神田 善伸

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 >= 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 < 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 < 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<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 < 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.

Limited data are available on prophylaxis for herpes simplex virus (HSV) and varicella zoster virus (VZV) disease following autologous hematopoietic stem cell transplantation (auto-HCT). We retrospectively reviewed the clinical charts of 105 consecutive patients who underwent their first auto-HCT at our institution between September 2007 and June 2014. Before August 2009, 30 patients received oral acyclovir at 1000 mg/day until engraftment, whereas after September 2009, 69 patients received oral acyclovir at 200 mg/day. After engraftment, acyclovir was continued at 200 mg/day at the discretion of the attending physicians in both groups. The cumulative incidence of HSV disease at 1 year after auto-HCT was 7.7 and 4.5 % in patients who received oral acyclovir at 1000 and 200 mg/day, respectively (P = 0.75). Patients were next divided into three groups according to the timing at which acyclovir prophylaxis was stopped after auto-HCT; at engraftment, between engraftment and 1 year after auto-HCT, and later than 1 year. The cumulative incidence of VZV disease was 25.8, 7.7, and 0.0 % at 1 year, respectively. This study suggests that low-dose acyclovir prophylaxis may be effective for preventing HSV and VZV disease after auto-HCT. Our findings support the recommendation of acyclovir prophylaxis within the first year after auto-HCT.

Objectives: Limited data are available on the effect of how cyclophosphamide (CY) and total body irradiation (TBI) are administered. We analyzed the effect of the interval from TBI to hematopoietic stem cell transplantation (HSCT) on the outcome of HSCT. Methods: Adult patients who underwent HSCT using myeloablative conditioning consisting of TBI and CY were retrospectively analyzed. They were divided into three groups according to the duration between the start of TBI and HSCT (Group A: 2-4 days, Group B: 5-8 days, Group C: 9-10 days). Results: Seventy-five adult patients were included. The 3-year overall survival rate was 56, 47, and 77% in Groups A, B, and C, respectively (P = 0.14). Similarly, there was no significant difference among the three groups with respect to progression-free survival (57, 47, and 72%, P = 0.17), relapse rate (32, 37, and 16%, P = 0.29), or non-relapse mortality (8, 14, and 12%, P = 0.81). In addition, we observed no significant difference among the three groups with respect to the incidence of grade II-IV acute graftversus- host disease (GVHD) (31, 47, and 32%, respectively, P = 0.56) and that of chronic GVHD (23, 23, and 22%, respectively, P = 0.97). Discussion and conclusion: Although recipient immune system at HSCT might be affected by the timing of TBI, the duration between the start of TBI and HSCT did not influence the outcome of HSCT using myeloablative conditioning with TBI and CY.

Objectives: We evaluated the incidence of and risk factors for false-positive Aspergillus galactomannan (GM) antigenemia in allogeneic hematopoietic stem cell transplantation (HSCT). We also focused on the GM index value and its kinetics. Methods: Patients who underwent their first allogeneic HSCT at our center between June 2007 and December 2012 were included (n = 172). Episodes of positive GM tests were classified as either "true-positive", which fulfilled the EORTC criteria for proven or probable invasive aspergillosis (IA), or "false-positive", which was not accompanied by clinical findings. The remaining cases were regarded as "inconclusive". Results: The one-year cumulative incidences of IA and positive GM tests were 10.1% and 48.1%, respectively. Among 148 episodes of positive GM tests, 97(65.5%), 23(15.5%), and 28(19.0%) were classified as false-positive, true-positive and inconclusive, respectively. In the first episodes of positive GM tests in each patient (false-positive = 67, others = 30), an increase in the GM value in the first two measurements, neutropenia, and use of anti-mold agents at positive GM episode were associated with a significantly lower possibility of false-positive results according to a multivariate analysis. Conclusions: A false-positive GM test was frequently seen after allogeneic HSCT. An increase in the GM value may increase its positive predictive value. (C) 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Background: Previous studies have shown that most patients lose immunity to measles, mumps, and rubella (MMR) during long-term follow-up after allogeneic hematopoietic stem cell transplantation (HSCT), and immunizations against them have been investigated. However, these previous studies mainly targeted pediatric patients and information in adult patients is still insufficient. Methods: We evaluated the immunity to MMR in 45 adult allogeneic HSCT patients. None of these patients received vaccination after HSCT. Results: The seropositive rates at six years after allogeneic HSCT were estimated to be less than 44% for measles, less than 10% for mumps, and less than 36% for rubella. Thirteen of the 16 female patients who were 16-39 years old were negative or equivocal for rubella. Patients who developed grade II-IV acute graft-versus-host disease tended to become seronegative for measles and rubella at two years after HSCT, although the difference was not statistically significant. Conclusions: This study showed that most adult patients lost immunity to MMR after allogeneic HSCT. Although we did not evaluate the safety and efficacy of vaccination in this study, most HSCT guidelines recommend vaccination for HSCT recipients without active chronic graft-versus-host disease or ongoing immunosuppressive therapy at 24 months after HSCT. Immunization against rubella is especially important for female patients of reproductive age. Further studies will be necessary to evaluate the effect of vaccination on the antibody response in adult allogeneic HSCT recipients.

The relative desirability of an unrelated donor with a bidirectional 1-locus mismatch (1MM-Bi), a 1-locus mismatch only in the graft-versus-host direction (1MM-GVH), or a 1-locus mismatch only in the host-versus-graft direction (1MM-HVG) is not yet clear. We analyzed adult patients with leukemia or myelodys-plastic syndrome who received a first allogeneic stem cell transplant from an HLA-A, -B, -C, and -DRB1 matched or 1-allele mismatched unrelated donor in Japan. The effects of 1MM-Bi (n = 1020), 1MM-GVH (n = 83), and 1MM-HVG (n = 83) compared with a zero mismatch (0MM) (n = 2570) were analyzed after adjusting for other significant variables. The risk of grades III to IV acute graft-versus-host disease (GVHD) was higher with marginal significance in the 1MM-GVH group than in the 0MM group (hazard ratio, 1.85; P = .014). However, there was no significant difference in overall or nonrelapse mortality between the 1MM-GVH and 0MM groups. There was no significant difference in acute GVHD or overall or nonrelapse mortality between the 1MM-HVG and 0MM groups. The risks of acute GVHD and overall mortality were significantly higher in the 1MM-Bi group than in the 0MM group. These findings indicate that unrelated donors with 1MM-GVH and 1MM-HVG are both good candidates for patients without an HLA-matched unrelated donor in a Japanese cohort. (C) 2015 American Society for Blood and Marrow Transplantation.

Elderly patients with non-Hodgkin lymphoma (NHL) have a poor prognosis. Owing to treatment-related toxicities, there is no standard chemotherapy for the elderly patients, especially those aged 70 years or older. In this study, we retrospectively evaluated the efficacy and toxicity of reduced-dose (two-thirds) R-CHOP chemotherapy as an initial chemotherapy for 45 patients aged 70 years or older with B-cell NHL. The WHO classification of NHL included diffuse large B-cell lymphoma (DLBCL) (31), mantle cell lymphoma (5), follicular lymphoma (4), extranodal marginal zone lymphoma (1), Burkitt lymphoma (1), and B-cell lymphoma whose further types were unclassified (3). The incidences of grade 4 neutropenia and febrile neutropenia (FN) were 51.1 and 15.6%, respectively. Efficacy was evaluated in patients with DLBCL. The overall and complete response (CR) rates were 96.7 and 90.0%, respectively. Two-year event-free survival (EFS) and overall survival (OS) were 84.4 and 89.2%, respectively. There was no treatment-related mortality. In conclusion, two-thirds R-CHOP chemotherapy is a promising treatment for elderly patients with B-cell NHL in terms of its efficacy and toxicity.

Risk of relapse during the unrelated donor coordination period biases comparisons between allogeneic hematopoietic stem cell transplantation from an HLA 8 of 8 allele-matched unrelated donor (8/8 MUD) and that from a related donor with an HLA-1 antigen mismatch in the graft-versus-host (GVH) direction (RD/1AGMM-GVH). To reduce this bias, we performed a decision analysis focusing on acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in first complete remission (CR1). The primary outcome measure was 5-year survival probability with or without quality-of-life (QOL) adjustment. A baseline analysis showed that the decision to perform MUD transplantation was superior to that to perform RD/1AGMM-GVH transplantation for patients with AML or ALL. However, in the ALL cohort, the direction of superiority was reversed when the interval between CR1 and 8/8 MUD transplantation was >5.5 months (without QOL adjustment) or >6 months (after QOL adjustment) or when overall survival of RD/1AGMM-GVH transplantation improved by 1.3% without QOL adjustment and 2.1% after QOL adjustment. In conclusion, 8/8 MUD should be prioritized in transplantation for AML and ALL in CR1. However, the MUD coordination period and improvements in RD/1AGMM-GVH transplantation might change the donor selection priority in transplantation for ALL in CR1.

In unrelated hematopoietic SCT (HSCT), HLA allele mismatch has been shown to have a significant role. To clarify the importance of HLA allele mismatch in the GVH direction in related HSCT, we retrospectively evaluated 2377 patients who received stem cells from an HLA serologically matched related donor in the GVH direction using the database of the Japan Society for Hematopoietic Cell Transplantation. The cumulative incidences of grade II-IV and grade III-IV acute GVHD in patients with an HLA allele-mismatched donor (n = 133, 5.6%) were significantly higher than those in patients with an HLA allele-matched donor. Multivariate analyses showed that the presence of HLA allele mismatch was associated with increased risks of grade II-IV and grade III-IV acute GVHD. In particular, HLA-B mismatch and multiple allele mismatches were associated with an increased risk of acute GVHD. The presence of HLA allele mismatch was associated with an inferior OS owing to an increased risk of non-relapse mortality (NRM). In conclusion, the presence of HLA allele mismatch in the GVH direction in related HSCT was associated with increased risks of GVHD and NRM, which led to an inferior OS. HLA allele typing is recommended in related HSCT.

Several high-risk HLA allele mismatch combinations (HR-MMs) for severe acute graft-versus-host disease (GVHD) have been identified by analyzing transplantation outcomes in Japanese unrelated hematopoietic stem cell transplant recipients. In this study, we analyzed the effects of HR-MMs in 3 transplantation time periods. We confirmed that the incidence of grade III to IV acute GVHD in the HR-MM group was significantly higher than that in the low-risk (LR) MM group (hazard ratio [HR], 2.74; P < .0001) in the early time period (1993 to 2001). However, the difference in the incidence of grade III to IV acute GVHD between the HR-MM and LR-MM groups was not statistically significant (HR, 1.06; P =.85 and HR,.40; P =.21, respectively) in the mid (2002 to 2007) and late (2008 to 2011) time periods. Similarly, survival in the HR-MM group was significantly inferior to that in the LR-MM group (HR, 1.46; P =.019) in the early time period, whereas the difference in survival between the 2 groups was not statistically significant in the mid and late time periods (HR, 1.06; P =.75 and HR,.82; P =.58, respectively). In conclusion, the adverse impact of HR-MM has become less significant over time. Unrelated transplantation with a single HR-MM could be a viable option in the absence of a matched unrelated donor or an unrelated donor with a single LR-MM. (C) 2014 American Society for Blood and Marrow Transplantation.

Varicella-zoster virus (VZV) reactivation is a frequent complication after allogeneic hematopoietic stem cell transplantation (HSCT). Although previous studies have revealed that cellular immunity is important for suppressing reactivation, the role of humoral immunity against VZV has been poorly evaluated. We analyzed inherited polymorphisms in the immunoglobulin G (IgG) heavy chain constant regions of 50 HSCT recipient-donor pairs to distinguish donor-derived and recipient-derived antibodies. Twelve pairs were informative regarding the origin of IgG, since either the donors (n = 3) or recipients (n = 9) were homozygous null for the IgG1m(f) allotype. In these 9 homozygous-null recipients, allotype-specific IgG against VZV were measured by enzyme-linked immunosorbent assay and compared with measles-IgG. All 9 homozygous-null recipients were monitored for more than 1 year after HSCT, with (n = 4, localized zoster) or without (n = 5) clinical VZV disease. In 3 patients with VZV disease, donor-derived IgG against VZV was elevated between 500 to 700 days after HSCT after the episode of VZV disease. In 1 patient who suffered from VZV disease just before HSCT, donor-derived VZV IgG was elevated within 3 months after HSCT. On the other hand, 2 patients who received reduced-intensity conditioning (RIC) transplantation from an IgG1m(f) null donor maintained recipient-derived IgG against VZV for more than 1 year, whereas it was decreased within 3 months in 1 recipient who received conventional conditioning. In conclusion, the production of anti-VZV IgG by recipient plasma cells persists long after RIC. In patients without symptomatic VZV reactivation, donor-derived anti-VZV IgG did not reach titers comparable to those measured in healthy virus carriers. (C) 2013 American Society for Blood and Marrow Transplantation.

Recent advances in unrelated cord blood transplantation have increased chances and options available in allogeneic stem cell transplantation. The effect of HLA disparity on outcomes after cord blood transplantation was studied recently in mainly pediatric populations. Results showed that HLA matching in combination with total nucleated cell dose positively affects survival. The effect of HLA disparity after single-unit cord blood transplantation may be different in adults because their total nucleated cell dose is much lower compared to pediatric patients. We investigated the effect of HLA disparity on the outcome of single-unit unrelated cord blood transplantation separately in 498 children aged 15 years or under (HLA-A, HLA-B low-resolution, and HLA-DRB1 high-resolution matched [6/6], n=82, and one locus- [5/6], n=222, two loci- [4/6], n=158, three loci- [3/6] mismatched, n=36) and 1,880 adults (6/6, n=71; 5/6, n=309; 4/6, n=1,025; 3/6, n=475) with leukemia. With adjusted analyses, in children, 4/6 showed significantly increased risks of overall mortality (relative risk [RR]=1.61, P=0.042) and transplant-related mortality (RR=3.55, P=0.005) compared to 6/6. The risk of grade 2 to 4 acute GVHD was increased in 5/6 (RR=2.13, P=0.004) and 4/6 (RR=2.65, P<0.001). In adults, the risk of mortality did not increase with the number of mismatched loci (RR=0.99, P=0.944 for 5/6; RR=0.88, P=0.436 for 4/6). The risk of relapse was significantly decreased in 4/6 (RR=0.67, P=0.034). The risk of transplant-related mortality (TRM) or acute GVHD was not increased in 5/6 or 4/6. The effect of HLA disparity on transplant outcome differed between children and adults. In children, an increased number of mismatched HLA loci correlated with an increased risk of mortality. In adults, there was no increase in mortality with an increase in the number of mismatched HLA loci.

The impact of the direction of HLA mismatch (MM) on outcome in unrelated cord blood (UCB) transplantation has not yet been clarified. We conducted a retrospective study using national registry data on 2977 patients who underwent transplantation using a single UCB for leukemia or myelodysplastic syndrome. HLA matching was assessed by serologic data for HLA-A, -B, and -DR loci. The median age of the recipients at transplantation was 41 years (range, 0-82 years), and 2300 recipients (77%) were age >= 16 years. The 2-year overall survival rate was 0.46. The presence of MM only in the graft-versus-host direction or only in the host-versus-graft direction was not associated with overall mortality (hazard ratio [HR], 0.88; P = .317 and HR, 0.95; P = .670, respectively) compared with 1 bidirectional MM. This finding was consistent in both the child and adult cohorts. The presence of MM only in the graft-versus-host direction was associated with a lower incidence of nonrelapse mortality (HR, 0.65; P = .040), significant only in the child cohort. No MM category was associated with relapse. Our findings suggest that the direction of HLA MM does not have a significant impact on overall survival after UCB transplantation. (C) 2013 American Society for Blood and Marrow Transplantation.

Hyperbilirubinemia in the early phase after allogeneic hematopoietic SCT (HSCT) is due to various causes. One of the most important causes of hyperbilirubinemia is veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS). However, the prognosis of patients who are clinically diagnosed as SOS varies. We retrospectively evaluated 82 patients who underwent their first allogeneic HSCT. GVHD prophylaxis was a combination of short-term MTX and CsA (n=77) or tacrolimus (n=5). Thirty-three patients developed hyperbilirubinemia, with a bilirubin level of at least 2 mg/dL, within 20 days after HSCT. Of these patients, 24 were diagnosed as VOD/SOS using the modified Seattle criteria. Twenty-six recovered to a bilirubin level of &lt 2 mg/dL. We focused on the serum alkaline phosphatase/total bilirubin ratio (ALP/TB) at the onset of hyperbilirubinemia and found that it significantly predicted the recovery from hyperbilirubinemia. OS was significantly higher in patients with a lower ALP/TB ratio (P=0.00056). In addition, a lower ALP/TB ratio was associated with better survival even in patients who were clinically diagnosed as SOS (P&lt 0.001). The ALP/TB ratio at the onset of hyperbilirubinemia may be a useful predictor for the prognosis of hyperbilirubinemia and SOS early after HSCT. © 2013 Macmillan Publishers Limited.

To clarify which is preferable, a related donor with an HLA-1 Ag mismatch at the HLA-A, HLA-B, or HLA-DR loci in the graft-versus-host (GVH) direction (RD/1AG-MM-GVH) or an HLA 8/8-allele (HLA-A, HLA-B, HLA-C, and HLA-DRB1)-matched unrelated donor (8/8-MUD), we evaluated 779 patients with acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome who received a T cell-replete graft from an RD/1AG-MM-GVH or 8/8-MUD. The use of an RD/1AG-MM-GVH donor was significantly associated with a higher overall mortality rate than the use of an 8/8-MUD in a multivariate analysis (hazard ratio, 1.49; P<.001), and this impact was statistically significant only in patients with standard-risk diseases (P=.001). Among patients with standard-risk diseases who received transplantation from an RD/1AG-MM-GVH donor, the presence of an HLA-B Ag mismatch was significantly associated with a lower overall survival rate than an HLA-DR Ag mismatch because of an increased risk of treatment-related mortality. The HLA-C Ag mismatch or multiple allelic mismatches were frequently observed in the HLA-B Ag-mismatched group, and were possibly associated with the poor outcome. In conclusion, an 8/8-MUD should be prioritized over an RD/1AG-MM-GVH donor during donor selection. In particular, an HLA-B Ag mismatch in the GVH direction has an adverse effect on overall survival and treatment-related mortality in patients with standard-risk diseases. (Blood. 2012;119(10):2409-2416)

To evaluate whether rescue with cord blood transplantation (CBT) could improve the poor survival after graft failure (GF), we surveyed the data of 80 adult patients (median age, 51 years) who received CBT within 3 months of GF (primary 64, secondary 16), with fludarabine-based reduced-intensity regimens with or without melphalan, busulfan, cyclophosphamide, and/or 2-4 Gy total-body irradiation (TBI). A median number of 2.4 x 10(7)/kg total nucleated cells (TNC) were infused, and among the 61 evaluable patients who survived for more than 28 days, 45 (74%) engrafted. The median follow-up of surviving patients was 325 days, and the 1-year overall survival rate was 33% despite poor performance status (2-4, 60%), carryover organ toxicities (grade 3/4, 14%), and infections (82%) prior to CBT. Day 100 transplantation-related mortality was 45%, with 60% related to infectious complications. Multivariate analysis showed that the infusion of TNC >= 2.5 x 10(7)/kg and an alkylating agent-containing regimen were associated with a higher probability of engraftment, and that high risk-status at the preceding transplantation and grade 3/4 organ toxicities before CBT were associated with an increased risk of mortality. In conclusion, in an older population of patients, our data support the feasibility of CBT with a reduced-intensity conditioning regimen for GE Biol Blood Marrow Transplant 17: 341-851 (2011) (C) 2011 American Society for Blood and Marrow Transplantation

Cyclosporine A (CsA) is the mainstay of pharmacologic prevention of acute graft-versus-host disease (GVHD). We previously reported that continuous infusion of CsA with a target blood level between 250 and 400 ng/ml significantly increased the incidence of acute GVHD compared to twice-daily infusion with a target trough level between 150 and 300 ng/ml. Thus, we raised the target level of CsA continuous infusion to 450-550 ng/ml. We treated 33 patients with the higher target level (CsA500) and compared the efficacy and toxicity with those in the 33 historical control patients (CsA300 group). Other transplantation procedures were not changed. The patients' characteristics were equivalent. The average CsA concentration was adjusted around 500 ng/ml and the actual daily dose was maintained at the initial dose (CsA 3mg/kg/day). Toxicities were equivalently observed among the two groups. The incidence of grades II-IV acute GVHD was significantly lower in the CsA500 group (27 vs. 52%, P = 0.033). The target level of CsA was identified as an independent significant risk factor for grades II-IV acute GVHD (P = 0.039), adjusted for the presence of HLA mismatch. The incidence of chronic GVHD was also decreased in the CsA500 group (47 vs. 73%, P = 0.016). We conclude that the toxicity of the continuous CsA infusion with a target level of 450-550 ng/ml is acceptable and the efficacy to prevent acute GVHD is significant. A larger comparative study is warranted to confirm these findings.