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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]

Summary: Patients with acute megakaryoblastic leukaemia of Down syndrome (DS‐AMKL) have an excellent survival rate; however, patients with non‐DS‐AMKL experience poor outcomes. Therefore, this study retrospectively analysed 203 children with non‐DS‐AMKL who underwent their first haematopoietic cell transplantation (HCT) from 1986 to 2015 using a nationwide Japanese HCT registry data to assess HCT outcomes for non‐DS‐AMKL. The 5‐year overall survival (OS) and event‐free survival (EFS) rates were 43% and 38% respectively. The 5‐year OS rate was significantly higher for patients who underwent HCT in the first complete remission (CR1, 72%) than for those in the second CR (CR2, 23%) and non‐CR (16%) (p < 0.001), and for those from a human leukocyte antigen (HLA)‐matched (52%) than for those from an HLA‐mismatched donor (27%) (p < 0.001). Multivariate analysis for OS revealed that HCT in CR2 and non‐CR was a significant risk factor (hazard ratio, 5.86; 95% confidence interval, 3.56–9.53; p < 0.001). The 3‐year EFS in patients who received HCT in CR1 using reduced‐intensity conditioning (RIC, 35%) was significantly lower than in those using myeloablative conditioning (busulfan‐based, 71%; total body irradiation‐based, 58%) (p < 0.001). Risk stratification in patients with non‐DS‐AMKL should be established to determine HCT indication in CR1. [ABSTRACT FROM AUTHOR]

Summary: In 2008, the World Health Organization proposed a new entity of childhood myelodysplastic syndrome (MDS), which was referred to as refractory cytopenia of childhood (RCC). However, whether this morphological classification reflects clinical outcomes remains unclear. We performed a prospective evaluation of bone marrow morphology in 252 children with acquired bone marrow failure between 2009 and 2013. Of 252 patients, 63 were diagnosed with aplastic anaemia (AA), 131 with RCC without multilineage dysplasia (RCC‐w/o‐MLD) and 58 with RCC with MLD (RCC‐MLD). One patient with AA, three with RCC‐w/o‐MLD and nine with RCC‐MLD presented with chromosomal abnormalities at diagnosis (P = 0·001). The response rates to immunosuppressive therapy (IST) at 6 months and the cumulative incidence of clonal evolution at 5 years did not significantly differ among the three groups. A multivariate analysis revealed that the morphological classification of RCC‐MLD was a significant risk factor for secondary graft failure after haematopoietic cell transplantation (HCT) (P = 0·003). In view of these findings, RCC could be divided into two categories, RCC‐w/o‐MLD and RCC‐MLD, because children with this condition exhibited a distinct morphology, frequent chromosomal abnormalities at diagnosis and a high frequency of secondary graft failure after HCT. [ABSTRACT FROM AUTHOR]

ES is a complication that occurs immediately before or at the timing of neutrophil engraftment following autologous or allogeneic SCT. It is characterized by fever, skin rash, and non-cardiac pulmonary infiltrates. We evaluated the incidence, risk factors, and outcomes of ES following allogeneic SCT in children. Of 100 pediatric patients, 20 (20%) developed ES occurring at a median of 14 days (range 8–27 days) post-transplant. Patients presented with fever (100%), skin rash (100%), diffuse pulmonary infiltration (25%), and body weight gain (85%). On multivariate analysis, significant risk factors for ES included younger age (<8 yr old) and human leukocyte antigen disparity between donors and recipients. Univariate analysis showed that patients with ES had a higher incidence of developing chronic graft-versus-host disease and ES was not associated with other complications. Event-free survival did not significantly differ between patients with and without ES regardless of the presence of malignant or non-malignant diseases. [ABSTRACT FROM AUTHOR]

Aplastic anaemia (AA) is defined as a pancytopenia caused by bone marrow failure, and its pathogenesis is thought to involve autoimmune processes. Several predictive markers of the response to immunosuppressive therapy (IST) have been proposed, which appear to reflect the immune pathophysiology. We prospectively investigated the presence of human leucocyte antigen (HLA)-DR15, a minor population of paroxysmal nocturnal haemoglobinuria (PNH)-type cells, and antibodies to the recently identified autoantigen postmeiotic segregation increased 1 (PMS1) in 103 children with AA enrolled in a multicentre study. In contrast to adults, children with AA did not show an increased frequency of HLA-DR15. In addition, a sensitive flow cytometric assay revealed that children with AA have a much lower prevalence of PNH-type cells (21·4%) than reported for adults with this disease. An immunoblotting assay detected anti-PMS1 antibody in 15 of 103 (14·6%) of the children. Finally, the response rate to IST was not significantly different between patients with and without DR15 (45·5% vs. 54·0%), PNH-type cells (68·2% vs. 53·1%) or anti-PMS1 antibody (40·0% vs. 59·1%). The current study did not confirm a correlation between these markers and the response to IST, suggesting that there is a difference in the pathophysiologies of adult and paediatric AA. [ABSTRACT FROM AUTHOR]

To characterize childhood acute megakaryoblastic leukaemia (AMKL), we reviewed 45 children with AMKL diagnosed between 1986 and 2005 at Nagoya University Hospital and Japanese Red Cross Nagoya First Hospital. Twenty-four patients (53%) had AMKL associated with Down syndrome (DS-AMKL) and 21 (47%) had non-DS-AMKL. The median age of the DS-AMKL patients was 21 months (range, 8–38 months) and that of non-DS-AMKL patients was 15 months (range, 2–185 months). The morphology of blast cells was categorized into three groups according to the stage of megakaryocyte maturation. The blast cells were more immature in DS-AMKL than in non-DS-AMKL in terms of morphology and immunophenotyping. Cytogenetic abnormalities of leukaemic cells were classified into seven categories: normal karyotype including constitutional trisomy 21 in DS-AMKL; numerical abnormalities only; t(1;22)(p13;q13); 3q21q26 abnormalities; t(16;21)(p11;q22); −5/del(5q) and/or −7/del(7q); and other structural changes. The outcome of children with either DS-AMKL or non-DS-AMKL is excellent. The 10-year overall survival estimate was 79% [95% confidence interval (CI): 54–90] for DS-AMKL and 76% (95% CI: 58–91) for non-DS-AMKL ( P = 0·81) with a median follow-up of 78 months (range, 20–243 months). Our study shows the diverse heterogeneity of childhood AMKL and the need for subclassification according to cytogenetic and morphological features. [ABSTRACT FROM AUTHOR]

Abstract: Midkine (MK) is a heparin-binding growth factor that is overexpressed in a number of solid cancers. However, expression in acute leukemia has not been clarified. We examined MK gene expression using real-time PCR in 94 children with acute leukemia. In 30 of the 41 patients with B-precursor ALL, MK gene expression was overexpressed than normal BM. MK gene was also overexpressed in more than half of patients with FAB M1 and M2 types of AML. Quantification of MK gene by real-time PCR offers particular promise as a prognostic marker and a marker for minimal residual disease in children with B-precursor ALL. [Copyright &y& Elsevier]

Background: Few population‐based surveys of childhood arterial ischemic stroke (AIS) have been conducted in Asian countries. The aim of this study was to investigate the clinical features, time to diagnosis, and prognosis of childhood AIS in a population‐based cohort in Japan. Methods: Children aged 29 days–15 years 11 months old, residing in the Aichi Prefecture of Japan with radiologically confirmed AIS during 2010–2014, were identified retrospectively through questionnaires. We analyzed 40 children (23 boys, 17 girls; median age, 7 years 3 months), and collected time interval information of 26 patients. The time from clinical onset to first physician assessment and the time to AIS diagnosis were calculated. Results: The most common presentation was paralysis or paresis in 27 patients (71%). No underlying disorders or possible trigger factors were identified in 14 patients (35%). The median time from symptom onset to first physician assessment was 2.9 h. The median time from symptom onset to the confirmed AIS diagnosis was 27.0 h. The diagnosis of AIS was made in the first 6 h after onset of symptoms in 27% of patients for whom the time was available. Radiological diagnosis took longer than 24 h in 54% of these patients. Conclusions: Long in‐hospital delays exist in the diagnosis of AIS in children, likely due to lack of awareness of stroke by doctors. Further efforts to increase public and physician awareness of childhood stroke are needed to ensure early diagnosis and treatment. [ABSTRACT FROM AUTHOR]

The clinical significance of paroxysmal nocturnal haemoglobinuria ( PNH) in children with aplastic anaemia ( AA) remains unclear. We retrospectively studied 57 children with AA between 1992 and 2010. During the follow-up, five patients developed clinical PNH, in whom somatic PIGA mutations were detected by targeted sequencing. The 10-year probability of clinical PNH development was 10·2% (95% confidence interval, 3·6-20·7%). Furthermore, the detection of minor PNH clones by flow cytometry at AA diagnosis was a risk factor for the subsequent development of clinical PNH. These patients with PNH clones at AA diagnosis should undergo periodic monitoring for potential clinical PNH development. [ABSTRACT FROM AUTHOR]

We analyzed the correlation between rabbit ATG (rATG) serum levels and clinical outcomes in 37 children who received rATG at a total dose of 10 or 15 mg/kg during HSCT conditioning from an alternative donor. Fourteen patients had advanced malignant diseases, 13 had severe AA, and 10 had inherited disorders. Complete engraftment was achieved in all patients, and no rejection occurred. The cumulative incidence of grades II- IV acute GVHD and extensive chronic GVHD was 27% (95% CI, 12.5-39.6%) and 8.1% (95% CI, 0-23.1%), respectively. Multivariate analysis identified lower rATG levels at week 4 as an independent risk factor in the development of grades II- IV acute GVHD (p = 0.037). Serious infections were not observed in any patient following HSCT. No correlation was found between EBV reactivation and rATG levels at week 2 and week 4 after HSCT. Furthermore, no correlation was found between relapse and rATG levels two and four wk post-transplantation. The probability of five-yr OS among patients was 70.3% (95% CI, 59.8-79.2%). Our results suggest that targeted rATG administration may protect patients from severe acute GVHD without increasing the risk of EBV reactivation or relapse. [ABSTRACT FROM AUTHOR]

Background Viral infection is one of the major causes of mortality in patients undergoing hematopoietic stem cell transplant (HSCT). Systemic infection of adenovirus (AdV) has emerged as a not uncommon viral infection with significant morbidity and mortality as with cytomegalovirus and Epstein–Barr virus infection. Routine surveillance for these viruses has become a clinical practice and subsequent preemptive therapy improves patients' outcomes; however, the effectiveness of preemptive therapy for AdV has not been fully investigated in patients with a lethal form of AdV infection. Methods Sequential AdV loads were retrospectively analyzed in children with fulminant AdV hepatitis after HSCT. Results The AdV DNA became detectable (1 × 10 4 copies/mL) as early as 2 weeks after HSCT. These levels reached >1 × 10 8 copies/mL at the onset of fulminant hepatitis. However, we determined that γ-glutamyltransferase levels were elevated to >100 IU/L at least 2 weeks before the diagnosis of hepatitis. Conclusions Our observation raises the possibility that elevated γ-glutamyltransferase could be a sentinel marker for AdV hepatitis, which prompts elaborated monitoring of AdV load and targeted treatment. [ABSTRACT FROM AUTHOR]

To evaluate haematopoietic stem cell transplantation ( HSCT) in children and adolescents, we reviewed the records of 47 patients who were ≤18 years, had relapsed or refractory anaplastic large cell lymphoma, and received HSCT between 1990 and 2010. At HSCT, complete remission ( CR) was less common in allogeneic HSCT recipients ( n = 24) than in autologous HSCT recipients ( n = 23) ( P = 0·01). The autologous and allogeneic HSCT groups differed in terms of 5-year event-free survival ( EFS) (38% vs. 50%, P = 0·63), cumulative incidence of progress or relapse (49% vs. 28%, P = 0·25), and treatment-related mortality (12% vs. 25%, P = 0·40). However, these differences were not significant. Patients with non- CR at autologous HSCT had a significantly lower EFS rate (14% vs. 48%, P = 0·03). Conversely, although those with non- CR at allogeneic HSCT had a lower EFS rate, this was not significant (44% vs. 63%, P = 0·26). Reduced-intensity conditioning regimens were used for three of the 16 allogeneic HSCTs received by patients with non- CR. These three patients achieved CR, surviving 32-65 months after HSCT. These results demonstrated that allogeneic HSCT might be a treatment option for patients who do not achieve CR through conventional chemotherapy. [ABSTRACT FROM AUTHOR]

Patients with severe aplastic anemia (SAA) and an absolute neutrophil count (ANC) of 0 typically have fatal outcomes. We defined fulminant AA (FAA) as ANC = 0 for at least 2 weeks prior to and after immunosuppressive therapy (IST). We analyzed the outcomes of 35 children with FAA among 288 children who enrolled in a prospective study for AA (AA-97 study). AA was classified as FAA ( n = 35), very SAA (vSAA; n = 129), or SAA ( n = 124). All of the children received the IST with horse anti-thymocyte globulin (ATG) and cyclosporine (CsA). A significantly lower response rate at 6 months was seen in children with FAA when compared to those with vSAA or SAA (40.0, 63.6, and 63.7 %, respectively; p = 0.027). Of 20 nonresponder patients in the FAA group, 11 were rescued by alternative donor transplantation, and 5 patients showed a late response after 6 months. Consequently, no significant difference was noted in overall survival when comparing the FAA, vSAA, and SAA groups (88.5, 95.8, and 96.8 %). These findings indicate that IST with ATG and CsA is justified as a first-line treatment for children with FAA who lack a human leukocyte antigen-matched sibling donor. [ABSTRACT FROM AUTHOR]

We report a favourable outcome in 15 patients with severe aplastic anaemia (SAA) who were < 20 years of age and who underwent bone marrow transplantation (BMT) from a human leucocyte antigen (HLA)-matched unrelated donor. All patients were non-responders to intensive immunosuppressive therapy (IST) and were multiply transfused. The conditioning regimen consisted of cyclophosphamide (60 mg/kg/d, on d -4 and -3), anti-thymocyte globulin (2·5 mg/kg/d, on d -5 to -2) and total body irradiation (2·5 Gy × 2/d, on d -2 and -1). Patients received cyclosporine and methotrexate for prophylaxis of graft-versus-host disease (GVHD), except for the last four who received tacrolimus instead of cyclosporine. Donor/recipient pairs were identical for HLA class I and II antigens by serological typing, but four pairs were found to have a mismatch at the HLA-A, -B or -DRB1 locus by high-resolution typing. All patients achieved rapid engraftment and are alive at 2–86 months after transplantation (median follow-up, 51 months). Moderate to severe acute GVHD occurred in 5 out of 15 patients (33%); only one patient developed extensive chronic GVHD. Considering our encouraging results, unrelated donor transplantation for SAA is recommended as a salvage therapy in non-responders to IST. [ABSTRACT FROM AUTHOR]

A total of 100 children under the age of 17 years with acquired aplastic anaemia (AA) were initially treated with immunosuppressive therapy (IST) (n = 63) or bone marrow transplantation (BMT) (n = 37) from an HLA-matched family donor. The projected 10-year survival rates were 55 ± 8% and 97 ± 3% respectively (P = 0·004). Because the IST group included 11 non-responders who were salvaged by BMT from an HLA-matched unrelated donor, we compared failure-free survival (FFS) between the groups. The probability of FFS at 10 years was 97 ± 3% for the BMT group, compared with 40 ± 8% for the IST group (P = 0·0001). Seven patients evolved to myelodysplastic syndrome (MDS) with monosomy 7 and the estimated cumulative incidence of MDS 10 years after diagnosis was 20 ± 7% in the IST group. We compared the outcome of children treated with IST during the two consecutive periods of 1983–91 (group A, n = 40) and 1991–8 (group B, n = 23) to assess the impact of combined therapy with anti-thymocyte globulin and cyclosporin. The probability of FFS at 7 years follow-up was the same in the two groups (50 ± 8% vs. 40 ± 15%, P = 0·40). We recommend BMT as first-line therapy in paediatric severe AA patients with an HLA-matched family donor. Alternative donor BMT is recommended as salvage therapy in patients who relapse or do not respond to initial IST. [ABSTRACT FROM AUTHOR]

The article focuses on association of aldehyde dehydrogenases (ALDHs) enzymes with progression of bone marrow failure (BMF) in children with idiopathic aplastic anaemia. It states that immunosuppressive therapy (IST) in children with suppressed aldehyde metabolism is negatively impacted by defects in haematopoietic stem cells (HSCs). The study concludes that endogenous aldehydes damages HSCs and leads to early-onset of BMF in children with idiopathic aplastic anaemia.

The article informs that mutation in THPO gene which encodes thrombopoietin is not associated with Aplastic Anaemia (AA). It mentions that THPO is the causative gene for congenital amegakaryocytic thrombocytopenia (CAMT). It further mentions that for the determination of THPO association, the gene sequence consisting of 12 exons were analyzed and these exons were amplified by polymerase chain reaction of genomic DNA from patients with AA. It concludes that no THPO mutations were found.