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In HLA haploidentical stem cell transplantation, patients and donors usually share one HLA haplotype and have one different HLA haplotype (hetero-to-hetero). However, there are rare cases of transplantation from HLA homozygous donors to heterozygous recipients (homo-to-hetero), resulting in mismatches only in the graft-versus-host direction. We previously reported that homo-to-hetero transplants have a lower survival rate in a mouse model than hetero-to-hetero transplants due to stronger graft-versus-host disease (GVHD) but inferior graft-versus-leukemia effect. To examine whether homo-to-hetero transplant effects also occur in humans, we retrospectively compared the results of 59 homo-to-hetero and 4,539 hetero-to-hetero cases in the Japanese transplant registry data. The results showed no statistical difference between the homo-to-hetero and hetero-to-hetero groups in the cumulative incidences of neutrophil engraftment (83.1% vs 89.0%), acute GVHD II–IV (36.8% vs 38.8%), III–IV (16.8% vs 17.4%), chronic GVHD (32.7% vs 30.7%), relapse (52.9% vs 49.0%), and non-relapse mortality (31.6% vs 28.2%). In contrast, overall survival was significantly lower in the homo-to-hetero group than in the hetero-to-hetero group (12.6% vs 26.2%, p = 0.0308). The inferior effect of homo-to-hetero transplantation on overall survival remained significant in multivariate analyses. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Therapy-related acute myeloid leukemia (t-AML) is a therapeutic challenge as a late complication of chemotherapy (CHT) and/or radiotherapy (RT) for primary malignancy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) presents itself as a curative approach. To establish the optimal allo-HSCT strategy for t-AML, we evaluated the relationship between characteristics of primary malignancy and allo-HSCT outcomes. Patients with t-AML or de novo acute myeloid leukemia (AML) who underwent first allo-HSCT in Japan from 2011 to 2018 were identified using a nationwide database. The detailed background of t-AML was obtained by additional questionnaires. Multivariate analysis and propensity score matching (PSM) analysis were performed to detect the prognostic factors associated with t-AML and compare outcomes with de novo AML. We analyzed 285 t-AML and 6761 de novo AML patients. In patients with t-AML, receiving both CHT and RT for primary malignancy was an independent poor-risk factor for relapse and overall survival (OS) (hazard ratio (HR) 1.62; p = 0.029 and HR 1.65; p = 0.009, reference: CHT alone group), whereas other primary malignancy-related factors had no effect on the outcome. Compared to the CHT alone group, complex karyotypes were significantly increased in the CHT + RT group (86.1% vs. 57.5%, p = 0.007). In the PSM cohort, t-AML patients with prior CHT and RT had significantly worse 3-year OS than those with de novo AML (25.2% and 42.7%; p = 0.009). Our results suggest that prior CHT and RT for primary malignancy may be associated with increased relapse and worse OS of allo-HSCT in t-AML. [ABSTRACT FROM AUTHOR]

Stenotrophomonas maltophilia (S. maltophilia) is an aerobic nonfermenting Gram-negative bacillus widely distributed in the environment that has inherent multidrug resistance to beta-lactam and carbapenem antibiotics. S. maltophilia infection (SMI) is known as an important fatal complication following allogeneic hematopoietic stem cell transplantation (HSCT), but its clinical characteristics have not been well clarified. A retrospective study to identify the incidence, risk factors, and outcomes of SMI after allogeneic HSCT was performed using the database of the Japanese nationwide registry, including 29,052 patients who received allogeneic HSCT in Japan between January 2007 and December 2016. A total of 665 patients developed SMI (sepsis/septic shock, 432; pneumonia, 171; other, 62). The cumulative incidence of SMI at 100 days after HSCT was 2.2%. Among risk factors identified for SMI (age ≥ 50 years, male, performance status 2–4, cord blood transplantation [CBT], myeloablative conditioning, Hematopoietic Cell Transplant-Comorbidity Index [HCT-CI] score 1–2, HCT-CI score ≥ 3, and active infectious disease at HSCT), CBT was the strongest risk factor (hazard ratio, 2.89; 95%CI, 1.94–4.32; p < 0.001). The survival rate at day 30 after SMI was 45.7%, and SMI before neutrophil engraftment was significantly associated with poor survival (survival rate 30 days after SMI, 40.1% and 53.8% in patients with SMI before and after engraftment, respectively; p = 0.002). SMI is rare after allogeneic HSCT, but its prognosis is extremely poor. CBT was a strong risk factor for SMI, and its development prior to neutrophil engraftment was associated with poor survival. [ABSTRACT FROM AUTHOR]

Non-infectious pulmonary complications after allogeneic hematopoietic stem cell transplantation (HSCT) remain fatal. In particular, information regarding late-onset interstitial lung disease predominantly including organizing pneumonia and interstitial pneumonia (IP) is limited. A retrospective nationwide survey was conducted using data collected from the Japanese transplant outcome registry database from 2005 to 2010. This study focused on patients (n = 73) with IP diagnosed after day 90 post-HSCT. A total of 69 (94.5%) patients were treated with systemic steroids, and 34 (46.6%) experienced improvement. The presence of chronic graft-versus-host disease at the onset of IP was significantly associated with non-improvement of symptoms (odds ratio [OR] 0.35). At the time of last follow-up (median, 1471 days), 26 patients were alive. Of the 47 deaths, 32 (68%) were due to IP. The 3-year overall survival (OS) and non-relapse mortality (NRM) rates were 38.8% and 51.8%, respectively. In the multivariate analysis, the predictive factors for OS were comorbidities at IP onset (hazard ratio [HR]: 2.19) and performance status (PS) score of 2–4 (HR 2.77). Furthermore, cytomegalovirus reactivation requiring early intervention (HR 2.04), PS score of 2–4 (HR 2.63), and comorbidities at IP onset (HR 2.90) were also significantly associated with increased risk of NRM. [ABSTRACT FROM AUTHOR]

Anti-thymocyte globulin (ATG) is widely used to reduce acute and chronic graft-versus-host disease (a/cGVHD), one of the leading causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). As the removal of alloreactive T cells by ATG may also reduce the graft-versus-leukemia effect, the question of whether ATG use affects relapse incidence and survival outcomes in acute leukemia patients with pre-transplant bone marrow residual blasts (PRB) remains controversial. Here, we evaluated the impact of ATG on transplant outcomes in acute leukemia patients with PRB (n = 994) who underwent HSCT from HLA 1-allele mismatched unrelated donors (MMUD) or HLA 1-antigen mismatched related donors (MMRD). In MMUD with PRB (n = 560), multivariate analysis demonstrated that ATG use significantly decreased grade II–IV aGVHD (hazard ratio [HR], 0.474; P = 0.007) and non-relapse mortality (HR, 0.414; P = 0.029) and marginally improved extensive cGVHD (HR, 0.321; P = 0.054) and GVHD-free/relapse-free survival (HR, 0.750; P = 0.069). We concluded that ATG had different effects on transplant outcomes using MMRD and MMUD, and its use would be beneficial to decrease a/cGVHD without increasing non-relapse mortality and relapse incidence in acute leukemia patients with PRB following HSCT from MMUD. [ABSTRACT FROM AUTHOR]

Unrelated donor bone marrow transplantation (UR-BMT), unrelated donor cord blood stem cell transplantation (UR-CBT), and haploidentical peripheral blood stem cell transplantation (Haplo-PBSCT) are the main alternative stem cell sources for allogeneic hematopoietic cell transplantation (HCT) in Japan. The present study aimed to identify factors associated with the outcomes of UR-BMT, UR-CBT, and Haplo-PBSCT in older patients with acute myeloid leukemia (AML) and intermediate- or poor-risk cytogenetics to improve the clinical efficacy and safety of allogeneic HCT. We retrospectively analyzed data for 448 AML patients aged > 65 years who received UR-BMT (n = 102), UR-CBT (n = 250), or Haplo-PBSCT (n = 96) between 2014 and 2020. Overall survival (OS) in the UR-BMT group was superior (P = 0.033) to that in the other groups. However, all patients without complete remission (non-CR) who had Karnofsky performance status (KPS) < 80 at HCT and poor-risk cytogenetics died within 1 year after HCT. Multivariate Cox regression analysis identified KPS <80 at HCT and poor-risk cytogenetics as independent predictors of worse OS in non-CR patients. KPS < 80 may be an alternative indicator for non-CR AML patients with poor-risk cytogenetics during the selection of HCT, alternative treatments, or best supportive therapy, and the optimal KPS is important for the success of HCT. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation between female donors and male recipients (female-to-male allo-HCT) is a well-established risk factor for inferior survival outcomes due to a higher incidence of graft-versus-host disease (GVHD). However, a clinical significance of anti-thymocyte globulin (ATG) in the female-to-male allo-HCT has not been elucidated. In this study, we retrospectively evaluated male patients who underwent allo-HCT between 2012 and 2019 in Japan. In the female-to-male allo-HCT cohort (n = 828), the use of ATG was not associated with a decreased risk of GVHD (HR of acute GVHD 0.691 [95% CI: 0.461–1.04], P = 0.074; HR of chronic GVHD 1.06 [95% CI: 0.738–1.52], P = 0.76), but was associated with favorable overall survival (OS) and a decreased risk of non-relapse mortality (NRM) (HR of OS 0.603 [95% CI: 0.400–0.909], P = 0.016; HR of NRM 0.506 [95% CI: 0.300–0.856], P = 0.011). The use of ATG in female-to-male allo-HCT resulted in survival outcomes that were almost equivalent to those in the male-to-male allo-HCT group. Therefore, GVHD prophylaxis with ATG might overcome the inferiority of survival outcomes in female-to-male allo-HCT. [ABSTRACT FROM AUTHOR]

Bone marrow (BM) and granulocyte colony-stimulating factor-mobilized peripheral blood stem cells (PBSC) are used as grafts from HLA-identical-related donors for adults with myelodysplastic syndrome (MDS). To assess the impact of graft sources on post-transplant outcomes in MDS patients, we conducted a retrospective analysis of a nationwide database. A total of 247 and 280 patients underwent transplantation with BM and PBSC, respectively. The inverse probability of treatment weighting (IPTW) methods revealed that overall survival (OS) was comparable between BM and PBSC (P =.129), but PBSC transplantation was associated with worse graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS) (hazard rate [HR], 1.24; 95% confidence intervals [CIs], 1.00–1.53; P = 0.049) and chronic GVHD-free and relapse-free survival (CRFS) (HR, 1.29; 95% CIs, 1.13–1.73; P = 0.002) than BM transplantation. In the propensity score matched cohort (BM, n = 216; PBSC, n = 216), no significant differences were observed in OS and relapse; 3-year OS rates were 64.7% and 60.0% (P = 0.107), while 3-year relapse rates were 27.1% and 23.5% (P = 0.255) in BM and PBSC, respectively. Three-year GRFS rates (36.6% vs. 29.2%; P = 0.006), CRFS rate (37.7% vs. 32.5%; P = 0.003), and non-relapse mortality rates (13.9% vs. 21.1%; P = 0.020) were better in BM than in PBSC. The present study showed that BM transplantation provides a comparable survival benefit with PBSC transplantation and did not identify an enhanced graft-versus-MDS effect to reduce the incidence of relapse in PBSC transplantation. [ABSTRACT FROM AUTHOR]

The incidence of severe adverse events (SAEs) and associated risk factors in hematopoietic cell transplantation donors needs to be clarified for related donors (relatives of the transplant recipient), whose criteria for donation are more lenient than for unrelated donors. Data from related donors registered in the Japanese national data registry database between 2005 and 2021 were evaluated to determine the association of short-term SAE incidence with donor characteristics at registration. Fourteen of 4339 bone marrow (BM) donors (0.32%) and 54 of 10,684 peripheral blood stem cell (PBSC) donors (0.51%) experienced confirmed SAEs during the short donation period. No deaths were observed. Past medical history was a common risk factor for SAEs in both BM and PBSC donors. Age of 60 years or older and female sex were identified as risk factors for SAEs in PBSC donors. Female sex was also a risk factor for poor mobilization, which resulted in discontinuation of PBSC collection. Although donors should be selected carefully, a certain level of safety is ensured for related donors in Japan. Donor safety should be further increased by improving the selection method for related donors and extending the follow-up period. [ABSTRACT FROM AUTHOR]

Although several studies have reported significant effects of patient age on outcomes of allogeneic hematopoietic cell transplantation (HCT), the prognostic relevance of age must be determined separately for myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC). We analyzed Japanese nationwide transplantation registry data of patients aged 20–79 years with acute myeloid leukemia who underwent allogeneic HCT using MAC (n = 7525) or RIC (n = 3154) between 2008 and 2019. Patient were divided into six groups by age, with each group representing a decade, and overall survival (OS), relapse, and non-relapse mortality (NRM) were compared between adjacent age groups. The adverse impact of age on OS increased each decade starting at age 40 among patients receiving MAC, but only differed significantly between patients in their 50s and 60s among those receiving RIC. In patients receiving both MAC and RIC, the detrimental effect of advanced age on OS was accompanied by an increased risk of NRM. These findings show that age affects NRM and OS significantly, but differs depending on conditioning intensity. RIC mitigates the adverse prognostic impact of older age and is thus considered a reasonable option for older patients. [ABSTRACT FROM AUTHOR]

Although bone marrow transplantation is the recommended form of allogeneic hematopoietic stem cell transplantation for aplastic anemia, some patients undergo peripheral blood stem cell transplantation (PBSCT). Therefore, there is critical demand to identify factors affecting transplantation outcomes. Using the Japanese registry database, we retrospectively analyzed outcomes of 94 adult patients with aplastic anemia who underwent PBSCT from HLA-identical sibling donors. The cumulative incidence of neutrophil engraftment was 94% (95% confidence interval [CI] 86–97%), and was significantly higher in patients who received anti-thymocyte globulin (ATG) in conditioning. The cumulative incidence rate was 26% (95% CI 17–35%) in grades II–IV acute graft-versus-host disease (GVHD) and 20% (95% CI 13–29%) in extensive chronic GVHD, and tended to be lower in patients with chronic GVHD who received ATG-based conditioning. The 5-year overall survival (OS) rate was 70% (95% CI 59–78%). In multivariate analysis, patient age < 40 years, shorter period from diagnosis to transplantation, better performance status, and ATG-based conditioning were significantly correlated with favorable OS. In conclusion, PBSCT from HLA-identical sibling donors for aplastic anemia would result in acceptable outcomes. Several risk factors identified in our study should be considered when selecting a stem cell source. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (HCT) offers a possible cure for patients with relapsed and refractory non-Hodgkin lymphoma (NHL) through potentially beneficial graft versus lymphoma effects. However, allogeneic HCT is associated with high nonrelapse mortality (NRM). Fludarabine with reduced-intensity busulfan (Flu/Bu2) and myeloablative busulfan (Flu/Bu4) are commonly used in conditioning regimens for allogeneic HCT; however, data on their use in patients with NHL is limited. We investigated the effect of busulfan dose on outcomes by comparing Flu/Bu2 and Flu/Bu4 in patients with NHL who underwent allogeneic HCT. Our study included 415 adult patients with NHL who received Flu/Bu2 (315 patients) or Flu/Bu4 (100 patients) between January 2008 and December 2019. All patients were enrolled in the Transplant Registry Unified Management Program 2 of the Japanese Data Center for Hematopoietic Cell Transplantation. The primary endpoint was the 5-year overall survival (OS). To minimize potential confounding factors that may influence outcomes, we performed propensity score matching. The 5-year OS was 50.6% (95% confidence interval (CI), 39.4%–60.8%) and 32.2% (95% CI, 22.4–42.4%) in the Flu/Bu2 and Flu/Bu4 groups, respectively (p = 0.006). The hazard ratio comparing the two groups was 2.13 (95% CI, 1.30–3.50; p = 0.003). Both groups had a similar 5-year cumulative incidence of relapse (38.2% vs 41.3%; p = 0.581), and the Flu/Bu4 group had a higher cumulative incidence of 5-year NRM (15.7% vs 31.9%; p = 0.043). In this study, Flu/Bu4 was associated with worse OS compared with Flu/Bu2 because of high NRM in patients with NHL. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate Karnofsky performance status (KPS) scores and visual analogue scale (VAS) scores to explain which domains in the standardized self-reported quality of life (QOL) are instrumental for long-term hematopoietic stem cell transplantation (HSCT) survivors. We conducted a nationwide cross-sectional questionnaire study on 221 survivors with allogeneic-HSCT in 28 pediatric centers. Patient-reported QOL was assessed at a single time point using the 36-item Short-Form Survey (SF-36), the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), and VAS scores. KPS scores were significantly correlated with both physical and role component summary scores of the SF-36, while the VAS provided by the patient (VASpt) was significantly correlated with the mental component summary score of the SF-36 and many subscales of the FACT-BMT. The VAS provided by the participants' attending physician (VASdoc) was correlated well with KPS scores. A VASpt score more than 40% lower than KPS scores suggested mental health problems. In conclusion, KPS scores might be considered as an indicator for physical and role/social components and VASpt score as an indicator for mental components and HSCT-specific QOL. [ABSTRACT FROM AUTHOR]

Haploidentical donors have emerged as an alternative donor source for salvage stem cell transplantation (SCT) after graft failure; however, data regarding salvage haploidentical SCT using posttransplant cyclophosphamide (PTCy) are limited. Using nationwide data (2011-2019), we retrospectively investigated transplant outcomes after salvage haploidentical SCT using PTCy for graft failure (n = 33, median age 34 years). The total dose of PTCy was 75-100 mg/kg (standard dose) in 26 patients (78.8%) and 40-50 mg/kg (lower dose) in 5 patients (15.2%). The neutrophil engraftment rate at 30 days was 81.8%. One-year overall survival (OS) and non-relapse mortality (NRM) rates were 47.4% and 46.0%, respectively. The standard-dose group exhibited better OS (61.1% vs. 0.0% at 1 year, P = 0.022) and NRM (35.1% vs. 80.0% at 1 year, P = 0.052) than the lower-dose group. Moreover, the standard-dose group was less prone to both grades II-IV (11.5% vs. 40.0%) and III-IV (0.0% vs. 40.0%) acute graft-versus-host disease (GVHD). Use of cyclophosphamide in previous SCT and conditioning did not affect OS or NRM. In conclusion, haploidentical salvage SCT using PTCy offers promising survival outcomes. Prospective studies are required to validate the efficacy of salvage haploidentical SCT using PTCy. [ABSTRACT FROM AUTHOR]

The BLd regimen, which is a triplet regimen of bortezomib (Bor), lenalidomide (Len), and dexamethasone (Dex), is effective against newly diagnosed multiple myeloma (NDMM). However, non-hematological toxicities, such as peripheral neuropathy (PN), often hamper long-term continuation of the regimen, particularly in older adult patients. In this study, we examined the efficacy and safety of the modified BLd regimen with reduced-intensity Bor and standard-dose Len. The chemotherapy regimen consisted of 1.3 mg/m2 Bor administered subcutaneously on days 1 and 8, 25 mg Len administered on days 1–14, and 20 mg Dex on days 1–2 and 8–9 of a 3 week cycle for 8 cycles, followed by a 4 week cycle of Dex (40 mg weekly). Among the 30 patients enrolled, 60.0% (95% CI 40.6–77.3) had a very good partial response or better, and the best overall response rate was 96.7% (95% CI 82.8–99.9). Eight patients (26.7%) achieved a complete response. Grade 3 or higher PN was not observed and hematological toxicity was the most common adverse event. The modified BLd regimen showed favorable efficacy with a manageable safety profile, which suggests it could be a treatment option for transplant-ineligible NDMM. [ABSTRACT FROM AUTHOR]

We compared the outcomes of autologous stem cell transplantation (auto-SCT) with those of allogeneic stem cell transplantation (allo-SCT) from a human leukocyte antigen-matched related donor in patients with Philadelphia chromosome-negative B-lineage acute lymphoblastic leukemia (ALL). Newly diagnosed patients who underwent allo-SCT (n = 486) or auto-SCT (n = 99) after achieving first complete remission (CR) were included. Propensity score matching (PS) and an inverse probability of the treatment weighting (IPTW) analysis were applied to compensate for imbalances in baseline characteristics. The 5 years rates of overall survival (OS) among those in the PS-matched cohorts were 57% [95% confidence interval (CI) 46–67%] for those who received allo-SCT and 44% (95% CI 33–54%) for those who received auto-SCT. Multivariable, propensity score-matched, and IPTW analyses all revealed no statistically significant differences in OS between the two groups [hazard ratios (HR) 0.81, 95% CI 0.53–1.27, p = 0.36; HR 0.84, 95% CI 0.40–1.78, p = 0.65; HR 0.71, 95% CI 0.25–2.02, p = 0.53, respectively]. Prospective trials that include autologous transplantation as a treatment option are needed to examine the potential of autologous transplantation. [ABSTRACT FROM AUTHOR]

In April 2014, the Japan Society for Hematopoietic Cell Transplantation started a prospective observational study entitled "A short-term follow-up investigation of related hematopoietic stem cell donors receiving biosimilar G-CSF to mobilize peripheral blood stem cells." A total of 106 donors were registered from 25 transplant facilities through the end of March 2017. The study cohort consisted of 47 men and 58 women, and their median age was 38.5 years (range 15–65 years). The mean total count of collected CD34-positive cells/recipient body weight for all 106 donors was 4.40 ± 2.38 × 10 6/kg. The yield of CD34-positive cells was weakly correlated with donor age was observed. However, gender, WBC count on day 4, G-CSF dose reduction, type of apheresis device, collection speed, and treated blood volume had no significant impact on the collection efficacy of CD34-positive cells. The safety profile of biosimilar G-CSF was also acceptable: 126 adverse events in 73 donors were reported, but none was serious. The most common adverse events were low back pain, headache, and bone pain. This prospective study confirmed that biosimilar G-CSF had comparable efficacy and safety to reference G-CSF for CD34-positive cell mobilization in healthy related donors. [ABSTRACT FROM AUTHOR]

Unrelated cord blood transplantation (CBT) is an alternative curative option for adult patients with acute myeloid leukemia (AML) who need allogeneic hematopoietic cell transplantation (HCT) but lack an HLA-matched related or unrelated donor. However, large-scale data are lacking on CBT outcomes for unselected adult AML. To investigate the trends of survival and engraftment after CBT over the past 22 years, we retrospectively evaluated the data of patients with AML in Japan according to the time period of CBT (1998–2007 vs 2008–2013 vs 2014–2019). A total of 5504 patients who received single-unit CBT as first allogeneic HCT for AML were included. Overall survival (OS) at 2 years significantly improved over time. The improved OS among patients in ≥ complete remission (CR)3 and active disease at CBT was mainly due to a reduction of relapse-related mortality, whereas among patients in first or second CR at CBT, this was due mainly to a reduction of non-relapse mortality. The trends of neutrophil engraftment also improved over time. This experience demonstrated that the survival and engraftment rate after CBT for this group has improved over the past 22 years. [ABSTRACT FROM AUTHOR]

Non-infectious pulmonary complications (NIPCs) following allogeneic hematopoietic stem cell transplantation (HSCT) are relatively rare, but frequently fatal. This study investigated the pre-transplant risk factors for developing NIPCs using Japanese transplant registry database entries from 2001 to 2009. Among 13,573 eligible patients, 535 experienced NIPCs (3.9%). Multivariate analysis identified high recipient age (60 + years: HR 1.85, P = 0.003), HLA mismatch (HR 1.61, P < 0.001), female to male HSCT (HR 1.54, P < 0.001), and unrelated bone marrow transplantation (UR-BMT) (HR 3.88, P < 0.001) as significantly associated with an increased risk of NIPCs. In contrast, a non-total body irradiation (TBI) regimen with reduced intensity conditioning (RIC) were associated with a decreased risk of NIPCs compared with a cyclophosphamide (CY) + TBI regimen (busulfan + CY: HR 0.67, P = 0.009, other non-TBI: HR 0.46, P < 0.001), fludarabine-based RIC (HR 0.52, P < 0.001), and other RIC (HR 0.42, P = 0.003). The mortality rate was significantly worse for patients with NIPCs than those without (HR 1.54, 71 P < 0.001). This large-scale retrospective study suggests that both allo-reactions to donor cells and conditioning regimen toxicity contributed to NIPCs following HSCT. [ABSTRACT FROM AUTHOR]

Purpose: Hematopoietic cell transplantation (HCT) is a curative therapy for most patients with inborn errors of immunity (IEI). We conducted a nationwide study on HCT for patients with IEI other than severe combined immunodeficiency (non-SCID) in Japan. Methods: Data from the Japanese national database (Transplant Registry Unified Management Program, TRUMP) for 566 patients with non-SCID IEI, who underwent their first HCT between 1985 and 2016, were retrospectively analyzed. Results: The 10-year overall survival (OS) and event-free survival (EFS) were 74% and 64%, respectively. The 10-year OS for HCT from unrelated bone marrow (URBM), accounting for 39% of HCTs, was comparable to that for HCT from matched sibling donor (MSD), 79% and 81%, respectively. HCT from unrelated cord blood (URCB), accounting for 28% of HCTs, was also common, with a 10-year OS of 69% but less robust engraftment. The intensity of conditioning was not associated with OS or neutrophil recovery; however, myeloablative conditioning was more frequently associated with infection-related death. Patients who received myeloablative irradiation showed poor OS. Multivariate analyses revealed that HCT in 1985–1995 (hazard ratio [HR], 2.0; P = 0.03), URCB (HR, 2.0; P = 0.01), and related donor other than MSD (ORD) (HR, 2.9; P < 0.001) were associated with poor OS, and URCB (HR, 3.6; P < 0.001) and ORD (HR, 2.7; P = 0.02) showed a higher incidence of retransplantation. Conclusions: We present the 1985–2016 status of HCT for non-SCID IEI in Japan with sufficient statistical power, highlighting the potential of URBM as an alternative donor and the feasibility of reduced intensity conditioning. [ABSTRACT FROM AUTHOR]

Although haploidentical donor lymphocyte infusion (DLI) is a valid treatment option for relapsed acute myeloid leukemia (AML), the incidence and risk factors for graft-versus-host disease (GVHD) and the efficacy of haploidentical DLI have not been fully evaluated. We retrospectively analyzed the outcomes after haploidentical DLI for 84 patients with AML using a nationwide database and additional questionnaires. The median number of DLI cycles and infused CD3+ cell dose was 1 and 1.0 × 106/kg, respectively. The infused CD3+ cell count of 5.0 × 105/kg or higher was associated with acute GVHD (grade II–IV, 32.1% vs. 10.5%, p = 0.03; grade III–IV, 21.4% vs. 5.3%, p = 0.10). Patients who developed grade III–IV acute GVHD more frequently succumbed to treatment-related mortality (46.7% vs. 15.8% at 1 year, p = 0.002), although the relapse-related mortality was significantly low (40.0% vs. 72.2% at 1 year, p = 0.025). The overall response to DLI was significantly higher in the preemptive DLI group (47.4%) than in the therapeutic group (13.9%, p = 0.002). In the multivariate analysis, preemptive DLI was the predictive factor for overall response (odds ratio, 5.58; p = 0.003). Our results indicated the substantial risk of acute GVHD after haploidentical DLI with CD3+ cell count of 5.0×105/kg or higher and the favorable outcomes after preemptive DLI. [ABSTRACT FROM AUTHOR]

A nationwide cross-sectional survey was conducted in long-term survivors of allogeneic hematopoietic stem cell transplantation (HSCT) in childhood to investigate the effect of chronic graft-versus-host disease (cGVHD) on quality of life (QOL) and differences in QOL assessments between raters. QOL was evaluated by a visual analogue scale (VAS). Assessments were compared between the survivor, guardian, and attending pediatrician for those aged 15 years or younger, and between the survivor and attending pediatrician for those aged 16 years or older. For cGVHD, severity scores were obtained by organ and their association with the VAS score was analyzed. The average pediatrician-rated VAS score was higher than that of other raters for both patient age groups (< 15 years and > 16 years). By organ, involvement of the skin, digestive organs, and joints in GVHD affected the VAS scores. A high joint score was associated with a low VAS score, and conversely, a high lung score was associated with a low pediatrician-rated VAS score. Our results indicate that differences between raters must be considered when evaluating QOL of HSCT survivors, because patients appeared to experience grater inconvenience and difficulties due to joint GVHD than their pediatricians perceived. [ABSTRACT FROM AUTHOR]

Thus far, there have been no large cohort studies on total body irradiation (TBI)-containing conditioning regimens without antithymocyte globulin (ATG) in adults with aplastic anemia (AA) undergoing umbilical cord blood (UCB) transplantation (UCBT). We retrospectively analyzed 115 adults with idiopathic AA undergoing UCBT using TBI-containing reduced-intensity conditioning (RIC) regimens without ATG between 2000 and 2018 on behalf of the Adult Aplastic Anemia Working Group of the Japanese Society for Hematopoietic Cell Transplantation. We then compared transplantation outcomes between a fludarabine (Flu)- and melphalan (Mel)-based regimen (FM) and a Flu- and cyclophosphamide (Cy)-based regimen (FC). The median patient age at UCBT was 41 years. The median total nucleated cell and total CD34+ cell doses in a UCB unit at cryopreservation were 2.5 × 107/kg and 0.7 × 105/kg, respectively. The median follow-up period for survivors was 47 months. The cumulative incidence rate of neutrophil engraftment was 76.5%, and the 4-year overall survival (OS) rate was 64.3%. In multivariate analysis, the covariates that were significantly associated with a higher neutrophil engraftment were total CD34+ cell dose in an UCB unit (≥ 0.7 × 105/kg; hazard ratio, 0.57, P = 0.01) and total dose of TBI (4 Gy of TBI; hazard ratio, 0.32, P = 0.01). There was no significant difference in the cumulative incidence of neutrophil engraftment and the 4-year OS between the FM and FC groups. In conclusion, TBI-containing RIC regimens without ATG are suitable for adults with AA undergoing UCBT. There were no significant differences in transplantation outcomes between the FM and FC groups. [ABSTRACT FROM AUTHOR]

There is a matter of debate about the clinical impact of cytomegalovirus (CMV) reactivation on the development of late-onset invasive aspergillosis (IA), which occurs 40 days or later after allogeneic hematopoietic stem cell transplantation (HSCT). Using a Japanese transplant registry database, we analyzed the risk factors for the development of late-onset IA in 21,015 patients who underwent their first allogeneic HSCT between 2006 and 2017. CMV reactivation was defined as the initiation of preemptive anti-CMV antiviral therapy. Overall, there were 582 cases of late-onset IA, which occurred at a median of 95 days after HSCT. The 2-year cumulative incidence was 3.4% (95% confidence interval (CI), 3.0–3.9) in patients with CMV reactivation within 40 days after HSCT and 2.5% (95% CI, 2.3–2.8) in those without it (P < 0.001). In a multivariate analysis, CMV reactivation as a time-dependent covariate was significantly associated with the development of late-onset IA (hazard ratio (HR) 1.40, P < 0.001), as well as grade II–IV acute GVHD, age > 50 and HCT-CI ≥ 3 in the entire cohort. If we focus on the subgroup without grade II–IV acute GVHD, which is generally an indication for systemic corticosteroid therapy (n = 12,622), CMV reactivation was still a significant factor for the development of late-onset IA (HR 1.37, P = 0.045) as well as age > 50 years, HCT-CI ≥ 3, and cord blood transplantation. In conclusion, CMV reactivation was associated with an increased risk of late-onset IA after allogeneic HSCT independently of acute GVHD. Close monitoring for late-onset IA is necessary for patients who develop CMV reactivation even without grade II–IV acute GVHD. [ABSTRACT FROM AUTHOR]

This study aimed to compare the effect of disease status at the time of allogeneic hematopoietic cell transplantation (HCT) on post-transplant outcomes between acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Japanese nationwide registry data for 6901 patients with AML and 2469 patients with ALL were analyzed. In this study, 2850 (41%), 937 (14%), 62 (1%), and 3052 (44%) AML patients and 1751 (71%), 265 (11%), 23 (1%), and 430 (17%) ALL patients underwent transplantation in first complete remission (CR1), second CR (CR2), third or subsequent CR (CR3 +), and non-CR, respectively. The probabilities of overall survival at 5 years for patients transplanted in CR1, CR2, CR3 + , and non-CR were 58%, 61%, 41%, and 26% for AML patients and 67%, 45%, 20%, and 21% for ALL patients, respectively. Multivariate analyses revealed that the risks of relapse and overall mortality were similar for AML patients transplanted in CR1 and CR2 (P = 0.672 and P = 0.703), whereas they were higher for ALL patients transplanted in CR2 than for those transplanted in CR1 (P < 0.001 for both). The risks of relapse and overall mortality for those transplanted in CR3 + and non-CR increased in a stepwise manner for both diseases, with the relevance being stronger for ALL than for AML patients. These results suggest a significant difference in the effect of disease status at HCT on post-transplant outcomes in AML and ALL. Further investigation to incorporate measurable residual disease data is warranted. [ABSTRACT FROM AUTHOR]

Purpose: Hematopoietic cell transplantation (HCT) is a curative therapy for patients with severe combined immunodeficiency (SCID). Here, we conducted a nationwide study to assess the outcome of SCID patients after HCT in Japan. Methods: A cohort of 181 SCID patients undergoing their first allogeneic HCT in 1974–2016 was studied by using the Japanese national database (Transplant Registry Unified Management Program, TRUMP). Results: The 10-year overall survival (OS) of the patients who received HCT in 2006–2016 was 67%. Umbilical cord blood (UCB) transplantation was performed in 81 patients (45%). The outcomes of HCT from HLA-matched UCB (n = 21) and matched sibling donors (n = 22) were comparable, including 10-year OS (91% vs. 91%), neutrophil recovery (cumulative incidence at 30 days, 89% vs. 100%), and platelet recovery (cumulative incidence at 60 days, 89% vs. 100%). Multivariate analysis of the patients who received HCT in 2006–2016 demonstrated that the following factors were associated with poor OS: bacterial or fungal infection at HCT (hazard ratio (HR): 3.8, P = 0.006), cytomegalovirus infection prior to HCT (HR: 9.4, P = 0.03), ≥ 4 months of age at HCT (HR: 25.5, P = 0.009), and mismatched UCB (HR: 19.8, P = 0.01). Conclusion: We showed the potential of HLA-matched UCB as a donor source with higher priority for SCID patients. We also demonstrated that early age at HCT without active infection is critical for a better prognosis, highlighting the importance of newborn screening for SCID. [ABSTRACT FROM AUTHOR]

The present study evaluated outcomes and prognostic factors in adult patients with acute myeloid leukemia (AML) after syngeneic hematopoietic stem cell transplantation (HSCT). Among patients in first complete remission (CR1), outcomes of syngeneic HSCT (Syn) were compared with those of autologous HSCT (Auto), allogeneic HSCT from human leukocyte antigen (HLA)-matched sibling donor (MSD), or allogeneic HSCT from HLA-matched unrelated donor (MUD). Among 11,866 patients receiving first HSCT, 26 in the Syn group were analyzed. The 5-year overall survival (OS) rate, the cumulative incidence of relapse, and the cumulative incidence of non-relapse mortality (NRM) were 47.8%, 59.6%, and 4.6%, respectively. The OS was significantly better in patients in CR1 (n = 13) than in patients in non-CR1 (P = 0.012). Furthermore, 39 patients in CR1 each were assigned to the Auto, MSD, and MUD groups using propensity score matching. The 5-year OS in the Syn (68.4%) was not significantly different from those in the Auto (55.9%, P = 0.265), MSD (62.4%, P = 0.419), or MUD (63.7%, P = 0.409) groups. A higher relapse in the Syn than in the MSD and MUD groups was offset by lower NRM. In summary, syngeneic HSCT might be an alternative option for AML patients in CR1. [ABSTRACT FROM AUTHOR]

Nucleobase and nucleoside analogs (NNA) are widely used as anti-viral and anti-cancer agents, and NNA phosphorylation is essential for the activity of this class of drugs. Recently, diphosphatase NUDT15 was linked to thiopurine metabolism with NUDT15 polymorphism associated with drug toxicity in patients. Profiling NNA drugs, we identify acyclovir (ACV) and ganciclovir (GCV) as two new NNAs metabolized by NUDT15. NUDT15 hydrolyzes ACV and GCV triphosphate metabolites, reducing their effects against cytomegalovirus (CMV) in vitro. Loss of NUDT15 potentiates cytotoxicity of ACV and GCV in host cells. In hematopoietic stem cell transplant patients, the risk of CMV viremia following ACV prophylaxis is associated with NUDT15 genotype (P = 0.015). Donor NUDT15 deficiency is linked to graft failure in patients receiving CMV-seropositive stem cells (P = 0.047). In conclusion, NUDT15 is an important metabolizing enzyme for ACV and GCV, and NUDT15 variation contributes to inter-patient variability in their therapeutic effects. Nucleoside analogs (NNA), such as acyclovir (ACV) and ganciclovir (GCV), are widely used as anti-virals to treat herpes virus infection. Here, Nishii et al. show that diphosphatase NUDT15 hydrolyzes ACV and GCV, therewith reducing NNA activity in vitro and link NUDT15 variation to inter-patient variability in ACV and GCV therapeutic effects. [ABSTRACT FROM AUTHOR]

The availability of alternative donor sources could allow elderly patients to receive allogeneic hematopoietic cell transplantation (HCT). We retrospectively evaluated the outcomes of single-unit cord blood transplantation (CBT) in 1577 patients aged ≥60 years with acute myeloid leukemia (AML) in Japan between 2002 and 2017. In total, 990 (63%) patients were not in complete remission (CR) at the time of CBT. A myeloablative conditioning regimen (52%) and calcineurin inhibitor (CI) + mycophenolate mofetil (MMF)–based graft-versus-host disease (GVHD) prophylaxis (45%) were more commonly used. With a median follow-up for survivors of 31 months, the probability of overall survival and the cumulative incidence of leukemia-related mortality at 3 years was 31% and 29%, respectively. The cumulative incidence of non-relapse mortality (NRM) at 100 days and 3 years were 24% and 41%, respectively. The cumulative incidences of grade II–IV and grade III–IV acute GVHD at 100 days and extensive chronic GVHD at 2 years were 44%, 16%, and 14%, respectively. The cumulative incidence of neutrophil engraftment was 80% at 42 days. Results of multivariate analysis indicated that the following factors were significantly associated with higher overall mortality: performance status ≥1, hematopoietic cell transplantation-specific comorbidity index ≥3, adverse cytogenetics, extramedullary disease at diagnosis, and non-CR status at CBT. By contrast, female sex, HLA disparities ≥2, mycophenolate mofetil–based GVHD prophylaxis, and recent CBT were significantly associated with lower overall mortality. In conclusion, single CBT offers a curative option for AML patients aged ≥60 years with careful patient selection. [ABSTRACT FROM AUTHOR]

To investigate the association between methotrexate (MTX) dosage and engraftment, graft-versus-host disease (GVHD) incidence, and survival in umbilical cord blood transplantation (UCBT), we compared transplant outcomes after UCBT with various GVHD prophylaxis regimens, using registry data with additional data collection. Patients transplanted for acute myeloid leukemia with a calcineurin inhibitor (CNI) and either MTX or mycophenolate mofetil (MMF) combination were selected. In total, 888 single-unit UCBTs (MTX15–10–10, 415; MTX10–7–7, 294; MTX5–5–5, 71; MMF, 108) were included. In multivariate analyses with MTX15–10–10 as the reference, the likelihood of neutrophil and platelet engraftment was significantly worse in the MTX10–7–7 group, and similarly better in MMF group compared with MTX15–10–10. All variables including CyA vs Tac and 4-group GVHD prophylaxis became significant for the risk of grade II–IV acute GVHD in the final multivariate model. We observed significant additional effects of combined MTX dose in the Tac group, which were larger with lower MTX dose and MMF. No significant difference was observed in survival risk among GVHD prophylaxis groups. Despite the potential background differences in the combined CNI and conditioning regimen, we conclude that the recommended GVHD prophylaxis is a combination of CyA plus MTX15–10–10 or Tac plus MMF. [ABSTRACT FROM AUTHOR]

Minimal residual disease (MRD) monitoring by quantitative real-time reverse transcription PCR (qRT-PCR) is the standard of care in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). We evaluated the impact of MRD status at hematopoietic cell transplantation (HCT) on relapse, as measured by a unified protocol at a central laboratory. Only patients with Ph-positive ALL who had minor transcripts (e1a2) and who underwent allogeneic HCT in first complete remission between 2008 and 2017 were included. First, patients with negative-MRD (n = 196) and positive-MRD (n = 61) at HCT were analyzed. As expected, MRD positivity at HCT was significantly associated with an increased risk of hematological relapse (hazard ratio [HR], 2.91; 95% CI 1.67–5.08; P < 0.001) in the multivariate analysis. Next, patients with positive-MRD were divided into low-MRD (n = 39) and high-MRD (n = 22) groups. In the multivariate analysis, high-MRD at HCT was not significantly associated with an increased risk of hematological relapse compared to the low-MRD group (HR 1.10; 95% CI 0.54–2.83; P = 0.620). These results indicate that the therapeutic decisions should be made based on MRD positivity, rather than on the MRD level, at HCT. [ABSTRACT FROM AUTHOR]

We conducted a cross-sectional observational study investigating socioeconomic status among Japanese survivors of pediatric hematopoietic stem cell transplantation (HCT) and the impact of chronic graft-versus-host disease (cGVHD) on socioeconomic outcomes, which are topics not well explored in the previous research. We collected data on socioeconomic outcomes from 442 HCT survivors through a questionnaire and obtained demographic and clinical information from their attending physicians and a national database between February 2013 and November 2014. We used logistic regression analysis to examine the relationship between cGVHD and socioeconomic outcomes in allogeneic HCT (allo-HCT) survivors. Most survivors did not experience socioeconomic problems. Nevertheless, allo-HCT survivors with cGVHD aged 8–15 years had poorer economic status (p = 0.013), and allo-HCT survivors with cGVHD aged ≥ 16 years were more likely to have never married (p = 0.034) and less likely to have more than a high school education (p = 0.023), compared with allo-HCT survivors without cGVHD. Thus, cGVHD in Japanese allo-HCT survivors was a risk factor for economic difficulties for those aged 8–15 years, and for never marrying and low educational achievement in those aged ≥ 16 years. [ABSTRACT FROM AUTHOR]

In the original publication of the article, the Tables 1 and 2 were published incorrectly. The correct tables are given in this correction. [ABSTRACT FROM AUTHOR]

This phase 1/2 study aimed to identify the maximum tolerated dose, the recommended phase 2 dose (RP2D), and efficacy of the clofarabine, etoposide, and cyclophosphamide combination regimen in adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Patients aged ≥ 15 years with relapsed/refractory ALL were enrolled. Escalating doses of clofarabine (20–30 mg/m2/day × 5 days), etoposide (50–100 mg/m2/day × 5 days), and cyclophosphamide (200–440 mg/m2/day × 5 days) were administered. Dose-limiting toxicity was defined as Grade 3 or more non-hematological toxicities and others. A total of 18 patients (B-ALL; n = 13, T-ALL; n = 5) were recruited in phase 1; however, the protocol was amended to close study without proceeding to phase 2. Three patients were enrolled in cohort 1, three in cohort 2, six in cohort 3, and six in cohort 4. The RP2D of clofarabine, etoposide, and cyclophosphamide was 30, 100, and 440 mg/m2 daily, respectively. Complete remission (CR) was achieved in four patients (22%) and CR without platelet recovery in four patients (22%), with an overall response rate of 44%. The RP2D of the combination therapy was successfully determined in this study. [ABSTRACT FROM AUTHOR]

The safety and efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) for paroxysmal nocturnal hemoglobinuria (PNH) remain unclear. Therefore, we retrospectively analyzed the outcomes of 42 adult patients with PNH who underwent allogeneic HSCT using the registry database of the Japan Society for Hematopoietic Cell Transplantation. The median patient age was 32.5 years. The number of packed red cell (PRC) transfusions was < 20 times in 19 patients and ≥ 20 times in 16; 7 patients had missing data. Stem cell sources were bone marrow (N = 15) or peripheral blood (N = 13) from a related donor or bone marrow (N = 11) and cord blood (N = 3) from an unrelated donor. The cumulative incidence of neutrophil engraftment at day 40 was 81%. Six patients died before engraftment, and the 6-year overall survival (OS) was 74%. The OS of patients with < 20 pretransplant PRC transfusions was significantly higher than that of patients with ≥ 20 pretransplant PRC transfusions (95% vs. 63%; P < 0.05). Moreover, the OS of patients aged < 30 years was significantly higher than that of patients aged ≥ 30 years (90% vs. 59%; P < 0.05). Allogeneic HSCT for PNH could provide favorable survival; however, pretransplant transfusion burden and patient age should be considered when deciding the timing of allogeneic HSCT. [ABSTRACT FROM AUTHOR]

The impact of calcineurin inhibitor types and anti-thymocyte globulin (ATG) in conditioning on overall survival (OS) and GVHD-free, relapse-free survival (GRFS) has not yet been analyzed in detail for aplastic anemia. We herein examined 517 adult patients with aplastic anemia who underwent BMT from HLA-matched sibling donors (MSD, n = 255) and unrelated donors (UD, n = 262) and were treated with cyclosporine A (CSA) + methotrexate (MTX) (n = 258) and tacrolimus (TAC) + MTX (n = 259). In total, 330 patients received ATG in conditioning. CSA + MTX versus TAC + MTX did not have a significant impact on acute and chronic GVHD, OS, or GRFS in each donor type. The use of ATG in conditioning reduced the risk of grade II–IV acute GVHD in the MSD and UD cohorts (HR 0.42, P = 0.014, and HR 0.3, P < 0.001, respectively); however, a differential impact on GRFS was identified, namely, better GRFS in MSD recipients (HR 0.56, P = 0.016), but not in UD recipients (HR 1.1, P = 0.657). In conclusion, CSA + MTX and TAC + MTX were similar as GVHD prophylaxis regardless of the donor type, and ATG in conditioning increased GRFS in MSD transplants, but not in UD transplants. [ABSTRACT FROM AUTHOR]

Many drugs are used for unapproved indications in Japan for post hematopoietic stem cell transplant (HCT) complications. To investigate unapproved or off-label drug usage for graft-versus-host disease (GVHD) and virus infections after allogeneic HCT, we analyzed the data of Japanese HCT registry. Between 2006 and 2017, 39,941 adults and children received HCT for a variety of disease and their transplant data were captured in the registry. Among them, 14,687 and 8914 patients receiving treatment for acute and/or chronic GVHD, 24,828 patients with cytomegalovirus (CMV) infection or receiving therapies for CMV, and 4943 who received treatment for other viral infections were included in the analyses of off-label or unapproved drugs. For GVHD, mycophenolate mofetil was the most frequently used off-label drug, followed by beclomethasone, infliximab, and etanercept. For viral infections other than CMV, foscarnet was the most frequently used off-label drug. Cidofovir, which is not approved for use in Japan, was mainly used for adenovirus infection. This study demonstrated that numerous off-label and unapproved drugs have been used as key drugs for GVHD and post-transplant viral infection, and the real world date in the transplant registry may serve as an important asset to regulatory purposes. [ABSTRACT FROM AUTHOR]

This study aimed to analyze the factors associated with outcomes of bone marrow transplantation (UR-BMT) or cord blood stem cell transplantation from unrelated donors (UR-CBT). We assessed the time from diagnosis to transplantation among acute myeloid leukemia (AML) patients with intermediate- or poor-risk cytogenetics to identify the potential clinical efficacy of transplantation. We retrospectively analyzed 5331 patients who received UR-BMT or UR-CBT between 2008 and 2017. Patients were divided into four groups according to time from diagnosis to transplantation: (1) UR-BMT and > 5 months (n = 2353), (2) UR-BMT and ≤ 5 months (n = 379), (3) UR-CBT and > 5 months (n = 1494), and (4) UR-CBT and ≤ 5 months (n = 1106). There was no difference in overall survival (OS) for transplantation at ≤5 months and > 5 months in patients with first complete remission for both UR-BMT and UR-CBT, but OS in patients with primary induction failure (PIF) and transplantation at ≤ 5 months was significantly higher in the UR-CBT group compared with that at >5 months (P < 0.001). Multivariate Cox regression analysis also showed that transplantation at >5 months in patients with PIF was an independent predictor of poorer OS. Therefore, UR-CBT at ≤ 5 months after diagnosis is an alternative option for AML patients with PIF. [ABSTRACT FROM AUTHOR]

Significant advancements have been achieved with regard to the outcomes of acute promyelocytic leukemia (APL) patients through the introduction of all-trans retinoic acid; however, early hemorrhagic death and differentiation syndrome remain the major causes of remission induction failure in patients with APL. To investigate early death, serious hemorrhage, and differentiation syndrome during remission induction therapy in terms of incidence, risk factors, influence on outcomes, and prophylactic effects of several new anticoagulants, the results of 344 patients enrolled in the Acute Promyelocytic Leukemia 204 study conducted by the Japan Adult Leukemia Study Group were analyzed. Early death was observed in 16 patients (4.7%), of whom 14 had serious hemorrhage and 2 had differentiation syndrome. Serious hemorrhage and differentiation syndrome of grade 2 or higher were observed in 21 and 54 patients, respectively. Patients who achieved complete remission had a 7-year disease-free survival of 84.8% if they did not experience serious hemorrhage and 40.0% if they experienced serious hemorrhage during remission induction therapy (P = 0.001). Risk factor analyses showed that higher white blood cell count was associated with early death, higher white blood cell count and lower platelet count with serious hemorrhage, and leukocytosis during induction therapy and higher body surface area with differentiation syndrome. In conclusion, these results indicate that patients with such high-risk features may benefit from more intensive supportive care. The hemorrhagic risk was not relieved by the introduction of new anticoagulants. Further studies are required to establish the predictive impact of body surface area on differentiation syndrome. This trial is registered with UMIN-CTR as C000000154 on September 13, 2005. [ABSTRACT FROM AUTHOR]

The prognostic impacts of BCR-ABL1 fusion gene mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) remain unknown. Using data from a nationwide Japanese registry, we have evaluated the prognostic impact of BCR-ABL1 mutations prior to the first allogeneic hematopoietic cell transplantation (HCT). The cohort included 289 patients with a median of 48 years of age (range: 16-70). Point mutations were detected in 110 patients. Of these, 90 (82%) harbored T315I mutations, while 20 had other mutations. With a median follow-up period of 29 months (range: 1-125), outcomes after 2 years were worse with mutations than without (overall survival [OS]: 34% vs 68%, p < 0.001; relapse rate [RR]: 48% vs 18%, p < 0.001), particularly with the presence of the T315I mutation (OS: 29% vs 68%, p < 0.001; RR: 54% vs 18%, p < 0.001). OS was significantly worse in the T315I group even among the cohort with hematological (p < 0.001) or molecular complete remission (p = 0.025) as compared to the no mutation group. Multivariate analysis determined the prognostic impact of the T315I mutation (OS: hazard ratio [HR] = 2.19, 95% confidence interval [CI]: 1.5-3.3, p < 0.001; RR: HR = 2.51, 95% CI: 1.5-4.2, p < 0.001). This study is the first to report on the prognostic significance of BCR-ABL1 mutations in Ph + ALL. [ABSTRACT FROM AUTHOR]

The role of stem cell transplantation (SCT) for patients with Waldenström's macroglobulinemia (WM) remains undetermined. Therefore, we retrospectively evaluated the outcome of autologous and allogeneic SCT for patients with WM using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Forty-six patients receiving autologous and 31 receiving allogeneic SCT were analyzed. The allogeneic SCT group included more patients with advanced disease status at transplant and received more lines of chemotherapy. The cumulative incidences of non-relapse mortality (NRM) at 1 year were 30.0% (95% CI, 14.7–46.9%) in the allogeneic SCT and 0% in the autologous SCT group. The estimated 3-year overall (OS) and progression-free (PFS) survival rates were 84.5% (95% CI, 66.0–93.4%) and 70.8% (95% CI, 53.0–82.9%) in the autologous SCT group, and 52.2% (95% CI, 32.5–68.6%) and 45.0% (95% CI, 26.3–62.0%) in the allogeneic SCT group. No patients died after the first 2 years following allogeneic SCT. In univariate analyses, disease status at SCT was significantly associated with PFS in autologous SCT, and with OS and PFS in allogeneic SCT. These results suggest that both autologous and allogeneic SCT have each potential role in WM. Allogeneic SCT is more curative for WM, but is associated with high NRM. [ABSTRACT FROM AUTHOR]

The impact of acute and chronic graft-versus-host disease (GVHD) on clinical outcomes was retrospectively analyzed in 960 patients with non-malignant diseases (NMD) who underwent a first allogeneic hematopoietic stem cell transplantation (HSCT). Grade III-IV acute GVHD (but not grade I-II) was significantly associated with a lower rate of overall survival (OS), and higher non-relapse mortality (NRM) than that seen in patients without acute GVHD. Extensive (but not limited) GVHD was significantly associated with a lower OS rate and higher NRM than that seen in patients without chronic GVHD. Any grade of acute (but not chronic) GVHD was significantly associated with a lower incidence of relapse and a lower proportion of patients requiring a second HSCT or donor lymphocyte infusion for graft failure or mixed chimerism, but its impact on OS was almost negligible. Acute GVHD was significantly associated with lower OS rates in all disease groups, whereas chronic GVHD was significantly associated with lower OS rates in the primary immunodeficiency and histiocytosis groups. In conclusion, acute and chronic GVHD, even if mild, was associated with reduced OS in patients receiving HSCT for NMD and effective strategies should, therefore, be implemented to minimize GVHD. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) represents the most common indication for allogeneic hematopoietic cell transplantation (HCT). This study aimed to address the implementation status of allogeneic HCT for adults with AML in Japan and to provide a comprehensive overview of post-transplant outcomes. For this purpose, we analyzed data of 15,186 patients undergoing allogeneic HCT between 1992 and 2016 who were consecutively reported to the Japanese nationwide transplantation registry. The constant increase in the annual number of transplantations was clearly attributable to the growth of unrelated transplantation, and umbilical cord blood transplantation currently accounts for one-third of all allogeneic HCTs. The proportion of older patients has increased steadily since 2000, approximately, in parallel with the introduction of reduced-intensity conditioning. The probability of overall survival (OS) was estimated at 41% (95% confidence interval (CI), 40-42%) for the entire cohort, 56% (95% CI, 55-57%) for patients transplanted in complete remission (CR), and 22% (95% CI, 21-23%) for those transplanted in non-CR. Multivariate analysis identified age, sex, performance status, disease status, cytogenetic risk, donor type, graft source, sex mismatch between the donor and the recipient, and year of transplantation as factors significantly associated with OS. These findings represent the real-world data in Japan, showing the changes in transplantation practice and a detailed estimation of post-transplant outcomes. [ABSTRACT FROM AUTHOR]

For patients without an HLA-matched donor, an HLA-mismatched unrelated donor (MMUD) has been considered as an alternative donor in allogeneic hematopoietic cell transplantation (allo-HCT). We conducted a nationwide retrospective study to compare the transplant outcomes among 1-, 2-, and 3-locus (allele/antigen) mismatched unrelated donors (1MMUD n = 2044, 2MMUD n = 492, and 3MMUD n = 73) in allo-HCT and to assess the impact of antithymocyte globulin (ATG) in allo-HCT from 1-3MMUD. 2MMUD and 3MMUD were independent significant adverse factors for grade III-IV acute graft-versus-host disease (GVHD) (hazard ratio [HR] 1.72, p < 0.001 and HR 2.48, p < 0.001), non-relapse mortality (NRM) (HR 1.47, p < 0.001 and HR 2.00, p < 0.001), and overall survival (OS) (HR 1.21, p = 0.0066 and HR 1.60, p = 0.0015). Conversely, the use of ATG was an independent favorable factor for grade III-IV acute GVHD (HR 0.43, p < 0.001), NRM (HR 0.51, p < 0.001), and OS (HR 0.74, p = 0.0012). On the other hand, HLA compatibility and the use of ATG were not associated with a risk of relapse. An interaction test between the number of HLA mismatches and the use of ATG revealed that the effect of ATG on NRM and OS in the 2MMUD group was significantly less than that in the 1MMUD group (HR 1.53, p = 0.036 and HR 2.34, p = 0.0046). This study indicated that the number of HLA mismatches and the use of ATG were significantly associated with not only GVHD, but also NRM and OS. Whereas the use of ATG could improve transplant outcomes in allo-HCT from 1MMUD, its effectiveness with 2MMUD and 3MMUD was limited. [ABSTRACT FROM AUTHOR]