BackgroundFor children with juvenile myelomonocytic leukemia (JMML) who undergo stem cell transplantation (SCT), the role of immunological interventions including withdrawal of immunosuppressive therapy (IST) and donor lymphocyte infusion (DLI) for treatment of disease recurrence remains uncertain.ProcedureWe analyzed serial chimerism status following SCT and evaluated the efficacy of immunological interventions for the management of mixed chimerism (MC) in children with JMML.ResultsChimerism analysis was available in 26 SCT cases following the first and second SCT. MC was observed in 16 cases and withdrawal of IST was performed in 14 cases immediately after identification of MC. Donor lymphocyte infusion (DLI) was performed in five MC cases. Eight MC cases were observed at the time of neutrophil recovery. Following withdrawal of IST, three cases achieved complete chimerism (CC) while the proportion of autologous cells increased rapidly in the remaining five cases. Six MC cases were observed after achievement of hematological remission (HR) and responses to withdrawal of IST were observed in two cases. In the remaining four cases, despite withdrawal of IST, the proportion of autologous cells increased. Five cases received DLI but only one case responded.ConclusionAlthough the benefits of immunological interventions for MC after SCT in JMML were limited, some patients did achieve HR as a result of these treatment modalities without a second SCT. Close monitoring of donor chimerism and early detection of MC is helpful in guiding treatment after SCT in children with JMML. Pediatr Blood Cancer 2013; 60: 116–120. © 2012 Wiley Periodicals, Inc.

Metabolic reprogramming of leukemia cells is important for survival, proliferation, and drug resistance under conditions of metabolic stress in the bone marrow. Deregulation of cellular metabolism, leading to development of leukemia, occurs through abnormally high expression of transcription factors such as MYC and Ecotropic Virus Integration site 1 protein homolog (EVI1). Overexpression of EVI1 in adults and children with mixed lineage leukemia-rearrangement acute myeloid leukemia (MLL-r AML) has a very poor prognosis. To identify a metabolic inhibitor for EVI1-induced metabolic reprogramming in MLL-r AML, we used an XFp extracellular flux analyzer to examine metabolic changes during leukemia development in mouse models of AML expressing MLL-AF9 and Evi1 (Evi1/MF9). Oxidative phosphorylation (OXPHOS) in Evi1/MF9 AML cells accelerated prior to activation of glycolysis, with a higher dependency on glutamine as an energy source. Furthermore, EVI1 played a role in glycolysis as well as driving production of metabolites in the tricarboxylic acid cycle. L-asparaginase (L-asp) exacerbated growth inhibition induced by glutamine starvation and suppressed OXPHOS and proliferation of Evi1/MF9 both in vitro and in vivo ; high sensitivity to L-asp was caused by low expression of asparagine synthetase (ASNS) and L-asp-induced suppression of glutamine metabolism. In addition, samples from patients with EVI1 + MF9 showed low ASNS expression, suggesting that it is a sensitive marker of L-asp treatment. Clarification of metabolic reprogramming in EVI1 + leukemia cells may aid development of treatments for EVI1 + MF9 refractory leukemia.

The outcomes for relapsed and metastatic Ewing sarcoma (EWS) is extremely poor. Therefore, it is important to identify the tumor‐specific targets in these intractable diseases. High focal adhesion kinase (FAK) transcript expression levels in EWS cell lines are known. TAE226 is a dual inhibitor of FAK and insulin‐like growth factor‐I receptor (IGF‐IR), while PF‐562,271 is a dual inhibitor of FAK and proline‐rich tyrosine kinase 2. We compared the cytotoxicity of TAE226 and PF‐562,271 toward three EWS cell lines. TAE226 strongly inhibited proliferation of three cell lines when compared with PF‐562,271. Furthermore, we investigated the efficacy of TAE226 as well as its mechanism of action against EWS. A stable EWS cell line with FAK and IGF‐IR knocked down was established, and microarray analysis revealed dysregulated expression in various pathways. TAE226 treatment of EWS cell lines induced cell cycle arrest, apoptosis, AKT dephosphorylation, and inhibition of invasion. We demonstrated that TAE226 drastically inhibits the local growth of primary tumors and metastasis in EWS using mouse models. Furthermore, the combination of TAE226 and conventional chemotherapy proved to exert synergistic effects. TAE226 may be a candidate single agent or combined therapy drug to be developed for patients who have relapse and metastatic EWS tumors in future.

A 3-year-old male presented with a large retroperitoneal mass and multiple metastases. Biopsy results suggested alveolar rhabdomyosarcoma bearing a methylated O6-methylguanine-DNA methyltransferase (MGMT) gene promoter. Serum microRNA-206 levels were elevated and remained high after three cycles of vincristine, dactinomycin, and cyclophosphamide (VAC).Replacement of vincristine, irinotecan, and temozolomide (VIT) for VAC induced a marked tumor reduction and normalization of the miR-206 levels. The patient completed 14 cycles of VIT with local radiotherapy and has been in remission for 31 months. Temozolomide could be effective for tumors with a methylated MGMT gene promoter. Individualized therapy is warranted for such patients.

Congenital malignant gliomas are rare brain tumors about which few reports have been published. We present the clinical course and genetic alterations in an infant with a congenital malignant glioma detected incidentally by ultrasonography at 36 weeks. The tumor occupied the right temporoparietal region, extended to the posterior fossa, and significantly compressed surrounding structures. The female infant was entirely normal without macrocrania, tense fontanel, or sucking difficulties. The tumor was subtotally resected by two-stage surgery; pathological diagnosis was anaplastic astrocytoma. Immunohistochemical staining was positive for p53 and negative for epidermal growth factor receptor. There was no O(6)-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation, no 1p/19q loss of heterozygosity, and no isocitrate dehydrogenase 1 (IDH1) mutation. She underwent postoperative chemotherapy and is alive and well 12 months after surgery.

Nishikawa T, Inagaki J, Nagatoshi Y, Fukano R, Nakashima K, Ito N, Sawa D, Kawano Y, Okamura J. The second therapeutic trial for children with hematological malignancies who relapsed after their first allogeneic SCT: Long‐term outcomes. Abstract:  The impact of a second all‐SCT on the long‐term outcomes of children who relapse after allo‐SCT has been unclear. We retrospectively analyzed the long‐term outcomes of different salvage treatments for such children. Sixty‐six children with hematological malignancies (40 ALL, 22 AML, three MDS, and one CML) who relapsed after a first allo‐SCT received either a second allo‐SCT (n = 16) or CTx and/or DLI (n = 50). The median follow‐up for all children was 9.1 yr. The five‐yr OS after relapse was significantly better in patients who underwent a second allo‐SCT (42.9%) than in patients treated with CTx and/or DLI (11.8%) (p < 0.05). However, this advantage diminished with increasing time. The eight‐yr OS for these groups of patients were 21.4% and 11.8%, respectively (p = n.s.). Among the 16 patients who received a second allo‐SCT, two died more than five yr after the second allo‐SCT. A second allo‐SCT can therefore lead to a prolonged OS in patients who relapse after allo‐SCT. However, a second allo‐SCT should be selected carefully. This is because the mortality rate is still high, even when there is an extensive duration of time following the second allo‐SCT.

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Systemic mastocytosis (SM) is a disorder characterized by abnormal proliferation of mast cells with KIT mutations, especially in codon 816. The prognosis of patients developing acute myeloid leukemia (AML) from SM is extremely poor, and hematopoietic cell transplantation is recommended. Herein, we describe a case of an 8-year-old female diagnosed with SM developing AML. A KIT M541L variant in SM was identified in leukemic cells, normal hematopoietic cells, and buccal mucosal cells, suggesting a germline polymorphism. The patient has remained in complete remission for 39 months after completion of chemotherapy. SM developing AML without a KIT D816 mutation may be not necessarily associated with a poor prognosis.