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Watanabe N, Takahashi Y, Matsumoto K, Horikoshi Y, Hama A, Muramatsu H, Yoshida N, Yagasaki H, Kudo K, Horibe K, Kato K, Kojima S. Total body irradiation and melphalan as a conditioning regimen for children with hematological malignancies undergoing transplantation with stem cells from HLA-identical related donors. Pediatr Transplantation 2011: 15: 642-649. © 2011 John Wiley & Sons A/S. Abstract: Although some studies have reported that TBI and MEL offer an effective conditioning regimen for autologous SCT in acute leukemia, little has been reported regarding outcomes of allogeneic SCT. We retrospectively evaluated outcomes for 50 pediatric patients who underwent allo-SCT conditioned with intravenous MEL (180-210 mg/m2) and fractionated TBI (12-13.2 Gy) from HLA-identical related donors. Nineteen patients were in CR1, 18 were in CR2, and 13 showed advanced-stage disease (≥CR3). Patients had received allo-SCT from HLA-identical siblings (n = 45) or phenotypically HLA-identical family donors (n = 5). Median duration of follow-up for all disease-free patients was 61 months (range, 8.8-177 months). At the time of analysis, 12 patients had died. Eleven of those died of relapse, and one died of TRM. DFS rates for all patients, patients with AML (n = 12), and patients with lymphoid malignancy (n = 38) were 61.4% and 82.1%, respectively. DFS rates for CR1, CR2, and ≥CR3 cases were 89.2%, 88.1%, and 23.1%, respectively (p < 0.05). MEL/TBI for pediatric patients with hematological malignancies was associated with lower relapse rates and no increase in toxicity, resulting in better survival. [ABSTRACT FROM AUTHOR]

Abstract: Recent molecular studies have revealed that the GM-CSF/RAS signaling pathway plays a central role in the pathogenesis of juvenile myelomonocytic leukemia (JMML). CFU-GM colony assay is an important test for GM-CSF hypersensitivity in patients with JMML, but requires specific skills. We established a simple and easy quantification method to test GM-CSF hypersensitivity, using a 3H-thymidine assay. With this quantification method, JMML patients with RAS mutations showed significantly higher GM-CSF sensitivity than JMML patients with PTPN11 mutations. This method will be useful not only in the diagnosis of JMML, but also to evaluate the difference of GM-CSF sensitivity among patients. [Copyright &y& Elsevier]

Juvenile myelomonocytic leukemia (JMML) is a rare heterogeneous hematological malignancy of early childhood characterized by causative RAS pathway mutations. Classifying patients with JMML using global DNA methylation profiles is useful for risk stratification. We implemented machine learning algorithms (decision tree, support vector machine, and naïve Bayes) to produce a DNA methylation-based classification according to recent international consensus definitions using a well-characterized pooled cohort of patients with JMML (n = 128). DNA methylation was originally categorized into three subgroups: high methylation (HM), intermediate methylation (IM), and low methylation (LM), which is a trichotomized classification. We also dichotomized the subgroups as HM/IM and LM. The decision tree model showed high concordances with 450k-based methylation [82.3% (106/128) for the dichotomized and 83.6% (107/128) for the trichotomized subgroups, respectively]. With an independent cohort (n = 72), we confirmed that these models using both the dichotomized and trichotomized classifications were highly predictive of survival. Our study demonstrates that machine learning algorithms can generate clinical parameter-based models that predict the survival outcomes of patients with JMML and high accuracy. These models enabled us to rapidly and effectively identify candidates for augmented treatment following diagnosis. [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]

Background: Advances in hematopoietic stem cell transplantation have improved the survival rate of malignant diseases and congenital immunodeficiencies. It has become important to assess long-term complications in survivors. To assess neurological abnormalities in children treated by transplantation, diffusion tensor imaging was performed.Methods: Forty children who underwent head diffusion tensor imaging before and after their first transplantation were enrolled. Patients with brain lesions on conventional MRI were excluded. Fractional anisotropy and mean diffusivity were compared between patients and 28 control subjects using tract-based spatial statistics. The Strengths and Difficulties Questionnaire was administered as a behavioral evaluation after transplantation, and diffusion tensor images of patients with and without behavioral abnormalities were compared.Results: The age of patients and controls was 0 to 19 years and 0 to 16 years, respectively. The date of diffusion tensor imaging was 10 to 57 days before and 40 to 153 days after transplantation. Tract-based spatial statistics showed fractional anisotropy reduction in widespread white matter in patients before and after transplantation. Mean diffusivity was high before transplantation and normalized after transplantation. Analysis comparing before and after hematopoietic stem cell transplantation shows no difference in fractional anisotropy and a higher mean diffusivity before hematopoietic stem cell transplantation. In patients with behavioral abnormalities, low fractional anisotropy and high mean diffusivity remained after transplantation.Conclusions: Longitudinal diffusion tensor imaging showed white matter abnormalities in children without conventional MRI abnormalities, which were related to behavioral problems after transplantation. Diffusion tensor imaging is useful for behavioral assessment in children undergoing transplantation. [ABSTRACT FROM AUTHOR]

• 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]

Summary While acute megakaryoblastic leukaemia (AMKL) occurs in children with (DS-AMKL) and without (paediatric non-DS-AMKL) Down syndrome, it can also affect adults without DS (adult non-DS-AMKL). We have analysed these subgroups of patients (11 children with DS-AMKL, 12 children and four adults with non-DS-AMKL) for the presence of molecular lesions, including mutations and chromosomal abnormalities studied by sequencing and single nucleotide polymorphism array-based karyotyping, respectively. In children, AMKL was associated with trisomy 21 (somatic in non-DS-AMKL), while numerical aberrations of chromosome 21 were only rarely associated with adult AMKL. DS-AMKL was also associated with recurrent somatic gains of 1q (4/11 DS-AMKL patients). In contrast to trisomy 21 and gains of 1q, other additional chromosomal lesions were evenly distributed between children and adults with AMKL. A mutational screen found GATA1 mutations in 11/12 DS-AMKL, but mutations were rare in paediatric non-DS-AMKL (1/12) and adult AMKL (0/4). JAK3 (1/11), JAK2 (1/11), and TP53 mutations (1/11) were found only in patients with DS-AMKL. ASXL1, IDH1/2, DNMT3A, RUNX1 and CBL mutations were not found in any of the patient group studied, while NRAS mutation was identified in two patients with paediatric non-DS-AMKL. [ABSTRACT FROM AUTHOR]

EBV-associated T/NK-cell lymphoproliferative disease (T/NK-LPD) is defined as a systemic illness characterized by clonal proliferation of EBV-infected T or NK cells. We prospectively enrolled 108 nonimmunocompromised patients with this disease (50 men and 58 women; median onset age, 8 years; age range, 1-50 years) evidenced by expansion of EBV+ T/NK cells in the peripheral blood; these were of the T-cell type in 64 cases and of the NK-cell type in 44, and were clinically categorized into 4 groups: 80 cases of chronic active EBV disease, 15 of EBV-associated hemophagocytic lymphohistiocytosis, 9 of severe mosquito bite allergy, and 4 of hydroa vacciniforme. These clinical profiles were closely linked with the EBV+ cell immunophenotypes. In a median follow-up period of 46 months, 47 patients (44%) died of severe organ complications. During the follow-up, 13 patients developed overt lymphoma or leukemia characterized by extranodal NK/T-cell lymphoma and aggressive NK-cell leukemia. Fifty-nine received hematopoietic stem cell transplantation, 66% of whom survived. Age at onset of disease (≥ 8 years) and liver dysfunction were risk factors for mortality, whereas patients who received transplantation had a better prognosis. These data depict clinical characteristics of systemic EBV+ T/NK-LPD and provide insight into the diagnostic and therapeutic approaches for distinct disease. [ABSTRACT FROM AUTHOR]