Ryosuke Kajiwara

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.

ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype

Fusion genes involving ZNF384 have recently been identified in B-cell precursor acute lymphoblastic leukemia, and 7 fusion partners have been reported. We further characterized this type of fusion gene by whole transcriptome sequencing and/or polymerase chain reaction. In addition to previously reported genes, we identified BMP2K as a novel fusion partner for ZNF384. Including the EP300-ZNF384 that we reported recently, the total frequency of ZNF384-related fusion genes was 4.1% in 291 B-cell precursor acute lymphoblastic leukemia patients enrolled in a single clinical trial, and TCF3-ZNF384 was the most recurrent, with a frequency of 2.4%. The characteristic immunophenotype of weak CD10 and aberrant CD13 and/or CD33 expression was revealed to be a common feature of the leukemic cells harboring ZNF384-related fusion genes. The signature gene expression profile in TCF3-ZNF384-positive patients was enriched in hematopoietic stem cell features and related to that of EP300-ZNF384-positive patients, but was significantly distinct from that of TCF3-PBX1-positive and ZNF384-fusion-negative patients. However, clinical features of TCF3-ZNF384-positive patients are markedly different from those of EP300-ZNF384-positive patients, exhibiting higher cell counts and a younger age at presentation. TCF3-ZNF384-positive patients revealed a significantly poorer steroid response and a higher frequency of relapse, and the additional activating mutations in RAS signaling pathway genes were detected by whole exome analysis in some of the cases. Our observations indicate that ZNF384-related fusion genes consist of a distinct subgroup of B-cell precursor acute lymphoblastic leukemia with a characteristic immunophenotype, while the clinical features depend on the functional properties of individual fusion partners.

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.

Suppressed neutrophil function in children with acute lymphoblastic leukemia

Infection is a major obstacle in cancer chemotherapy. Neutropenia has been considered to be the most important risk factor for severe infection; however, other factors, such as impaired neutrophil function, may be involved in susceptibility to infection in patients undergoing chemotherapy. In this study, we analyzed neutrophil function in children with acute lymphoblastic leukemia (ALL). Whole blood samples were obtained from 16 children with ALL at diagnosis, after induction chemotherapy, and after consolidation chemotherapy. Oxidative burst and phagocytic activity of neutrophils were analyzed by flow cytometry. Oxidative burst of neutrophils was impaired in ALL patients. The percentage of neutrophils with normal oxidative burst after PMA stimulation was 59.0 ± 13.2 or 70.0 ± 21.0% at diagnosis or after induction chemotherapy, respectively, which was significantly lower compared with 93.8 ± 6.1% in healthy control subjects (P = 0.00004, or 0.002, respectively); however, this value was normal after consolidation chemotherapy. No significant differences were noted in phagocytic activity in children with ALL compared with healthy control subjects. Impaired oxidative burst of neutrophils may be one risk factor for infections in children with ALL, especially in the initial periods of treatment.

Methylated chrysin reduced cell proliferation, but antagonized cytotoxicity of other anticancer drugs in acute lymphoblastic leukemia.

The efficacy of 5,7-dimethoxyflavone (DMF), a methylated analog of chrysin, as a therapeutic agent to treat acute lymphoblastic leukemia (ALL) was investigated. Using a panel of ALL cell lines, the IC50 (half-maximal inhibitory concentration) of DMF varied between 2.8 and 7.0 &mgr;g/ml. DMF induced G0/G1 cell cycle arrest, concomitant with a decreased expression of phosphorylated retinoblastoma-associated protein 1. DMF increased the rate of apoptosis, although it was apparent only after a long period of exposure (96 h). The accumulation of oxidative stress was not involved in the growth-inhibitory effects of DMF. As DMF reduced the intracellular levels of glutathione, the combination effects of DMF with other anticancer drugs were evaluated using the improved Isobologram and the combination index method. In the simultaneous drug combination assay, DMF antagonized the cytotoxicity of 4-hydroperoxy-cyclophosphamide, cytarabine, vincristine, and L-asparaginase in all tested ALL cells. This study demonstrated that DMF, a methylated flavone, was an effective chemotherapy agent that could inhibit cell cycle arrest and induce apoptosis in ALL cell lines. However, combination therapy with DMF and other anticancer drugs is not recommended.

Allogeneic hematopoietic stem cell transplantation for Chediak–Higashi syndrome

The clinical outcome of allogeneic HSCT was retrospectively analyzed in eight patients with CHS. In total, six of these eight patients are alive. Four of five patients transplanted with MAC achieved prompt engraftment, and three of the four patients, including two patients with AP before transplant, are alive without disease. In contrast, three patients transplanted with RIC without active AP disease achieved prompt engraftment and survive long term. RIC‐HSCT might be an alternative treatment for CHS similar to other types of HLH, at least for patients without active AP disease.

Leukostasis in Children and Adolescents with Chronic Myeloid Leukemia: Japanese Pediatric Leukemia/Lymphoma Study Group

The details of leukostasis in children and adolescents with chronic myeloid leukemia (CML) are unknown. This study determined the characteristics of leukostasis in children and adolescents with CML.

Kaposiform hemangioendothelioma infiltrates the gut wall: a rare case report.

yotype: 46,XY,t(5;15)(p15.3;q11.2)[3]/ 46,XY[17] (Fig. 1). The multiplex RT-PCR for recurrent genetic abnormalities showed negative results. The cerebrospinal fluid analysis showed no evidence of leukemic infiltration. The patient was treated again with CCG 106B protocol. Recently, he achieved remission after reinduction chemotherapy and was prepared for cord blood transplantation. Although we could not perform the cytogenetic analysis at initial diagnosis in this case, considering the similar immunophenotyping profiles and morphologies between the initial and the relapsed clones, the initial clone was expected to have the same cytogenetic abnormality with t(5;15)(p15.3;q11.2) of the relapsed one. Therefore, we could make a diagnosis in this patient with t(5;15) (p15.3;q11.2) at his age of 21 months. The previously described 7 infant patients in the literature with t(5;15) (p15;q11-13)1–3 were treated on intense protocols and they achieved complete remission (100%) and event-free survival (71%), with a relatively good prognosis, clearly less severe than the 11q23 rearrangement cases.5,6 Our case and Kwon and colleagues’4 case presented leukemia at the age of 21 months and 45 months, respectively, and showed the relatively late onset of the disease compared with the previously reported 7 infant cases.1–3 The case reported by Kwon and colleagues showed leukocytosis and a good response to steroid and continuous complete remission at 20 months, whereas our case revealed cytopenia and a failure to induction chemotherapy, and a recurrence of the disease, which means unfavorable treatment outcome compared with the previously reported ones.1–4 To our knowledge, this case with t(5;15)(p15;q11-q13) is the first report of refractoriness and recurrence of the disease, which means unfavorable treatment outcome and the second case of childhood onset after the one reported by Kwon and colleagues. Although this cytogenetic abnormality in infant ALL has been reported as a favorable prognostic indicator, this case suggests that the prognostic implication of t(5;15)(p15;q11-q13) in childhood ALL should be considered carefully. Larger studies would be required to confirm the prognostic significance of t(5;15)(p15;q11-q13), not only in infant ALL but also in childhood ALL. Seung Hee Lee, MD* In-Suk Kim, MD, PhD* So Eun Jun, MDw Young Tak Lim, MDw Eun Yup Lee, MD* Departments of *Laboratory Medicine wPediatrics, Pusan National University Busan, Korea

Role of Second Transplantation for Children With Acute Myeloid Leukemia Following Posttransplantation Relapse.

In children with acute myeloid leukemia (AML), hematopoietic stem cell transplantation (HSCT) in first remission is indicated for patients with a relatively high risk of relapse. Second HSCT is a curative option; however, few reports have been published about a second HSCT in children for AML with posttransplantation relapse.

Comparison of second transplantation and donor lymphocyte infusion for donor mixed chimerism after allogeneic stem cell transplantation for nonmalignant diseases

Donor mixed chimerism (MC) is an increasing problem after hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases.