仲宗根 秀樹

Choosing an optimal alternative donor is an important clinical concern in allogeneic hematopoietic cell transplantation (HCT). In Japan, single-unit umbilical cord blood transplantation (UCBT) has been widely used in the last two decades, whereas HCT from HLA-haploidentical related donors (haplo-HCT) has been increasingly used following the advent of posttransplant cyclophosphamide (PTCY) for graft-versus-host disease (GVHD) prophylaxis. This registry-based study aimed to compare outcomes between single-unit UCBT (n = 848) and PTCY-based haplo-HCT (n = 241) performed during first complete remission in patients with acute myeloid leukemia. UCBT was associated with a lower likelihood of engraftment (P < 0.001), a higher risk of grade 2-4 and grade 3-4 acute GVHD (P = 0.003 each), and a lower risk of extensive chronic GVHD (P = 0.048). The UCBT and haplo-HCT groups did not significantly differ in 3-year probabilities of overall survival (68% versus 69%, P = 0.686), GVHD/relapse-free survival (55% versus 54%, P = 0.866), relapse (14% versus 16%, P = 0.463), and non-relapse mortality (21% versus 19%, P = 0.403), respectively, which were confirmed with multivariate analysis. These results indicate that both procedures should be considered viable options for patients lacking a matched donor.

In this Japanese registry-based analysis of 9105 adult patients with acute leukemia undergoing allogeneic hematopoietic stem cell transplantation, a marked difference in survival was observed based on platelet levels: ≤ 20 × 109/L, 20-50 × 109/L, and > 50 × 109/L. The number of patients with thrombocytopenia receiving cord blood (CB, 39%) was significantly larger than those receiving unrelated bone marrow (uBM, 17%) on Day 50 (p < 0.001); however, this difference disappeared on Day 100 posttransplantation (both 11%, p = 0.4).

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.

BACKGROUND: The hematopoietic cell transplantation comorbidity index (HCT-CI) assigns a score of 2 to Rheumatologic (RD), reflecting its presumed association with increased nonrelapse mortality (NRM) based on data from earlier transplant eras, when disease control and immunosuppressive management were inadequate. Given recent advances in transplant-related supportive care and RD treatment, reassessment of the prognostic impact of preexisting RD in contemporary risk models is warranted. OBJECTIVES: We assessed the impact of preexisting RDs on outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT). STUDY DESIGN: In this retrospective cohort study, using Japan's nationwide Transplant Registry Unified Management Program database, we analyzed the data of adults (≥16 yr) who underwent first allo-HSCT for hematologic malignancies between 2006 and 2018. Patients with a prior diagnosis of RD at the time of transplantation were compared with those without. To minimize confounders, we performed 1:4 (RD:control) propensity score matching (PSM) based on 14 transplant-related variables. RESULTS: Overall, the data of 216 patients with RD and 864 matched controls were analyzed. The standardized mean difference for all variables except HSCT year was below the threshold of .1. The 3-yr overall survival (OS) was 41.1% (95% CI: 33.9-48.1) in the RD group versus 44.7% (95% CI: 41.2-48.2) in the control group. NRM was 31.8% (95% CI: 25.2-38.5) versus 26.0% (95% CI: 23.0-29.0), and CIR was 31.8% (95% CI: 25.4-38.4) versus 34.3% (95% CI: 31.0-37.5), without significance differences. Rates of grade II-IV acute graft versus host disease (GVHD) were comparable between the RD (33.2%, 95% CI: 27.0-39.6) and control (32.7%, 95% CI: 29.6-35.9) groups, as were chronic GVHD rates (22.9%, 95% CI: 17.3-29.0 versus 24.3%, 95% CI: 21.3-27.3). Day-30 neutrophil engraftment occurred in 89.8% (95% CI: 84.9-93.2) of patients with RD and 87.0% (95% CI: 84.6-89.1) of controls. In univariate Cox regression, RD was not a significant predictor for OS, NRM, or relapse. Subgroup analyses stratified by donor type and conditioning regimen showed consistent findings, with no excess mortality or GVHD attributable to RD history. To assess the applicability of our findings to older or more comorbid patients, we conducted a subgroup analysis of those aged >59 yr and those with HCT-CI >0 (excluding the RD component) in the prematching cohort. The 3-yr OS was 38.0% (95% CI, 23.6-52.3) in the RD group and 33.6% (95% CI, 31.9-35.3) in the control group (P = .71), and the 3-yr NRM was 37.4% (95% CI, 22.7-52.1) and 34.7% (95% CI, 33.0-36.4), respectively (P = .79). Thus, a history of RD had little effect on OS or NRM even in these higher-risk subgroups. CONCLUSIONS: In the contemporary allo-HSCT era, the unfavorable impact of preexisting RD on survival and NRM appears insignificant. Further studies incorporating detailed information on RD type and treatment history are warranted to refine comorbidity risk models and to reassess if RD should be weighted in the HCT-CI.

Overall response (OR) that combines complete (CR) and partial responses (PR) is the conventional end point for acute graft-versus-host disease (GVHD) trials. Because PR includes heterogeneous clinical presentations, reclassifying PR could produce a better end point. Patients in the primary treatment cohort from the Japanese Society for Transplantation and Cellular Therapy (JSTCT) were randomly divided into training and validation sets. In the training set, a classification and regression tree algorithm generated day 28 refined response (RR) criteria based on symptoms at treatment and day 28. We then evaluated RR for primary and second-line treatments, using the area under the receiver operating characteristic curve (AUC) and negative predictive value (NPV) for 6-month nonrelapse mortality as performance measures. RR considered patients with grade 0/1 at day 28 without additional treatment as responders. RR for primary treatment produced higher AUCs than OR with small improvement of NPVs in both validation sets: JSTCT (AUC, 0.73 vs 0.69 [P < .001]; NPV, 92.0% vs 89.6% [P < .001]) and the Mount Sinai Acute GVHD International Consortium (MAGIC; AUC, 0.71 vs 0.68 [P = .032]; NPV, 90.9% vs 89.8% [P = .009]). RR for second-line treatment produced similar AUCs but much higher NPVs than OR in both validation sets of JSTCT (AUC, 0.64 vs 0.63 [P = .775]; NPV, 74.5% vs 66.0% [P < .001]) and MAGIC (AUC, 0.67 vs 0.64 [P = .105]; NPV, 86.8% vs 76.1% [P = .004]). Classifying persistent but mild skin symptoms as responses and residual lower gastrointestinal GVHD as nonresponses were major drivers in improving the prognostic performance of RR. Our externally validated day 28 RR would serve as a better end point than conventional criteria in future first- and second-line treatment trials.

The optimal alternative donor type for patients lacking human leucocyte antigen (HLA)-matched related or unrelated donors remains unclear. In comparative studies evaluating donor types, graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) represents a well-established end-point but has limitations. The win ratio approach addresses these limitations by analysing multiple end-points with varying severities to account for the relative component priorities. We compared HLA-mismatched unrelated donors, haploidentical donors and cord blood using both the hazard ratio (HR) of GRFS and the win ratio related to GRFS. The haploidentical donor group had a similar HR of GRFS (HR: 1.01, 95% confidence interval [CI]: 0.85-1.19, p = 0.916) and win ratio (win ratio: 0.86, 95% CI: 0.72-1.02, p = 0.081) to HLA-mismatched unrelated donors. Cord blood transplantation showed similar GRFS compared to HLA-mismatched unrelated donors in the Cox proportional model (HR: 1.14, 95% CI: 0.98-1.32, p = 0.085), significantly lower win ratio (win ratio: 0.80, 95% CI: 0.68-0.93, p = 0.004) and similar outcomes to haploidentical donors. HLA-mismatched unrelated donor transplantation showed comparable to superior outcomes among alternative donor types. Our results indicate the need to present the win ratio alongside conventional methods to assess the end-point robustly.

Unrelated single-unit cord blood transplantation (CBT) is a valuable alternative donor source for patients without matched related or unrelated donors. Although initial concerns included limited cell dose, delayed haematopoietic recovery and higher early mortality, advancements in transplant practices may have led to improved outcomes. However, it remains uncertain whether these improvements extend to the most recent years. We conducted a nationwide, registry-based retrospective study of 15 816 patients who received unrelated single-unit CBT in Japan and analysed across four time periods: 2003-2007, 2008-2012, 2013-2017 and 2018-2022. Overall survival (OS) improved significantly across time periods, with 3-year OS increasing from 38.8% (2003-2007) to 54.4% (2018-2022; p < 0.001). Similarly, 100-day non-relapse mortality declined from 19.6% to 9.5% (p < 0.001). Neutrophil and platelet engraftment rates also rose steadily, reaching 89.6% and 78.0%, respectively, in the most recent period. The most notable improvement in 100-day OS occurred among patients aged ≥60 years. Early mortality within 100 days due to bacterial and fungal infections, graft failure, haemorrhage and graft-versus-host disease (GVHD) significantly decreased over time. This study shows clear and consistent improvements in transplant outcomes, especially in the most recent 5-year period.

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.

Allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-matched donors is the gold standard. However, haploidentical stem cell transplantation using posttransplant cyclophosphamide (PTCY-haplo) and cord blood transplants (CBTs) are alternatives when HLA-matched donors are not available. Using Japanese registry data, we evaluated the impact of haploidentical donor age on posttransplant outcomes by comparing PTCY-haplo and CBT. We analyzed data for 5161 patients aged 16 to 70 years who received their first HSCT for acute leukemia, myelodysplastic syndrome, or chronic myeloid leukemia. Haploidentical donors were categorized as "younger" (aged <40 years) or "older" (aged ≥40 years), and the patients were divided into younger (aged <50 years) and older (aged ≥50 years) cohorts. In the older cohort, PTCY-haplo from younger donors had better overall survival (OS; 55.5% vs 50.8%, P = .006), lower nonrelapse mortality (NRM; 17.3% vs 28.6%, P < .001), and higher relapse rates (33.0% vs 24.9%, P = .017) than with CBT. PTCY-haplo from older donors had comparable OS (44.1% vs 50.8%, P = 1.00), NRM (27.3% vs 28.6%, P = 1.00), and relapse (29.2% vs 24.9%, P = .90) to that with CBT. In the younger cohort, PTCY-haplo from younger and older donors showed OS, NRM, and relapse comparable with CBT. In the older cohort, cumulative incidence of acute graft-versus-host disease (GVHD) was higher with CBT than with PTCY-haplo, regardless of donor age. However, in the younger cohort, acute GVHD was lower in PTCY-haplo from younger donors than with CBT. PTCY-haplo from younger donors to older patients offers better clinical outcomes than CBT.

The SARS-CoV-2 pandemic disrupted healthcare systems worldwide, particularly affecting hematopoietic stem cell transplantation (HSCT) activities. Understanding the impact of the SARS-CoV-2 pandemic on transplant practices, especially in Japan, where cord blood transplantation (CBT) is prevalent, is crucial. A total of 40,444 allogeneic HSCT cases in Japan between 2011 and 2021 were examined using an interrupted time series analysis to assess the impact of COVID-19 on CBT utilization. Following the SARS-CoV-2 pandemic, CBT cases demonstrated a significant increase (11.06 [95% confidence interval (CI): 1.87 to 20.25] cases per month), whereas bone marrow transplantation cases decreased, by 10.74 cases per month (95% CI, -19.84 to -1.63 cases per month). Total HSCT cases remained stable with a level change of 5.47 cases per month (95% CI, -10.07 to 21.01 cases per month) and a trend change of -1.11 cases per month (95% CI, -2.22 to 0.004 cases per month). The interrupted time series analysis showed significantly increased CBT cases in Japan, highlighting its crucial role as an alternative transplant source during the pandemic. CBT offset the impact of the decrease in bone marrow transplantation and contributed to the maintenance of HSCT activity in Japan during the unprecedented crisis.

Although second allogeneic hematopoietic cell transplantation HCT (HCT2) is a potentially curative treatment for patients relapsing after their first HCT (HCT1), it is associated with higher non-relapse mortality (NRM) compared with HCT1. Furthermore, while reduced-intensity conditioning (RIC) in HCT2 might decrease NRM, there is no consensus on which patients may benefit from RIC. We retrospectively analyzed 2478 patients who underwent HCT2 for relapse of hematologic malignancies after HCT1. In a multivariate analysis, older recipient age, short duration between HCT1 and HCT2, RIC in HCT1, HCT-CI ≥ 2, and ECOG PS ≥ 2 were associated with an increased risk of NRM. RIC in HCT2 was associated with better NRM compared to myeloablative conditioning (MAC) (hazard ratio [HR] 0.83, 95% confidence interval [CI]: 0.72-0.97; p = 0.018), but was not significantly associated with overall survival (OS) (HR 0.91, 95% CI: 0.82-1.01; p = 0.075). We observed a significant interaction for NRM between extensive cGVHD in HCT1 and the conditioning intensity of HCT2 (interaction p < 0.001), meaning that the benefit of RIC in HCT2 was seen in patients with extensive cGVHD in HCT1, but not in those without cGVHD. RIC in HCT2 was also associated with superior OS in patients with extensive cGVHD in HCT1 (HR 0.68, 95% CI: 0.49-0.93; p = 0.02), with significant interaction between the conditioning intensity and the prior history of extensive cGVHD (interaction p = 0.01). This study suggests that RIC in HCT2 reduces NRM for HCT2 and improves OS, especially in patients with a history of extensive cGVHD.

The prognosis for multiple myeloma (MM) has continued to improve with the development of a series of novel molecular targeted drugs over time. However, the prognosis remains poor for cases with high-risk chromosomal abnormalities. Of such abnormalities, t(4;14) is the second most common, occurring in 15% of patients with MM. MM cells carrying t(4;14) strongly express histone methyltransferase with a SET domain, called NSD2, making them resistant to drugs against MM. Therefore, NSD2 is a promising therapeutic target for MM carrying t(4;14). Subsequently, we performed high-throughput screening and identified RK-0080552 (RK-552) as a novel class NSD2 inhibitor. RK-552 was significantly cytotoxic against t(4;14)+ MM compared with t(4;14)- MM cells in vitro and in vivo via transcriptional suppression of the IRF4 gene, coincided with a decrease in histone H3 lysine 36 dimethylation. Moreover, RK-552 acted additively with pomalidomide in vitro and prolonged the survival of recipient mice without side effects. These results suggest that RK-552 may be a clinically relevant NSD2 inhibitor with specific cytotoxicity to MM cells carrying t(4;14). Our study also provides a molecular basis and rationale for the inclusion in current treatment strategies. Therefore, the clinical use of RK-552 may significantly improve the treatment outcome of MM with t(4;14).

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.

Talaromyces columbinus was previously reported in two patients with lung infections under the name Penicillium piceum and one case of dual infection with Aspergillus calidoustus was recently reported.; currently, no treatment has been established. We identified a 61-year-old woman with fatal pneumonia with repeated detection of T. columbinus that developed two years after haploidentical transplantation using alemtuzumab for chronic myeloid leukemia in the blast phase. Seven months after transplantation, her minimal residual disease (MRD) turned positive. Thus, ponatinib was restarted, which resulted in MRD becoming negative again. Nine months after transplantation, she developed autoimmune hemolytic anemia (AIHA); treatment with prednisone (PSL) 35 mg was started. PSL was discontinued one year ten months after transplantation, but was resumed at 5 mg after relapse one year eleven months after transplantation. Two years after transplantation, she developed cough, and a CT scan showed bilateral pulmonary infiltrates. Initiation of antibiotics, voriconazole (VRCZ), posaconazole (PSCZ) and liposomal amphotericin B (L-AMB) did not improve her condition. Sputum culture detected Penicillium species, which was identified as T. columbinus by polymerase chain reaction (PCR). Since the minimal inhibitory concentration (MIC)/minimal effective concentration (MEC) ratio was lower for echinocandins, micafungin (MCFG) was added to L-AMB. However, the patient died of respiratory failure on day 38 of admission. This is the first reported case of T. columbinus infection in Japan. Managing this infection is challenging due to the lack of established diagnostic methods and treatments. Proactive diagnostic testing and case accumulation are needed.

The effects of donor characteristics on outcomes after T-cell-replete (TCR) haploidentical donor peripheral blood stem cell transplantation (PBSCT) with post-transplant cyclophosphamide (PTCy) or low-dose antithymocyte globulin (ATG) remain unclear. We evaluated the impact in 1,677 patients who received a PTCy protocol (PTCy-haplo; n = 1,107) or low-dose ATG protocol (ATG-haplo; n = 570). A low CD34+ cell dose (<4 ×106/kg) was the only donor characteristic associated with worse overall survival (OS) after PTCy-haplo (adjusted hazard ratios [aHR] = 1.49, P = 0.008), whereas increasing donor age by decade (aHR = 1.12, P = 0.008) and human leukocyte antigen 2-3 antigen mismatches (aHR = 1.46, P = 0.010), compared to HLA 0-1 antigen mismatches, were associated with worse OS after ATG-haplo. Increasing donor age was associated with a high risk of grade III-IV acute GVHD both after PTCy-haplo (HR: 1.32, P = 0.009) and ATG-haplo (HR: 1.22, P = 0.006). Offspring donors had better relapse-free survival and GVHD-free relapse-free survival than sibling donors after ATG-haplo. Our data highlights the donor characteristics associated with improved transplant outcomes after TCR haploidentical donor PBSCT with PTCy or low-dose ATG.

BACKGROUND: Patients with adult T-cell leukemia/lymphoma (ATL) are considered to have worse outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) than patients with other hematological malignancies, owing to high risk of relapse and immunocompromised status. However, no studies have compared transplant outcomes between patients with ATL and those with other hematological malignancies using a large-scale database. OBJECTIVES: To compare transplant outcomes between patients with ATL and those with other leukemias and to identify factors contributing to worse transplant outcomes in ATL patients. STUDY DESIGN: Using Japanese registry data, we retrospectively compared transplant outcomes between patients with ATL and those with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). As ATL often develops in patients in their 60s or older, patients with ATL, AML, or ALL aged ≥50 years were included in order to compare patients in the same age group. A total of 7764 patients (ATL, n = 1151; AML, n = 5393; ALL, n = 1220) who underwent their first allo-HSCT between January 1, 2006 and December 31, 2017 were included in this study. RESULTS: Compared with AML, ATL showed significantly worse overall survival (OS) (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.14 to 1.34; P < .001) and higher risk of relapse (HR, 1.33; 95% CI, 1.2 to 1.47; P < .001), while there were no significant differences between AML and ALL. Among patients in complete remission (CR) at transplantation, ATL showed worse OS (HR, 1.30; 95% CI, 1.08 to 1.56; P = .006), higher risk of relapse (HR, 1.78; 95% CI, 1.48 to 2.14; P < .001), and higher risk of nonrelapse mortality (NRM) (HR, 1.38; 95% CI, 1.14 to 1.33; P = .001) in comparison with AML, whereas there were no significant differences between AML and ALL. CONCLUSION: We found that ATL patients have poor transplant outcomes compared with AML or ALL patients. In ATL patients, survival is poor, relapse is more frequent, and NRM is significantly higher, especially in cases of CR. These findings suggest that prevention of relapse and transplant-related complications is important for successful allo-HSCT in ATL.

Multiple myeloma (MM) is the second most common hematologic malignancy and has a poor prognosis. Although the outcomes of MM have markedly improved with the approval of novel agents, the high incidence of relapse means that MM remains incurable. The bone marrow microenvironment (BMME) contributes to drug resistance and minimal residual disease (MRD), which is a major source of relapse in patients with MM. However, the underlying molecular mechanisms are not fully understood. We have previously shown that the upregulation of the AP-1 transcription factor c-FOS confers lenalidomide resistance by maintaining IRF4 expression in MM cells. In this study, we show that upregulated expression of c-FOS confers a poor prognosis and cancer stem cell-like features, including drug resistance, within BMME, both in vitro and in vivo, via IRF4 upregulation; and that inhibition of c-FOS by the AP-1 inhibitor, T-5224, prevents regeneration of MM cells via IRF4 downregulation in a murine serial transplantation assay. These results suggest a functional role for c-FOS in conferring cancer stem cell-like features to MM cells in the BMME for the first time. Therefore, c-FOS inhibition may be an effective treatment strategy for improving the outcomes of patients with MM by eliminating drug-resistant cancer stem cell-like MM cells in MRD.

Rapid tapering of cyclosporine (CsA) in the early phase after allogeneic transplantation may induce a potent graft-versus-leukemia/lymphoma (GVL) effect. We retrospectively reviewed the outcomes of patients with high-risk hematological malignancies who underwent their first transplantation at our institution. The blood CsA concentration was maintained at around 300 ng/ml. Our planned schedule for tapering CsA in patients without graft-versus-host disease (GVHD) or with limited GVHD was to reduce the dose by 10% per week starting from day 30 for related HSCT or from day 50 for unrelated HSCT. In total, we began tapering CsA in 36, and classified them into 2 an "On-schedule group" or "Delayed group" based on the timing of starting tapering. The cumulative incidences of grade II-IV acute GVHD overall were 33.8% and 39.4% (P = 0.746) in the On-schedule and Delayed groups. The On-schedule group showed no significant difference in non-relapse mortality, but showed a trend toward a higher relapse rate, resulting in significantly worse overall survival (55.6% vs 72.2% at 1y, P = 0.025) and worse disease-free survival (38.9% vs 66.7% at 1y, P = 0.059). These findings suggest that early CsA tapering after HSCT in high-risk patients was not effective.

Fludarabine and myeloablative busulfan (FluBu4) in allogeneic hematopoietic stem cell transplantation (HSCT) for older people have not been adequately examined. This retrospective study analyzed data from a large-scale, nationwide database in Japan. Adult patients (> 15 years old, y/o) who received their first HSCT with FluBu4 for hematological malignancies were included. They were categorized into the younger (< 60 y/o, N = 1295) and the older group (≥ 60 y/o, N = 993). The 3-year overall survival (OS) rate after HSCT was significantly worse in the older group than in the other (p < 0.01, 39.9% vs. 48.5%). The 3-year non-relapse mortality (NRM) was significantly higher in the older group than in the other (p < 0.01, 30.9% vs. 23.0%), and the 3-year cumulative incidence of relapse was comparable between them. According to the multivariate analysis, age ≥ 60 years was significantly associated with poor OS and high NRM. In a subgroup analysis of the older group, the use of additional chemotherapeutic drugs to FluBu4 was significantly associated with poor OS and high NRM. Total body irradiation was significantly associated with high NRM and 1-year incidence of sinusoidal obstruction syndrome but not with OS. Thus, FluBu4 should be used with caution in older people.

In unrelated allogeneic hematopoietic cell transplantation (allo-HCT), older and/or HLA-mismatched donors are known risk factors for survival outcomes. In healthy individuals, cytomegalovirus (CMV) seropositivity is associated with impaired adaptive immune systems. We assessed whether the adverse effects of donor risk factors are influenced by the donor CMV serostatus. We analyzed 5836 CMV seropositive patients who received unrelated allo-HCT. We divided the entire cohort into two cohorts according to the donor CMV serostatus: CMV-positive (DP) and -negative (DN). We also stratified each cohort into four groups based on donor age (≥ 40 or < 40) and HLA parity (8/8 or 7/8): Young88, Old88, Young78, and Old78. In the CMV-DP cohort, the Old88 (HR 1.20, P = 0.012), Young78 (HR 1.35, P < 0.001), and Old78 (HR 1.60, P < 0.001) groups were associated with inferior OS compared with the Young88 group. On the other hand, in the CMV-DN cohort, neither donor age nor HLA disparity was associated with inferior OS. The adverse impact of donor age was different between the cohorts (CMV-DP; HR 1.19, P = 0.001, CMV-DN; HR 1.04, P = 0.53; P for interaction 0.070), as was the impact of HLA (CMV-DP; HR 1.34, P < 0.001, CMV-DN; HR 1.08 P = 0.23; P for interaction 0.012). The impacts of donor age and HLA mismatch on OS might differ according to the donor CMV serostatus. In unrelated allo-HCT from a CMV seronegative donor, an HLA-mismatched older donor may be able to be selected without affecting OS.

We developed SiPc-1, an IR700 analog, as a photoactivatable near-infrared dye for the near-infrared photoimmunotherapy (NIR-PIT). We confirmed its cytotoxic efficacy against the tumor cells from ATL (adult T-cell leukemia–lymphoma) clinical samples.

We retrospectively evaluated the impacts of using granulocyte colony-stimulating factor (G-CSF) and its timing on posttransplant outcomes for 9766 adults with acute myeloid leukemia (AML) between 2013 and 2022 using a Japanese database. We separately evaluated three distinct cohorts based on graft type: 3248 received bone marrow transplantation (BMT), 3066 received peripheral blood stem cell transplantation (PBSCT), and 3452 received single-unit cord blood transplantation (CBT). Multivariate analysis showed that G-CSF administration significantly accelerated neutrophil recovery after BMT, PBSCT, and CBT. However, it was associated with a higher risk of grades II-IV acute graft-versus-host disease (GVHD) across all graft types. Moreover, an increased incidence of overall chronic GVHD was observed with G-CSF administration in BMT and CBT patients, but not in PBSCT patients. G-CSF administration significantly improved overall survival (OS) and leukemia-free survival (LFS) only following CBT. Regarding the timing of G-CSF, in comparison with late initiation of G-CSF (Days 5-10), early initiation (Days 0-4) did not provide benefits for hematopoietic recovery regardless of graft type. In contrast, late initiation was significantly associated with a lower risk of grades II-IV acute GVHD and better OS and LFS in CBT patients. These data demonstrated that G-CSF administration accelerated neutrophil recovery and increased the risk of grades II-IV acute GVHD across all graft types, but significantly improved survival outcomes but only following CBT. Therefore, routine use of G-CSF should be considered for CBT in adult patients with AML.

Unrelated cord blood transplantation (UCBT) and haploidentical transplantation using posttransplant cyclophosphamide (PTCy-haplo) are alternatives for patients lacking a human leukocyte antigen-matched donor. CD34+ cell counts in cord blood affect transplantation outcomes, particularly nonrelapse mortality (NRM). The primary objective of this study was to compare the transplantation outcomes after UCBT and PTCy-haplo focusing on CD34+ cell counts in cord blood. This retrospective study used data from 2014 to 2020 from a Japanese nationwide database. UCBT cases were divided into those with UCBT with higher (UCB-H; ≥.84 × 105/kg) and lower (UCB-L; <.84 × 105/kg) CD34+ cell counts, depending on the median CD34+ cell count. The study cohort comprised cases of PTCy-haplo (n = 1142), UCB-H (n = 3185), and UCB-L (n = 3172). In the multivariate analysis, neutrophil engraftment was significantly better in the PTCy-haplo than in the UCB-H (hazard ratio [HR], .64; 95% confidence interval [CI], .57 to .70; P < .001) and UCB-L groups (HR, .45; 95% CI, .41 to .50; P < .001). The UCB-H group showed similar NRM (HR, 1.19, 95% CI, 1.00 to 1.43, P = .051) and OS (HR, 1.05, 95% CI, .94 to 1.18, P = .38) compared with PTCy-haplo, whereas UCB-L was significantly associated with poor NRM (HR, 1.35, 95% CI, 1.13 to 1.61, P = .001) and OS (HR, 1.13, 95% CI, 1.01 to 1.26, P = .038). In contrast, the UCB-H (HR, .86; 95% CI, .75 to .98; P = .027) and UCB-L groups (HR, .80; 95% CI, .70 to .92; P = .001) were associated with lower relapse rate. Regarding the graft-versus-host disease (GVHD), the UCB-H and UCB-L groups were identified as significant risk factors for the development of grade II-IV acute GVHD (UCB-H: HR, 1.73; 95% CI, 1.51 to 1.99; P < .001; UCB-L: HR, 1.55; 95% CI, 1.35 to 1.78; P < .001) and grade III-IV acute GVHD (UCB-H: HR, 2.28; 95% CI, 1.78 to 2.91; P < .001; UCB-L: HR, 1.85; 95% CI, 1.44 to 2.37; P < .001), but neither were associated with the incidence of all-grade GVHD (UCB-H: HR, 1.12; 95% CI, .95 to 1.32; P = .16; UCB-L: HR, 1.08; 95% CI, .91 to 1.27; P = .37) or extensive chronic GVHD (UCB-H: HR, .86; 95% CI, .68 to 1.09; P = .21; UCB-L: HR, .88; 95% CI, .69 to 1.12; P = .31). Furthermore, higher NRM in UCB-L was attributed to higher infection-related mortality (HR, 1.50; 95% CI, 1.15 to 1.95; P = .003) but not GVHD-related mortality (HR, 1.15; 95% CI, .82 to 1.62; P = .43), whereas UCB-H was not a significant risk factor for both infection-related mortality (HR, 1.29; 95% CI, .99 to 1.69; P = .06) and GVHD-related mortality (HR, 1.28; 95% CI, .90 to 1.80; P = .16). UCB-H offered similar NRM and OS to PTCy-haplo, whereas UCB-L had worse outcomes. Our results can provide useful information for optimal donor selection.

Background: Thrombocytopenia is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HCT), which can lead to increased mortality and impaired quality of life with prolonged transfusion dependency and high risk of bleeding. However, it is not clear how many patients survive without sufficient platelet recovery after allo-HCT. Here, we visualized the kinetics of neutrophil and platelet recovery and the impact on outcomes using multistate models with transplant registry data. We also compared the effects of different graft sources. Methods: We analyzed Japanese nationwide registry data of adult patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in complete remission who underwent first allo-HCT from 2010 to 2022. Second transplantation was treated as a censoring event. Transitional changes of the population with neutrophil &amp;lt;0.5×109/L (state 0), neutrophil ≥0.5×109/L and platelet &amp;lt;20×109/L (state 1), 20×109/L≤ platelet &amp;lt;50×109/L (state 2), and platelet ≥50×109/L (state 3), death, relapse, and non-relapse mortality (NRM) were estimated by multistate model analysis using transition probability plot and proportional transition hazard model. The effects of hematopoietic recovery on mortality, relapse, and NRM were estimated by Simon-Makuch plot and proportional hazard model with time-dependent covariates. Influences of the background factors (age, recipient sex, performance status, comorbidity, diagnoses, disease risk, graft sources, ABO major mismatch, conditioning intensity, and year of transplantation) were adjusted. Results: A total of 9105 patients (5802 AML and 3303 ALL) were extracted from the database. The number of the transplant sources were: 2398 HLA-matched unrelated bone marrow (uBM), 782 HLA-matched related BM (rBM), 326 HLA-matched unrelated peripheral-blood stem cells (uPB), 1283 HLA-matched rPB, 622 HLA-haploidentical PB (Haplo), and 3694 single-unit cord blood (CB). The median age at allo-HCT was 49 (range, 16-85) years. Neutrophil ≥0.5×109/L at day 60, platelet ≥20×109/L and ≥50×109/L at day 100 were 99%, 91%, and 85% in uBM, 99%, 96%, and 92% in rBM, 99%, 95%, and 90% in uPB, 99%, 96%, and 93% in rPB, 98%, 91%, and 84% in Haplo, and 94%, 87%, and 82% in CB, respectively. Multistate model analysis with the entire patient population showed that the proportions in states 0, 1, 2, 3, relapse, and NRM were 1.4%, 9.9%, 7.4%, 77%, 1.3%, and 3.4% at day 60; and 0.1%, 3.8%, 4.3%, 80%, 5.4%, and 6.6% at day 120, respectively. Patients surviving without adequate platelet recovery (the sum of states 0, 1, and 2) was significantly higher in CB (25%) than in other sources (11-13%) at day 60. Interestingly, the difference became marginal at day 120 (8.3% in CB, and 6.5-8.7% in other sources). Survival probabilities by the Simon-Makuch method in states 0, 1, 2, and 3 were 83%, 93%, 98%, and 100% at day 60, and 44%, 71%, 91%, and 98% at day 120, respectively (P&amp;lt;0.001). Time-dependent covariate analysis showed that the hazard ratios (HRs) of the patients in states 0, 1, and 2 (vs. state 3) were 40, 5.3, and 2.4 for mortality; 57, 7.6, and 3.1 for NRM (all P&amp;lt;0.001), respectively, after adjustment for the background factors. The NRM causes of patients in states 1 and 2 were infection (24%), organ failure (19%), SOS/TMA (12%), and acute GVHD (10%), with the proportion of SOS/TMA and acute GVHD being more than double that of patients in state 3. Multistate model analysis showed that although the transition probabilities (TPs) to mortality from states 1 and 2 were higher in CB (HR 1.4 and 1.7, respectively) compared with uBM, the TP to mortality from state 3 was significantly lower in CB (HR 0.86; P=0.008; vs. uBM) with lower trends for both relapse and NRM. Conclusions: In this largest retrospective study on hematopoietic recovery to date, the kinetics of survivors without platelet recovery and the detrimental impact of thrombocytopenia on overall mortality and NRM were clearly demonstrated. SOS/TMA and acute GVHD had a greater influence on the NRM of thrombocytopenic patients. Although the platelet recovery was delayed in CB, the proportion of survivors with thrombocytopenia at day 120 was comparable to other sources. The higher risk for mortality in CB was transient, and the risk in CB became less than in uBM after platelet recovery (≥50×109/L). This analysis provides baseline data for future studies of hematopoietic recovery.

HLA-haploidentical haematopoietic cell transplantation with post-transplant cyclophosphamide (PTCy-haplo) is emerging as an effective alternative due to donor availability and safety. We conducted a nationwide retrospective study comparing the outcomes of PTCy-haplo with both anti-thymocyte globulin (ATG)-free and ATG-administered matched unrelated donors (MUD) transplantation, using peripheral blood stem cells as the first transplantation for acute myeloid leukaemia (AML). Our study showed a lower and slower haematopoietic recovery and a higher incidence of infection-related deaths after PTCy-haplo than after MUD transplantation. In addition, we revealed an increased risk of acute and chronic graft-versus-host disease (GVHD) in ATG-free MUD transplantation in comparison to PTCy-haplo. For grades III-IV acute GVHD, the hazard ratio (HR) was 2.71 (95% CI, 1.46-5.01), and for extensive chronic GVHD, the HR was 3.11 (95% CI, 2.07-4.68). There was no significant difference regarding overall survival amongst the groups. In addition, GVHD-free relapse-free survival (GRFS) was lower in ATG-free MUD transplantation than in PTCy-haplo (HR, 1.46; 95% CI, 1.17-1.82). Notably, ATG-administered MUD transplantation showed no significant difference in GRFS from PTCy-haplo, negating the advantage of PTCy. Our results suggest that PTCy-haplo could be viable for AML patients without an HLA-matched related donor.

Allogeneic hematopoietic stem cell transplantation from a female donor to a male recipient (female-to-male allo-HCT) is a well-established risk factor for chronic graft-versus-host disease (GVHD) and non-relapse mortality (NRM). The inferior outcomes of female-to-male allo-HCT are considered to be due to allo-immunity against H-Y antigens. However, the influence of minor histocompatibility antigens in haplo-identical allo-HCT remains to be elucidated. We investigated the impact of female-to-male allo-HCT according to the haplo-HCT subtype. In the post-transplant cyclophosphamide (PTCY) cohort (n = 660), a female-to-male sex-mismatch was significantly associated with a decreased risk of relapse (HR: 0.70 [95% CI: 0.49-0.99], P = 0.045), but not with overall survival (OS) or NRM (HR: OS 0.89 [95% CI: 0.68-1.16], P = 0.40; NRM 0.98 [95% CI: 0.68-1.41], P = 0.90). On the other hand, in the non-PTCY cohort (n = 219), a female-to-male sex-mismatch was associated with inferior risks of OS and NRM, but was not associated with relapse. These results suggested that the survival impact of the haplo-HCT subtype differed according to the presence of a sex-mismatch. PTCY might be feasible for overcoming the inferiority of female-to-male allo-HCT and might preserve a GVL effect against H-Y antigens.

Systemic corticosteroid therapy is a well-established first-line treatment for grades II-IV acute graft-versus-host disease (aGVHD). Recently, several developments have occurred, including the introduction of transplantation from human leukocyte antigen (HLA) haploidentical donors using post-transplant cyclophosphamide (PTCY-Haplo), and improvements in prognosis after cord blood transplantation (CBT) in Japan. This study aimed to analyze the association between donor sources and outcomes in patients with aGVHD. Our study included 2732 patients who developed grades II-IV aGVHD, and were treated with systemic corticosteroids. We compared HLA-matched related donors (MRD), HLA-matched unrelated donors (MUD), PTCY-Haplo, and CBT. We set endpoint as response rate, 1-year cumulative incidence of non-relapse mortality (NRM), and overall survival (OS). The adjusted odds ratios for a complete response (CR) were 0.99 (95% confidence interval [CI]: 0.74-1.31, P = 0.925) for MUD, 2.08 (95% CI: 1.35-3.25, P = 0.001) for PTCY-Haplo, and 1.08 (95% CI: 0.83-1.41, P = 0.550) for CBT compared with MRD. A significant increase in response rates for PTCY were only found in a single-organ involvement. No significant association was observed between the donor source and NRM or OS. In conclusion, PTCY-Haplo is associated with a high response rate in patients with a single-organ aGVHD; however, MUD and CBT were not associated with treatment response.

BACKGROUND: Mobilized peripheral blood stem cells (PBSC) have been widely used instead of bone marrow (BM) as the graft source for allogeneic hematopoietic cell transplantation (HCT). Although early studies demonstrated no significant differences in survival between PBSC transplantation (PBSCT) and BM transplantation (BMT) from human leukocyte antigen (HLA)-identical sibling donors to adults with hematological malignancies, recent results have been unclear. OBJECTIVE: The objective of this retrospective study was to compare overall survival (OS), relapse, non-relapse mortality (NRM), hematopoietic recovery and graft-versus-host disease (GVHD) between PBSCT and BMT according to the time period of HCT (2003-2008, 2009-2014, or 2015-2020). STUDY DESIGN: We retrospectively compared the outcomes after PBSCT versus BMT in 6064 adults with hematological malignancies using a Japanese registry database between 2003 and 2020. RESULTS: The adjusted probability of OS was significantly higher in BMT recipients compared to PBSCT recipients during the early period of 2003-2008 (adjusted hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.70-0.91; P < 0.001) and the middle period of 2009-2014 (adjusted HR, 0.80; 95% CI, 0.70-0.91; P < 0.001). However, during the late period of 2015-2020, the adjusted probability of OS was comparable between BMT and PBSCT recipients (adjusted HR, 0.94; 95% CI, 0.79-1.13; P = 0.564), which were mainly due to the reduction of NRM. There was no significant difference in the relapse rate between the groups, irrespective of the time period. Compared to BMT, PBSCT led to faster neutrophil and platelet recovery and the cumulative incidences of grades II-IV and grades III-IV acute and overall and extensive chronic GVHD were significantly higher in PBSCT recipients, irrespective of the time period. CONCLUSIONS: PBSCT and BMT had similar survival outcomes and relapse rates in adult patients with hematological malignancies during the late time period of 2015-2020 despite the hematopoietic recovery and acute and chronic GVHD being higher in PBSCT recipients in all time periods.

BACKGROUND: A change in empirical antibiotics or the addition of glycopeptide antibiotics is often applied in cases of persistent febrile neutropenia (FN) despite the administration of broad-spectrum antibiotics. However, the clinical benefit of these approaches remains unclear. METHODS: We conducted a retrospective study to evaluate the effectiveness of a change in antibiotics or the addition of glycopeptide antibiotics for persistent FN after autologous hematopoietic cell transplantation (auto-HCT). We retrospectively reviewed the records of 208 patients who received auto-HCT at our institution between 2007 and 2019. FN that lasted for 4 days or longer was defined as persistent FN. We compared the time to defervescence between patients whose initial antibiotics were changed and/or who additionally received glycopeptide antibiotics, and those without these antibiotic modifications. RESULTS: Among patients who fulfilled the criteria of persistent FN (n = 125), changes in antibiotics were not significantly associated with the time to defervescence in a multivariate analysis (hazard ratio [HR] 0.72, p = 0.27). On the other hand, the addition of glycopeptide antibiotics was paradoxically associated with a delay in defervescence (HR 0.56, p = 0.033). CONCLUSIONS: Although there may be differences in patient backgrounds, no significant differences were observed in either a univariate or multivariate analysis. Since neither a change in antibiotics nor the addition of glycopeptide antibiotics was associated with earlier defervescence in persistent FN after auto-HCT, routine antibiotic modifications might not be necessary in this setting.

Not available.

BACKGROUND AIMS: Pre-transplant lung dysfunction is known to be a risk factor for non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (allo-HCT). It is unclear which cell source gives better outcomes for patients with pulmonary dysfunction. METHODS: We analyzed 3289 adult patients with standard-risk disease who had received HLA-matched allo-HCT, and compared outcomes between those who received peripheral blood stem cell (PBSC) vs. bone marrow (BM) in two cohorts based on the presence of a lung score by the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI): the Lung-scored (LS) and non-LS cohorts. RESULTS: In the LS cohort, the 2-year overall survival (OS) in the BM group tended to be higher than that in the PBSC group (72.4% vs. 61.4%; P = 0.044). In the non-LS cohort, there was no significant difference between the two groups (71.7% vs. 73.2%; P = 0.13). Multivariate analyses confirmed that PBSC was significantly associated with inferior OS in the LS cohort (hazard ratio [HR], 1.66; 95% CI, 1.09-2.54; P = 0.019). On the other hand, the cell source did not affect OS in the non-LS cohort (HR, 0.92; 95% CI, 0.76-1.12; P = 0.41). We found that PBSC was associated with an increased risk of NRM in the LS cohort (HR, 2.17; 95% CI, 1.16-4.05; P = 0.016), while the cell source did not significantly affect NRM in the non-LS cohort. PBSC was not identified as a risk factor for relapse in either cohort. CONCLUSIONS: Our results suggest that BM might be beneficial for recipients with lung dysfunction in HLA-matched allo-HCT.

Various complications can influence hematopoietic cell transplantation (HCT) outcomes. Renal complications can occur during the early to late phases of HCT along with various factors. However, studies focusing on fatal renal complications (FRCs) are scarce. Herein, we analyzed 36,596 first allogeneic HCT recipients retrospectively. Overall, 782 patients died of FRCs at a median of 108 (range, 0-3,440) days after HCT. The cumulative incidence of FRCs was 1.7% and 2.2% at one and five years, respectively. FRCs were associated with older age, male sex, non-complete remission (non-CR), lower performance status (PS), and HCT comorbidity index (HCT-CI) associated with renal comorbidity in multivariate analysis. The risk factors within 100 days included older age, multiple myeloma, PS, and HCT-CI comorbidities (psychiatric disturbance, hepatic disease, obesity, and renal disease). Older age and male sex were risk factors between 100 days and one year. After one year, HCT-CI was associated with the presence of diabetes and prior solid tumor; total body irradiation was identified as a risk factor. Non-CR was a common risk factor in all three phases. Furthermore, acute and chronic graft-versus-host disease, reactivation of cytomegalovirus, and relapse of underlying disease also affected FRCs. Systematic follow-up may be necessary based on the patients' risk factors and post-HCT events.

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.

We retrospectively evaluated the effect of 17 individual comorbidities, defined by the hematopoietic cell transplantation (HCT)-specific comorbidity index, on non-relapse mortality (NRM) and overall survival (OS) in 9531 patients aged between 16 and 70 years who underwent their first allogeneic HCT from 8/8 and 7/8 allele-matched unrelated donors (8/8 and 7/8 MUDs) or single-unit unrelated cord blood (UCB) between 2011 and 2020 using data from a Japanese registry database. In the multivariate analysis, infection (adjusted hazard ratio [HR], 1.62, 95% confidence interval [CI], 1.33-1.99 for 8/8 and 7/8 MUDs; adjusted HR, 1.33, 95%CI, 1.12-1.58 for UCB) and moderate/severe hepatic comorbidity (adjusted HR, 1.57, 95%CI, 1.04-2.38 for 8/8 and 7/8 MUDs; adjusted HR, 1.53, 95%CI, 1.09-2.15 for UCB) had a significant impact on NRM in both donor groups. Cardiac comorbidity (adjusted HR, 1.40, 95%CI, 1.08-1.80), mild hepatic comorbidity (adjusted HR, 1.22, 95%CI, 1.01-1.48), rheumatologic comorbidity (adjusted HR, 1.67, 95%CI, 1.11-2.51), renal comorbidity (adjusted HR, 2.44, 95%CI, 1.46-4.09), and severe pulmonary comorbidity (adjusted HR, 1.40, 95%CI, 1.11-1.77) were significantly associated with an increased risk of NRM but only in UCB recipients. Renal comorbidity had the strongest impact on poor OS in both donor groups (adjusted HR, 1.73, 95%CI, 1.10-2.72 for 8/8 and 7/8 MUDs; adjusted HR, 2.24, 95%CI, 1.54-3.24 for UCB). Therefore, unrelated donor selection should be taken into consideration along with the presence of specific comorbidities, such as cardiac, rheumatologic, renal, mild hepatic, and severe pulmonary comorbidities.

Adult T-cell leukemia/lymphoma (ATL) develops from the infection of T cells with human T lymphotropic virus type 1 (HTLV-1). There are an estimated 5-20 million HTLV-1 carriers worldwide and the patients are frequently observed in subtropical Africa, the Caribbean, Middle East, South America, and South West Japan. The prognosis of ATL remains dismal due to rapid acquired resistance to treatment with cytotoxic chemotherapeutic agents. In particular, the development of novel therapies for relapsed or refractory (R/R) ATL is an unmet need. Previous clinical trials revealed that bendamustine (BDM) was effective as the first-line treatment for indolent lymphoma and R/R cases of diffuse large B-cell lymphoma. Its major advantage is that it has few side effects such as hair loss and peripheral neuropathy, and does not impair the quality of life. However, its efficacy has not been verified for ATL in pre-clinical or clinical studies. In this study, we have shown the cytotoxicity of BDM alone and in combination with novel agents including the histone deacetylase (HDAC) inhibitor tucidinostat, the enhancer of zeste homolog 1/2 (EZH1/2) dual inhibitor valemetostat, and the Bcl2 family inhibitor ABT-737. The combined in vitro effects of BDM and tucidinostat were reproduced in a murine model without any obvious hematological toxicity. Our present results suggest that the combination of tucidinostat and BDM could additively prolong the survival of patients with R/R progressive ATL. The efficacy and safety of this combination are thus worthy of investigation in clinical settings.

Higher rate of non-relapse mortality (NRM) remains yet to be resolved in umbilical cord blood transplantation (UCBT). Considering that UCBT has some unique features compared with allogeneic hematopoietic cell transplantation from other graft sources, a UCBT-specific NRM risk assessment system is required. Thus, in this study, we sought to develop a UCBT-specific NRM Risk Assessment (CoBRA) score. Using a nationwide registry database, we retrospectively analyzed 4437 recipients who had received their first single-unit UCBT. Using the backward elimination method, we constructed the CoBRA score in a training cohort (n = 2687), which consisted of recipients age ≥ 55 (score 2), hematopoietic cell transplantation-specific comorbidity index (HCT-CI) ≥ 3 (score 2), male recipient, graft-versus-host disease (GVHD) prophylaxis other than tacrolimus in combination with methotrexate, performance status (PS) 2-4, HLA allele mismatch ≥ 2, refined disease risk index (DRI) high-risk, myeloablative conditioning (MAC), and CD34+ cell doses < 0.82 x 105/kg (score 1 in each). The recipients were categorized into three groups: Low (0-4 points), Intermediate (5-7 points), and High (8-11 points) groups according to the CoBRA score. In the validation cohort (n = 1750), the cumulative incidence of NRM at 2 years was 14.9%, 25.5%, and 47.1% (P < 0.001), and 2-year overall survival (OS) was 74.2%, 52.7%, and 26.3% (P < 0.001) in the Low, Intermediate, and High groups, respectively. In summary, the CoBRA score could predict the NRM risk as well as OS after UCBT. Further external validation will be needed to confirm the significance of the CoBRA score.

Cytomegalovirus (CMV) infection is a major infectious complication following allogeneic hematopoietic cell transplantation (allo-HCT). Although letermovir (LMV) prophylaxis dramatically reduces the incidence of early clinically significant CMV (csCMV) infection, it remains unclear whether it has a beneficial effect on nonrelapse mortality (NRM) and overall survival (OS). Herein, we evaluated the impact of LMV prophylaxis on posttransplant outcomes using the registry database of the Japanese Society for Transplantation and Cellular Therapy. Adult patients who underwent allo-HCT between 2017 and 2019 were analyzed (n = 6004). LMV prophylaxis was administered to 1640 patients (LMV group) and it significantly reduced the incidence of csCMV infection compared with those not administered LMV prophylaxis (15.4% vs 54.1%; p < 0.01). However, it did not improve the 1-year NRM (hazard ratio [HR], 0.93; p = 0.40) and OS (HR, 0.96; p = 0.49). In the LMV group, 74 patients had breakthrough csCMV infection and showed inferior NRM (HR, 3.44; p < 0.01) and OS (HR, 1.93; p = 0.02) compared with those without infection. After completing LMV prophylaxis, 252 patients had late csCMV infection and showed inferior NRM (HR, 1.83; p < 0.01) and OS (HR, 1.58; p < 0.01). Our findings suggest that managing breakthrough and late csCMV infections is important for improving long-term outcomes.

BACKGROUND AIMS: This study aimed to comprehensively assess the impact of stem cell selection between bone marrow (BM) and peripheral blood (PB) in unrelated hematopoietic stem cell transplantation (HSCT) for hematological malignancies. Our objective was to identify specific factors associated with better transplant outcomes. METHODS: A retrospective analysis was conducted using data from the Japanese HSCT registry. Inclusion criteria were patients aged 0-70 years who underwent their first unrelated HSCT with BM or PB, with an 8/8 or 7/8 allele HLA match for hematological malignancies between 2010 and 2020. RESULTS: Among 10 295 patients, no significant difference was observed in overall survival, relapse, graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) or non-relapse mortality between the groups. Patients who received PB showed no clear difference in acute GVHD but had a greater rate of chronic GVHD, resulting in poor chronic GVHD-free, relapse-free survival (CRFS). Subgroup analyses highlighted the importance of patient-specific factors in source selection. Patients with non-Hodgkin lymphoma and a greater hematopoietic cell transplantation-comorbidity index showed better CRFS and GRFS when BM was the preferred source. Similar trends were observed among patients with standard-risk disease for CRFS. However, no such trends were evident among patients aged 0-24 years, indicating that both sources are viable choices for young patients. CONCLUSIONS: This real-world retrospective analysis showed similar basic outcomes for BM and PB in an unrelated setting. The results support that BM may still be preferred over PB, especially when the long-term quality of life is a major concern. A consideration of individual factors can further optimize transplant success. Further research is warranted to explore the long-term implications of stem cell source selection.

BACKGROUND: Acute myeloid leukemia (AML) is the most common indication for allogeneic hematopoietic cell transplantation (HCT). The increased availability of alternative donor sources has broadened donor types for older patients without HLA-matched sibling donors (MSD). It is uncertain if an MSD should be the first option for allogeneic HCT in patients with AML over 50 years of age. OBJECTIVE: The objective of this study was to compare survival and other posttransplant outcomes between MSDs, 8/8 allele-matched unrelated donors (MUDs), 7/8 allele-MUDs, unrelated cord blood (UCB), and haploidentical donors for patients with AML over 50 years of age. STUDY DESIGN: We conducted a retrospective study to compare outcomes in 5,704 patients with AML over 50 years of age and receiving allogeneic HCT between 2013 and 2021, using either MSD, 8/8 allele-MUD, 7/8 allele-MUD, UCB, or haploidentical donors in Japan. Complete remission (CR) and non-remission at HCT were analyzed separately for all analyses. RESULTS: In total, 3041 patients were CR, and 2663 patients were non-remission at the time of HCT. In multivariate analysis, donor type did not determine overall survival, irrespective of disease status at HCT. Leukemia-free survival (LFS) was significantly better for 8/8 allele-MUD (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.64 to 0.93; P = 0.005) and UCB (HR, 0.76; 95% CI, 0.65 to 0.88; P = 0.001), but not for 7/8 allele-MUD (HR, 0.97; 95% CI, 0.79 to 1.19; P=0.794), and haploidentical donor (HR, 0.86; 95% CI, 0.70 to 1.05; P=0.146) compared to the MSD group in non-remission status. However, donor type did not determine LFS among CR status. Relapse rates were significantly lower for 8/8 allele-MUD and UCB, whereas non-relapse mortality was higher for UCB compared to the MSD group among both CR and non-remission status. CONCLUSION: Our registry-based study demonstrated that MSDs do not lead to superior survival compared to alternative donors for patients with AML over 50 years of age. Furthermore, 8/8 allele-MUDs and UCB provide better LFS compared with MSDs during non-remission status. Therefore, MSD is not necessarily the best donor option for allogeneic HCT in this population.