Reo Tanoshima

Serum sickness with an elevated level of human anti-chimeric antibody following treatment with rituximab in a child with chronic immune thrombocytopenic purpura.

Rituximab, a chimeric murine/human monoclonal anti-CD20 antibody, was licensed for the treatment of B-cell lymphoma and has also shown efficacy against autoimmune diseases such as immune thrombocytopenic purpura (ITP). It is relatively safe; however, about 1–20% of patients were reported to have developed rituximab-induced serum sickness, which is more common among patients with autoimmune conditions than among those with hematologic malignancies. Here we describe a pediatric patient with steroid-dependent chronic ITP who presented with arthralgia and fever ten days after the second infusion of rituximab (on day 10), and presented with malaise and maculopapular rash on day 21. Oral prednisolone was started and his symptoms resolved. He had an elevated level of human anti-chimeric antibody (HACA) on day 27; thereafter, the HACA level slowly decreased. To our knowledge, among pediatric patients who received rituximab for chronic ITP, this is the sixth documented case of serum sickness and the only one who manifested an elevated level of HACA. Rituximab is a beneficial treatment option against chronic ITP; however, the risk of serum sickness should be considered. Steroid, usually used for the treatment of serum sickness, may prevent the development of severe serum sickness when administered during and after rituximab treatment.

Influence of CYP3A5 and ABCB1 gene polymorphisms on calcineurin inhibitor-related neurotoxicity after hematopoietic stem cell transplantation

Yanagimachi M, Naruto T, Tanoshima R, Kato H, Yokosuka T, Kajiwara R, Fujii H, Tanaka F, Goto H, Yagihashi T, Kosaki K, Yokota S. Influence of CYP3A5 and ABCB1 gene polymorphisms on calcineurin inhibitor‐related neurotoxicity after hematopoietic stem cell transplantation. 
Clin Transplant 2010: 24: 855–861.

Graft versus leukemia effect against juvenile myelomonocytic leukemia after unrelated cord blood transplantation.

A 13‐month‐old female underwent unrelated cord blood transplantation (CBT) for juvenile myelomonocytic leukemia (JMML). In spite of progression of the disease after a conditioning regimen with high‐dose chemotherapy, a complete remission was induced in concordance with development of acute GVHD after reduction of the immunosupressant. She has been in complete remission for 1 year after transplantation. This case illustrates that CBT can provide a potent graft versus leukemia (GVL) effect against JMML. Pediatr Blood Cancer 2008;50:665–667.

Chemo-sensitivity in a panel of B-cell precursor acute lymphoblastic leukemia cell lines, YCUB series, derived from children

Sensitivity to 10 anticancer drugs was evaluated in 6 childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cell lines. Authenticity of newly established cell lines was confirmed by genomic fingerprinting. The line YCUB-5R established at relapse was more resistant to 4-hydroperoxy-cyclophosphamide, cytarabine, L-asparaginase, topotecan, fludarabine, and etoposide than YCUB-5 from the same patient at diagnosis. Of the drugs tested, etoposide and SN-38 (irinotecan) showed highest efficacy in the panel, with 50% growth inhibition at 0.22-1.8 microg/ml and 0.57-3.6 ng/ml, respectively. This cell line panel offers an in vitro model for the development of new therapies for childhood BCP-ALL.

High PRDM16 expression identifies a prognostic subgroup of pediatric acute myeloid leukaemia correlated to FLT3-ITD, KMT2A-PTD, and NUP98-NSD1: the results of the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 trial.

Recent reports described the NUP98‐NSD1 fusion as an adverse prognostic marker for acute myeloid leukaemia (AML) and PRDM16 (also known as MEL1) as the representative overexpressed gene in patients harbouring NUP98‐NSD1 fusion. PRDM16 gene expression levels were measured via real‐time polymerase chain reaction in 369 paediatric patients with de novo AML, of whom 84 (23%) exhibited PRDM16 overexpression (PRDM16/ABL1 ratio ≥0·010). The frequencies of patients with high or low PRDM16 expression differed widely with respect to each genetic alteration, as follows: t(8;21), 4% vs. 96%, P < 0·001; inv(16), 0% vs. 100%, P < 0·001; KMT2A (also termed MLL)‐ partial tandem duplication, 100% vs. 0%, P < 0·001; NUP98‐NSD1, 100% vs. 0%, P < 0·001. The overall survival (OS) and event‐free survival (EFS) among PRDM16‐overexpressing patients were significantly worse than in patients with low PRDM16 expression (3‐year OS: 51% vs. 81%, P < 0·001, 3‐year EFS: 32% vs. 64%, P < 0·001) irrespective of other cytogenetic alterations except for NPM1. PRDM16 gene expression was particularly useful for stratifying FLT3‐internal tandem duplication‐positive AML patients (3‐year OS: high = 30% vs. low = 70%, P < 0·001). PRDM16 overexpression was highly recurrent in de novo paediatric AML patients with high/intermediate‐risk cytogenetic profiles and was independently associated with an adverse outcome.

Influence of ADORA2A gene polymorphism on leukoencephalopathy risk in MTX‐treated pediatric patients affected by hematological malignancies

Methotrexate (MTX) can lead to neurotoxicity and asymptomatic leukoencephalopathy. However, the mechanism of MTX‐related leukoencephalopathy is obscure. MTX and its metabolites inhibit 5‐aminoimidazole‐4‐carboxamide ribonucleotide formiltransferase (ATIC) and promote adenosine release. Recently, it has been reported that adenosine and its receptor are related to certain central nervous system diseases. We investigated whether adenosine pathway gene polymorphisms and clinical factors were related to MTX‐related leukoencephalopathy in pediatric patients affected by hematological malignancies.

Hemophagocytic lymphohistiocytosis in very young infants.

We report three cases of hemophagocytic lymphohistiocytosis (HLH) in infants within the first 6 weeks of life. Diagnosis of HLH was made early after symptoms started. All three cases were successfully treated with dexamethasone and none relapsed, indicating that not all cases of HLH in very young infants are familial. Pediatr Blood Cancer 2009;52:137–139.

Association of isochromosome (7)(q10) in Shwachman-Diamond syndrome with the severity of cytopenia

We report two male siblings with SDS. They have the same compound heterozygous mutations. Only one of the siblings acquired cytogenetic abnormality of i(7q) 2 years after diagnosis, became transfusion‐dependent, and underwent allogeneic hematopoietic stem cell transplantation. These cases indicate that i(7q) is associated with significant cytopenia in SDS patients.

Population pharmacokinetics of thrombomodulin alfa in pediatric patients with hematological malignancy and disseminated intravascular coagulation

Thrombomodulin alfa (TM‐α) is a new class of anticoagulant drug for patients with disseminated intravascular coagulation (DIC). This study aimed to determine the pharmacokinetics of TM‐α and determine the optimal dose in pediatric patients with hematological malignancy and DIC.

Encouraging option of multi-staged gross total resection for a C11orf - RelA fusion-positive supratentorial anaplastic ependymoma

Ependymomas are primary neuroepithelial malignancies that mainly occur during childhood, and arise from ependymal cells along the ventricular systems of the CNS. Recently, it was elucidated that two-thirds of supratentorial (ST) ependymomas harbor oncogenic fusions of RELA, whose protein product is the principal effector of canonical NF-κB signaling. RELA fusion proteins activate signaling for tumor proliferation and malignant progression, resulting in poorer prognoses in these patients compared to those in patients with other ST ependymomas. In this study, we encountered a case of C11orf–RelA fusion-positive ST anaplastic ependymoma that was diagnosed in first tumor resection surgery of multi-staged gross total resection with molecular evidence. In ependymomas, regardless of tumor location or pathological grade, subtotal resection is associated with higher rates of mortality compared with GTR. Molecular analysis based on the application of recent molecular knowledge for ST ependymomas performs a role in appropriate and individualized treatment strategies.