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Mogamulizumab (MOG), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, has recently played an important role in the treatment of adult T cell leukemia/lymphoma (ATLL). Because CCR4 is expressed on normal regulatory T cells as well as on ATLL cells, MOG may accelerate graft-versus-host disease (GVHD) by eradicating regulatory T cells in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is limited information about its safety and efficacy in patients treated with MOG before allo-HSCT. In the present study, 25 patients with ATLL were treated with MOG before allo-HSCT, after which 18 patients (72%) achieved remission. The overall survival and progression-free survival at 1 year post-transplantation were 20.2% (95% CI, 6.0% to 40.3%) and 15.0% (95% CI, 4.3% to 32.0%), respectively. The cumulative incidence of acute GVHD was 64.0% (95% CI, 40.7% to 80.1%) for grade II-IV and 34.7% (95% CI, 15.8% to 54.4%) for grade III-IV. The cumulative incidence of transplantation-related mortality (TRM) was 49.0% (95% CI, 27.0% to 67.8%). Six of 7 patients with acute GVHD grade III-IV died from GVHD, which was the leading cause of death. In particular, a shorter interval from the last administration of MOG to allo-HSCT was associated with more severe GVHD. MOG use before allo-HSCT may decrease the ATLL burden; however, it is associated with an increase in TRM due to severe GVHD. Because MOG is a potent anti-ATLL agent, new treatment protocols should be developed to integrate MOG at suitable doses and timing of administration to minimize unwanted GVHD development. [ABSTRACT FROM AUTHOR]

Allogeneic bone marrow and peripheral blood stem cell transplantations are curative treatment modalities for adult T cell leukemia/lymphoma (ATLL) because of the intrinsic graft-versus-ATLL effect. However, limited information is available regarding whether cord blood transplantation (CBT) induces a curative graft-versus-ATLL effect against aggressive ATLL. To evaluate the effect of CBT against ATLL, we retrospectively analyzed data from 175 patients with ATLL who initially underwent single-unit CBT. The 2-year overall survival (OS) rate was 20.6% (95% confidence interval [CI], 13.8% to 27.4%). A multivariate analysis revealed that the development of graft-versus-host disease (GVHD) was a favorable prognostic factor for OS (hazard ratio, .10; 95% CI, .01 to .94; P = .044). Furthermore, the 2-year OS (42.7%; 95% CI, 28.1% to 56.6%) of patients with grade 1 to 2 acute GVHD was higher than that of patients without acute GVHD (24.2%; 95% CI, 11.2% to 39.8%; P = .048). However, the cumulative incidence of treatment-related mortality (TRM) was high (46.1%; 95% CI, 38.2% to 53.7%), and early death was particularly problematic. In conclusion, CBT cures patients with ATLL partly through a graft-versus-ATLL effect. However, novel interventions will be required, particularly in the early phase, to reduce TRM and optimize GVHD. [ABSTRACT FROM AUTHOR]

Cord blood transplantation (CBT) from an unrelated donor is recognized as one of the major treatment modalities in allogeneic stem cell transplantation (SCT) for children with hematologic malignancies. We analyzed the clinical outcomes of CBT for children with acute lymphoblastic leukemia (ALL) in Japan and identified the risk factors for the transplant outcomes. From 1997 to 2006, 332 children with ALL underwent CBT from unrelated donors, 270 of which had no prior transplant. Their disease statuses at transplant were first complete remission (CR) (n = 120), second CR (n = 71), and more advanced stages (n = 75). As preconditioning for SCT, total body irradiation (TBI) was given to 194 patients and, for the prophylaxis of graft-versus-host disease (GVHD), methotrexate (MTX) was given to 159 patients. The cumulative incidents of neutrophil and platelet recovery (>20 K) were 88.5% and 78.4%, respectively. The incidents of grade II-IV, III-IV acute GVHD (aGVHD), and chronic GVHD (cGVHD) were 45.6%, 20.4%, and 19.2%, respectively, and treatment-related mortality was 22.6%. The 5-year event-free survival (EFS) and overall survival (OS) at CR1, CR2, and advanced status were 47.4%, 45.5%, 15.0%, and 63.7%, 59.7%, and 20.7%, respectively. Multivariate analysis revealed that MTX with calcineurin inhibitor (CNI) was associated with decreased incidence of grade II-IV GVHD (CNI alone: hazard ratio [HR] = 1.74, 95% confidence interval [CI] = 1.06-2.83, P = .027; CNI + prednisolone (PSL), HR = 1.61, 95% CI = 1.03-2.50, P = .036), III-IV aGVHD (CNI alone: HR = 3.02, 95% CI = 1.55-5.91, P = 0.001; CNI + PSL, HR = 1.89, 95% CI = 0.93-3.83, P = .078), or cGVHD (CNI alone: HR = 1.78, 95% CI = 0.83-3.82, P = .143; CNI + PSL, HR = 2.44, 95% CI = 1.24-4.82, P = .01), compared with CNI alone or CNI + PSL. At an advanced stage of disease, GVHD prophylaxis with MTX + CNI is associated with improved OS compared with CNI alone (CNI alone: HR = 3.20, 95% CI = 1.43-7.15, P = .005; CNI + PSL, HR = 1.47, CI = 0.67-3.20, P = .332). Our retrospective study showed that CBT for children with ALL is feasible and GVHD prophylaxis with MTX + CNI is associated with significant favorable outcomes in prevention of aGVHD and cGVHD as well as survival advantage in advanced cases. [ABSTRACT FROM AUTHOR]

A hallmark of graft-versus-host-disease (GVHD), a life-threatening complication after allogeneic hematopoietic stem cell transplantation, is the cytopathic injury of host tissues mediated by persistent alloreactive effector T cells (TE). However, the mechanisms that regulate the persistence of alloreactive TE during GVHD remain largely unknown. Using mouse GVHD models, we demonstrate that alloreactive CD8+ TE rapidly diminished in vivo when adoptively transferred into irradiated secondary congenic recipient mice. In contrast, although alloreactive CD8+ TE underwent massive apoptosis upon chronic exposure to alloantigens, they proliferated in vivo in secondary allogeneic recipients, persisted, and caused severe GVHD. Thus, the continuous proliferation of alloreactive CD8+ TE, which is mediated by alloantigenic stimuli rather than homeostatic factors, is critical to maintaining their persistence. Gene expression profile analysis revealed that although alloreactive CD8+ TE increased the expression of genes associated with cell death, they activated a group of stem cell genes normally expressed in embryonic and neural stem cells. Most of these stem cell genes are associated with cell cycle regulation, DNA replication, chromatin modification, and transcription. One of these genes, Ezh2, which encodes a chromatin modifying enzyme, was abundantly expressed in CD8+ TE. Silencing Ezh2 significantly reduced the proliferation of alloantigen-activated CD8+ T cells. Thus, these findings identify that a group of stem cell genes could play important roles in sustaining terminally differentiated alloreactive CD8+ TE and may be therapeutic targets for controlling GVHD. [Copyright &y& Elsevier]

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]

Highlights • HHV6-associated myelitis (2.5%) and CIPS (1.8%) were rarely documented in 435 HSCT recipients. • These 2 diseases had similar sensory-related symptoms, such as pruritus and severe pain. • Diagnostic images did not provide definite evidence specific for each disease. • HHV6 encephalitis/myelitis but not CIPS was associated with poor overall survival. • Detection of HHV6 is crucial for differential diagnoses and immediate treatment of the 2 diseases. Abstract Human herpes virus-6 (HHV6)-associated myelitis and calcineurin inhibitor–induced pain syndrome (CIPS) are serious complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because these 2 complications cause similar sensory nerve–related symptoms, such as paresthesia, pruritus, and severe pain occurring around the engraftment, it can be difficult to differentially diagnose the 2 conditions. We retrospectively analyzed 435 recipients to distinguish clinical symptoms of these 2 complications. Twenty-four patients (5.5%) developed HHV6-associated encephalitis/myelitis; of these, 11 (2.5%) presented only with myelitis-related symptoms (HHV6-associated myelitis), which was confirmed by the detection of HHV6 DNA, and 8 (1.8%) had CIPS, with undetected HHV6 DNA. All patients with HHV6-associated myelitis or CIPS exhibited similar sensory nerve–related symptoms. Diagnostic images did not provide definite evidence specific for each disease. Symptoms of all patients with CIPS improved after switching to another immunosuppressant. Overall survival rate at 2 years for patients with HHV6-associated encephalitis/myelitis was significantly lower than that of CIPS (13.1% versus 29.2%; P =.049) or that of patients without HHV6-associated encephalitis/myelitis or CIPS (42.4%; P =.036), whereas there was no significant difference among the latter 2 groups (P =.889). The development of HHV6-associated encephalitis/myelitis but not CIPS was significantly associated with poor prognosis. Thus, transplant physicians should be aware that sensory nerve–related symptoms indicate early manifestations that might be correlated with reactivation of HHV6 or CIPS. Therefore, identification of HHV6 DNA is crucial for making a differential diagnosis and immediately starting appropriate treatments for each complication. [ABSTRACT FROM AUTHOR]

Disease status at allogeneic hematopoietic cell transplantation (HCT) is an important pretransplant prognostic factor of HCT in adult T cell leukemia/lymphoma (ATL); however, other prognostic factors, including comorbidities, were not predictive in small cohort analyses. Several scoring systems (HCT-specific comorbidity index [HCT-CI]/modified European Group for Blood and Marrow Transplantation risk score [mEBMT]) have been adopted to predict HCT outcomes in other hematologic malignancies. We retrospectively evaluated HCT-CI and mEBMT to predict nonrelapse mortality (NRM) in 824 ATL patients registered in the Japan Society for Hematopoietic Cell Transplantation TRUMP database, from 2008 until 2013. A higher HCT-CI was associated with greater NRM when comparing HCT-CI 0 versus HCT-CI 1 to 3 and HCT-CI 0 versus HCT-CI ≥ 4. A higher mEBMT score was not associated with higher NRM when comparing mEBMT 0 to 3 with 4 to 6. Because ATL patients are older and consequently at risk of additional complications, we developed an optimized prognostic index for ATL (ATL-HCT-PI) using known risk factors: age, HCT-CI, and donor–recipient sex combination. The ATL-HCT-PI scores effectively predicted the 2-year NRM (22.0%, 27.7%, and 44.4%, respectively). Therefore, the newly developed ATL-HCT-PI, in combination with other risk factors, is more useful for predicting NRM in HCT for ATL patients. [ABSTRACT FROM AUTHOR]

Abstract: Allogeneic hematopoietic cell transplantation (HCT), but not autologous HCT, can provide long-term remission in some patients with adult T cell leukemia-lymphoma (ATL). We retrospectively analyzed the effects of acute graft-versus-host disease (GVHD) among the 616 patients with ATL who survived at least 30 days after allogeneic HCT with other than cord blood grafts. Multivariate analyses treating the occurrence of GVHD as a time-varying covariate demonstrated an association between grade I-II acute GVHD and favorable overall survival (OS) (hazard ratio [HR], 0.634; 95% confidence interval [CI], 0.477 to 0.843), whereas grade III-IV acute GVHD showed a trend toward unfavorable OS (HR, 1.380; 95% CI, 0.988 to 1.927) compared with nonacute GVHD. In subsequent multivariate analyses of patients who survived at least 100 days after HCT (n = 431), the presence of limited chronic GVHD showed a trend toward favorable OS (HR, 0.597; 95% CI, 0.354 to 1.007), and extensive chronic GVHD had a significant effect on OS (HR, 0.585; 95% CI, 0.389 to 0.880). There were no significant interactions between myeloablative conditioning or reduced-intensity conditioning with OS even when acute GVHD was absent or present at grade I-II or grade III-IV or when chronic GVHD was absent, limited, or extensive. This study demonstrates the actual existence of graft-versus-ATL effects in patients with ATL regardless of whether myeloablative conditioning or reduced-intensity conditioning is used. [Copyright &y& Elsevier]

Virus-associated hemorrhagic cystitis (HC) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Although numerous studies have attempted to identify factors that predispose patients to viral HC, its causes remain controversial. We analyzed retrospectively the results of 266 allogeneic HSCTs to identify factors associated with HC. Of this group, 42 patients (15.8%) were diagnosed with viral HC, because of either adenovirus (ADV; n = 26; 9.8%) or BK virus (BKV; n = 16; 6.0%). ADV-HC was frequently associated with T cell purging, and was less common in patients with acute graft-versus-host-disease (GVHD). Conversely, BKV-HC was more frequently observed in patients with excessive immune reactions such as GVHD, preengraftment immune reaction, and hemophagocytic syndrome. These observations indicate that ADV- and BKV-HC may differ significantly in their risk factors and pathogenesis. Profound immune deficiency is more likely to be associated with ADV-HC, whereas immune hyperactivity might play a key role in BKV-HC. [ABSTRACT FROM AUTHOR]

Abstract: Incidence and characteristics of early bacterial infection within 100 days after unrelated cord blood transplantation (UCBT) were assessed for 664 pediatric and 1208 adult recipients in Japan. Cumulative incidence of early bacterial infection at day 100 post-UCBT was 11% (95% confidence interval [CI], 8%-13%) for children and 21% (CI, 19%-24%) for adults (P < .0001). Early bacterial infection in adults had a significant impact on mortality (hazard ratio [HR] = 2.1, CI, 1.7-2.6; P < .0001), although no significant risk factors were identified. Multivariate analysis identified older age group (6-10, and 11-15 years versus 0-5 years of age) at transplant (HR = 2.0 and 2.7, CI, 1.1-3.5 and 1.4-4.9; P = .020 and .002, respectively) as an independent risk factor of early bacterial infection for children. Early bacterial infection in children did not have a significant impact on mortality when adjusted. Of 315 bacteremia, 74% were caused by Gram-positive microorganisms. Pneumonia occurred in 39 patients including 13 cases of Stenotrophomonas maltophilia pneumonia. Early bacterial infection had a negative effect on survival for adults and the median day of development was 10 days after transplant, suggesting that the prevention of bacterial infection in the very early post-UCBT phase is important. [Copyright &y& Elsevier]

• Hematopoietic cell transplantation is the only curative therapy for juvenile myelomonocytic leukemia. • Busulfan/fludarabine/melphalan seems to offer the best chance of long-term survival. • Chronic graft-versus-host disease correlates with improved survival by reducing relapse. • Treatment strategies enhancing graft-versus-leukemia effects may further improve outcome. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for juvenile myelomonocytic leukemia (JMML), but few large studies of HSCT for JMML exist. Using data from the Japan Society for Hematopoietic Cell Transplantation registry, we analyzed the outcomes of 129 children with JMML who underwent HSCT between 2000 and 2011. The 5-year overall survival (OS) rate and cumulative incidence of relapse were 64% and 34%, respectively. A regimen of busulfan/fludarabine/melphalan was the most commonly used (59 patients) and provided the best outcomes; the 5-year OS rate reached 73%, and the cumulative incidences of relapse and transplantation-related mortality were 26% and 9%, respectively. In contrast, the use of the irradiation-based myeloablative regimen was the most significant risk factor for OS (hazard ratio [HR], 2.92; P =.004) in the multivariate model. In addition, chronic graft-versus-host disease (GVHD) was strongly associated with lower relapse (HR, 0.37; P =.029) and favorable survival (HR, 0.22; P =.006). The current study has shown that a significant proportion of children with JMML can be cured with HSCT, especially those receiving the busulfan/fludarabine/melphalan regimen. Based on the lower relapse and better survival observed in patients with chronic GVHD, additional treatment strategies that focus on enhancing graft-versus-leukemia effects may further improve survival. [ABSTRACT FROM AUTHOR]

• We assessed the effect of donor human T cell leukemia virus 1 serostatus on outcomes of allogeneic hematopoietic stem cell transplantation (allo-HCT) in adult T cell leukemia-lymphoma. • There was no significant difference in overall survival or incidence of mortality. • This might aid the choice of appropriate and timely alternative donors for allo-HCT. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only available curative treatment option for patients with aggressive adult T cell leukemia-lymphoma (ATL). Donor human T cell leukemia virus (HTLV) 1 seropositivity is a critical concern when choosing relative donors, as they are not usually recommended due solely to the occurrence of donor-derived ATL. A previous report suggested that allo-HCT with an HTLV-1-seropositive donor increased ATL-related mortality. We updated the risk assessment for choosing an HTLV-1-seropositive allo-HCT donor for ATL. Our current registry data, which include larger numbers of HTLV-1-seropositive donors and longer observation periods, revealed no significant difference in overall survival (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.70-1.24; P =.61) or cumulative incidence of either ATL-related (HR, 0.96; 95% CI, 0.64 to 1.45; P =.80) or non-ATL-related mortality (HR, 0.91; 95% CI, 0.61 to 1.37; P =.66). Similarly, when considering only patients with ATL in complete remission, there was no significant difference in overall survival (HR, 1.02; 95% CI, 0.70 to 1.49; P =.91) or cumulative incidence of either ATL-related (HR, 1.20; 95% CI, 0.66 to 2.20; P=0.54) or non-ATL-related mortality (HR, 0.86; 95% CI, 0.52-1.42; P =.66). These data indicate that selecting HTLV-1-seropositive donors might not be contraindicated for patients with ATL receiving allo-HCT if alternative donors are unavailable. Further risk assessment remains to be performed. [ABSTRACT FROM AUTHOR]

• HLA-A, -B, -C, and -DRB1 allele mismatch effects were examined in 4050 cases of cord blood transplants. • Overall survival (OS) deteriorated in HLA 5-allele and higher mismatch in adult cord blood transplantation (CBT). • OS deteriorated in HLA 4-allele and higher mismatch in pediatric CBT. • In adult cases, 8/8 match mitigated severe acute graft-versus-host disease (GVHD) but increased the relapse rate. • In pediatric cases, 8/8 match and 1-allele mismatch mitigated acute GVHD. The impact of allele-level HLA mismatch on outcomes of cord blood transplantation has not been well established. We retrospectively analyzed the effects of HLA allele matching at HLA-A, -B, -C, and -DRB1 in cord blood transplantation for acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome. In multivariate analysis, overall survival (OS) significantly deteriorated in the 4-allele or higher mismatch in pediatric cases (hazard ratio, 1.8 for 4/8 match [reference, 6/8 match] and 2.85 for 3-1/8 match) and the 5-allele or higher mismatch in adult cases (hazard ratio, 1.23 for 3-0/8 match). Incidence of grade Ⅲ to Ⅳ acute graft-versus-host disease was low in the 8/8 match and 1-allele mismatch in pediatric cases (hazard ratio, 0.19 for 8/8 match and 0.41 for 7/8 match) and the 8/8 match in adult cases (hazard ratio, 0.41 for 8/8 match). On the other hand, a higher incidence of relapse was noted in the 8/8 match in adults (hazard ratio, 1.53). The incidence of neutrophil and platelet engraftment decreased in the 3-allele or higher mismatch in adults. In subgroup analysis of graft-versus-host disease prophylaxis in adult cases, a deteriorating effect on OS of HLA 5-allele or higher mismatch was more significant in cases with calcineurin inhibitor with methotrexate than with mycophenolate mofetil. These results suggest that allele-level HLA mismatch affects the outcomes of cord blood transplantation. Information on HLA allele matching at HLA-A, -B, -C, and -DRB1 may be useful for cord blood unit selection. [ABSTRACT FROM AUTHOR]

• Hematopoietic stem cell transplantation (HSCT) recipients exhibited low seropositivity for measles, rubella, mumps, and varicella zoster virus. • History of chronic graft-versus-host disease (GVHD) was associated with a high seropositivity rate for measles. • Nineteen of 32 HSCT recipients seronegative for measles became seropositive after vaccination. • Thirty percent of 20 HSCT recipients seronegative for rubella became seropositive after vaccination. • History of cGVHD was associated with seroconversion after vaccination. Vaccination against vaccine-preventable diseases (VPDs) is highly recommended for hematopoietic stem cell transplantation (HSCT) recipients by several guidelines; however, the safety and seropositivity after live attenuated vaccines remain unclear in adult HSCT recipients. We analyzed titers of antibodies against measles, rubella, mumps, and varicella zoster virus (VZV) from Japanese adult patients who underwent allogeneic HSCT (allo-HSCT) (n = 74), autologous HSCT (auto-HSCT) (n = 39), or chemotherapy (n = 93). The seropositive rates for measles, rubella, mumps, and VZV in allo-HSCT recipients were 20.2%, 36.4%, 5.4%, and 55.4%, respectively. These rates were equivalent to those in auto-HSCT recipients but were significantly lower than those in patients receiving chemotherapy. Antibody titers tended to gradually decrease with time. Twenty-nine allo-HSCT recipients and 8 auto-HSCT recipients received live attenuated vaccines against VPDs for which they tested seronegative. The titers of antibodies against measles, rubella, and mumps significantly increased after 2 shots of vaccine, and the seropositive rate increased up to 19%, 30%, and 27%, respectively. Three patients (8.1%) experienced mild adverse events, which resolved promptly, indicating safe administration of the live attenuated vaccines. In multivariate analysis, history of chronic graft-versus-host disease was significantly associated with high seropositivity for measles as well as high seroconversion rate for measles after vaccination. Live attenuated vaccines against VPDs were safely administered in seronegative adult HSCT recipients. A further observational study is crucial to evaluate the efficacy of vaccination in seronegative HSCT patients. [ABSTRACT FROM AUTHOR]

• Mortality was higher in adolescent and young adults with acute lymphoblastic leukemia (ALL) than in children with ALL. • Infection was the most common cause of treatment-related death among adolescents. • Relapse rates were similar in adolescents and young adults compared with children. • There was no difference in outcomes for older adolescents treated at pediatric centers and those treated at adult centers. Hematologic stem cell transplantation (HSCT) is the most potent consolidation therapy for high-risk acute lymphoblastic leukemia (ALL), but their outcomes and complications in adolescent and young adult (AYA) patients remain unclear. We compared outcomes after HSCT for ALL among children (age 1 to 9 years; n = 607), adolescents (age 10 to 19 years; n = 783), and young adults (age 20 to 29 years old, n = 603), based on Japanese nationwide registry data. The 5-year overall survival (OS) rate among AYA patients was worse than that of children, at 64% (95% confidence interval [CI], 60% to 68%). In the AYA, the 5-year treatment-related mortality (TRM) after HSCT was 19% (95% CI, 16% to 22%), significantly higher than that in younger patients. The most common cause of TRM in the AYA was infection. The relapse rate was not different across the 3 age groups. When focusing on older adolescents (age 15 to 19 years), there was no difference in outcomes between those treated in pediatric centers and those treated in adult centers. In conclusion, the AYA had a greater risk of nonrelapse death than younger patients, and infection was the most common cause. Further optimization is required for HSCT in AYAs with ALL. [ABSTRACT FROM AUTHOR]

Highlights • Bloodstream infection was documented in 13.6% of allogeneic transplant recipients. • Enteric bacteria/fungi were major (58%) causes of this infectious complication. • Bloodstream infection correlated with gastrointestinal graft-versus-host disease. • Patients with bloodstream infection showed an inferior prognosis. Abstract Bloodstream infection (BSI) is a well-known cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Here, we conducted a retrospective study to assess the morbidity, etiology, risk factors, and outcomes of BSI in the postengraftment period (PE-BSI) after allo-HSCT. Forty-three of 316 patients (13.6%) developed 57 PE-BSI episodes, in which 62 pathogens were isolated: Gram-positive bacteria, gram-negative bacteria, and fungi, respectively, accounted for 54.8%, 35.5%, and 9.7% of the isolates. Multivariate analysis revealed methylprednisolone use for graft-versus-host disease (GVHD) prophylaxis (odds ratio [OR], 6.49; 95% confidence interval [CI], 1.49 to 28.2; P =.013) and acute gastrointestinal GVHD (GI-GVHD) (OR, 8.82; 95% CI, 3.99 to 19.5; P <.0001) as risk factors for developing PE-BSI. This finding suggested that GI-GVHD increases the risk of bacterial translocation and subsequent septicemia. Moreover, among patients with GI-GVHD, insufficient response to corticosteroids, presumably related to an intestinal dysbiosis, significantly correlated with this complication. Patients with PE-BSI presented worse outcome compared with those without (3-year overall survival, 47.0% versus 18.6%; P <.001). Close microbiologic monitoring for BSIs and minimizing intestinal dysbiosis may be crucial to break the vicious cycle between GI-GVHD and bacteremia and to improve transplant outcomes especially in patients who require additional immunosuppressants. [ABSTRACT FROM AUTHOR]

Cord blood transplantation (CBT) is a distinct risk factor for human herpesvirus-6 (HHV-6) reactivation and HHV-6 encephalitis. In a prospective multicenter trial we investigated the effects of prophylactic foscarnet (90 mg/kg i.v. infusion from days 7 to 27 after CBT) on the occurrence of HHV-6 reactivation, HHV-6 encephalitis, and acute graft-versus-host disease (aGVHD) in CBT recipients. Between 2014 and 2016, 57 patients were included in a foscarnet-prophylaxis group. Outcomes were compared with an historical control group who received CBT between 2010 and 2014 (standard-treatment group, n = 63). The cumulative incidence of high-level HHV-6 reactivation, defined as plasma HHV-6 DNA ≥ 10 4 copies/mL, at 60 days after CBT was significantly lower in the foscarnet-prophylaxis group than in the standard-treatment group (18.3% versus 57.3%, P  < .001). Multivariate analysis revealed that myeloablative preconditioning and standard treatment were significant risk factors for high-level HHV-6 reactivation. The cumulative incidence of HHV-6 encephalitis at 60 days after CBT was not different between the groups (foscarnet-prophylaxis group, 12.4%; standard-treatment group, 4.9%; P  = .14). The cumulative incidences of grades II to IV and grades III to IV aGVHD at 60 days after CBT were not different between the groups (grades II to IV aGVHD: foscarnet-prophylaxis group, 42.0%; standard-treatment group, 40.5%; P  = .96; grades III to IV aGVHD: foscarnet-prophylaxis group, 14.5%; standard-treatment group, 14.5%; P  = 1.00). In the setting of this study foscarnet significantly suppressed systemic HHV-6 reactivation in CBT recipients but failed to prevent the development of HHV-6 encephalitis. Suppression of HHV-6 reactivation by foscarnet did not show any effects against the incidence of aGVHD. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapeutic option for patients with chronic myelomonocytic leukemia (CMML). We retrospectively compared the post-transplantation outcomes of 159 patients with CMML who underwent allo-HSCT using 4 types of donor sources: HLA-matched related donor graft, unrelated bone marrow (U-BM), unrelated cord blood (U-CB), and HLA-mismatched related donor graft. The median patient age at allo-HSCT was 54 years (range, 16 to 75 years). In multivariate analyses, the use of HLA-matched related donor grafts correlated with better overall survival than U-BM (hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.21 to 3.48; P  = .008), U-CB (HR, 3.80; 95% CI, 2.07 to 6.95; P  < .001), or HLA-mismatched related donor grafts (HR, 6.18; 95% CI, 2.70 to 14.15; P  < .001). Mortality after the relapse or progression of CMML did not significantly differ among the 4 types of donor source. Transplantation-related mortality was highest in recipients of U-CB (HR, 3.32; 95% CI, 1.33 to 8.26; P  = .010). In patients with CMML, allo-HSCT using an alternative donor may contribute to durable remission; however, further improvements in transplantation-related mortality are required for this type of transplantation. [ABSTRACT FROM AUTHOR]

Graft failure (GF) is the most critical life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT) for aplastic anemia, for which a second transplantation is the only effective treatment. Optimal procedures have not been established for the second transplantation in this setting, however. Here we retrospectively analyzed the outcomes of 22 patients with aplastic anemia, age ≥16 years, who underwent umbilical cord blood transplantation for GF after the first HSCT using the registry database of the Japan Society for Hematopoietic Cell Transplantation. The median age of patients was 36 years (range, 16 to 72 years), and the median time from the first to the second transplant was 77 days (range, 29 to 1061 days). The cumulative incidence of neutrophil engraftment at day 60 post-transplantation was 45.5% (95% confidence interval [CI], 23.6% to 65.0%). With a median follow-up of 50 months, the 4-year overall survival (OS) was 38.5% (95% CI, 18.4% to 58.5%). Mycofenolate mofetil–based graft-versus-host disease prophylaxis demonstrated greater neutrophil recovery than prophylaxis with calcineurin inhibitor alone or methotrexate-based prophylaxis (66.7% versus 37.5%; P  = .04). The use of such conditioning regimens as fludarabine + melphalan or cyclophosphamide + low-dose total body irradiation was associated with better engraftment (58.3% versus 30%; P  = .05) and better 4-year OS (55.6% versus 20%; P  = .05) than other regimens. Although further investigation is needed, umbilical cord blood could be an effective and promising option for stem cell source for urgent second transplantation in patients with aplastic anemia who develop GF after the first HSCT. [ABSTRACT FROM AUTHOR]

Few reports have focused on adolescent and young adult (AYA) patients with acute myeloid leukemia (AML) treated with hematopoietic stem cell transplantation (HSCT). We performed a retrospective analysis based on data obtained from a Japanese nationwide registration database to compare HSCT outcomes in AYA patients with AML with those in children with AML. An analysis of the 2973 patients with de novo AML who received allogeneic HSCT from 1990 to 2013 showed inferior 5-year overall survival (OS) (54% versus 58%, P  <   .01) and increased treatment-related mortality (TRM) (16% versus 13%, P  = .02) in AYA patients. Multivariate analysis for both OS and TRM showed a significant negative impact on AYAs. However, the negative impact of older age lost its significance in an additional analysis focusing on 1407 recent transplant recipients with high-resolution HLA typing (2000 to 2013). Finally, we analyzed the impact of transplantation center type on HSCT outcomes in 317 adolescent patients (15 to 18 years old) and found no difference in outcomes between patients treated at a pediatric or an adult hospital. Higher age was a strong predictive factor for inferior OS resulting from increased TRM, which can be eliminated with better donor selection using high-resolution HLA typing. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the best therapeutic option for childhood high-risk acute leukemia. However, which donor source is optimal for children lacking an identical sibling remains unclear. To evaluate the clinical impact of donor source on allo-HSCT in childhood acute leukemia, we analyzed data from 577 children who underwent allo-HSCT after a myeloablative regimen during first or second complete remission from 2005 to 2012, using registry data of the Japan Society for Hematopoietic Cell Transplantation, and we compared outcomes of 7/8 to 8/8 HLA allelic–matched unrelated bone marrow transplantation (UR-BMT, n = 218) and 4/6 to 6/6 HLA allelic–matched unrelated cord blood transplantation (UR-CBT, n = 200) to those of HLA-identical related bone marrow transplantation (ID-BMT, n = 159). The median follow-up of survivors was 40.0 months. Three-year overall survival (OS) and leukemia-free survival (LFS) rates for ID-BMT, UR-BMT, and UR-CBT were 74.8% and 69.0%, 75.0% and 69.6%, and 71.8% and 63.8%, respectively. The multivariate analysis demonstrated that OS and LFS for the 3 groups are comparable, although UR-CBT carries a greater risk of nonrelapse mortality (hazard ratio, 2.20; P  = .03, compared to ID-BMT) in the myeloablative setting for childhood high-risk acute leukemia. [ABSTRACT FROM AUTHOR]

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 [HR], .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. [ABSTRACT FROM AUTHOR]

We sought to assess the late mortality risks and causes of death among long-term survivors of allogeneic hematopoietic stem cell transplantation (HCT). The cases of 11,047 relapse-free survivors of a first HCT at least 2 years after HCT were analyzed. Standardized mortality ratios (SMR) were calculated and specific causes of death were compared with those of the Japanese population. Among relapse-free survivors at 2 years, overall survival percentages at 10 and 15 years were 87% and 83%, respectively. The overall risk of mortality was significantly higher compared with that of the general population. The risk of mortality was significantly higher from infection (SMR = 57.0), new hematologic malignancies (SMR = 2.2), other new malignancies (SMR = 3.0), respiratory causes (SMR = 109.3), gastrointestinal causes (SMR = 3.8), liver dysfunction (SMR = 6.1), genitourinary dysfunction (SMR = 17.6), and external or accidental causes (SMR = 2.3). The overall annual mortality rate showed a steep decrease from 2 to 5 years after HCT; however, the decrease rate slowed after 10 years but was still higher than that of the general population at 20 years after HCT. SMRs in the earlier period of 2 to 4 years after HCT and 5 years or longer after HCT were 16.1 and 7.4, respectively. Long-term survivors after allogeneic HCT are at higher risk of mortality from various causes other than the underlying disease that led to HCT. Screening and preventive measures should be given a central role in reducing the morbidity and mortality of HCT recipients on long-term follow-up. [ABSTRACT FROM AUTHOR]

Bone marrow (BM) is the preferred graft source for hematopoietic stem cell transplantation (HSCT) in severe aplastic anemia (SAA) compared with mobilized peripheral blood stem cells (PBSCs). We hypothesized that this recommendation may not apply to those regions where patients present later in their disease course, with heavier transfusion load and with higher graft failure rates. Patients with SAA who received HSCT from an HLA-matched sibling donor from 1995 to 2009 and reported to the Center for International Blood and Marrow Transplant Research or the Japan Society for Hematopoietic Cell Transplantation were analyzed. The study population was categorized by gross national income per capita and region/countries into 4 groups. Groups analyzed were high-income countries (HIC), which were further divided into United States–Canada (n = 486) and other HIC (n = 1264); upper middle income (UMIC) (n = 482); and combined lower-middle, low-income countries (LM-LIC) (n = 142). In multivariate analysis, overall survival (OS) was highest with BM as graft source in HIC compared with PBSCs in all countries or BM in UMIC or LM-LIC ( P < .001). There was no significant difference in OS between BM and PBSCs in UMIC ( P = .32) or LM-LIC ( P = .23). In LM-LIC the 28-day neutrophil engraftment was higher with PBSCs compared with BM (97% versus 77%, P = .002). Chronic graft-versus-host disease was significantly higher with PBSCs in all groups. Whereas BM should definitely be the preferred graft source for HLA-matched sibling HSCT in SAA, PBSCs may be an acceptable alternative in countries with limited resources when treating patients at high risk of graft failure and infective complications. [ABSTRACT FROM AUTHOR]

Pediatric patients with acute myeloid leukemia (AML) mainly receive myeloablative conditioning regimens based on busulfan (BU) or total body irradiation (TBI) before allogeneic hematopoietic cell transplantation (allo-HCT); however, the optimal conditioning regimen remains unclear. To identify which of these regimens is better for pediatric patients, we performed a retrospective analysis of nationwide registration data collected in Japan between 2006 and 2011 to assess the outcomes of patients receiving these regimens before a first allo-HCT. Myeloablative conditioning regimens based on i.v. BU (i.v. BU-MAC) (n = 69) or TBI (TBI-MAC) (n = 151) were compared in pediatric AML patients in first or second complete remission (CR1/CR2). The incidences of sinusoid obstruction syndrome, acute and chronic graft-versus-host disease, and early nonrelapse mortality (NRM) before day 100 were similar for both conditioning groups; however, the incidence of bacterial infection during the acute period was higher in the TBI-MAC group ( P = .008). Both groups showed a similar incidence of NRM, and there was no significant difference in the incidence of relapse between the groups. Univariate and multivariate analyses revealed no significant differences in the 2-year relapse-free survival rates for the i.v. BU-MAC and TBI-MAC groups in the CR1/CR2 setting (71% versus 67%, P = .36; hazard ratio, .73; 95% CI, .43 to 1.24, respectively). TBI-MAC was no better than i.v. BU-MAC for pediatric AML patients in remission. Although this retrospective registry-based analysis has several limitations, i.v. BU-MAC warrants further evaluation in a prospective trial. [ABSTRACT FROM AUTHOR]

Granulocyte colony–stimulating factor (G-CSF) increases the susceptibility of dormant malignant or nonmalignant hematopoietic cells to cytarabine arabinoside (Ara-C) through the induction of cell cycle entry. Therefore, G-CSF–combined conditioning before allogeneic stem cell transplantation might positively contribute to decreased incidences of relapse and graft failure without having to increase the dose of cytotoxic drugs. We conducted a retrospective nationwide study of 336 adult patients with myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (sAML) after single-unit cord blood transplantation (CBT) who underwent 4 different kinds of conditioning regimens: total body irradiation (TBI) ≥ 8 Gy + Ara-C/G-CSF + cyclophosphamide (CY) (n = 65), TBI ≥ 8 Gy + Ara-C + CY (n = 119), TBI ≥ 8 Gy + other (n = 104), or TBI < 8 Gy or non-TBI (n = 48). The TBI ≥ 8 Gy + Ara-C/G-CSF + CY regimen showed significantly higher incidence of neutrophil engraftment (hazard ratio, 1.52; 95% confidence interval [CI], 1.10 to 2.08; P = .009) and lower overall mortality (hazard ratio, .46; 95% CI, .26 to .82; P = .008) rates compared with those without a G-CSF regimen. This retrospective study shows that the G-CSF–combined conditioning regimen provides better engraftment and survival results in CBT for adults with MDS and sAML. [ABSTRACT FROM AUTHOR]

Cord blood has been investigated as an alternative source for hematopoietic stem cell transplantation, but information about its use for multiple myeloma is limited. The purpose of this study was to evaluate the feasibility of cord blood transplantation (CBT) for patients with multiple myeloma. Eighty-six patients with multiple myeloma who underwent a first CBT between 2001 and 2011 were included in this retrospective study. Sixty-two of them had received other types of stem cell transplantation before CBT. The cumulative incidences of neutrophil engraftment at day 50, grade II to IV acute graft-versus-host disease (GVHD), and chronic GVHD were 81.4%, 39.0%, and 19.5%, respectively. The incidence of nonrelapse mortality at 2 years was 39.0%, but it was only 6.2% in patients who underwent planned tandem autologous/reduced-intensity conditioning CBT (auto/RIC-CBT). Progression-free survival (PFS) and overall survival (OS) at 6 years were 13.0% and 15.2%, respectively. Less than a partial response before CBT and lack of prior transplantation were independent significant adverse factors for PFS, whereas the presence of prior transplantation and planned tandem transplantation were associated with better OS. OS at 6 years in patients who underwent auto/RIC-CBT was 45.9%. In addition, the development of chronic GVHD was associated with superior PFS. In conclusion, we demonstrated that cord blood is feasible as an alternative graft source for myeloma patients. Although CBT provided long-term survival for a fraction of patients, optimal use of this graft requires further clinical studies. [ABSTRACT FROM AUTHOR]

Abstract: The number of elderly patients with diffuse large B cell lymphoma (DLBCL) continues to increase but the data regarding autologous stem cell transplantation (ASCT) for elderly patients are limited. We analyzed 484 patients, ages 60 years or over, diagnosed with relapsed/refractory DLBCL who received ASCT from 1993 to 2010 in the Japan Society for Hematopoietic Cell Transplantation database. Median age was 64 years (range, 60 to 78). To evaluate the impact of age at ASCT, patients were classified into 3 groups: those between the ages of 60 to 64, 65 to 69, and 70 years or over. Overall nonrelapse mortality (NRM) at day 100, 1 year, and 2 years was 4.1%, 5.9% and 7.7%, respectively. NRM did not significantly differ among age groups (P = .60). Two-year progression-free survival (PFS) and overall survival (OS) were 48% and 58%, respectively. PFS and OS were significantly longer in patients 60 to 64 years old; however, the survival rate was acceptable even in those 70 or over, with a 2-year OS of 46%. ASCT is feasible in selected elderly patients and age alone should not be a contraindication for ASCT. Eligibility should be individualized and identification of a subset of elderly patients at high risk of treatment-related morbidity or mortality warrants investigation. [Copyright &y& Elsevier]

Abstract: An earlier report identified higher risks of acute and chronic graft-versus-host disease (GVHD) in White children compared with the Japanese after HLA-matched sibling transplantations. The current analysis explored whether racial differences are associated with GVHD risks after unrelated umbilical cord blood transplantation. Included are patients of Japanese descent (n = 257) and Whites (n = 260; 168 of 260 received antithymocyte globulin [ATG]). Transplants were performed in the United States or Japan between 2000 and 2009; patients were aged 16 years or younger, had acute leukemia, were in complete remission, and received a myeloablative conditioning regimen. The median ages of the Japanese and Whites who received ATG were younger at 5 years compared with 8 years for Whites who did not receive ATG. In all groups most transplants were mismatched at 1 or 2 HLA loci. Multivariate analysis found no differences in risks of acute GVHD between the Japanese and Whites. However, chronic GVHD was higher in Whites who did not receive ATG compared with the Japanese (hazard ratio, 2.16; P < .001), and treatment-related mortality was higher in Whites who received ATG compared with the Japanese (relative risk, 1.81; P = .01). Nevertheless, there were no significant differences in overall survival between the 3 groups. [Copyright &y& Elsevier]

Recent reports revealed that intravenous (iv) busulfan (BU) may not only reduce early nonrelapse mortality (NRM) but also improve overall survival (OS) probability in adults. Therefore, we retrospectively compared outcomes for 460 children with acute leukemia who underwent hematopoietic stem cell transplantation with either iv-BU (n = 198) or oral busulfan (oral-BU) (n = 262) myeloablative conditioning. OS at 3 years was 53.4% ± 3.7% with iv-BU and 55.1% ± 3.1% with oral-BU; the difference was not statistically significant (P = .77). OS at 3 years in 241 acute lymphoblastic leukemia and 219 acute myeloid leukemia patients was 56.4% ± 5.5% with iv-BU and 54.6% ± 4.1 with oral-BU (P = .51) and 51.0% ± 5.0% with iv-BU and 55.8% ± 4.8% with oral-BU (P = .83), respectively. Cumulative incidence of relapse at 3 years with iv-BU was similar to that with oral-BU (39.0% ± 3.6% and 36.4% ± 3.1%, respectively; P = .67). Cumulative incidence of NRM at 3 years was 16.6% ± 2.7% with iv-BU and 18.3% ± 2.5% with oral-BU (P = .51). Furthermore, multivariate analysis showed no significant survival advantage with iv-BU. In conclusion, iv-BU failed to show a significant survival advantage in children with acute leukemia. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

To compare the different stem cell sources used in salvage transplantation for graft failure (GF) after cord blood transplantation (CBT), we retrospectively analyzed data of 220 patients who developed GF after undergoing CBT between January 2001 and December 2007 and underwent a second hematopoietic stem cell transplantation (HSCT) within 3 months. The donor sources for salvage HSCT were cord blood (n = 180), peripheral blood stem cells (PBSCs; n = 24), and bone marrow (BM; n = 16). The cumulative incidence of neutrophil engraftment on day 30 after the second HSCT was 39% with CB, 71% with PBSCs, and 75% with BM. Multivariate analysis revealed that PBSC and BM grafts were associated with a significantly higher engraftment rate than CB (hazard ratio [HR], 7.77; P < .001 and HR, 2.81; P = .016, respectively). Although the incidence of grade II-IV acute graft-versus-host disease was significantly higher in the PBSC group than in the CB group (HR, 2.83; P = .011), the incidence of 1-year nonrelapse mortality was lower in the PBSC group than in the CB group (HR, 0.43; P = .019), and 1-year overall survival was superior in the PBSC group compared with the CB group (HR, 0.45; P = .036). Our results suggest that PBSC is the preferable source of stem cells in salvage HSCT for GF after CBT. [ABSTRACT FROM AUTHOR]

Allogeneic stem cell transplantation (SCT) is the only curative therapy for patients with refractory or relapsed acute leukemia, although the prognosis remains poor. Few reports have described outcomes of SCT in pediatric patients with refractory acute leukemia. To identify prognostic factors for these patients, we retrospectively evaluated SCT outcomes for advanced acute leukemia in 82 pediatric patients from 3 transplant units in Nagoya City between 1990 and 2008. Median age at transplantation was 8 years (range, 0.5-17 years). Transplantation was performed in the first refractory relapse for 53 patients (64.6%), in the second or subsequent relapse for 16 patients (19.5%), and during primary induction failure for 13 patients (15.9%). Only 4 patients (4.9%) underwent transplantation in the untreated first relapse, and 39 patients (47.6%) received unrelated donor progenitor cells. Of the 82 patients, 61 died (77.9%), with a median survival of 7.1 months (95% confidence interval [CI], 4.2-10.0 months). Median disease-free survival (DFS) was 4.7 months (95% CI, 2.6-6.9 months). In multivariate analysis, peripheral blood blasts, cord blood transplantation, and more than 3 courses of previous salvage chemotherapy were predictive of DFS. These results support the notion that allogeneic SCT offers only a small chance of cure for most pediatric patients with refractory or relapsed acute leukemia, and suggest that reduction of the leukemia burden and earlier optimal timing of transplantation are essential for long-term survival even in patients with refractory acute leukemia. [ABSTRACT FROM AUTHOR]

Human herpes virus (HHV)6-associated limbic encephalitis and/or myelitis is one of the life-threatening central nervous system complications following allogeneic hematopoietic stem cell transplantation (HSCT). Recent reports have shown significant correlations of these complications with unrelated cord blood transplantation (UCBT). We retrospectively analyzed 228 allogeneic HSCT recipients in our single institution; 13 patients (5.7%) were diagnosed with HHV6-associated encephalitis/myelitis. This complication was documented in 8 of 51 UCBT recipients (15.7%) and 5 of 177 recipients (2.8%) transplanted with bone marrow or peripheral blood stem cells, indicating a higher incidence of this complication occurring in UCBT recipients (P = .0005). In addition, HHV6-associated encephalitis/myelitis occurred more frequently in recipients who underwent 2 or more HSCTs (7 of 59 recipients [11.9%]), compared to those who received only 1 HSCT (6 of 169 recipients [3.6%], P = .018). Of note, the incidence of this complication increased to 28.6% (6 of 21 recipients), when the analysis was restricted to a second or more UCBT recipients. All 13 patients presented preengraftment immune response prior to the onset of encephalitis. Two patients manifested typical symptoms at the onset of HHV6-associated encephalitis/myelitis, such as memory dysfunction, disorientation, and consciousness disturbance. However, 4 patients presented only with dysesthesia and pruritus, described as typical manifestations of patients with calcineurin-inhibitor-induced pain syndrome (CIPS), and the remaining 7 showed both symptoms, indicating that CIPS-like symptoms might be manifestations of HHV6-associated myelitis. Thus, physicians should be alert to this rare but often fatal complication, particularly for those who receive 2 or more HSCTs using UCB. [ABSTRACT FROM AUTHOR]

Because of a small number of patients, only a few studies have addressed the outcome of bone marrow transplantation (BMT) in children with Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML), who receive graft from a volunteer-unrelated donor (VUD), especially after practical application of imatinib mesylate. The outcomes of BMT from a VUD in 125 children with Ph+ CML were retrospectively reviewed. Patients were identified through the Japan Marrow Donor Program as having undergone BMT between 1993 and 2005 and were aged 1-19 years at the time of transplant (median age, 14 years). The probabilities of 5-year overall survival (OS) and leukemia-free survival (LFS) were 59.3% and 55.5%, respectively. Multivariate analysis identified the following unfavorable survival factors: infused total nucleated cell dose<314×106 /kg (relative risk [RR]=2.43; 95% confidence interval [CI]=1.33-4.44; P =.004), advanced phase (RR=2.43; 95% CI=1.37-4.31; P =.004), and no major cytogenetic response (MCyR) at the time of BMT (RR=6.55; 95% CI=1.98-21.6; P =.002). Of the 17 patients treated with imatinib, 15 (88%) achieved MCyR at the time of BMT, and this group had an excellent 5-year OS of 81.9%. Disease phase, infused total nucleated cell dose, and cytogenetic response were independent risk factors for survival of unrelated BMT. These findings provide important information for assessing the indications for and improving outcome in unrelated BMT for the treatment of pediatric CML. [Copyright &y& Elsevier]

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]

Abstract: Umbilical cord blood (UCB) transplantation is limited by the low number of hematopoietic stem cells in UCB units, which results in a low engraftment rate in transplant recipients. Here, we measured the total nucleated cell count and CD34+, CD3+, CD4+, CD8+, CD14+, and CD16+/56+ cell doses in each UCB unit and evaluated their influence on engraftment and other outcomes in 146 recipients. Multivariate analysis showed a significant association between a higher incidence of successful engraftment and a dose of CD34+ and CD8+ cells above the median (1.4 × 105 and 15.7 × 105 cells/kg, respectively). Engraftment occurred 4 days earlier in patients who received UCB with more than the median dose of CD34+ cells than those receiving UCB at or below the median. Stratification of the group according to CD34+ cell dose revealed a significant influence of the CD8+ cell dose on the time to achieve neutrophil engraftment in patients receiving a lower CD34+ cell dose, whereas there was no significant influence in the patients receiving a higher CD34+ cell dose. These results suggest that consideration of CD34+ and CD8+ cell doses in UCB units may improve the engraftment in recipients of UCB transplantation. [Copyright &y& Elsevier]