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A total of 216 patients with IEM were treated by allogeneic HSCT in Japan from 1985 until 2010. The results of UCBT have improved, and the OS rate of UCBT (81.9%) was not different from those of RBMT (87.2%) or UBMT (73.9%) in 2000-2010. However, EFS rates in RBMT (73.2%) and UBMT (62.2%) were better than that in UCBT (49.5%), and the difference between RBMT and UCBT was significant (p = 0.01). The EFS rate of patients conditioned by RIC (74.6%) was comparable or slightly better than in those who underwent MAC with irradiation (57.9%) or without irradiation (54.2%) in 2000-2010. A more pronounced trend was observed toward differential EFS for UCBT in 2000-2010: RIC (62.9%), MAC with irradiation (20.0%), and MAC without irradiation (42.1%). The difference between RIC and MAC with irradiation was significant (p < 0.03). In summary, we report a Japanese registry analysis of HSCT for IEM with improving survival in UCBT. The introduction of RIC after 2000 was considered to contribute to this improvement. UCBT could be recommended for those who lack an HLA-identical sibling donor. [ABSTRACT FROM AUTHOR]

Morquio A syndrome features systemic skeletal dysplasia. To date, there has been no curative therapy for this skeletal dysplasia. No systemic report on a long-term effect of hematopoietic stem cell transplantation (HSCT) for Morquio A has been described. We conducted HSCT for 4 cases with Morquio A (age at HSCT: 4–15 years, mean 10.5 years) and followed them at least 10 years (range 11–28 years; mean 19 years). Current age ranged between 25 and 36 years of age (mean 29.5 years). All cases had a successful full engraftment of allogeneic bone marrow transplantation without serious GVHD. Transplanted bone marrow derived from HLA-identical siblings (three cases) or HLA-identical unrelated donor. The levels of the enzyme activity in the recipient's lymphocytes reached the levels of donors' enzyme activities within two years after HSCT. For the successive over 10 years post-BMT, GALNS activity in lymphocytes was maintained at the same level as the donors. Except one case who had osteotomy in both legs one year later post BMT, other three cases had no orthopedic surgical intervention. All cases remained ambulatory, and three of them could walk over 400 m. Activity of daily living (ADL) in patients with HSCT was better than untreated patients. The patient who underwent HSCT at four years of age showed the best ADL score. In conclusion, the long-term study of HSCT has demonstrated therapeutic effect in amelioration of progression of the disease in respiratory function, ADL, and biochemical findings, suggesting that HSCT is a therapeutic option for patients with Morquio A. [ABSTRACT FROM AUTHOR]

Abstract: The significance of patient and donor ethnicity on risk of acute graft-versus-host disease (GVHD) and disease relapse after unrelated donor hematopoietic cell transplantation (HCT) is not known. A total of 4335 patient–donor pairs from the International Histocompatibility Working Group in HCT met the following 3 criteria: (1) HLA-A, -B, -C, -DRB1, and -DQB1 allele matched donor, (2) diagnosis of leukemia, and (3) non–T cell depleted GVHD prophylaxis. Posttransplantation risks of acute GVHD and leukemia relapse were defined in Asian/Pacific Islander, white, African American, Hispanic, and Native American patients that underwent transplantation from donors with the same self-described background. Asian patients had a significantly lower incidence of acute GVHD (Japanese patients: 40.0% grades II to IV and 15.3% grades III to IV; non-Japanese Asian patients: 42.1% grades II to IV and 15.7% grades III to IV) compared with white patients (56.5% grades II to IV and 22.6% grades III to IV) (P < .001). The hazard ratio of acute GVHD for white patients was significantly higher than for Japanese patients. Unexpectedly, the hazard ratio of leukemia relapse in white patients with early disease status was also significantly higher than that in Japanese patients. These results provide a platform for future investigation into the genetic factors for unrelated donor HCT and clinical implications of diverse ethnic background. [Copyright &y& Elsevier]

Recent advances in unrelated cord blood transplantation (UCBT) and high-resolution typing of human leukocyte antigen (HLA) from an unrelated donor have increased choices in alternative donor/stem cell source selection. We assessed HLA-mismatched locus-specific comparison of the outcomes of 351 single-unit UCB and 1,028 unrelated bone marrow (UBM) adult recipients 16 years old or older at the time of transplantation who received first stem cell transplantation with myeloablative conditioning for acute leukemia or myelodysplastic syndromes. With adjusted analyses, HLA 0 to 2 mismatched UCBT showed similar overall mortality (relative risk [RR] = 0.85, 95% confidence interval [CI], 0.68-1.06; P = .149) compared with that of single-HLA-DRB1-mismatched UBMT. UCBT showed inferior neutrophil recovery (RR = 0.50, 95% CI, 0.42-0.60; P < .001), lower risk of acute graft-versus-host disease (RR = 0.55, 95% CI, 0.42-0.72; P < .001), and lower risk of transplantation-related mortality (RR = 0.68, 95% CI, 0.50-0.92; P = .011) compared with single-HLA-DRB1-mismatched UBMT. No significant difference was observed for risk of relapse (RR = 1.28, 95% CI, 0.93-1.76; P = .125). HLA 0 to 2 antigen-mismatched UCBT is a reasonable second alternative donor/stem cell source with a survival outcome similar to that of single-HLA-DRB1-mismatched or other 7 of 8 UBMT. [Copyright &y& Elsevier]

The outcome of cord blood transplantation following reduced-intensity conditioning is suboptimal because of fatal infection triggered by prolonged neutropenia and graft-versus-host disease (GVHD) in addition to graft rejection. Intrabone marrow injection (IBMI) may improve the outcome by providing better hematopoietic engraftment and less GVHD. We therefore evaluated IBMI safety in reduced-intensity stem cell transplantation. Furthermore, we used unwashed cord blood to avoid stem cell loss. Ten patients (median age = 61 years old) were enrolled. Cord blood cells were thawed at the bedside and injected into 4 iliac bone sites (2 at each hemipelvis). The procedure was well tolerated with no injection-related complications. Nine patients achieved donor engraftment. The median time to neutrophil recovery (>0.5 × 109/L) was 17 days, and platelet recovery was achieved in 8 patients. Early full donor chimerism was achieved (median of 15 and 20 days in T cells and myeloid cells, respectively). Three of 9 evaluable patients developed grade II to III GVHD, and 5 of 10 patients died of treatment-related toxicities. The probability of survival at 1 year was 46.7%. IBMI of unwashed cord blood following reduced-intensity conditioning is safe, well tolerated, and may lead to an increased donor engraftment rate. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (HCT) is an effective treatment for adult T-cell leukemia (ATL), raising the question about the role of graft-versus-leukemia effect against ATL. In this study, we retrospectively analyzed the effects of acute and chronic graft-versus-host disease (GVHD) on overall survival, disease-associated mortality, and treatment-related mortality among 294 ATL patients who received allogeneic HCT and survived at least 30 days posttransplant with sustained engraftment. Multivariate analyses treating the occurrence of GVHD as a time-varying covariate demonstrated that the development of grade 1-2 acute GVHD was significantly associated with higher overall survival (hazard ratio [HR] for death, 0.65; P= .018) compared with the absence of acute GVHD. Occurrence of either grade 1-2 or grade 3-4 acute GVHD was associated with lower disease-associated mortality compared with the absence of acute GVHD, whereas grade 3-4 acute GVHD was associated with a higher risk for treatment-related mortality (HR, 3.50; P < .001). The development of extensive chronic GVHD was associated with higher treatment-related mortality (HR, 2.75; P = .006) compared with the absence of chronic GVHD. Collectively, these results indicate that the development of mild-to-moderate acute GVHD confers a lower risk of disease progression and a beneficial influence on survival of allografted patients with ATL. [ABSTRACT FROM AUTHOR]

Tacrolimus (FK) and cyclosporine (CsA) have been shown to be effective in the prophylaxis of graft-versus-host disease (GVHD). However, no comparative studies have yet been conducted to examine the efficacy of FK/methotrexate (MTX) and CsA/MTX in patients with severe aplastic anemia (SAA) given unrelated donor bone marrow transplantation (U-BMT). We used matched-pair analysis to compare FK/MTX with CsA/MTX in patients with SAA who received U-BMT through the Japan Marrow Donor Program. Forty-seven pairs could be matched exactly for recipient age and conditioning regimens. Forty-five patients achieved engraftment in the FK group and 42 patients in the CsA group. The probability of grade II-IV acute GVHD (aGVHD) was 28.9% in the FK group and 32.6% in the CsA group (P =.558). The probability of chronic GVHD (cGVHD) was 13.3% in the FK group and 36.0% in the CsA group (P =.104). The 5-year survival rate was 82.8% in the FK group and 49.5% in the CsA group (P =.012). The study shows the superiority of FK/MTX over CsA/MTX in overall survival because of the lower incidence of transplantation-related deaths. A prospective randomized study comparing FK/MTX and CsA/MTX is warranted. [Copyright &y& Elsevier]

Abstract: In the present study we evaluated the feasibility of unrelated cord blood transplantation (UCBT) in patients with severe aplastic anemia (SAA). The outcome of 31 SAA patients (median age 28; range: 0.9-72.3 years old) who received UCBT was analyzed. The cumulative incidences of the neutrophil and platelet recovery after UCBT were 54.8 and 72.2%, respectively (95% confidence interval [CI] = 36.0%-70.3% and 51.3%-85.3%, respectively). The cumulative incidences of grade ≥II acute and chronic graft-versus-host disease (aGVHD, cGVHD) were 17.1% (95% CI = 6.2%-32.8%) and 19.7% (95% CI = 6.2%-38.8%), respectively. Currently, 13 patients are alive, having survived for 33.7 months (median; range: 6-77 months) after UCBT. The probability of overall survival (OS) at 2 years was 41.1% (95% CI = 23.8%-57.7%). A conditioning regimen that included low-dose total body irradiation (TBI) (2-5 Gy), fludarabine, and cyclophosphamide resulted in a favorable OS (80%; 95% CI = 20.4%-96.9%). This result suggests that UCBT using the optimal conditioning regimen can be a salvage treatment for patients without a suitable bone marrow donor and warrants evaluation in further prospective studies. [Copyright &y& Elsevier]

Chronic graft- versus-host disease (GVHD) remains the major cause of late morbidity and mortality after allogeneic stem cell transplantation. We retrospectively analysed 2937 patients who underwent bone marrow transplantation from an unrelated donor (UR-BMT) facilitated by the Japan Marrow Donor Program (JMDP) and survived beyond day 100 after transplantation. The cumulative incidence of chronic GVHD (limited + extensive) or extensive chronic GVHD at 5 years post-transplant was 45·8% and 28·2%, respectively. On multivariate analysis, seven variables predicting chronic GVHD were identified: recipient age over 20 years, donor age over 30 years, primary diagnosis of chronic myeloid leukaemia, human leucocyte antigen (HLA)-A or -B mismatch, total body irradiation-containing regimen, platelet count not having reached 50 × 109/l by day 100, and prior acute GVHD. Among 2609 patients with haematological malignancy, overall survival was significantly higher in patients with limited chronic GVHD but lower in patients with extensive chronic GVHD compared with those without chronic GVHD. The cumulative incidence of relapse among patients with limited or extensive chronic GVHD was significantly lower than that among patients without chronic GVHD. Our results suggest that limited chronic GVHD provides a survival benefit to patients with haematological malignancies by reducing the risk of relapse without increasing the risk of death from chronic GVHD. [ABSTRACT FROM AUTHOR]

Abstract: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an HLA-matched related donor has been suggested to improve the poor prognosis of adult T-cell leukemia/lymphoma (ATLL). However, the infusion of HTLV-I–infected cells from HTLV-I–positive related donors could lead to the development of donor-derived ATLL under immunosuppressive conditions. Although most ATLL patients lack a suitable HLA-matched related donor and require an HTLV-I–negative unrelated donor, little information is currently available regarding the outcome of unrelated bone marrow transplantation (UBMT) for ATLL. To evaluate the role of UBMT in treating ATLL, we retrospectively analyzed data from 33 patients with ATLL treated by UBMT through the Japan Marrow Donor Program (JMDP). Overall survival (OS), progression-free survival, and cumulative incidence of disease progression and progression-free mortality at 1 year after UBMT were 49.5%, 49.2%, 18.6%, and 32.3%, respectively. Multivariate analysis identified recipient age as an independent prognostic factor for OS (P = .044). Patients age ≥50 years who showed nonremission at transplantation tended to have higher rates of treatment-related mortality. Our observations suggest that UBMT could represent a feasible treatment option for ATLL patients and warrant further investigation based on these risk factors. [Copyright &y& Elsevier]

Summary. Cryopreserved umbilical cord blood (CB) from unrelated donors can restore haematopoiesis after myeloablative therapy in patients with haematological malignancy. We investigated the clinical outcomes of CB transplantation (CBT) with special emphasis on graft-versus-host disease (GVHD) prophylaxis. Patients with haematological malignancies (n = 216) received intensive chemotherapy or immunosuppressive therapy, followed by transplantation of cryopreserved CB cells from unrelated donors. The clinical outcomes, i.e. haematological reconstitution, the incidence of acute or chronic GVHD, relapse and event-free survival (EFS), were evaluated. The estimated probability of neutrophil recovery was 88·2%. The median follow-up for the survivors was 557 d (range 21–1492 d). The overall and EFS rates were 32·6% and 25·5%, respectively, 3·5 years after transplantation. Multivariate analysis using Cox's proportional hazards model showed that high-risk disease status at CBT and single-drug GVHD prophylaxis were associated with worse 2-year EFS rates [P = 0·0013, relative risk (RR) 1·90, 95% confidence interval (CI) 1·28–2·81 and P = 0·0007, RR 1·91, 95% CI 1·31–2·79 respectively). Age at CBT had no significant influence on EFS. Cryopreserved CB from unrelated donors can restore haematopoiesis in patients with haematological malignancy. Although the incidence is low, the prophylaxis for acute GVHD is an important factor for survival of CBT from unrelated donors. A high rate of suitable donors was found, with a probability of 1 to every 18 CB units, when compared with human leucocyte antigen matching at other haematopoietic stem cell banks. [ABSTRACT FROM AUTHOR]