Chitose Ogawa

Characterization of pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia with kinase fusions in Japan

Recent studies revealed that a substantial proportion of patients with high-risk B-cell precursor acute lymphoblastic leukemia (BCP-ALL) harbor fusions involving tyrosine kinase and cytokine receptors, such as ABL1, PDGFRB, JAK2 and CRLF2, which are targeted by tyrosine kinase inhibitors (TKIs). In the present study, transcriptome analysis or multiplex reverse transcriptase–PCR analysis of 373 BCP-ALL patients without recurrent genetic abnormalities identified 29 patients with kinase fusions. Clinically, male predominance (male/female: 22/7), older age at onset (mean age at onset: 8.8 years) and a high white blood cell count at diagnosis (mean: 94u2009200/μl) reflected the predominance of National Cancer Institute high-risk (NCI-HR) patients (NCI-standard risk/HR: 8/21). Genetic analysis identified three patients with ABL1 rearrangements, eight with PDGFRB rearrangements, two with JAK2 rearrangements, three with IgH-EPOR and one with NCOR1-LYN. Of the 14 patients with CRLF2 rearrangements, two harbored IgH-EPOR and PDGFRB rearrangements. IKZF1 deletion was present in 16 of the 22 patients. The 5-year event-free and overall survival rates were 48.6±9.7% and 73.5±8.6%, respectively. The outcome was not satisfactory without sophisticated minimal residual disease-based stratification. Furthermore, the efficacy of TKIs combined with conventional chemotherapy without allogeneic hematopoietic stem cell transplantation in this cohort should be determined.

Acute lymphoblastic leukemia and Down syndrome: the collaborative study of the Tokyo Children’s Cancer Study Group and the Kyushu Yamaguchi Children’s Cancer Study Group

The Tokyo Children’s Cancer Study Group (TCCSG) and the Kyushu Yamaguchi Children’s Cancer Study Group (KYCCSG) performed a collaborative analysis of data on children with Down syndrome and acute lymphoblastic leukemia (DS-ALL). Among the 1,139 patients who were enrolled in the TCCSG L99-15, L99-1502, or the KYCCSG ALL 96 study, 13 patients with newly diagnosed ALL had DS. In the DS patients, a significantly higher proportion of patients developed ALL at age 5xa0years or older compared with the non-DS ALL patients (Pxa0<xa00.001). The 5-year relapse-free or overall survival of DS-ALL patients was 50.0 or 61.5%, respectively. Relapse accounted for all causes of death. In the TCCSG L99-15 cohort, the overall survival of DS-ALL patients was 42.9%, which was significantly worse compared with 87.9% in the non-DS population (Pxa0<xa00.001). The survival of patients who received reduced-dose chemotherapy was significantly worse than those who received full-dose chemotherapy (Pxa0<xa00.001). However, a higher dose of methotrexate was not associated with a better outcome. Results of our preliminary study suggest that the survival of DS-ALL patients could be improved by treatment without dose reduction if possible, although the appropriate dose of methotrexate for DS-ALL needs to be determined.

Iodine-131-metaiodobenzylguanidine therapy with reduced-intensity allogeneic stem cell transplantation in recurrent neuroblastoma.

Neuroblastoma is the most common extracranial solid tumor of childhood, and iodine‐131‐metaiodobenzylguanidine (MIBG) therapy is a new approach for grade IV neuroblastoma. We describe the case history of a 3‐year‐old girl with recurrent neuroblastoma who received MIBG therapy with reduced‐intensity allogeneic stem cell transplantation (RIST) because of an extensive bone marrow involvement. The post‐transplant course was uneventful and complete chimerism was obtained. Neither acute nor chronic graft‐versus‐host disease (GVHD) was observed. The patient remained in remission for 3 months after RIST until the second relapse. MIBG therapy combined with RIST warrants further trials. Pediatr Blood Cancer 2008;50:676–678.

Loss of mismatched HLA in myeloid/NK cell precursor acute leukemia relapse after T cell-replete haploidentical hematopoietic stem cell transplantation.

Myeloid/natural killer cell precursor acute leukemia (MNKL) is an aggressive disease with a high relapse rate even after allogeneic hematopoietic stem cell transplantation (SCT). We report a patient with MNKL who had a donor lymphocyte infusion (DLI) for relapse after T cell‐replete human leukocyte antigen (HLA)‐haploidentical SCT, but relapsed again 20 months later with loss of mismatched HLA. This case suggests that a strong graft‐versus‐leukemia effect of haploidentical SCT can be expected in MNKL patients. In the haploidentical setting, DLI should be considered for patients with relapsed leukemia whose leukemic cells have not lost HLA cell surface expression. Pediatr Blood Cancer 2014; 61:1880–1882.

Comprehensive technical and patient-care optimization in the management of pediatric apheresis for peripheral blood stem cell harvesting

BACKGROUNDnPediatric apheresis for peripheral blood stem cell transplantation should be carried out with due concern for low corporeal blood volume and vulnerability to hypocalcemia-related complications, hypovolemic shock, and hypervolemic cardiac overload.nnnSTUDY DESIGN AND METHODSnWe retrospectively investigated a total of 267 apheresis procedures from 1990 to 2013 on 93 children between 0 and 10 years old, including 89 patients and 4 healthy donors, with body weights of 6.3 to 44.0u2009kg.nnnRESULTSnThe median CD34+ cell yield per apheresis procedure was 2.3u2009×u2009106 CD34+ cells/kg (0.2-77.9u2009×u2009106 CD34+ cells/kg). Adverse events occurred in 11.6% of procedures (nu2009=u200931), including mild perivascular pain (nu2009=u200912), emesis (nu2009=u20099), hypotension (nu2009=u20093), urticaria (nu2009=u20092), numbness (nu2009=u20092), chest pain (nu2009=u20091), facial flush (nu2009=u20091), and abdominal pain (nu2009=u20091). Among hypotensive events, shock in a 9.6u2009kg one-year-old boy required emergency treatment in 1996. Thereafter, we adopted continuous injection of calcium gluconate, ionized calcium monitoring, central venous catheter access and circuit priming with albumin in addition to concentrated red cells. Since then we have had fewer complications: 16.4% per apheresis during 1990-1997 versus 5.8% during 1998-2013. No healthy pediatric donors suffered from any late-onset complications related to apheresis or G-CSF administration.nnnCONCLUSIONnBy employing appropriate measures, peripheral blood stem cell apheresis for small children can have an improved safety profile, even for children weighing <10u2009kg.

Pharmacokinetics and Safety of Defibrotide in Healthy Japanese Subjects

Veno-occlusive disease (VOD) is a serious complication commonly occurring after stem cell transplantation (SCT). In VOD, sinusoidal endothelial cells and hepatocytes are damaged because of progressive venular occlusions, leading to hepatocellular necrosis.1–3 VOD severity ranges from mild to severe; severe VOD is defined by the presence of multiorgan failure and is associated with a greater than 85% 100-day mortality rate.4–6 VOD currently has no approved prophylactic or curative treatment in Japan. Defibrotide (DF) is a polydisperse mixture of 90% single-stranded polydeoxyribonucleotides that has antithrombotic, antiischemic, and profibrinolytic functions.7–10 DF, which is given 4 times a day at a dose of 6.25mg/kg, has been approved by the European Medicines Agency for the treatment of severe hepatic VOD in SCT therapy. It is an investigational drug that has been granted orphan drug status by the Food and Drug Administration. To support the clinical development of DF for VOD treatment in Japan, we investigated the pharmacokinetics and evaluated the safety of DF in healthy Japanese subjects.

Treatment outcome of children with acute lymphoblastic leukemia: the Tokyo Children’s Cancer Study Group (TCCSG) Study L04-16

The survival rate of children with acute lymphoblastic leukemia (ALL) has increased to approximately 90% after substantial progress in risk-oriented treatment strategies. Between 2005 and 2013, the Tokyo Children’s Cancer Study Group (TCCSG) conducted a risk-oriented, non-randomized study, L04-16. The principal aim of this study was to assemble background characteristicsxa0and treatment outcomes, and gather genetic information on leukemic cells under central diagnosis. This report outlines the background characteristics and treatment outcomes of 1033 children with ALL treated according to a TCCSG platform. The 5-year event-free and overall survival (OS) rates for all children were 78.1u2009±u20091.3 and 89.6u2009±u20091.0%, respectively. The OS rate was significantly higher in children with B-cell precursor (BCP)-ALL (91.9u2009±u20091.0%, nu2009=u2009916) than in those with T-ALL (71.9u2009±u20094.3%, nu2009=u2009117, pu2009<u20090.001). In univariate analysis for BCP-ALL, children aged 1–6xa0years (5y-OS: 94.2u2009±u20091.0%), with an initial white blood cell count ofu2009<u200920,000/μL (94.0u2009±u20091.0%), high hyperdiploidy (95.4u2009±u20091.6%), ETV6-RUNX1 (97.4u2009±u20091.2%) or TCF3-PBX1 (96.9u2009±u20092.1%), and “Day8NoBlasts” (96.4u2009±u20091.1%) had the best outcomes. Genetic investigation revealed two novel fusion genesxa0within this cohort: ETV6-ZNF385A and ZNF362-TCF4. Our study highlighted the clinical aspects of genomic features of ALL in Japanese children. We provide fundamental information for the further molecular investigation of this disease.

A case of recurrent histiocytic sarcoma with MAP2K1 pathogenic variant treated with the MEK inhibitor trametinib

Histiocytic sarcoma in advanced clinical stages is typically an aggressive neoplasm, with poor response to conventional chemotherapy. An 18-year-old male with refractory histiocytic sarcoma that had transformed from Rosai–Dorfman disease was admitted to our hospital. A pathogenic variant of MAP2K1 was detected by next-generation sequencing of tumor specimens. Affected regions showed excellent responses to the MEK inhibitor trametinib. It has been reported that RAS/MEK/ERK pathway is activated in many cases of histiocytic sarcoma. MEK inhibition may represent a useful treatment option in histiocytic sarcoma.

Cyclophosphamide-induced hemorrhagic cystitis in young patients with solid tumors: A single institution study

Although hemorrhagic cystitis (HC) is a significant complication in young patients who undergo chemotherapy with cyclophosphamide (CPA), risk factors and supportive care to prevent HC are unclear. This study attempted to identify optimal supportive care to prevent CPA‐induced HC.

Haploidentical hematopoietic cell transplantation for disseminated Ewing sarcoma

We describe the case of a 13‐year‐old girl with multifocal disseminated Ewing sarcoma family of tumor (ESFT) who received a 5/8 human leukocyte antigen‐matched haploidentical hematopoietic cell transplantation to generate a graft‐versus‐tumor effect. The patient had grade 2 acute graft‐versus‐host disease (GVHD) of the skin and chronic GVHD nausea and abdominal pain that required prednisolone for 17 months, but has been free from ESFT for 3 years 10 months after therapy. The present case suggests a beneficial effect of haploidentical hematopoietic cell transplantation in disseminated ESFT.