神田 善伸

Impact of donor age considering HLA disparity on hematopoietic cell transplantation (HCT) outcomes has not been fully evaluated. We evaluated 8486 patients who received unrelated bone marrow transplantation (UR-BMT) from 8/8 or 7/8 HLA-matched donors. Compared to 8/8 HLA-matched younger donors (<40 years), 8/8 HLA-matched older donors (subdistribution hazard ratio [SHR], 1.16; 95% CI, 0.97-1.38) and 7/8 HLA-matched younger donors (SHR, 1.33; 95% CI, 1.11-1.58) were associated with increased risk of grade III-IV acute graft-versus-host disease (aGVHD). 7/8 HLA-matched older donors had further increased risk (SHR, 2.00; 95% CI, 1.68-2.38) due to interaction between donor age and HLA disparity (p for interaction = 0.038). Progression-free survival (PFS) after UR-BMT with 8/8 HLA-matched younger donors was comparable to that after UR-BMT with 8/8 HLA-matched older donors, whereas UR-BMT with 7/8 HLA-matched younger or older donors was significantly associated with lower PFS than UR-BMT with 8/8 HLA-matched younger donors (younger donor; HR, 1.12; 95% CI, 1.04-1.21, older donor; HR, 1.28; 95% CI, 1.17-1.40; p for interaction = 0.079). In conclusion, adverse effect of increased donor age requires attention, especially in HLA-mismatched UR-BMT due to interaction between donor age and HLA disparity. Intensive aGVHD prophylaxis may be required to improve outcomes after HCT with mismatched older donors.

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative post-remission therapy for adult patients with acute myeloid leukemia (AML) in complete remission (CR). The availability of alternative human leukocyte antigen (HLA)-mismatched donors, such as cord blood and haploidentical related donors, could allow patients to receive allogeneic HCT who are without an HLA-matched sibling or unrelated donor. The use of these alternative donors is preferable for patients with advanced disease due to the rapid availability. However, comparative data for cord blood transplantation (CBT) and haploidentical related donor transplantation (haplo-HCT) are limited for adult patients with AML in CR. We sought to compare overall survival (OS); leukemia-free survival (LFS); graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS); and chronic GVHD-free, relapse-free survival (CRFS) between single-unit CBT (SCBT) and haplo-HCT recipients for adult patients with intermediate- or poor-risk AML in CR. We retrospectively analyzed and compared the results of allogeneic hematopoietic cell transplantation in 1313 adult patients with intermediate- or poor-risk AML in CR who received either SCBT (n = 1102) or unmanipulated haplo-HCT (n = 211) between 2007 and 2018 in Japan. Among the whole cohort, the cumulative incidences of neutrophil and platelet recovery were significantly lower in SCBT recipients compared with those in haplo-HCT recipients (P < .001 for neutrophil, P < .001 for platelet). SCBT was significantly associated with a higher incidence of grade II to IV acute GVHD and lower incidence of extensive chronic GVHD compared to haplo-HCT (P = .013 for grades II to IV acute GVHD; P = .006 for extensive chronic GVHD). Haplo-HCT recipients developed a higher incidence of cytomegalovirus (CMV) antigenemia compared to SCBT recipients (P = .004). In the multivariate analysis, there were no significant differences for grades III or IV acute GVHD (hazard ratio [HR], 1.17; 95% confidence interval [CI], .88 to 1.57; P = .26), relapse incidence (HR, 1.09; 95% CI, .76 to 1.58; P = .61), non-relapse mortality (HR, .83; 95% CI, .58 to 1.18; P = .32), OS (HR, .92; 95% CI, .70 to 1.20; P = .56), LFS (HR, .94; 95% CI, .73 to 1.21; P = .67), GRFS (HR, 1.12; 95% CI, .90 to 1.40; P = .27), or CRFS (HR, 1.15; 95% CI, .92 to 1.44; P = .19) between the two donor types. In the propensity score matching analysis, which identified 180 patients in each cohort, there were no significant differences in transplant outcomes between the two donor types, except for delayed neutrophil (P < .001) and platelet recovery (P < .001) and a higher incidence of grades II to IV acute GVHD (P = .052) in SCBT. SCBT and unmanipulated haplo-HCT had similar survival outcomes for adult patients with AML in CR despite the lower hematopoietic recovery and higher grade II to IV acute GVHD in SCBT recipients and the higher CMV antigenemia in haplo-HCT recipients.

Most acute leukemia patients receive consecutive intensive chemotherapy, which usually takes several months before allogeneic hematopoietic stem cell transplantation (allo-HCT). Intensive chemotherapy often induces gastrointestinal adverse events. These adverse events leave patients in a state of malnutrition, leading to a reduction in body weight. In this study, we analyzed the impact of body weight loss before allo-HCT on survival outcomes of acute leukemia patients (acute myeloid leukemia, acute lymphoid leukemia and mixed phenotype acute leukemia). A loss of body weight (LBW), which was a reduction of body weight from diagnosis or relapse to transplantation, was calculated in 182 acute leukemia patients who received first allo-HCT at our center between June 2006 and September 2019. A receiver operating characteristics curve for nonrelapse mortality (NRM) was plotted for defining the cut-off value of LBW. The cutoff value of LBW was defined as 13.2%. A higher LBW was significantly associated with inferior NRM and overall survival (OS) (2-year [2y] NRM 36.1% versus 11.5%, P = .0025; 2y-OS 39.9% versus 65.8%, P = .020). The adverse impact of LBW was also confirmed in multivariate analyses for NRM and OS (HR of NRM 2.74 [1.25-6.03], P = .0012; HR of OS 2.06 [1.00-3.07], P = .0049). The main cause of death included disease progression (n = 34) and infection (n = 35). Death cause by infection was more frequently observed in the high-LBW group (15 cases [35.7%] versus 20 cases [14.3%]; P = .0035). In addition, subgroup analyses based on a combination of the body mass index at diagnosis and LBW were performed. When the non-overweight-low LBW group (body mass index [BMI] ≤25 and LBW ≤13.2%) was used as a reference in multivariate analysis, the overweight-high LBW group (BMI >25 and LBW >13.2%) showed an increased risk of poor survival outcomes (HR of NRM 4.27 [95% confidence interval {CI}, 1.82-10.0], P < .001; HR of OS 1.93 [95%, CI 1.00-3.71], P = .050). High LBW was significantly associated with inferior survival outcomes, and the adverse effect of malnutrition might be greater than the favorable effect of the reduction in overweight.

Mesenchymal stromal cells (MSCs) have been shown to inhibit aerobic glycolysis in activated T cells, leading to increased autophagy. Although tryptophan depletion induced by indoleamine 2,3-dioxygenase (IDO) generated by MSCs has been suggested as a potential mechanism, we found that this inhibition was completely abolished when T cells were physically separated from MSCs using the Transwell system. Instead, in the current study, we demonstrate that programmed cell death 1 receptor (PD-1) and its ligand PD-L1, the expression of which is induced on activated T cells and MSCs, respectively, in response to IFN-γ are involved in this inhibition. Blockade of PD-1/PD-L1 interaction by blocking antibodies significantly restored glucose uptake, glycolytic activity, and cluster formation of activated T cells, whereas a specific inhibitor of IDO, 1-methyl-DL-tryptophan, had no effect. Neither surface nor cytoplasmic glucose transporter-1 expression on T cells was changed by MSCs. In addition, glycolytic gene expression in activated T cells was not inhibited despite the presence of MSCs. However, we found that hexokinase II (HK2) protein expression was markedly decreased in activated T cells that had been cocultured with MSCs. PD-1 blocking antibody restored HK2 expression. Taken together, our findings indicate that the PD-1/PD-L1 axis is involved in the MSC-mediated suppression of T cell glycolysis by negatively regulating HK2 activity at the protein level, but not at the mRNA level.

BACKGROUND: We retrospectively compared the impact of the areas over and under the lymphocyte curve (L_AOC vs L_AUC) on cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: Among 394 consecutive patients who underwent their first allogeneic HSCT at our center between 2007 and 2018, 301 patients met the inclusion criteria. L_AOC was calculated as the area over the lymphocyte curve during lymphopenia (absolute lymphocyte count [ALC] <700/μL). We calculated L_AOC and L_AUC from day 0 to day 15 (L_AOC15, L_AUC15) and from day 0 to day 30 (L_AOC30, L_AUC30). RESULTS: CMV antigenemia was defined as more than 3 cells/2 slides by the C10/11 method and detected in 204 cases (CMV reactivation) at a median of 39 days after HSCT. Although there were significant differences in L_AOC15, L_AOC30, L_AUC15, and L_AUC30 between patients with and without CMV reactivation, there was no difference in accuracy for predicting CMV reactivation between L_AOC and L_AUC. In a multivariate analysis, L_AOC15 and L_AUC15 were each identified as independent predictive factors for CMV reactivation, along with advanced age and CMV serostatus. However, ALC at day 14 or day 21 was as accurate as area-based indexes such as L_AOC15 and L_AUC15. L_AOC15 and L_AUC15 were significantly associated with longer duration of anti-CMV antiviral therapy while ALC was not. CONCLUSIONS: L_AOC15 and L_AUC15 had similar impacts on CMV reactivation. Although these area-based indexes were not superior to ALC for predicting CMV reactivation, they might predict patients who need longer duration of antiviral therapy more accurately.

Although measurable residual disease (MRD) at the time of allogeneic hematopoietic cell transplantation (allo-HCT) has been reported to be an important prognostic factor for Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) during first complete remission (CR1), the prognostic impact of MRD is unclear during second CR (CR2). To clarify the impact of MRD for both CR1 and CR2, we analyzed data from a registry database including 1625 adult patients with Ph+ ALL who underwent first allo-HCT during either CR1 or CR2 between 2002 and 2017. Adjusted overall and leukemia-free survival rates at 4 years were 71% and 64%, respectively, for patients undergoing allo-HCT during CR1 with MRD-, 55% and 43% during CR1 with MRD+, 51% and 49% during CR2 with MRD-, and 38% and 29% during CR2 with MRD+. Although survival rates were significantly better among patients with CR1 MRD- than among patients with CR2 MRD-, no significant difference was observed in survival rate between patients with CR1 MRD+ and CR2 MRD-. Relapse rates after 4 years were 16% in patients with CR1 MRD-, 29% in CR1 MRD+, 21% in patients with CR2 MRD-, and 46% in patients with CR2 MRD+. No significant difference was identified in relapse rate between patients with CR1 MRD- and CR2 MRD-. CR2 MRD- was not a significant risk factor for relapse in multivariate analysis (hazard ratio, 1.26; 95% confidence interval, 0.69-2.29; P = .45 vs CR1 MRD-). MRD at time of allo-HCT was an important risk factor in patients with Ph+ ALL during both CR1 and CR2.

A multicenter retrospective study was conducted to evaluate the clinical significance of preconditioning intervention (PCI) before allogeneic hematopoietic cell transplantation (HCT) in patients with acute myelogenous leukemia (AML) not in remission. The study cohort consisted of 519 patients classified according to the intensity (intensive/moderate) of PCI and their response to PCI. The group treated with PCI had higher blast counts in the peripheral blood (PB) and had a lower overall survival (OS) rate (P < .001) and higher nonrelapse mortality (NRM) rate (P = .035) compared with those without PCI (no PCI group). Approximately 40% of the patients (68 of 236) achieved a good response to PCI (good PCI group), and those patients had lower blast counts in the PB compared with the group with poor response to PCI (poor PCI group). OS in the good PCI group was comparable to that in the no PCI group and significantly better than that in the poor PCI group (hazard ratio, .54; 95% confidence interval, .39 to .77; P < .001). However, OS was significantly lower in patients with intensive/moderate PCI compared with the no PCI group. These results suggest that PCI increases NRM without decreasing the post-transplantation relapse rate, but may be beneficial for patients with lower blast counts in PB irrespective of its intensity.

Graft-versus-host disease is a major complication after allogeneic hematopoietic stem cell transplantation for hematological malignancies. Immunosuppressive drugs, such as anti-thymocyte globulin, alemtuzumab, and post-transplant cyclophosphamide, have been used to prevent graft-versus-host disease in HLA-mismatched haploidentical hematopoietic stem cell transplantation. Here, we investigated whether these drugs could ameliorate graft-versus-host disease without diminishing the graft-versus-leukemia effect by using a xenogeneic transplanted graft-versus-host disease/graft-versus-leukemia model. Anti-thymocyte globulin treatment diminished graft-versus-host disease symptoms, completely depleted the infiltration of inflammatory cells in the liver and intestine, and led to prolonged survival. By contrast, improvement after post-transplant cyclophosphamide treatment remained minimal. Alemtuzumab treatment modestly prolonged survival despite an apparent decrease of Tregs. In the graft-versus-leukemia model, 1.5 to 2.0 mg/kg of anti-thymocyte globulin and 0.6 to 0.9 mg/kg of alemtuzumab reduced graft-versus-host disease with minimal loss of graft-versus-leukemia effect. Mice treated with 400 mg/kg of post-transplant cyclophosphamide did not develop graft-versus-host disease or leukemia, but it was difficult to evaluate the graft-versus-leukemia effect due to the sensitivity of A20 cells to cyclophosphamide. Although the current settings provide narrow optimal therapeutic windows, further studies are warranted to maximize the benefits of each immunosuppressant.

BACKGROUND: Despite a strong association between acute graft-versus-host disease (GVHD) and cytomegalovirus reactivation (CMVR), the joint effect of acute GVHD and CMVR on nonrelapse mortality (NRM) has not been well studied. METHODS: We evaluated the impact of CMVR on NRM stratified according to the development of acute GVHD using a landmark method. This study included 6078 patients who received their first allogeneic hematopoietic cell transplantation (HCT) with a pre-emptive strategy for CMVR between 2008 and 2017. RESULTS: The cumulative incidences of grade II-IV acute GVHD (G24GVHD), CMVR by day 100, and CMV disease by day 365 were 37.3%, 52.1%, and 2.9%, respectively. Patients with G24GVHD were associated with the subsequent development of CMVR, and the presence of CMVR also increased the risk of G24GVHD. In a landmark analysis at day 65, the cumulative incidence of NRM at 1 year was 5.4%, 10.0%, 13.9%, and 19.7% in patients with G24GVHD-/CMVR-, G24GVHD-/CMVR+, G24GVHD+/CMVR-, and G24GVHD+/CMVR+, respectively. In a multivariate analysis, CMVR was respectively associated with an increased risk of NRM by day 365 in patients without G24GVHD (HR [hazard ratio], 1.59, 95% CI, 1.24-2.05, P < 0.001) and with G24GVHD (HR, 1.34, 95% CI, 1.06-1.70, P = 0.014), but the interaction between G24GVHD and CMVR was not significant (P = 0.326). Subgroup analyses suggested that the joint effect of acute GVHD and CMVR might vary according to the baseline characteristics. CONCLUSIONS: These data regarding the close relationship between acute GVHD and CMVR should provide important implications for the treatment strategy after HCT.

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.

BACKGROUND: We retrospectively evaluated the association between the D-index, which reflects both the depth and duration of neutropenia, and proven/probable invasive fungal disease (IFD) early after allogeneic hematopoietic stem cell transplantation (HSCT) at our center (n = 394). METHODS: The D-index was defined as the area over the neutrophil curve during neutropenia. The cumulative D-index from the start of neutropenia until the development of infection (c-D-index) was also evaluated as a real-time assessment of neutropenia. RESULTS: There were 19 cases of early proven/probable IFD before and within 1 week after engraftment. Fifteen cases (78.9%) were seen as breakthrough infection while on empiric (n = 7), preemptive (n = 4) or prophylactic (n = 4) antifungal administration with mold-active agents. The c-D-index and lower performance status were identified as independent significant predictive factors for IFD. A receiver operating characteristic (ROC) curve analysis showed that the D-index and c-D-index were more accurate than the simple duration of neutropenia and as accurate as the duration of profound neutropenia for predicting IFD. The sensitivity, specificity, and positive and negative predictive values of the c-D-index using an appropriate cutoff (CO) value (10 644) determined by ROC curve analysis were 73.1%, 63.2%, 9.1%, and 97.9%, respectively. The advantage of the c-D-index to cumulative days of neutropenia in terms of positive and negative predictive values seemed to be small. CONCLUSIONS: The appropriate CO value for the c-D-index for predicting IFD was as high as 10 644 in allogeneic HSCT with a more frequent use of empiric antifungal therapy. The c-D-index is useful for assessing the risk of breakthrough IFD.

The pulmonary function test (PFT) is an important test for risk stratification before allogeneic transplantation (allo-HCT). However, it might be preferable to avoid PFT as much as possible in the recent era of coronavirus disease 2019 (COVID-19), because PFT requires forced expirations and might produce aerosols, increasing the risk of COVID-19 transmission. Therefore, we tried to predict normal PFT results before allo-HCT based on computed tomography (CT) findings. This study included 390 allo-HCT recipients at our center for whom lung CT images and PFT results before allo-HCT were available. Abnormal CT findings were less likely to be observed in the normal PFT group (47.0% versus 67.4%, P = .015), with a high negative predictive value of 92.9%. In a multivariate analysis, normal CT was significantly associated with normal PFT (odds ratio, 2.47; 95% confidence interval, 1.22 to 4.97; P = .012). A model for predicting normal PFT was constructed based on the results of a multivariate analysis, and the area under the curve of the receiver operating characteristic analysis was 0.656, which gave a sensitivity of 45.5% and a specificity of 86.0%. The relatively high specificity of the model suggested that PFT can be omitted in patients with normal CT findings before allo-HCT.

Graft failure (GF) is a life-threatening complication after allogeneic stem cell transplantation (SCT). Although salvage SCTs can be performed with haploidentical donor (HID) or cord blood (CB), no study has compared the performances of these two sources. Using nationwide registration data, we compared the transplant outcomes of patients who developed GF and underwent salvage transplantation from HID (n = 129) and CB (n = 570) from 2007 to 2016. The HID group demonstrated better neutrophil recovery (79.7 vs. 52.5% at 30 days, P < 0.001). With a median follow-up of 3 years, both groups demonstrated similar overall survival (OS) and nonrelapse mortality (NRM; 1-year OS, 33.1 vs. 34.6% and 1-year NRM, 45.1 vs. 49.8% for the HID and CB groups). After adjustments for other covariates, OS did not differ in both groups. However, HID was associated with a lower NRM (hazard ratio, 0.71; P = 0.038) than CB. The incidence of acute graft-versus-host disease (GVHD)-related deaths was significantly higher in the HID group, although infection-related deaths were observed more frequently in the CB group. HID may be a promising salvage SCT option after GF due to its faster engraftment and low NRM.

The major limitation of cord blood transplantation (CBT) for adults remains the delayed hematopoietic recovery and higher incidence of graft failure, which result in a higher risk of early mortality in CBT. We evaluated early overall survival (OS), non-relapse mortality (NRM), neutrophil engraftment, acute graft-vs-host disease, and cause of early death among 9678 adult patients who received single-unit CBT in Japan between 1998 and 2017. The probability of OS at 100 days was 64.4%, 71.7%, and 78.9% for the periods 1998 to 2007, 2008 to 2012, and 2013 to 2017, respectively (P < .001). The cumulative incidences of NRM at 100 days during the same period were 28.3%, 20.8%, and 14.6%, respectively (P < .001). The cumulative incidences of neutrophil engraftment were also improved during the same period (P < .001). The most common cause of death within 100 days after CBT was bacterial infection in 1998 to 2007 and primary disease in the latter two time periods. Across the three time periods, the proportions of deaths from bacterial and fungal infection, graft failure, hemorrhage, sinusoidal obstructive syndrome, and organ failure decreased in a stepwise fashion. Landmark analysis of OS and NRM after 100 days showed that OS did not change over time in the multivariate analysis. Our registry-based data demonstrated a significant improvement of early OS after CBT for adults over the past 20 years. The landmark analysis suggested that improvement of early mortality could lead to an improvement of long-term OS after CBT.

Pulmonary complications are fatal adverse events after allogeneic hematopoietic cell transplantation (allo-HCT). On the other hand, smoking is a well-known risk factor for various pulmonary diseases and also increases the incidence of pulmonary complications and overall mortality in allo-HCT recipients. In this study, we retrospectively assessed the impact of smoking intensity on survival outcomes. This study included consecutive allo-HCT recipients at our center between June 2007 and May 2019 whose smoking profiles were available (n = 408); they were divided into high (pack-years >10, n = 171) and low (pack-years ≤10, n = 231) pack-years groups. In univariate analyses, nonrelapse mortality (NRM) and overall survival (OS) were significantly inferior in the high pack-years group (1-year NRM 26.6% versus 13.9%, P < .001; 1-year OS 58.4% versus 70.1%, P = .0067). However, this association was not observed in multivariate analyses. In subgroup analyses according to sex, the survival outcomes in the high pack-years group were significantly inferior in males (NRM hazard ratio [HR], 2.24 [95% confidence interval (CI), 1.23 to 4.07], P = .0082; OS HR, 1.54 [95% CI, 1.04 to 2.28], P = .031), but not in females (NRM HR, 0.587 [95% CI, 0.241 to 1.43], P = .24; OS HR, 0.689 [95% CI, 0.400 to 1.19], P = .18). In summary, high pack-years were associated with inferior survival of allo-HCT recipients, especially in males.

Natural killer (NK) cells expressing killer cell immunoglobulin-like receptors (KIRs) can recognize specific HLA class I molecules as their ligands. By studying a large Japanese transplant registry, we compared transplant outcomes between patients heterozygous for HLA-CAsn80/CLys80 (HLA-C1/C2) and those homozygous for HLA-C1 (HLA-C1/C1) among patients who had undergone HLA-matched hematopoietic stem cell transplantation (HSCT). A high frequency of KIR2DL1 with strong HLA-C2 binding capacity and a low frequency of HLA-C2 and KIR haplotype B are characteristic of the Japanese population. In our previous report, HLA-C1/C1 patients with myeloid leukemia were less likely to relapse than HLA-C1/C2 patients. We newly assessed 2884 patients with acute lymphoblastic leukemia (ALL) who received HLA-matched allogeneic HSCT and analyzed their leukemia relapses by using adjusted competing-risk methods. HLA-C1/C1 patients with ALL experienced significantly higher relapse rates than HLA-C1/C2 patients (hazard ratio [HR] = 1.55, P = .003), contrary to our results in patients with myeloid leukemia. We allocated patients with ALL to several subgroups and found a higher frequency of relapse (HR >1.8) in the HLA-C1/C1 group than in the HLA-C1/C2 group among patients with Ph-negative ALL, those who had no cytomegalovirus reactivation, those who received transplants from donors who were aged 41 years or older, and those who experienced acute graft-versus-host disease, especially if it required systemic treatment. One interpretation of our results is that KIR2DL1-positive NK cells disrupt T cells, antigen-presenting cells, or both from working efficiently in transplant immunity in HLA-C1/C1 patients with ALL. Another is that KIR2DS1-positive NK cells directly attack HLA-C2-positive ALL blasts in HLA-C1/C2 patients. Whether HLA-C2 can cause recurrence to decrease or increase in patients depending on the disease (ALL or myeloid leukemia) will be a very important finding. We hope that our results will provide clues to the real mechanisms behind relapse after transplantation in patients with different HLA profiles.

Some studies support the hypothesis that HLA genes and haplotypes evolved by natural selection through their protective abilities against specific infectious pathogens. However, very little is known regarding the impact of high-frequency HLA haplotypes on the risk of relevant infectious diseases among a given ethnic group. We evaluated the impact of high-frequency HLA haplotypes on cytomegalovirus (CMV) reactivation and infection in allogeneic hematopoietic stem cell transplantation (allo-HSCT) in a Japanese population as a model of infectious disease that has coexisted with humans. A total of 21,127 donor-patient pairs were analyzed. HLA-A-B-DRB1 haplotypes were estimated using the maximum probability algorithm. Seven haplotypes with >1% frequency were defined as high-frequency haplotypes (HfHPs). Homozygotes of HfHP and heterozygotes had significantly lower risk of CMV reactivation and infection (hazard ratio [HR] = 0.88, P = .009 and HR = 0.93, P = .003, respectively) than homozygotes of low-frequency HLA haplotypes (LfHPs). In subgroup analyses of a different donor source, these associations were statistically significant in unrelated donor transplants. Finally, CMV risk for homozygotes and heterozygotes of each HfHP was compared with that of homozygotes of LfHPs. The 2 most predominant HfHP groups (A*24:02-B*52:01-DRB1*15:02 group and A*24:02-B*07:02-DRB1*01:01 group) had a significantly lower risk of CMV reactivation and infection (HR = 0.86, P < .001 and HR = 0.91, P = .033, respectively). Our findings suggest that HfHPs may be protective against CMV reactivation and infection and that increased care regarding CMV reactivation and infection may be necessary for patients with LfHP after allo-HSCT.

The prognostic significance of FLT3-tyrosine kinase domain (TKD) mutations remains unknown. To investigate the prognostic impact of FLT3-TKD, 676 de novo acute myeloid leukemia (AML), we retrospectively analyzed cases and conducted a review of the literature. Of the 676 de novo AML cases, 34 (5.0%) were FLT3-TKD-positive; both FLT3-TKD and FLT3-ITD were noted in only two cases (0.3%). Although no significant differences in relapse-free survival (RFS) were noted, FLT3-TKD-positive cases showed better prognoses than FLT3-ITD-positive cases (FLT3-TKD versus FLT3-ITD, p = 0.152). For overall survival (OS), although FLT3-TKD-positive cases showed prognoses similar to those for FLT3-WT cases, their prognoses were significantly better than those of FLT3-ITD-positive cases (FLT3-TKD versus FLT3-ITD, p = 0.032). Moreover, the 5-year OS for FLT3-TKD-positive cases was 46.1%, indicating that this as an intermediate prognosis group. Although no reports from Asia have indicated a frequency of FLT3-TKD-positive cases > 10%, several reports from Europe and the United States have indicated frequencies > 10%. This suggests the possibility that FLT3-TKD-positive cases are less common in Asia than in Europe and the United States. We anticipate that in the future, the appearance of targeting agents, such as FLT3 inhibitors, will improve the prognosis of FLT3-TKD-positive AML relative to that of FLT3-WT AML.

To investigate optimal unit selection for umbilical cord blood transplantation (UCBT), we conducted a registry-based study of 1355 adults with acute myeloid leukemia in first or second complete remission who underwent single-unit UCBT. To be eligible for analysis, UCB units had to contain a total nucleated cell (TNC) dose of 2.0 × 107/kg or higher and present at least a 4/6-match for HLA-A, -B, and -DR antigens in line with clinical practice in Japan, both of which are less stringent criteria than those used in Western countries. Neither TNC dose nor the degree of HLA matching affected survival (P = 0.138 and P = 0.696, respectively). As for HLA-A, -B antigens and -DRB1 allele, better HLA matching was associated with lower non-relapse mortality (P = 0.011) but higher relapse (P = 0.046), resulting in no improvement in survival (P = 0.680). Taking the allele level for each HLA-A, -B, and -DRB1 into consideration was less useful for predicting non-relapse mortality (P = 0.198). These findings suggest that the less stringent criteria for UCB unit selection are acceptable for Japanese patient population and perhaps even more beneficial in terms of providing a better chance to find a suitable UCB unit.

Though second allogenic haematopoietic stem cell transplantation (HSCT) is considered a curative treatment option after myelodysplastic syndrome (MDS) relapse, scant epidemiological data are available. We investigated the outcomes and prognostic factors of second allogenic HSCT in 99 patients with MDS who relapsed after the first HSCT. The median age was 53 years (interquartile; 45-59) and 57 patients (57 center dot 6%) were male. Five-year overall survival was 25 center dot 3%. Early relapse (adjusted hazard ratio: 2 center dot 78, 95% confidence interval: 1 center dot 08-7 center dot 21, P = 0 center dot 035) and poor performance (3 center dot 03, 1 center dot 71-5 center dot 37, P < 0 center dot 001) were associated with a significantly poor 5-year overall survival compared to the other groups (P < 0 center dot 001).

Although human leukocyte antigen (HLA) mismatch is often thought to be associated with a high incidence of cytomegalovirus (CMV) reactivation, it is not clear whether this process is mediated by HLA mismatch or other factors, such as acute graft-versus-host disease (aGVHD). Here we focused on cord blood transplantation (CBT) and examined the effects of HLA mismatch on the incidence of CMV reactivation while minimizing the effects of aGVHD. In a multivariate analysis considering aGVHD as a time-dependent covariate, a significant effect on the incidence of CMV reactivation was noted for HLA disparity (hazard ratio [HR]: 0.54 for 8/8 match compared with 3-allele mismatch) and development of aGVHD (HR: 1.26). Next, in an analysis excluding cases that developed aGVHD, the incidences of CMV reactivation for 8/8 match and 1-allele mismatch were low compared with those for other mismatches. These findings were supported by the multivariate analysis (HR: 0.49 for 8/8 match and 0.64 for 1-allele mismatch compared with 3-allele mismatch). Together, these results suggested that HLA mismatch was involved in CMV reactivation and was associated with high morbidity of opportunistic infection after CBT.

We compared the effect of HLA single-antigen and single-allele mismatched unrelated bone marrow transplantation (UBMT) without in vivo/ex vivo T cell depletion. Becasue a single DRB1 mismatch is preferred among 1-allele or 1-antigen mismatched donors, we performed mismatched allele- or antigen-specific analyses with a single DRB1 mismatch as the reference. In adjusted comparison by multivariate analyses, an HLA-DRB1 single-allele mismatch resulted in a decreased risk of nonrelapse mortality (NRM; relative risk [RR], 1.33; 95% confidence interval [CI], 1.08 to 1.63, P = .006) compared with an HLA-DR single-antigen mismatch and conferred a decreased risk of NRM (RR, 1.25; 95% CI, 1.01 to 1.57; P = .025) and overall mortality (RR, 1.16; 95% CI, 1.00 to 1.37; P = .046) compared with an HLA-C single-antigen mismatch. Relative to an HLA-DRB1 single-allele mismatch, 2-mismatch transplants, including those with 1 or more antigen mismatches, resulted in a significantly increased risk of NRM (1-antigen/1-allele mismatch: RR, 1.68; 95% CI, 1.03 to 2.05; P < .001; 2-antigen mismatch: RR, 1.58; 95% CI, 1.04 to 2.02; P = .001) and overall mortality (1-antigen/1-allele mismatch: RR, 1.27; 95% CI, 1.09 to 1.47; P = .002; 2-antigen mismatch: RR, 1.27; 95% CI, 1.03 to 1.57; P = .02). NRM correlated with the combined number of mismatches and allele or antigen mismatches, with rates of 22%, 27%, 32%, 31%, and 38% at 4years for full match, single-allele mismatch, single-antigen mismatch, 2-allele mismatch, and 2 mismatches that included an antigen mismatch, respectively. Our results support the preference for an allele mismatch rather than an antigen mismatch in unrelated bone marrow donors with 1 DR mismatch or 2 mismatches for T cell-replete UBMT.

Antithymocyte globulin (ATG) is widely used to reduce acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD). To clarify the different impacts of ATG for conditioning across different donor types, we retrospectively analyzed patients with acute leukemia (n = 6617) who underwent hematopoietic stem cell transplantation between 2008 and 2015 with ATG (n = 279) or without ATG (n = 6338). Because thymoglobulin is the only ATG drug approved for GVHD prophylaxis in Japan since September 2008, we included thymoglobulin alone in the present analysis. The survivors' median follow-up time was 1081 days. Patients were categorized into 5 groups: cord blood (CB; n = 1915), matched related donor (n = 1772), 1-antigen mismatched related donor (1-MMRD; n = 225), matched unrelated donor (MUD; n = 1742), and 1-allele mismatched unrelated donor (1-MMUD; n = 963). In multivariate analysis, ATG decreased overall survival (hazard ratio [HR], 1.403; P = .054) and GVHD-free/relapse-free survival (GRFS) (HR, 1.458; P = .053) in association with increased nonrelapse mortality (NRM) (HR, 1.608; P =03) with CB, whereas it improved GRFS (HR, 0.515; P < .01) and decreased grades II to IV aGVHD (HR, 0.576; P < .01), extensive cGVHD (HR, 0.460; P = .02), and NRM (HR, 0.545; P = .03) with 1-MMUD. ATG did not impact survival with 1-MMRD and MUD. The use of ATG in conditioning is beneficial due to the reduction in acute/chronic GVHD without increasing NRM or disease relapse only in 1-MMUD transplantation. On the other hand, ATG is not recommended for CB transplantation.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare skin-tropic hematological malignancy of uncertain pathogenesis and poor prognosis. We examined 118 BPDCN cases for cytomorphology, MYC locus rearrangement, and MYC expression. Sixty-two (53%) and 41 (35%) cases showed the classic and immunoblastoid cytomorphology, respectively. Forty-one (38%) MYC+BPDCN (positive for rearrangement and expression) and 59 (54%) MYC-BPDCN (both negative) cases were identified. Immunoblastoid cytomorphology was significantly associated with MYC+BPDCN. All examined MYC+BPDCNs were negative for MYB/MYBL1 rearrangement (0/36). Clinically, MYC+BPDCN showed older onset, poorer outcome, and localized skin tumors more commonly than MYC-BPDCN. MYC was demonstrated by expression profiling as one of the clearest discriminators between CAL-1 (MYC+BPDCN) and PMDC05 (MYC-BPDCN) cell lines, and its shRNA knockdown suppressed CAL-1 viability. Inhibitors for bromodomain and extra-terminal protein (BETis), and aurora kinases (AKis) inhibited CAL-1 growth more effectively than PMDC05. We further showed that a BCL2 inhibitor was effective in both CAL-1 and PMDC05, indicating that this inhibitor can be used to treat MYC-BPDCN, to which BETis and AKis are probably less effective. Our data will provide a rationale for the development of new treatment strategies for patients with BPDCN, in accordance with precision medicine.

In the opinion of the European LeukemiaNet (ELN), nucleophosmin member 1 gene mutation (NPM1 mut)-positive acute myeloid leukemia (AML) with an fms-like kinase 3-internal tandem duplication (FLT3-ITD) allele ratio (AR) <0.5 (low AR) has a favorable prognosis, and allogeneic hematopoietic stem cell transplant (allo-HSCT) in the first complete remission (CR1) period is not actively recommended. We studied 147 patients with FLT3-ITD gene mutation-positive AML, dividing them into those with low AR and those with AR of ≥0.5 (high AR), and examined the prognostic impact according to allo-HSCT in CR1. Although FLT3-ITD AR and NPM1 mut are used in the prognostic stratification, we found that NPM1 mut-positive AML with FLT3-ITD low AR was not associated with favorable outcome (overall survival [OS], 41.3%). Moreover, patients in this group who underwent allo-HSCT in CR1 had a significantly more favorable outcome than those who did not (relapse-free survival [RFS] P = .013; OS P = .003). Multivariate analysis identified allo-HSCT in CR1 as the sole favorable prognostic factor (RFS P < .001; OS P < .001). The present study found that prognosis was unfavorable in NPM1 mut-positive AML with FLT3-ITD low AR when allo-HSCT was not carried out in CR1.

High-dose melphalan followed by autologous hematopoietic stem cell transplantation (ASCT) is a standard treatment for younger myeloma patients. However, the correlation between its toxicity and renal impairment is not clear. We analyzed this relationship, focusing on estimated glomerular filtration rate (eGFR) as an index of renal function. We evaluated 78 multiple myeloma patients who underwent ASCT following high-dose melphalan at our center. Patients were divided into a higher eGFR group (eGFR ≥ 60) and a lower eGFR group (eGFR < 60). Multivariate analyses revealed that lower eGFR was independently associated with alkaline phosphatase elevation (OR 10.2, P = 0.038), mucositis (OR 10.5, P = 0.032), grade 2-4 co-elevation of both aspartate aminotransferase and alanine aminotransferase (OR 21.3, P = 0.016), delay of reticulocyte engraftment (HR 0.524, P = 0.034), and delay of platelet engraftment (HR 0.535, P = 0.0016). However, lower eGFR was not correlated with overall survival or time-to-next treatment. In summary, renal dysfunction secondary to administration of high-dose melphalan was associated with increased hepatic and mucosal toxicity and delay of hematological recovery, but did not affect survival outcomes.

The optimal treatment strategy for gastrointestinal graft-versus-host disease (GI-GVHD) after allogeneic hematopoietic cell transplantation remains to be established. We retrospectively analyzed 68 cases of GI-GVHD at our institution between 2007 and 2017. The survival outcomes were significantly inferior in patients who did not respond to the first-line treatment (1-year overall survival 27.3 vs 69.2%, P = 0.0017; non-relapse mortality 50.0 vs 18.6%, P = 0.026). After subsequent treatments, 18 patients were refractory to all steroid-based treatments such as steroid pulse therapy and oral beclomethasone dipropionate (BDP). However, these steroid-refractory cases showed a gradual increase in the response rate after the initial diagnosis of steroid refractoriness. This result may be explained by the problem of evaluating the response based solely on the volume of diarrhea, i.e., severe mucosal damage due to refractory GI-GVHD may require a long recovery and sometimes be complicated with other diseases. In conclusion, patients with GI-GVHD who failed to respond to the first-line treatment had inferior survival. However, later improvement may be observed without additional immunosuppressant other than steroid among patients who initially do not respond to steroid therapy. It is important to repeat colonoscopy in patients with refractory GI-GVHD to monitor the activity of GVHD.

Autologous stem cell transplantation (ASCT) is a treatment option for HIV-positive patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). However, the prognosis after ASCT in HIV-positive Japanese patients remains unclear. The aim of this study was to evaluate the impact of HIV infection on transplant outcomes after ASCT in Japan. Using the national database of the Japan Society for Hematopoietic Cell Transplantation, we retrospectively evaluated patients with NHL (n = 3862) and MM (n = 2670) who underwent their first ASCT between 2001 and 2014. The presence of HIV antibody was used to diagnose HIV infection. Fifty-six patients with NHL (1.4%) and 23 with MM (.8%) were positive for HIV antibody. Among patients with NHL overall survival (OS) was lower in HIV-positive patients than in HIV-negative patients (5-year OS: HIV-positive patients, 44% versus HIV-negative patients, 65%; P < .001). In a multivariate analysis HIV infection was significantly associated with an increased risk of overall mortality (hazard ratio, 2.30; P < .001). The incidence of relapse was higher in HIV-positive patients (P = .036), whereas there was a similar incidence of nonrelapse mortality (P = .879). OS in patients with MM was similar between those with/without HIV infection (5-year OS: HIV-positive patients, 61% versus HIV-negative patients, 63%; P = .988). HIV infection was associated with a higher risk of overall mortality and relapse after ASCT for NHL in a Japanese population.

BACKGROUND: No standard method for measuring renal function has been established in allogeneic hematopoietic cell transplantation (allo-HCT). METHODS: We retrospectively analyzed 80 patients with hematological diseases who underwent allo-HCT at our center. We assessed renal function using creatinine clearance (Ccr), estimated glomerular filtration rate (eGFR) based on creatinine (eGFRcre), eGFR based on cystatin C (eGFRcys), and the average of eGFRcre and eGFRcys (eGFRave). We then evaluated the impact of pre-transplant renal function on the exacerbation of renal function and non-relapse mortality after transplantation. RESULTS: There was a significant correlation between Ccr and eGFRcre, eGFRcys, and eGFRave. eGFRave best predicted the exacerbation of renal function according to the area under the receiver-operating characteristic curve. The cumulative incidence of renal function exacerbation at 1 year was higher in the lower eGFRave group (<90 ml/min/1.73 m2) than in the higher eGFRave group (≥90 ml/min/1.73 m2; 0.85 vs. 0.39, p < 0.001), which was confirmed by a multivariate analysis (HR 2.75, p = 0.001). A lower eGFRave value was a marginally significant factor for non-relapse mortality (HR 3.29, p = 0.076). CONCLUSION: Among the four parameters, eGFRave best predicted the exacerbation of renal function in allo-HCT. Further, the marginal association between low eGFRave and high non-relapse mortality warrants further study in a prospective study in allo-HCT.

Abstract: The aim of this study was to assess the safety and optimal dose of deferasirox for the treatment of iron overload after allogeneic hematopoietic cell transplantation (HCT). The primary endpoint was the maximum tolerated dose of deferasirox that was determined by the intrapatient dose escalation methods. A total of 16 patients with post-HCT iron overload were enrolled in the study. After excluding one case of early relapse, 15 remained evaluable. Their median age was 42 years (range 22–68). Median time from HCT to deferasirox administration was 9 months (range 6–84). Deferasirox was started at a dose of 5 mg/kg, and the dose was increased to 7.5 and 10 mg/kg every 4 weeks unless there were no grade ≥ 2 of adverse events. Achievement rates of planned medication were 80% in 5 mg/kg (12 of 15), 73% in 7.5 mg/kg (11 of 15), and 60% in 10 mg/kg (9 of 15), respectively. The reasons for discontinuation of the drug were grade 2 of adverse events (n = 4), late relapse (n = 1), and self-cessation (n = 1). None of the patients developed grade ≥ 3 of adverse events or exacerbation of GVHD. Among 11 evaluable cases, mean value of ferritin decreased from 1560 ng/ml pre-treatment to 1285 ng/ml post-treatment. These data suggested that 10 mg/kg of deferasirox may be maximum tolerated dose when given after HCT. Our dose escalating method of deferasirox is useful to identify the optimal dosage of the drug in each patient.

Natural killer (NK) cells assume graft-versus-leukemia alloreactivity after hematopoietic stem cell transplantation (HSCT) through their inhibitory killer cell immunoglobulin-like receptors (KIRs). KIR2D family members recognize HLA-C alleles with Asn80 (HLA-C1) or Lys80 (HLA-C2). The predominance of HLA-C1 over HLA-C2 and the frequent presence of KIR2DL1 are characteristic of Japanese people. We compared clinical outcomes among homozygous HLA-C1 (HLA-C1/C1) patients and heterozygous HLA-C1/C2 patients who underwent HLA-matched HSCT for hematologic malignancies by assessing the data of 10,638 patients from the Japanese national registry. HLA-C1/C1 recipients had a lower rate of relapse than HLA-C1/C2 recipients after transplantation for acute myelogenous leukemia (AML) (hazard ratio [HR],.79 P =.006) and chronic myelogenous leukemia (CML) (HR,.48 P =.025), but not for acute lymphoblastic leukemia (HR, 1.36), lymphoma (HR,.97), or low-grade myelodysplastic syndrome (HR, 1.40). We then grouped AML and CML patients together and divided them into several subgroups. Advantages of HLA-C1/C1 recipients over HLA-C1/C2 recipients regarding relapse were observed irrespective of donor relation (related: HR,.79, P =.069 unrelated: HR,.77, P =.022), preparative regimen (myeloablative: HR,.79, P =.014 reduced intensity: HR,.73, P =.084), and occurrence of acute graft-versus-host disease (yes: HR,.70, P =.122 no, HR.71, P =.026) or cytomegalovirus reactivation (reactivated: HR.67,P =.054 nonreactivated: HR.71, P =.033) however, these advantages were not observed in recipients with a delay in achieving complete chimerism (HR, 1.06). The advantage of decreasing relapse and extending relapse-free survival of C1/1 over C1/2 KIR-ligand status was most pronounced in T cell-depleted HSCT (HR,.27 P &lt .001 and HR,.30 P =.002, respectively) and in children age &lt 15 years (HR,.29 P &lt .001 and HR.31 P &lt .001, respectively). Our findings represent an important mechanism responsible for the immunity against HLA-C2–negative myeloid leukemia cells after HLA-matched transplantation.

BACKGROUND: Consensus has yet to be reached regarding secondary prophylaxis in allogeneic hematopoietic stem cell transplantation (HSCT) with a complete resolution of invasive aspergillosis (IA) confirmed by chest computed tomography (CT). METHODS: We retrospectively evaluated the feasibility of antifungal prophylaxis with fluconazole in allogeneic HSCT recipients who had previously developed IA which showed complete resolution as confirmed by chest CT before HSCT. Consecutive adult patients who underwent allogeneic HSCT at our institution and who had received fluconazole as systemic antifungal prophylaxis from June 2007 to January 2015 were included. We compared the clinical outcomes between patients with a past history of IA who showed a complete resolution of chest CT abnormalities (n = 13) and those without a previous history of IA (n = 137). RESULTS: The cumulative incidence of proven or probable IA was 8.8% in the group without a past history of IA and 0.0% in the group with a past history of IA (p = .268). The cumulative incidence of proven or probable invasive fungal disease (IFD) within 100 days after allogeneic HSCT was 10.9% in the group without a past history of IA and 15.4% in the group with a past history of IA (p = .647). Fluconazole was switched to anti-mould agents in two-thirds of the patients in each group by day 100 after HSCT. CONCLUSIONS: Fluconazole was confirmed to be an acceptable prophylactic agent early after allogeneic HSCT in appropriately selected patients.

Delayed platelet recovery (DPR) despite prompt neutrophil engraftment is frequently observed after allogeneic hematopoietic stem cell transplantation (HSCT). However, few studies have evaluated the risk factors and long-term outcome. Therefore, we retrospectively analysed 219 adult patients who underwent their first allogenic HSCT with neutrophil engraftment. Of these 219 patients, 50 (22.8%) had DPR that was defined as relapse-free survival at day 60 after HSCT without primary platelet recovery despite neutrophil engraftment. The results of a multivariate analysis showed that a high-risk underlying disease (odds ratio [OR], 2.38; 95% confidence interval [CI], 1.04-5.48; P = .041) and human leukocyte antigen-mismatched HSCT (OR, 2.63; 95% CI, 1.28-5.43; P = .009) were associated with an increased risk of DPR. In univariate analyses, the occurrence of DPR was significantly associated with inferior overall survival, high nonrelapse mortality, and a low incidence of chronic graft-versus-host disease (GVHD), despite a comparable relapse rate. In multivariate analyses, DPR was associated with inferior overall survival (hazard ratio [HR], 2.00; 95% CI, 1.23-3.27; P = .005) and a low incidence of chronic GVHD (HR, 0.42; 95% CI, 0.22-0.78; P = .002). In conclusion, DPR was a strong predictor of shorter survival but also less frequent chronic GVHD.

Donor-derived malignancy is a rare morbidity after allogeneic hematopoietic stem cell transplantation (HSCT), in which most previous cases have presented as acute leukemia or myelodysplastic syndrome. There have, however, been very few reports of donor-derived lymphoma. Here, we present a case of donor-derived mantle cell lymphoma 12 years after allogeneic HSCT, which was successfully treated with chemotherapy followed by pseudo-autologous HSCT (pASCT), i.e., an autologous HSC transplant following allogeneic HSCT in which the infused stem cell is considered to be derived from the donor cells. Although pASCT carries the risk of graft-versus-host disease (GVHD) due to the reinfusion of donor-derived peripheral blood cells, the present case did not develop GVHD without prophylaxis. The current case and a small number of previous reports suggest that the duration between allogeneic HSCT and pASCT may be important to the induction of immune tolerance, but further study in a larger number of cases is needed.

We hypothesized that systemic corticosteroid administration would be safely avoided not only in grade I acute graft-versus-host disease (GVHD) but also in selected patients with grade II acute GVHD limited to the skin (grade IIs GVHD). We retrospectively evaluated risk factors for subsequent GVHD progression, defined as the involvement of other organs or progression to grade III to IV GVHD, in 50 patients with acute GVHD of grade IIs at its onset. Sixteen patients received systemic corticosteroid administration before GVHD progression. The cumulative incidence of GVHD progression at 28 days from the onset of grade IIs GVHD was 24%. Twenty-five patients did not require systemic corticosteroid administration throughout the entire episode of acute GVHD. Systemic corticosteroid administration before GVHD progression did not affect GVHD progression, chronic GVHD, or non-relapse mortality. Early onset (less than 26 days from transplantation) of grade IIs GVHD was identified as the only statistically significant risk factor for GVHD progression (hazard ratio 6.73, 95% confidence interval 1.5-31.1, P = 0.01). In conclusion, avoiding systemic corticosteroid administration for selected patients with grade IIs GVHD before GVHD progression did not compromise the transplantation outcomes. Patients with early-onset grade IIs GVHD were at high risk for GVHD progression.

Knowing the impact of chronic graft-versus-host disease (GVHD) on quality of life (QoL) after allogeneic hematopoietic stem cell transplantation (allo-HCT) by GVHD type and severity is critical for providing care to transplant survivors. We conducted a cross-sectional questionnaire study to examine the relationship between patient reported QoL as measured by the Medical Outcomes Study 36-Item Short-Form Health Survey, Functional Assessment of Cancer Therapy-Bone Marrow Transplant, and visual analogue scale (VAS) and chronic GVHD defined by the National Institutes of Health (NIH) criteria. Recipients of allo-HCT for hematologic disease between 1995 and 2009 aged 16 years at transplant and &gt;= 20 years at the time of the survey who were relapse-free were eligible. A total of 1140 pairs of patient and physician questionnaires were included in the analysis. By NIH global severity score, QoL scores in all aspects were significantly lower in patients with higher global and organ-specific severity grades, independent of background variables. Compared with patients without GVHD symptoms, those with mild symptoms had impaired physical and general QoL according to global severity score and organ-specific scores except for the genital tract. Mild symptoms in the lungs, gastrointestinal tract, and joints and fascia were associated with clinically meaningful deterioration of physical QoL. VAS scores provided by physicians were generally higher than those provided by patients. Differences between scores reported by patients and physicians were larger for patients with no or mild GVHD symptoms. Our findings based on more than 1000 long-term survivors after HCT enabled us to identify a target of care, informing survivorship care protocols to improve post-transplantation QoL. (C) 2017 American Society for Blood and Marrow Transplantation.

HLA 1-locus-mismatched unrelated donors (1MMUD) have been used in allogeneic hematopoietic stem cell transplantation (allo-HCT) for patients who lack an HLA-matched donor. We retrospectively analyzed 3313 patients with acute leukemia or myelodysplastic syndrome who underwent bone marrow transplantation from an HLA allele-matched unrelated donor (MUD) or 1MMUD between 2009 and 2014. We compared the outcomes of MUD (n = 2089) and 1MMUD with antithymocyte globulin (ATG) (1MM-ATG(+); n= 109) with those of 1MMUD without ATG (1MM-ATG(-); n = 1115). The median total dose of ATG (thymoglobulin) was 2.5 mg/kg (range 1.0-11.0 mg/kg) in the 1MM-ATG(+) group. The rates of grade III-IV acute GvHD, non-relapse mortality (NRM) and overall mortality were significantly lower in the MUD group than in the 1MM-ATG(-) group (hazard ratio (HR) 0.77, P = 0.016; HR 0.74; P &lt; 0.001; and HR 0.87, P = 0.020, respectively). Likewise, the rates of grade III-IV acute GVHD, NRM and overall mortality were significantly lower in the 1MM-ATG(+) group than in the 1MM-ATG(-) group (HR 0.42, P = 0.035; HR 0.35, P &lt; 0.001; and HR 0.71, P = 0.042, respectively). The outcome of allo-HCT from 1MM-ATG(-) was inferior to that of allo-HCT from MUD even in the recent cohort. However, the negative impact of 1MMUD disappeared with the use of low-dose ATG without increasing the risk of relapse.

Aldehyde dehydrogenase 2 (ALDH2) is involved in critically important biological processes, such as the metabolism of aldehydes and aldehyde-induced genotoxicity in hematopoietic stem cells. Given its role in these biological processes, we hypothesized that a functional ALDH2 polymorphism could affect transplantation outcomes after hematopoietic stem cell transplantation. Here, we analyzed the Japanese national registry data for 409 patients who underwent allogeneic bone marrow transplantation (BMT) from HLA-matched unrelated donors. To evaluate the impact of the recipient and donor ALDH2 polymorphism on transplantation outcomes, we estimated hazard ratios (HRs) and 95% confidence intervals (Cls).adjusted for potential confounders. The recipient ALDH2 Lys/Lys genotype was significantly associated with higher transplantation related mortality (TRM), with an HR relative to Glu/Glu genotype of 2.45 (95% CI, 1.22 to 4.90). The recipient Lys/Lys genotype also tended to be associated with delayed platelet engraftment (HR,.66; 95% CI,.43 to 1.03). In conclusion, we observed increased TRM among recipients with the ALDH2 Lys/Lys genotype in HLA fully matched BMT. We also observed a suggestive association with delayed platelet engraftment, which warrants further examination. These results may suggest that the recipient ALDH2 genotype affects the metabolism of endogenous aldehydes, leading to a significant impact on transplantation outcomes. (C) 2017 American Society for Blood and Marrow Transplantation.

ClinicalTrials.gov Identifier: NCT01903928.

The impact of HLA mismatch in hematopoietic stem cell transplantation with reduced-intensity conditioning (RIC) has not been fully examined. We analyzed a total of 1130 cases to examine the effects of HLA allele mismatch in unrelated bone marrow transplantation (BMT) with RIC in the Japan Marrow Donor Program registry cohort. Compared with HLA 8/8–allele match (n = 720, 8/8 match), both 1 (n = 295, 7/8 match) and 2 allele mismatches (n = 115, 6/8 match) were associated with significant reduction of overall survival (OS) (hazard ratio [HR],  1.34; P = .0024 and HR, 1.33; P = .035 for 7/8 and 6/8 match, respectively). The incidence of grades 2 to 4 acute graft-versus-host disease (aGVHD) increased with increasing number of mismatched alleles (HR, 1.36 and HR, 2.08 for 7/8 and 6/8 match, respectively). Nonrelapse mortality showed a similar tendency to aGVHD (HR, 1.35 for 7/8 and HR, 1.63 for 6/8). One-allele mismatches at the HLA-A or -B and HLA-C loci were significantly associated with inferior OS compared with 8/8 match (HR, 1.64 for A or B mismatch and HR, 1.41 for C mismatch), whereas HLA-DRB1 allele mismatch was not (HR, 1.16; P = .30). However, the effect of HLA-A or -B and -C mismatch on OS was not observed in those who received RIC BMT since 2010, in contrast to recipients before 2010. These results suggested that in unrelated RIC BMT, 1-allele mismatch is associated with poorer outcome, and the impact of HLA mismatch may differ depending on the HLA locus, although these HLA mismatch effects may be different in recent cases.

Earlier reports suggested that umbilical cord blood transplantation (UCBT) for aplastic anemia (AA) was feasible in alternative transplantation. To identify differences in outcomes of UCBT and HLA-matched or mismatched unrelated bone marrow transplantation (UBMT) in adults with AA, we analyzed registry data of the Japan Society for Hematopoietic Cell Transplantation and compared results of UCBT (n = 69) to 8/8-matched (n = 101), 7/8 matched (n = 65), or 6/8-matched (n = 37) UBMT. The transplantation period was from 2002 to 2012, and patients 16 years or older with AA were eligible. Median ages were 49, 35, 28, and 30 years for UCBT, 8/8-matched, 7/8-matched, and 6/8-matched UBMT, respectively. In multivariate analysis, risk of mortality was lower for 8/8-matched UBMT compared with that of UCBT (hazard ratio pin.55; 95% confidence interval [CI],.32 to.94; P=.029), adjusted for age and graft-versus-host disease (GVHD) prophylaxis, which were other associated factors. Mortality risks of 7/8-matched UBMT (HR,.55; 95% CI,.29 to 1.02) or 6/8-matched UBMT (HR,.67; 95% CI,.32 to 1.39) were not significantly different from those of UCBT. Risks of grade 3 or 4 acute and chronic GVHD were not different among the 4 groups. The most prevalent cause of death was graft failure in UCBT and 6/8-matched UBMT and infection in 8/8-matched and 7/8-matched UBMT. Under 40 years old, survival of UCBT was similar to that of UBMT (76%, 79%, 83%, and 83% for UCBT and 8/8-matched, 7/8-matched, and 6/8-matched UBMT, respectively, at 3 years), adjusted for transplantation period, which was another associated factor; however, for ages over 40 years, that of UCBT tended to be lower (47%, 64%, 64%, and 75% for UCBT, 8/8-matched, 7/8-matched, and 6/8-matched UBMT, respectively, at 3 years). To conclude, these data suggest that UCBT could be an alternative treatment option for younger adults when matched sibling or adequate UBMT donors are not available. (C) 2016 American Society for Blood and Marrow Transplantation.

Hepatic acute GvHD (aGvHD) is associated with high mortality owing to poor response to immunosuppressive therapy. The pathogenesis of hepatic aGvHD differs from that of other lesions, and specific risk factors related to pre-transplant liver conditions should be determined. We conducted a cohort study by using a Japanese transplant registry database (N=8378). Of these subjects, 1.5% had hepatitis C virus Ab (HCV-Ab) and 9.4% had liver dysfunction (elevated transaminase or bilirubin levels) before hematopoietic cell transplantation (HCT). After Ha, the cumulative incidence of hepatic aGvHD was 6.7%. On multivariate analyses, HCV-Ab positivity (hazard ratio (HR), 1.93; P=0.02) and pre-transplant liver dysfunction (HR, 1.85; P&lt;0.01), as well as advanced HCT risk, unrelated donors, HLA mismatch and cyclosporine as GvHD prophylaxis, were significant risk factors for hepatic aGvHD, whereas hepatitis B virus surface Ag was not. Hepatic aGvHD was a significant risk factor for low overall survival and high transplant-related mortality in all aGvHD grades (P &lt; 0.01). This study is the first to show the relationship between pre-transplant liver conditions and hepatic aGvHD. A prospective study is awaited to validate the results of this study and establish a new strategy especially for high-risk patients.

Objective: The purpose of this study was to review the high-resolution computed tomography (CT) findings in patients with pulmonary complications after allogeneic hematopoietic stem cell transplantation (HSCT), and to evaluate the relationship between CT findings and clinical outcomes. Patients and methods: We collected the clinical data in 96 consecutive patients who underwent CT scan for pulmonary complications after allogeneic HSCT and analyzed the relationships among these clinical characteristics, CT findings and clinical responses. Radiologists who were blinded to clinical information evaluated the CT findings. Results: In multivariate analyses, the presence of chronic graft-versus-host disease (GVHD) and nonsegmental multiple consolidations were significantly associated with a poor response to antimicrobial therapies, and the disease risk was significantly associated with a poor corticosteroid response. In addition, the existence of cavity formation and pleural effusion were significantly associated with a fatal prognosis. Twenty-five patients underwent bronchoscopic examination and 4 of them also underwent transbronchial lung biopsy (TBLB), but diagnostic information was not obtained in 15 patients. There was no significant association between specific CT findings and the diagnosis based on bronchoscopic examination. Conclusions: No specific CT finding was identified as a predictor for either an antimicrobial response or for a corticosteroid response in this study. The presence of cavity formation and pleural effusion may predict a poor prognosis. (C) 2015 Elsevier Ireland Ltd. All rights reserved.