Tetsuo Mitsui

Background: The benefit of adding rituximab to standard lymphomes malins B (LMB) chemotherapy for children with high‐risk mature B‐cell non‐Hodgkin lymphoma (B‐NHL) has previously been demonstrated in an international randomized phase III trial, to which the Japanese Pediatric Leukemia/Lymphoma Study Group could not participate.Methods: To evaluate the efficacy and safety of rituximab in combination with LMB chemotherapy in Japanese patients, we conducted a single‐arm multicenter trial.Results: In this study, 45 patients were enrolled between April 2016 and September 2018. A total of 33 (73.3%), 5 (11.1%), and 6 (13.3%) patients had Burkitt lymphoma/leukemia, diffuse large B‐cell lymphoma, and aggressive mature B‐NHL, not otherwise specified, respectively. Ten (22.2%) and 21 (46.7%) patients had central nervous system disease and leukemic disease, respectively. The median follow‐up period was 47.5 months. Three‐year event‐free survival and overall survival were 97.7% (95% confidence interval, 84.9–99.7) and 100%, respectively. The only event was relapse, which occurred in a patient with diffuse large B‐cell lymphoma. Seven patients (15.6%) developed Grade 4 or higher non‐hematologic adverse events. Febrile neutropenia was the most frequent Grade 3 or higher adverse event after the pre‐phase treatment, with a frequency of 54.5%.Conclusion: The efficacy and safety of rituximab in combination with LMB chemotherapy in children with high‐risk mature B‐NHL was observed in Japan.

The arachidonic acid (AA) cascade plays a significant role in platelet aggregation. AA released from membrane phospholipids is metabolized by cyclooxygenase (COX) pathway to thromboxane A₂ (TXA₂) or by 12S-lipoxygenase (ALOX12) to 12-hydroperoxyeicosatetraenoic acid (12-HPETE). In contrast to a well-known role of the COX pathway in platelet aggregation, the role of ALOX12 is not well understood. Platelets of ALOX12-deficient mice exhibit increased sensitivity for ADP-induced aggregation. However, recent evidence strongly suggests a significant role of ALOX12 in platelet aggregation and calcium signaling. 12-HPETE potentiates thrombin- and thromboxane-induced platelet aggregation, and calcium signaling. Inhibition experiments of ALOX12 demonstrated decreased platelet aggregation and calcium signaling in stimulated platelets. We studied a family with a dominantly inherited bleeding diathesis using next-generation sequencing analysis. Platelet aggregation studies revealed that the proband’s platelets had defective aggregation responses to ADP, TXA₂ mimetic U46619, collagen, and AA, normal affinity of TXA₂ receptor for U46619, and normal induction of GTPase activity upon stimulation with U46619. However, the production of inositol 1,4,5-triphosphate (IP₃) was only increased up to 30% of the control upon U46619 stimulation, suggesting a defect in phospholipase C-β2 (PLCB2) activation downstream from TXA₂ receptors. Affected family members had no mutation of PLCB2, but had a heterozygous c.1946A > G (p.Tyr649Cys) mutation of ALOX12. ALOX12 activity in platelets from the affected members was decreased to 25–35% of the control. Our data strongly suggested that a heterozygous c.1946A > G ALOX12 mutation was a disease-causing mutation; however, further experiments are required to confirm the pathogenesis of ALOX12 mutation in platelet aggregation.

Background: Patients with relapsed or refractory lymphoblastic lymphoma (LBL) have a poor prognosis. The efficacy of allogeneic blood stem cell transplantation for treatment of this disease remains unclear in terms of transplantation‐related toxicity. Acute and chronic graft‐versus‐host diseases (GVHD) are both harmful to patients after allogeneic transplantation, but may have some positive effects through a substitute graft‐versus‐lymphoma effect.Methods: To investigate the effect of GVHD on the survival of patients with refractory LBL, we retrospectively studied the outcomes of 213 patients with LBL who underwent first allogeneic stem cell transplantation before the age of 18 years, between 1990 and 2015 in Japan.Results: The five‐year overall survival (OS) and event‐free survival rates after stem cell transplantation were 50.3% (95% confidence interval [CI], 43.2‐56.9) and 47.8% (95% CI, 40.8‐54.4), respectively. In univariate landmark analyses, the probability of OS was significantly better in patients with aGVHD than in those without (P = 0.002, five‐year OS 58.1% vs 39.0%). The probability of OS was also better in patients with cGVHD than in those without (P = 0.036, five‐year OS 72.2% vs 54.7%). Multivariate analysis demonstrated that only aGVHD was associated with better OS (hazard ratio, 0.63; 95% CI, 0.42‐0.94, P = 0.024). Progression and recurrence statuses at SCT were associated with poor prognosis. The patients with grade II aGVHD showed the best prognosis (five‐year OS: 65.6%).Conclusion: Our results suggest that the occurrence of aGVHD may be associated with better outcomes in patients with relapsed/refractory LBL who undergo allogeneic transplantation.

Journal of Human Genetics, official journal of the Japan Society of Human Genetics, publishes original articles and reviews on all aspects of human genetics, including medical genetics and genomics

A 6-year-old boy was diagnosed with FLT3-ITD+acute monoblastic leukemia (AMoL). He showed resistance to 2 cycles of induction chemotherapy with etoposide, cytarabine, and mitoxantrone or idarubicin performed according to the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 protocol. His condition was also refractory to salvage FLAI-GO (fludarabine, cytarabine, idarubicin, and gemtuzumab ozogamicin) chemotherapy. Sequential administration of sorafenib at doses of up to 300 mg/day resulted in the first remission. He underwent bone marrow transplantation from his HLA 2-locus mismatched father. Recurrence was observed on post-transplantation day 71. A sustained partial response was observed after alternate-day readministration of sorafenib 150mg/day. In spite of a donor lymphocyte infusion, his blast cell count increased on day 245. Chemotherapy with an increased dose of sorafenib reduced the blast cell count. Although a second HLA-mismatched allogeneic peripheral blood stem cell transfusion was performed, the patient died of regimen-related toxicity. Herein, we report a pediatric case of primary refractory FLT3-ITD+ AMoL. Further prospective studies are necessary to validate the efficacy of sorafenib treatment.

Background and Procedure: To assess the clinical course with response to second‐line treatment and to evaluate the role of hematopoietic stem cell transplantation (SCT) in children with relapsed or primary refractory lymphoblastic lymphoma (LBL), we analyzed data of 48 patients with relapsed/primary refractory diseases among 260 LBL patients identified in a national survey of 1996–2004.Results: Twenty‐six patients achieved second complete remission; 9 achieved partial remission. Of 13 patients who showed progression despite first and second line therapy, only one patient was alive on the second relapse after unrelated cord blood transplantation. Among 40 relapsed patients, the median time between initial diagnosis and relapse was 12.5 months (range 3–56 months). The sites of relapse were isolated BM (n = 9), primary local site with BM (9), primary local site (6), isolated CNS (4), local site with mediastinum (4), primary local site with other site (4), and others (4). Of all 48 patients, 3 were alive after chemotherapy alone. Of the 33 patients, 14 were alive after high dose chemotherapy (HDC)/SCT. With a 27.5‐month median follow up period, the 3‐year OS rate was 43.2 ± 7.4% (estimate ± SE). Univariate analysis identified two features (relapse within 12 months, T cell phenotype) as significant variables that predicted poor survival. Multivariate analysis showed novel statistically significant variables including relapse within 12 months from initial diagnosis (Hazard ratio 3.60) and absence of HDC/SCT (2.64).Conclusion: Outcomes of patients with relapsed/primary refractory LBL were poor, but HDC/SCT for these patients was associated with good results. Pediatr Blood Cancer 2009;52:591–595.

Shwachman-Diamond syndrome (SDS) is a rare congenital disorder featuring exocrine pancreatic insufficiency, growth retardation, and bone marrow dysfunction. Reports suggest that nearly 25% of all...