Hematopoietic Stem Cell Transplantation In Japan Research Articles

HLA Class I Genotypes Predict the Survival after Hematopoietic Stem Cell Transplantation in Immune Aplastic Anemia

Introduction Immune aplastic anemia (AA) is a bone marrow failure syndrome mediated by cytotoxic T cells, leading to the loss of HLA class I allele expression in hematopoietic stem and progenitor cells. In unrelated hematopoietic stem cell transplantation (HSCT), we recently reported an association between HLA loss and a short time to transplantation (TTT), consistent with an abrupt onset of immune AA. In addition, patients who lost HLA-A*02:06 or HLA-B*40:02 showed better survival outcomes after HSCT than those with other HLA allele losses. To clarify the clinical significance of the loss of specific HLA class I alleles in AA, we correlated loss-prone HLA class I allele genotypes with HSCT outcomes in patients with a short TTT, assuming the frequent absence of these alleles in this subgroup. Methods We conducted a nationwide retrospective analysis of patients with acquired AA ≥16 years old who underwent their first allogeneic HSCT in Japan between 2006 and 2020. Patient data were obtained from the Transplant Registry Unified Management Program (TRUMP ®), a comprehensive Japanese HSCT registry. Results From 1025 patients with acquired AA, we excluded patients with drug-induced AA and those missing 2-field HLA allele information and TTT information, leaving 874 patients for the analysis. The median patient age at HSCT was 34 years old, and the median TTT was 14 months. When focusing on the most frequently absent HLA class I alleles in Japanese patients with AA, including HLA-B*40:02, HLA-A*02:06, HLA-A*02:01, HLA-B*54:01, and HLA-A*31:01, all 5 alleles were associated with higher survival rates than in 220 patients without these alleles (Figure 1A). As expected, this association was more pronounced with a shorter TTT. For instance, among the 424 patients with a TTT <14 months, the 5-year survival rates were 79%, 78%, 85%, 78%, and 81% in patient groups with the respective HLA class I alleles above, while it was 55% in the other 101 patients (Figure 1B). Of note, having any of the 5 alleles (5-allele +) proved to be the best predictor of a survival out of 242792 combinations of 2 to 5 HLA-A, HLA-B, and HLA-DRB1 alleles. To adjust for potential confounders, such as age and graft sources, we performed propensity score matching and confirmed that the overall survival was significantly lower in patients without any of the 5 alleles (5-allele -) than in 5-allele + patients ( P = .00018). A multivariable Cox regression analysis including age, AA severity, prior IST, graft sources, HLA disparity, and HLA-B leader peptide dimorphism as covariates further demonstrated that the 5-allele genotype was an independent predictor of the survival. The consistent effect of the 5 alleles on the survival has been internally validated across various subgroups. In contrast, the 5 HLA class I alleles did not affect the survival in patients with hematological malignancies, including acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome. Regarding other post-HSCT complications, 5-allele - AA patients had a higher incidence of primary graft failure (GF) than 5-allele + AA patients, even when deaths before engraftment were censored and when compared to the propensity score-matched patients. Nevertheless, the 5 HLA alleles continued to stratify the survival among patients who achieved engraftment ( P < .0001). There were no significant differences in the incidence of acute and chronic graft-versus-host disease, late GF, or cause of death between 5-allele -and 5-allele + AA patients. To further stratify the survival rate in 5-allele - AA patients with a short TTT, we examined the impact of other HLA class I alleles and found that patients carrying HLA-B*07:02 or HLA-B*48:01, in which HLA loss had been previously detected in some AA patients, showed a particularly poor survival (Figure 1C; P = .0082). This association remained significant even after propensity score matching ( P = .031). Conclusions Significant associations between specific loss-prone HLA class I alleles and diverse survival outcomes after HSCT in AA patients with short TTT indicate the relevance of HLA information in patient selection for allogeneic HSCT. These findings also support the existence of a distinct immune pathogenesis affecting the clinical manifestations of AA differently, as observed in IST-treated patients. Further investigations in other ethnic groups are required to validate these observations.

Single-unit unrelated cord blood transplantation versus HLA-matched sibling transplantation in adults with advanced myelodysplastic syndrome: A registry-based study from the adult MDS working group of the Japanese society for transplantation and cellular therapy.

Allogeneic hematopoietic stem cell transplantation (HCT) remains the only potential curative therapeutic modality for advanced myelodysplastic syndrome (MDS). Within HCT, the advancement of cord blood transplantation (CBT) procedures has resulted in a drastic expansion of CBT as a donor source for MDS. However, data comparing matched sibling donors (MSDs) HCT with CBT for advanced MDS, which was defined as refractory anemia with an excess of blasts (RAEB)-1 and RAEB-2 according to the World Health Organization classification at the time of HCT, have not been explored. We retrospectively compared survival and other posttransplant outcomes in 999 adult patients with advanced MDS after receiving allogeneic HCT in Japan between 2011 and 2020, using either MSD (n=331) or single-unit unrelated cord blood (UCB) (n=668). In the multivariate analysis, there were no significant differences in overall survival (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.90-1.34; P=0.347), disease-free survival (HR, 1.01; 95% CI, 0.84-1.23; P=0.845), relapse (HR, 0.88; 95% CI, 0.68-1.15; P=0.370), or non-relapse mortality (HR, 1.15; 95% CI, 0.87-1.50; P=0.310) between MSD recipients and UCB recipients. UCB was significantly associated with lower neutrophil (HR, 0.28; 95% CI, 0.24-0.33; P<0.001) and lower platelet (HR, 0.29; 95% CI, 0.23-0.36; P<0.001) recovery compared to MSD. UCB was significantly associated with a lower incidence of chronic graft-versus-host disease (GVHD) (HR, 0.57; 95% CI, 0.44-0.75; P<0.001) and extensive chronic GVHD (HR, 0.46; 95% CI, 0.32-0.67; P<0.001) compared to MSD. Similar results were observed after adjusting for differences between MSD and UCB recipients by propensity score matching analysis. Our study demonstrated that single CBT and MSD HCT had similar survival outcomes for adult patients with advanced MDS despite the lower hematopoietic recovery in CBT recipients and higher chronic GVHD in MSD recipients.

Risk factors and outcome of Stenotrophomonas maltophilia infection after allogeneic hematopoietic stem cell transplantation: JSTCT, Transplant Complications Working Group.

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 100days after HSCT was 2.2%. Among risk factors identified for SMI (age ≥ 50years, 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 30days 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.

Effect of the COVID-19 pandemic on allogeneic stem cell transplantation in Japan.

The coronavirus disease 2019 (COVID-19) pandemic affected healthcare quality and access worldwide and may also have negatively affected the frequency and outcomes of allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the effect of the pandemic on allogeneic HSCT in Japan. Our subjects were patients who received allogeneic HSCT during January 2018-December 2020 in Japan. We assessed differences in yearly number of allogeneic HSCTs and 1-year outcomes in 2020 versus both 2019 and 2018. The total number of patients who received allogeneic HSCT increased from 3621 patients in 2018 and 3708 patients in 2019 to 3865 patients in 2020. Some following changes in allogeneic HSCT methods were observed: patients were older, fewer patients received bone marrow transplantation, fewer patients received transplants from unrelated donors, fewer patients received transplants from matched donors, more patients received reduced-intensity conditioning, and fewer patients received anti-thymocyte globulin in 2020 compared with previous years. HSCT outcomes were not affected, as 1-year overall survival was not significantly different (65.8% in 2020, vs. 66.5% in 2019 and 66.4% in 2018). Our results suggest that we can maintain transplant care during the pandemic by controlling the spread of COVID-19 and modifying HSCT methods.

Allogeneic Hematopoietic Stem Cell Transplantation for Post-essential Thrombocythemia and Post-polycythemia Vera Myelofibrosis.

Objective Little information is available about the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with secondary myelofibrosis from essential thrombocythemia (ET) and polycythemia vera (PV). A nationwide retrospective study of the outcome of HSCT for post-ET and post-PV myelofibrosis was conducted in Japan. Patients and Methods Clinical data for patients with post-ET (n=29) and post-PV (n=9) myelofibrosis who had received first allogeneic HSCT were extracted from the Transplant Registry Unified Management Program, which is a registry of the outcomes of HSCT in Japan. Results Five patients died without neutrophil recovery within 60 days after transplantation. The incidence of neutrophil recovery was significantly lower in umbilical cord blood (UCB) transplantation than in related donor transplantation (40% vs. 92%, p=0.010). The 1-year non-relapse mortality for post-ET and post-PV myelofibrosis was 35% and 27%, respectively (p=0.972). No patient or transplantation characteristics were associated with non-relapse mortality. The 4-year overall survival for post-ET and post-PV myelofibrosis was 46% and 65%, respectively (p=0.362). A univariate analysis identified UCB transplantation (vs. related donor, p=0.017) and ≥10 times red blood cell transfusions before transplantation (vs. <10 times, p=0.037) as predictive of a lower overall survival. Conclusion Allogeneic HSCT provides a long-term survival for at least some patients with post-ET and post-PV myelofibrosis. Further studies with more patients are required to determine the best alternative donor.

Nationwide retrospective review of hematopoietic stem cell transplantation in children with refractory Langerhans cell histiocytosis.

The efficacy of and indications for hematopoietic stem cell transplantation (HSCT) in pediatric Langerhans cell histiocytosis (LCH) remain undetermined. This retrospective study analyzed 30 children with refractory LCH who underwent HSCT in Japan between 1996 and 2014. Eleven patients received a myeloablative conditioning (MAC) regimen, while 19 patients received a reduced-intensity conditioning (RIC) regimen. Among the 26 patients with complete data, 23 patients had risk organ (RO) involvement during clinical course. Disease status at HSCT was no active disease (NAD) (4), active disease-regression (AD-r) (2), active disease-stable (AD-s) (4), and active disease-progressive (AD-p) (16). Seventeen of the 30 patients (57%) were alive with a median follow-up of 433days (range 9-5307) after HSCT. Death occurred within 3 months after HSCT in eight of 13 patients. RIC and MAC patients were similar in both overall survival (OS) (56.8% vs. 63.6%, respectively, p = 0.789) and failure-free survival (56.8% vs. 54.6%, respectively, p = 0.938). Regarding disease status at HSCT, the six patients with NAD/AD-r experienced better outcomes than the 20 with AD-s/AD-p (5-year OS, 100% vs. 54.5%, respectively, p = 0.040). Disease state at the time of HSCT was the most important prognostic factor.

Hematopoietic Stem Cell Transplantation for XIAP Deficiency in Japan.

BackgroundX-linked inhibitor of apoptosis protein (XIAP) deficiency is a rare immunodeficiency that is characterized by recurrent hemophagocytic lymphohistiocytosis (HLH) and splenomegaly and sometimes associated with refractory inflammatory bowel disease (IBD). Although hematopoietic stem cell transplantation (HSCT) is the only curative therapy, the outcomes of HSCT for XIAP deficiency remain unsatisfactory compared with those for SLAM-associated protein deficiency and familial HLH.AimTo investigate the outcomes and adverse events of HSCT for patients with XIAP deficiency, a national survey was conducted.MethodsA spreadsheet questionnaire was sent to physicians who had provided HSCT treatment for patients with XIAP deficiency in Japan.ResultsUp to the end of September 2016, 10 patients with XIAP deficiency had undergone HSCT in Japan, 9 of whom (90%) had survived. All surviving patients had received a fludarabine-based reduced intensity conditioning (RIC) regimen. Although 5 patients developed post-HSCT HLH, 4 of them survived after etoposide administration. In addition, the IBD associated with XIAP deficiency improved remarkably after HSCT in all affected cases.ConclusionThe RIC regimen and HLH control might be important factors for successful HSCT outcomes, with improved IBD, in patients with XIAP deficiency.Electronic supplementary materialThe online version of this article (doi:10.1007/s10875-016-0348-4) contains supplementary material, which is available to authorized users.

Is cord blood worth saving for public or private banking?

Is cord blood worth saving for public or private banking?

Acute exacerbation of Toxoplasma gondii infection after hematopoietic stem cell transplantation: five case reports among 279 recipients

Toxoplasmosis is a rare and possibly underestimated complication following hematopoietic stem cell transplantation (HSCT) associated with a high mortality rate, although the incidence of toxoplasmosis after HSCT in Japan has not been established. We retrospectively studied patients with toxoplasmosis after HSCT, and identified five patients who had been diagnosed with an acute exacerbation of toxoplasmosis among 279 HSCT recipients at our institution between 1998 and 2011, representing an incidence of 1.8%. Among 87 autologous HSCT recipients, one definite case was diagnosed. The serological test for Toxoplasma gondii before HSCT was positive in 18 of 192 allogeneic HSCT recipients. Of the 18 seropositive patients, three had definite infections, and one had possible infection. All four definite cases were diagnosed at autopsy. In the definite cases, three allogeneic HSCT recipients had disseminated or pulmonary toxoplasmosis and one autologous HSCT recipient had toxoplasmic encephalitis, although toxoplasmosis was not suspected at the premortem examination due to non-specific clinical and radiological manifestations. Thus, acute exacerbation of toxoplasmosis should be suspected in recipients after HSCT. Early diagnosis and treatment for toxoplasmosis would certainly contribute to a decrease in mortality after HSCT.

Less Maintenance Immunosuppression in Lung Transplantation Following Hematopoietic Stem Cell Transplantation From the Same Living Donor

Living-donor lobar lung transplantation (LDLLT) is one of the final options for saving patients with pulmonary complications after hematopoietic stem cell transplantation (HSCT). We retrospectively investigated 19 patients who had undergone LDLLT after HSCT in Japan. Eight patients underwent LDLLT after HSCT in which one of the donors was the same living donor as in HSCT (SD group), while 11 received LDLLT from relatives who were not the HSCT donors (non-SD group). In the SD group, three patients underwent single LDLLT. The 5-year survival rate was 100% and 58% in the SD and non-SD groups, respectively. In the SD group, postoperative immunosuppression was significantly lower than in the non-SD group. Two patients died of infection and one died of post-transplant lymphoproliferative disease (PTLD) in the non-SD group, while only one patient died of PTLD 7 years after LDLLT in the SD group. Hematologic malignancy relapsed in two patients in the non-SD group. For the three single LDLLTs in the SD group, immunosuppression was carefully tapered. In our study, LDLLT involving the same donor as for HSCT appeared to have advantages related to lower immunosuppression compared to LDLLT from relatives who were not the HSCT donors.