Published papers

Chronic graft-versus-host disease (cGVHD) is a long-term complication of allogeneic hematopoietic stem cell transplantation. The clinical importance of long-term corticosteroid dependency in steroid-responsive cGVHD is undetermined. We retrospectively reviewed the data of 120 consecutive patients who received systemic steroid therapy for cGVHD between January 2007 and December 2018 at three institutions. Among patients with steroid-responsive cGVHD, those who successfully tapered off corticosteroids within 1 year were defined as the early withdrawal group (EW-cGVHD) and others were defined as the dependent group (Dp-cGVHD). Twenty-six patients were classified as EW-cGVHD and 55 as Dp-cGVHD. The proportion of men was significantly higher and performance status was significantly better in EW-cGVHD. The 5-year overall survival and cGVHD recurrence-free survival rates were significantly higher in EW-cGVHD than Dp-cGVHD (96% vs. 68%, p = 0.017 and 84% vs. 41%, p = 0.002, respectively). While the relapse-free survival rate did not differ significantly (84% vs. 65%, p = 0.15), the proportion of patients requiring readmission, mainly due to cGVHD recurrence or infection, was significantly increased in Dp-cGVHD (38% vs. 84%, p < 0.001). In summary, steroid dependency in cGVHD for more than 1 year was significantly associated with poor transplant outcomes.

The precise manipulation of immune tolerance is the holy grail of immunotherapies for both autoimmunity and cancer immunity. Thymomas are well known to be associated with autoimmune diseases. The exact mechanism by which autoreactivity is induced after thymectomy remains to be elucidated. We herein present the case of a 50-year-old lady with concurrent de novo type 1 autoimmune hepatitis (AIH) and pure red cell aplasia (PRCA), 1 month after undergoing a successful total thymectomy for combined squamous cell carcinoma and thymoma (Masaoka stage II). Corticosteroids yielded short-term effects for both AIH and PRCA. Literature on thymoma-associated AIH, an extremely rare immune-related comorbidity, was also reviewed.

Objectives: This study aimed to evaluate the antiemetic efficacy of a 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA), ondansetron, in patients with malignant lymphoma receiving multi-day cisplatin-based combination chemotherapy. Methods: We conducted a single-institution retrospective analysis of patients receiving the first course of an ESHAP (etoposide, cisplatin, methylprednisolone, cytarabine) regimen including 4-day continuous infusion of cisplatin (25 mg/m2/day). All patients received ondansetron 4 mg intravenously during 5-day administration of ESHAP. The primary endpoint was complete response (CR) for emesis, which was defined as absence of both emesis and rescue medications. Total control (TC) was defined as an absence of emetic episodes, including nausea and emesis, and complete protection (CP) was defined as an absence of emesis with addition of rescue antiemetics. Nausea and vomiting were assessed and graded daily by medical staff. Results: Eighty-two patients were analyzed. Nausea and vomiting were generally well controlled, with the CR rates of emesis being 79% in the overall phase, 82% in the early phase (days 1–6), and 89% in the delayed phase (days 7–10). TC and CP were achieved in 51 patients (62%) and 77 patients (94%) in the overall phase. Discussion: Most of the chemotherapy regimens for lymphoid malignancies include high-dose corticosteroid which may be also effective as antiemetics. Although NK1 receptor antagonist (NK1RA) is generally recommended for cisplatin-containing chemotherapy, it can interact with variety drugs. Conclusion: Although NK1RA is generally recommended for cisplatin-containing regimen, our results suggest that ondansetron effectively controlled emesis in patients receiving ESHAP therapy which includes high-dose corticosteroid.

We evaluated 413 adult patients with lymphoma who underwent unrelated cord blood transplantation (UCBT) with fludarabine and melphalan (FM)-based reduced-intensity conditioning between 2002 and 2017 to investigate longitudinal changes in outcomes and the optimal melphalan dose and graft-versus-host disease (GVHD) prophylaxis regimen. Outcomes were compared between FM80/100 (melphalan dose: 80 or 100 mg/m2) and FM140 (melphalan dose: 140 mg/m2), as well as between calcineurin inhibitor (CNI) plus methotrexate (MTX), CNI plus mycophenolate mofetil (MMF), and CNI alone. The 3-year overall survival (OS) and non-relapse mortality (NRM) rates improved over time (OS: 27% in 2000s vs. 42% in 2010s, p < 0.001; NRM: 43% in 2000s vs. 26% in 2010s, p < 0.001). Multivariable analysis showed that in the 2000s, melphalan dose and GVHD prophylaxis regimen did not affect any outcomes. In the 2010s, FM80/100 (vs. FM140) related to better OS (hazard ratio [HR] 0.62, p = 0.01) and NRM (HR 0.52, p = 0.016). MTX + CNI and CNI alone (vs. CNI + MMF) related to worse OS (CNI + MTX, HR 2.01, p < 0.001; CNI alone, HR 2.65, p < 0.001) and relapse/progression (CNI + MTX, HR 2.40, p < 0.001; CNI alone, HR 2.13, p = 0.023). In recent years, the use of FM80/100 and CNI + MMF significantly reduced the risk of NRM and relapse/progression, respectively, and resulted in better OS after UCBT for lymphoma.

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a lethal complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). According to the 2016 European Society for Blood and Marrow Transplantation criteria, SOS/VOD is classified into classical SOS/VOD and late-onset SOS/VOD, but their similarities and differences remain unclear. Here we retrospectively investigated the incidence, risk factors, and impact on transplant outcomes of classical and late-onset SOS/VOD in 16 518 allo-HSCT recipients using the Japanese nationwide registry data. The cumulative incidences of classical and late-onset SOS/VOD were 2.5% and 2.2%, with a median onset of 13 and 42 days after transplantation, respectively. Both patients with classical (hazard ratio [HR], 3.45; 95% CI, 3.07–3.87) and late-onset (HR, 3.98; 95% CI, 3.51–4.51) SOS/VOD had a significantly worse overall survival compared with those without. The risk factors for classical and late-onset SOS/VOD are different. Hepatic comorbidities, high-risk diseases, use of melphalan (MEL), and myeloablative conditioning are associated with both types of SOS/VOD. Whereas poor performance status, a prior history of transplantation, and positive hepatitis C virus are associated with only classical SOS/VOD, allo-HSCT from cord blood or related human leukocyte antigen-haploidentical donors, use of total body irradiation and busulfan (BU), and tacrolimus-based graft-versus-host disease prophylaxis are associated with only late-onset SOS/VOD. In particular, the incidence of late-onset SOS/VOD is much higher in patients receiving both BU- and MEL-containing conditioning regimens. These findings suggest that different monitoring and treatment approaches are necessary for allo-HSCT recipients at high risk for classical and late-onset SOS/VOD.

Background: As the Japanese population may have less genetic diversity than other ethnic groups, treatment outcomes may be affected when allogeneic hematopoietic cell transplantation is performed in other races. However, evidence explaining the effect of racial differences is limited. Methods: We used the Japanese National Database to examine the outcomes of first allogeneic bone marrow transplantations (BMTs) performed between Japanese and non-Japanese patients from 1996 to 2021. We performed propensity score matching using sex, age group, underlying disease group, HLA mismatch, conditioning regimen intensity, and BMT implementation age to select Japanese-to-Japanese BMT patients as the controls. Results: The numbers of non-Japanese-to-Japanese and Japanese-to-non-Japanese BMT cases included in the analysis were 48 and 75, respectively, and the following outcomes were compared: overall survival, non-relapse mortality, acute graft-vs-host disease (GVHD) ≥ grade II, chronic GVHD, and engraftment of neutrophils and platelets. Most parameters did not differ when comparing BMTs according to ethnicity; only platelet engraftment was delayed in Japanese-to-non-Japanese BMT but not in non-Japanese-to-Japanese BMT. Conclusions: The results of this study suggested that BMT performed in Japanese and non-Japanese patients has little effect on treatment outcomes. The results of this study may be useful for donor selection in Japan, where internationalization has progressed in recent years.

Although allogeneic hematopoietic cell transplantation (HCT) is an alternative treatment for relapsed or refractory (R/R) acute promyelocytic leukemia (APL), little is known regarding the utility of allogeneic HCT for R/R therapy-related APL (t-APL). We retrospectively analyzed data for 144 patients with APL (t-APL, n = 20 and de novo APL, n = 124) who received a first allogeneic HCT between 2008 and 2020. We found no significant differences in survival between the t-APL and de novo APL groups. The 3-year overall survival (OS) rates were 53.8% in the t-APL group and 52.4% in the de novo APL group. However, as previously reported, patients without complete remission (CR) at HCT had significantly worse OS than those with CR (P = 0.004). The 3-year OS rates were 61.1% in patients with CR and 36.5% in those without CR. These findings suggest that allogeneic HCT may be considered a viable treatment option for patients with t-APL and de novo APL, with an emphasis on achieving CR before transplantation to optimize outcomes. However, clinicians should be aware of the potential for worse outcomes in male patients and those with lower performance status, highlighting the need for personalized treatment approaches and careful patient selection.

Background: The advent of novel therapeutic agents has improved the prognosis of multiple myeloma (MM). However, autologous stem cell transplantation (ASCT) remains a key treatment option for eligible patients. While stem cell mobilization using cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) has long been the standard approach, the introduction of plerixafor (PLER) has led to broader adoption of G-CSF±PLER-based mobilization, offering improved scheduling flexibility. Nevertheless, real-world data on current mobilization practices and their effects on post-ASCT outcomes remain limited. Methods: We evaluated mobilization strategies and their associations with clinical outcomes in MM patients who underwent ASCT between 2019 and 2022. A total of 3,319 patients were analyzed, including 743 patients mobilized with cyclophosphamide and 2,576 mobilized with G-CSF±PLER. The primary endpoint was 2-year overall survival (OS). Multivariate analysis and propensity score matching were performed to identify factors associated with superior OS. Results: The 2-year OS rates were 89.7% (95% CI: 87.0–91.8) and 93.2% (95% CI: 91.8–94.3) in the cyclophosphamide and G-CSF groups, respectively. Multivariate analysis showed that age <65 years (P < 0.001), lower ISS stage (P < 0.001), good performance status (P < 0.001), G-CSF mobilization (P = 0.005), and deep response pre-ASCT (P < 0.001) were independent predictors of superior OS. Propensity score matching analysis demonstrated significantly better OS in the G-CSF group than in the cyclophosphamide group (P = 0.041). Among patients achieving complete or very good partial response (CR/VGPR) pre-ASCT, OS did not differ between the groups; however, among patients who did not reach CR or VGPR pre-ASCT, the G-CSF group showed significantly better OS than the cyclophosphamide group. Conclusions: G-CSF‒based mobilization may offer prognostic advantages after ASCT, particularly in patients with suboptimal pre-ASCT response.

Cytokine release syndrome (CRS) remains a major toxicity of chimeric antigen receptor (CAR) T-cell therapy in large B-cell lymphoma (LBCL), and robust pre-infusion predictors are needed for risk-adapted management. We retrospectively analysed LBCL patients in the Japanese nationwide registry who underwent CD19 CAR-T-cell therapy between 2019 and 2024. Among 900 patients (median age 62 years), cumulative incidences of CRS within 30 days after infusion were 75.0% for any grade, 20.8% for grade ≥ 2 and 14.0% for grade ≥ 3. In multivariable analysis, lower estimated glomerular filtration rate (eGFR) (adjusted hazard ratio [aHR] 1.108 per 10 mL/min per 1.73 m2 decrease; 95% confidence interval [CI] 1.015–1.209; p = 0.022), higher ferritin (aHR 1.006 per 100 ng/mL; 95% CI 1.001–1.010; p = 0.016), C-reactive protein (CRP) (aHR 1.142 per mg/dL; 95% CI 1.091–1.195; p < 0.001) and lactate dehydrogenase (LDH) (aHR 1.073 per 100 U/L; 95% CI 1.008–1.142; p = 0.028) independently predicted grade ≥ 2 CRS. We then built a four-factor CRS pre-infusion risk evaluation model, cytokine release syndrome-pre-infusion risk evaluation (CRS-PRE), that stratified grade ≥ 2 CRS risk into low, intermediate and high groups with incidences of 2.8%, 26.0% and 50.0% respectively. Decreased eGFR, a surrogate of host renal reserve, with elevated ferritin, CRP and LDH emerged as predictors of high-grade CRS. The CRS-PRE may facilitate risk-adapted monitoring and intervention in clinical practice.

Clinically significant cytomegalovirus infection (csCMVi) is frequently observed after allogeneic hematopoietic stem cell transplantation (HSCT) and prophylaxis with letermovir is commonly adopted. However, the clinical benefit of letermovir prophylaxis according to graft sources has not been sufficiently elucidated. We retrospectively analyzed 2194 recipients of HSCT who were CMV-seropositive (236 with letermovir prophylaxis and 1958 without prophylaxis against CMV). csCMVi was significantly less frequent in patients with letermovir prophylaxis than in those without (23.7% vs 58.7% at 100 days after HSCT, P < .001) and the same trend was seen when recipients of bone marrow (BM), peripheral blood stem cell (PBSC), or cord blood (CB) transplantation were separately analyzed. In recipients of BM, nonrelapse mortality (NRM) was significantly lower in the letermovir group at 6 months after HSCT (5.0% vs 14.9%, P = .018), and the same trend was observed in recipients of PBSCs (14.7% vs 24.8%, P = .062); however, there was no statistical significance at 1 year (BM, 21.1% vs 30.4%, P = .67; PBSCs, 21.2% vs 30.4%, P = .096). In contrast, NRM was comparable between recipients of CB with and without letermovir prophylaxis throughout the clinical course (6 months, 23.6% vs 24.3%, P =.92; 1 year, 29.3% vs 31.0%, P = .77), which was confirmed by multivariate analyses. In conclusion, the impact of letermovir prophylaxis on NRM and csCMVi should be separately considered according to graft sources.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides curative outcomes for chronic myelomonocytic leukemia (CMML). We conducted a retrospective study to clarify the protective impact of acute and chronic graft-versus-host disease (aGVHD and cGVHD) on relapse by transplant procedures in 314 CMML patients. Interaction effects of conditioning intensity were observed with aGVHD (Pinteraction=0.181) and cGVHD (Pinteraction=0.256) for the cumulative incidence of relapse (CIR), whereas interaction effects of donor type were not detected with GVHD. In patients with the myeloablative conditioning regimens, the multivariate analysis showed that the development of aGVHD was not associated with overall survival (OS). The development of limited cGVHD correlated with better OS (HR [95 % CI], 0.34 [0.14–0.81]; P = 0.015); and that of extensive cGVHD correlated with better OS (HR, 0.44 [0.21–0.91]; P = 0.026) and lower CIR (HR, 0.28 [0.08–0.94]; P = 0.040). In patients with the reduced-intensity conditioning regimens, the development of grade I-II aGVHD correlated with better OS (HR, 0.39 [0.20–0.76]; P = 0.005) and lower CIR (HR, 0.30 [0.13–0.70]; P = 0.006). The development of extensive cGVHD correlated with better OS (HR, 0.44 [0.20–0.96]; P = 0.039). The present results suggest that the type and severity of GVHD mediating graft-versus-leukemia effects against relapse were influenced by conditioning intensity in CMML patients.

This study aimed to determine the clinical profile and disease burden of patients with paroxysmal nocturnal hemoglobinuria (PNH) in Japan using real-world data from the Adelphi Real World PNH Disease Specific Programme (DSP)™, a cross-sectional survey conducted between January and December 2022. Data included demographics, treatment, and clinical values (hemoglobin [Hb] and lactate dehydrogenase [LDH]). Patient-reported outcome measures included the EQ-5D-5L and the FACIT-Fatigue. Seventeen physicians provided information on 45 patients, among whom 86.7% were receiving treatment with complement 5 inhibitors (C5i). Median (IQR) age was 65.0 (54.5, 73.0) years; 55.6% were male. Among C5i-treated patients (n = 39), 51.3% received ravulizumab and 48.7% eculizumab, for a median (IQR) duration of 1.6 (1.0, 2.7) years. Median (IQR) Hb level was 7.2 (7.0, 8.1) g/dL at diagnosis and 10.0 (8.8, 10.6) g/dL at survey; 91.4% had LDH levels exceeding 1.5 times the upper limit of normal at diagnosis, 11.4% at survey. Twelve patients returned a self-completed questionnaire. Patient-reported symptoms included tiredness (83.3%), shortness of breath (75.0%), and anemia (58.3%). Mean (SD) EQ-5D-5L and FACIT-Fatigue scores were 0.73 (0.16) and 32.3 (7.1). Even C5i-treated patients continued to experience substantial disease burden, highlighting the need for more effective treatments to improve quality of life.

Real-world CD19 chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL) is characterized by expanded eligibility and evolving management practices. However, the prognostic impact of these changes remains inconsistent, and the specific drivers of outcomes remain unclear. This study analyzed 913 patients with relapsed/refractory (R/R) LBCL from a Japanese registry and compared the outcomes between 2 calendar periods (2019-2021 vs 2022-2024). The 2022-2024 cohort was older, had more adverse baseline features, and was less pretreated. Treatment patterns have shifted toward higher utilization of second-line therapy, a growing preference for axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel), and improved disease control before infusion. Accordingly, the 2022-2024 cohort achieved a longer progression-free survival (PFS; 6-month PFS, 63.2% vs 55.2%; P = .005), which persisted after adjusting for baseline characteristics using propensity score matching. Multivariable analysis identified second-line therapy, improved preinfusion disease control, and a shift in product selection from tisagenlecleucel to axi-cel or liso-cel as the primary drivers of this improvement. This benefit was pronounced in high-risk populations, including patients with stable or progressive disease at infusion (6-month PFS, 54.6% vs 43.8%; P = .012) and those who were refractory to first-line therapy (6-month PFS, 51.7% vs 40.3%; P = .013). Despite broader use in higher-risk populations and greater axi-cel exposure, 6-month nonrelapse mortality remained low (2.1% vs 1.5%). Real-world outcomes of CD19 CAR T-cell therapy for R/R LBCL have improved, predominantly driven by second-line therapy, enhanced preinfusion disease control, and increased use of more potent CAR T products.

Hematopoietic stem cells (HSCs) are a rare population of cells found in the bone marrow that play a critical role in lifelong hematopoiesis and the reconstitution of the hematopoietic system after hematopoietic stem cell transplantation. Hematopoietic stem cell transplantation remains the only curative treatment for patients with refractory hematologic disorders, and umbilical cord blood (CB) serves as an alternative stem cell source due to its several advantageous characteristics, including human leukocyte antigen flexibility and reduced donor burden. However, CB also has the disadvantage of containing a small number of cells, resulting in limited donor selection and a longer time for engraftment. Therefore, the development of techniques to expand HSCs ex vivo, particularly umbilical CB, is a goal in hematology. While various combinations of cytokines were once the mainstream approach, these protocols had limited expansion rates and did not lead to clinical application. However, in recent years, the development of a technique in which small molecules are added to cytokines has enabled the stable, long-term ex vivo expansion of human HSCs. Clinical trials of expanded umbilical CB using these techniques have been undertaken and have confirmed their efficacy and safety. In addition, we have successfully developed a recombinant-cytokine-free and albumin-free culture system for the long-term expansion of human HSCs. This approach could offer the potential for more selective expansion of human HSCs compared to previous protocols. This review discusses ex vivo culture protocols for expanding human HSCs and presents the results of clinical trials using these techniques, along with future perspectives.

Despite the increasing number of cancer survivors, the impact of prior solid tumors and their treatment modality on outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. This multi-center retrospective study compared transplant outcomes in allo-HSCT recipients with and without a history of solid tumors. Of 5,850 adult patients who underwent first allo-HSCT, 303 (5.2%) had a prior solid tumor. After propensity score matching, overall survival (OS) and cumulative incidences of relapse, non-relapse mortality (NRM), and acute and chronic graft-versus-host diseases were almost comparable between the two groups. Progression or recurrence of solid tumors after allo-HSCT occurred in only eight cases (2.8%). Importantly, patients who received both chemotherapy and radiation therapy (Chemo + RT) for prior solid tumors had significantly worse OS (35.3% vs. 54.1% [P < 0.001] vs. 56.8% [P < 0.001] at 2 years) and higher NRM (36.2% vs. 18.7% [P = 0.002] vs. 19.3% [P = 0.001] at 2 years) compared to patients who received other treatment modalities for prior solid tumors or patients without prior solid tumors. These findings highlight the feasibility of allo-HSCT in selected patients with prior solid tumors, while demonstrating the negative impact of Chemo + RT on outcomes after allo-HSCT.

Autoimmune diseases (AIDs) are associated with an increased risk of lymphoma. Although treatment strategies have changed substantially in AIDs, recent evidence regarding this association is lacking. Particularly, the impact of novel immunosuppressive/immunomodulatory agents and the cumulative effect of multiple medication use on lymphoma risk have not been well investigated. To address these, we used the LIFE Study database, which contains health care claims data from 2014 to 2023 in 15 municipalities in Japan. Of 2,229,423 individuals, 211,592 had AIDs and 530 subsequently developed lymphoma. Overall, AID cases had a significantly higher incidence of lymphoma than non-AID cases (hazard ratio [HR] 1.9). Among 23 AIDs, lymphoma risk was significantly elevated in 14, including Takayasu arteritis (6.6) and adult-onset Still’s disease (4.7). Among immunosuppressive/immunomodulatory agents, calcineurin inhibitors, iguratimod, or methotrexate were associated with higher lymphoma risks. Importantly, the use of two or more medications strongly increased lymphoma risk (HR 2.7) in AID cases. Lymphoma subtype-specific analysis revealed novel associations, including T/NK-cell lymphoma in systemic lupus erythematosus. Our large-scale cohort study reveals an increased risk of lymphoma in AID patients, particularly those receiving multiple immunosuppressants/immunomodulators, underscoring the need for careful monitoring in these patients.

Corynebacterium amycolatum is a part of the normal skin flora and has been underestimated as a pathogen. However, in recent years, the species has gained recognition as an important pathogen causing severe infections, particularly in immunocompromised patients. Nevertheless, identifying these organisms at the species level is difficult in routine clinical microbiology, leading to limited knowledge of their clinical manifestations in infectious diseases. In this study, we report a rare case of multiple subcutaneous abscesses in a patient with severe neutropenia, wherein C.amycolatum was identified as the causative organism through genotyping tests. This case highlights the importance of this organism as an aetiological agent of severe skin infections in patients with compromised immune systems.