute the entire blood and immune systems after transplantation and can be used as a curative cell therapy for a variety of haematological diseases1,2. However, the low number of HSCs in the body makes both biological analyses and clinical application difficult, and the limited extent to which human HSCs can be expanded ex vivo remains a substantial barrier to the wider and safer therapeutic use of HSC transplantation3. Although various reagents have been tested in attempts to stimulate the expansion of human HSCs, cytokines have long been thought to be essential for supporting HSCs ex vivo4. Here we report the establishment of a culture system that allows the long-term ex vivo expansion of human HSCs, achieved through the complete replacement of exogenous cytokines and albumin with chemical agonists and a caprolactam-based polymer. A phosphoinositide 3-kinase activator, in combination with a thrombopoietin-receptor agonist and the pyrimidoindole derivative UM171, were sufficient to stimulate the expansion of umbilical cord blood HSCs that are capable of serial engraftment in xenotransplantation assays. Ex vivo HSC expansion was further supported by split-clone transplantation assays and single-cell RNA-sequencing analysis. Our chemically defined expansion culture system will help to advance clinical HSC therapies.