工藤 寿子

P>In childhood acute promyelocytic leukaemia (APL), the efficacy of therapy combining cytarabine with all-trans retinoic acid (ATRA) and anthracyclines remains unclear in terms of long-term prognosis. Between August 1997 and March 2004, 58 children with APL (median age: 11 years) were enrolled into an acute myeloid leukaemia (AML) study (AML99-M3) and followed up for a median time of 86 months. The regimen included ATRA and anthracyclines combined with cytarabine in both induction and consolidation. In induction, two patients died of haemorrhage and four patients developed retinoic acid syndrome. Of 58 patients, 56 (96 center dot 6%) achieved complete remission, two of whom relapsed in the bone marrow after 15 and 19 months respectively. Sepsis was a major complication, with an incidence of 5 center dot 6-10 center dot 9% in the consolidation blocks, from which all but one of patients recovered. Consequently, 7-year overall and event-free survival rates were 93 center dot 1% and 91 center dot 4% respectively, and cumulative incidence of relapse plateaued at 3 center dot 6% after 2 years. Follow-up survey of 54 patients revealed no patients with late cardiotoxicity or secondary malignancy, except one with asymptomatic prolongation of QTc interval. This study suggests that the combination of cytarabine with ATRA and anthracycline-based therapy may have useful implications in the perspective of long-term prognosis and late adverse effects for childhood APL.

Background Several studies have suggested that Langerhans cell histiocytosis (LCH) is responsive to treatment with bisphosphonates (BPs) However the efficacy and safety of BPs therapy for childhood LCH is unknown Procedure Data on children with LCH who had received BPs therapy were collected retrospectively from hospitals participating in the Japanese Pediatric Leukemia/Lymphoma Study Group Results Twenty one children with histologically proven LCH were identified Of these the case histories of 16 children who had been treated with pamidronate (PAM) for disease reactivation were analyzed in detail The median post PAM therapy follow up period was 2 8 years (range 0 9-9 3 years) The median age at commencement of PAM therapy was 9 4 years (range 2 3-15 0 years) All children had one or more bone lesions but none had risk organ(RO) involvement In the majority of the children, six courses of PAM were administered at a dose of 1 0 mg/kg/course at 4 week intervals In 12 of the 16 children all active lesions including lesions of the skin (n = 3) and soft tissues (n = 3) resolved Of these children, eight children had no active disease for a median of 3 3 years post PAM therapy (range 1 8-9 3 years) Progression free survival (PFS) was 56 3 +/- 12 4% at 3 years PFS was significantly higher in children with a first reactivation compared with children experiencing a second or subsequent reactivation Conclusions PAM may be an effective treatment for reactivated LCH with bone lesions A prospective trial of the efficacy of PAM in recurrent pediatric LCH is warranted Pediatr Blood Cancer 2011 56 110-115 (C) 2010 Wiley Liss Inc

We present the case of a 15-year-old adolescent boy with recurrent precursor B-cell acute lymphoblastic leukemia, which appeared 9 years and 7 months after a first unrelated allogeneic hematopoietic stem cell transplantation (HSCT). The patient received chemotherapy and a subsequent second unrelated allogeneic HSCT, and was free of the disease 3 years after the second HSCT. A molecular study revealed the same rearrangement pattern at IGK@ in both the first relapse and the later relapse, confirming the common origin of the leukemic blasts at different time points. However, a new V delta 2-D delta 3 rearrangement of TRD@ emerged at the later relapse. A subsequent, more sensitive examination revealed a minor subpopulation with rearrangements at both IGK@ and TRD@, even during the first relapse. This finding suggests that the minor clone, related to the major clone, was present at the first relapse, leading to the later recurrence, even though the major clone at the first relapse had been eradicated by the first allogeneic HSCT. Although a later relapse after allogeneic HSCT is a rare phenomenon, clinicians should keep in mind that later relapses can occur, even after allogeneic HSCT.

From January 1991 to March 2007, 61 children and adolescent with acquired severe aplastic anemia received BMT in our institutions. We retrospectively compared the outcome of 30 cases of matched-sibling donor BMT (MSD-BMT) and 31 cases of unrelated donor BMT (URD-BMT). We observed one graft failure among MSD-BMT recipients and three graft failures among URD-BMT recipients, respectively. No patients in the MSD-BMT group developed grades II-IV acute GVHD compared with 11 of 30 patients (37%) in the URD-BMT group (P < 0.001). One of 30 MSD-BMT recipients (3%) developed chronic GVHD compared with 8 of 30 URD-BMT recipients (27%) (P = 0.013). The incidence of EBV and CMV reactivation was 11 of 20 URD-BMT recipients and 23 of 30, respectively. One patient in the URD-BMT group died of a motor accident 5.5 years after BMT. Ten-year OS was 100% in MSD-BMT recipients and 93.8% (95% CI, 81.9-100%) in URD-BMT recipients, respectively (P = 0.252). Ten-year failure-free survival was 96.7% (95% CI, 90.2-100%) in the MSD-BMT group and 84.7% (95% CI, 70.2-99.2%) in the URD-BMT group, respectively (P = 0.161). Bone Marrow Transplantation (2010) 45, 1508-1513; doi:10.1038/bmt.2009.378; published online 1 February 2010

Langerhans cell histiocytosis (LCH) that is refractory to conventional chemotherapy has a poor outcome. Hematopoietic stem cell transplanta tion (SCT) is a promising approach for refractory LCH because of its immunomodulatory effect. In this study, the outcomes of children with refractory LCH undergoing SCT in Japan were analyzed. Between November 1995 and March 2007, 15 children younger than 15 years (9 males, 6 females) with refractory LCH underwent SCT. The patients' median age at diagnosis was 8 months (range, 28 days to 28 months), and all had failed conventional chemotherapy. The median age at SCT was 23 months (range, 13-178 months). Nine had risk organ involvement at diagnosis, including liver (n = 6), spleen (n = 5), lung (n = 5), and/or hematopoietic system (n = 4). For SCT, a myeloablative regimen was used for 10 patients, and a reduced-intensity conditioning regimen (RIC) was used for five. The donor source varied among the patients, but allogeneic cord blood was primarily used (n = 10). Subsequently, 11 of 15 patients have survived with no evidence of disease, with a 10-year overall survival (OS) rate (median +/- standard error) of 73.3 +/- 11.4%. The 10-year OS rate of nine patients with risk organ involvement at diagnosis was 55.6 +/- 16.6%, whereas six without risk organ involvement have all survived with no evidence of disease (P = 0.07). These results indicate that SCT is promising as a salvage approach for children with refractory LCH. Bone Marrow Transplantation (2010) 45, 901-906; doi: 10.1038/bmt.2009.245; published online 21 September 2009

The present study aimed to identify optimal treatment intensity in children with mosaic Down syndrome (DS) and acute megakaryoblastic leukemia (AMKL). A retrospective review of AMKL patients was undertaken to identify mosaic DS children. Between November 1992 and November 2007, seven children were diagnosed as mosaic DS and AMKL. The median age at diagnosis was 29 months (range 4-34 months). Three patients had a past history of transient abnormal myelopoiesis. UPN1-4 were treated with intermediate-dose cytarabine and UPN4 received additional one course of high-dose cytarabine. All of these patients were remained in first CR. UPN5-7 were treated with high-dose cytarabine according to the AML99 protocol. UPN5 with GATA1 mutation suffered from acute pneumonia and pancreatitis and discontinued chemotherapy. UPN7 relapsed after cessation of chemotherapy and was rescued with allo-PBSCT. The cumulative doses of cytarabine were 3.5-10.65 g/m(2) in the UPN1-4 and 40.4-78.4 g/m(2) in the UPN5-7. The 8-year overall survival was 100% and the 8-year event-free survival 85.7%, respectively. Our retrospective study reveals that patients with mosaic DS and AMKL have a good prognosis. Reduction in intensity may work in patients with mosaic DS as well as with AML-DS.

The aim of this study was to assess the outcome of treatment with 2-chlorodeoxyadenosine (2-CdA) in pediatric patients with Langerhans cell histiocytosis (LCH) in Japan. We retrospectively identified 17 pediatric LCH patients treated with 2-CdA. All patients were refractory or reactivated cases who had been initially treated according to the JLSG-02 protocol of the Japan LCH study group. At initiation of 2-CdA therapy, 4 patients had primary refractory multisystem (MS) disease with risk organ (RO) involvement (MS+), 9 patients had reactivated MS disease [5 MS+ and 4 without RO involvement (MS-)], and the remaining 4 patients had refractory/reactivated multifocal bone disease (MFB). Treatment with 2-CdA (4-9 mg/m(2)/day) was administered on 2-5 consecutive days and repeated every 3-4 weeks for a period that ranged from 2 to 12 months. Four primary refractory patients were treated with 2-CdA combined with high dose of cytarabine. In MS+ patients, response to treatment was observed in 5 of the 9 patients. In MS-/MFB patients, 5 of the 8 patients showed response to treatment. In the patients who were primary refractory or had reactivation during initial chemotherapy, 4 of 10 patients showed good response. On the other hand, in the patients having reactivation while off therapy, 6 of 7 patients showed good response. These findings suggest that 2-CdA is effective for reactivated LCH while off therapy.

Background. Post-transplant outcomes of hemophagocytic lymphohistiocytosis (HLH) patients were analyzed in Japan where Epstein-Barr virus (EBV)-associated severe forms are problematic. Methods. Fifty-seven patients (43 familial HLH [12 FHL2, 11 FHL3, 20 undefined], 14 EBV-HLH) who Underwent Stem Cell transplantation (SCT) between 1995 and 2005 were enrolled based oil the nationwide registration. Results. Fifty-seven patients underwent 61 SCTs, including 4 consecutive SCTs. SCTs were employed using allogeneic donors in 93% of cases (allo 53, twin 1, auto 3). Unrelated donor cord blood transplantation (UCBT) was employed in half of cases (21 FHL, 7 EBV-HLH). Reduced intensity conditioning was used in 26% of cases. The 10-year overall Survival rates (rnedian +/- SE%) were 65.0 +/- 7.9%. in FHL and 85.7 +/- 9.4%. in EBV-HLH patients, respectively. The Survival of UCBT recipients was >65%. in both FHL and EBV-HLH patients. Three Out Of four patients were alive with Successful engraftment after second UCBT. FHL patients showed a Poorer Outcome due to early treatment-related deaths (<100 days, seven patients) and a higher incidence of sequelae than EBV-HLH patients (P=0.02). The risk of death for FHL patients having received all unrelated donor bone marrow transplant was marginally higher than that for a related donor SCT (P=0.05) and that for UCBT (P=0.07). Conclusions. EBV-HLH patients had a better prognosis after SCT than FHL patients. FHL patients showed either an equal or better Outcome even after UCBT compared with the recent reports. UCB might therefore be acceptable as all alternate SCT source for HLH patients, although the optimal conditioning remains to be determined. Pediatr Blood Cancer 2010;54:299-306. (C) 2009 Wiley-Liss, Inc.

Background. Since neither a standard treatment nor a protocol study for single-system single site (SS-s)-type Langerhans cell histiocytosis (LCH) exists, we conducted a nationwide survey in Japan to clarify the epidemiology and clinical outcome of this subtype. Procedure. Questionnaires regarding the clinical course of children with SS-s-type LCH diagnosed between 1995 and 2006 were sent to all members of the Japanese Society of Pediatric Hematology. Results. One hundred forty-six children with histologically proven SS-s LCH were evaluable. The most frequently affected organ was bone (82%), followed by skin (12%). Few patients (14%) had a CNS-RISK lesion defined by the Histiocyte Society. Patients with a skin lesion were diagnosed at a significantly younger age than patients with a bone lesion (median: 6 months vs. 5 years 11 months, P<0.001). The treatment regimen varied, but one-third of the patients in total and 71% of patients with a CNS-RISK lesion received chemotherapy that did not include etoposide. All but one patient attained remission. Ten patients (7%) showed reactivation. Of these, all eight with an initial bone lesion only exhibited reactivation in the bone(s). One patient with an initial skin lesion exhibited reactivation in the thymus. None of the patients died from disease progression or treatment complications. Conclusions. Our retrospective study, in which a relatively large proportion of the patients received chemotherapy, reveals that patients with SS-s LCH have a good prognosis. A prospective study should be conducted to confirm this and to identify the most effective and least toxic therapy for SS-s LCH. Pediatr Blood Cancer 2010;54:98-102. (C) 2009 Wiley-Liss, Inc.

ES is a complication that occurs immediately before or at the timing of neutrophil engraftment following autologous or allogeneic SCT. It is characterized by fever, skin rash, and non-cardiac pulmonary infiltrates. We evaluated the incidence, risk factors, and outcomes of ES following allogeneic SCT in children. Of 100 pediatric patients, 20 (20%) developed ES occurring at a median of 14 days (range 8-27 days) post-transplant. Patients presented with fever (100%), skin rash (100%), diffuse pulmonary infiltration (25%), and body weight gain (85%). On multivariate analysis, significant risk factors for ES included younger age (< 8 yr old) and human leukocyte antigen disparity between donors and recipients. Univariate analysis showed that patients with ES had a higher incidence of developing chronic graft-versus-host disease and ES was not associated with other complications. Event-free survival did not significantly differ between patients with and without ES regardless of the presence of malignant or non-malignant diseases.

Late-onset non-infectious pulmonary complications (LONIPCs) that arise beyond 3 months after allogeneic hematopoietic SCT include bronchiolitis obliterans (BO), bronchiolitis obliterans with organizing pneumonia (BOOP) and idiopathic pneumonia syndrome (IPS). We retrospectively analyzed the incidence and outcome of LONIPCs among pediatric hematopoietic SCT recipients. We included 97 patients who survived for more than 3 months among the 114 who underwent allogeneic hematopoietic SCT between April 1997 and May 2007. Of the 97 enrolled patients, 10 (10.3%) developed LONIPCs at a median of 187 days after hematopoietic SCT (range, 123-826 days). Of the 10 patients with LONIPCs, eight had BO and two had IPS. Multivariate analysis showed that the onset of LONIPCs was associated with high-risk underlying disease and extensive chronic GVHD (hazard ratio, 5.42 (95% confidence interval, 1.36-21.7) and hazard ratio, 11.7 (95% confidence interval, 2.40-57.1), respectively). Only two patients responded to therapy with steroids and six of the 10 patients died. The 5-year OS rate was significantly lower among patients with, than without LONIPCs (28.0 vs 87.2%, P = 0.000). Considering that we are lacking optimal therapies for LONIPCs, strategies aimed at the prevention of LONIPCs should be attempted. Bone Marrow Transplantation (2009) 44, 303-308; doi: 10.1038/bmt.2009.33; published online 6 April 2009

Objective To assess the etiology, prognosis, and appropriate treatment of hemophagocytic lymphohistiocytosis (HLH) in neonates. Study design We collected information on neonates in whom HLH was diagnosed between 1997 and 2007 from participating members of the Japanese Society of Pediatric Hematology. Results HLH was diagnosed in 20 patients within 4 weeks after birth. Of the diagnostic criteria for HLH-2004, the incidence of fever was quite low in preterm infants, and hypertriglyceridemia and neutropenia were uncommon. Familial HLH (n = 6) or severe combined immunodeficiency-associated HLH (n = 1) was diagnosed in 7 patients, and 2 of them have survived. Herpes simplex virus-associated HLH was diagnosed in 6 patients, and 2 of them have survived. The overall survival rate for the 20 patients was 40%. Conclusions HLH is rare in neonates and has a poor prognosis. Early diagnosis and immediate treatment are required when considering the possibility of herpes simplex virus-associated or familial HLH. (J Pediatr 2009; 155:235-8).

Purpose To improve the prognosis in children with newly diagnosed acute myeloid leukemia (AML) by introducing a dose-dense intensive chemotherapy regimen and an appropriate risk stratification system. Patients and Methods Two hundred forty children with de novo AML were treated with continuous cytarabine-based induction therapy and stratified to three risk groups based on the initial treatment response, age, and WBC at diagnosis and cytogenetics. All of the patients were treated with intensive consolidation chemotherapy including three or four courses of high-dose cytarabine. Allogeneic hematopoietic stem-cell transplantation (HSCT) was indicated for only the intermediate-risk patients with matched related donors and for all the high-risk subsets. Results Two hundred twenty-seven children (94.6%) achieved a complete remission (CR). Four children demonstrated induction death. The median follow-up of the live patients was 55 months (range, 37 to 73 months). The 5-year overall survival of all 240 children was 75.6% (95% CI, 70.3% to 81.4%) and event-free survival was 61.6% (95% CI, 55.8% to 68.1%). The 5-year disease- free survival in each risk group were 71.3% ( 95% CI, 63.4% to 80.2%) in the low-risk group (n = 112), 59.8% (95% CI, 50.6% to 70.7%) in the intermediate-risk group (n = 92), and 56.5% (95% CI, 39.5% to 80.9%) in the high-risk group (n = 23). Eight children died during the first CR, including four after HSCT. Conclusion A high survival rate, 75.6% at 5 years, was achieved for childhood with de novo AML in the AML99 trial. The treatment strategy was well tolerated with only 1.7% induction death rate and 3.5% remission death rate. Low-risk children were successfully treated with chemotherapy alone.

Although the known clinical courses of non-severe aplastic anemia (NSAA) in children comprise spontaneous resolution, persistent NSAA, or progression to severe aplastic anemia (SAA), only a few published reports have indicated the outcome of transfusion-independent NSAA. We retrospectively evaluated the incidence and time of progression from transfusion-independent to transfusion-dependent NSAA or SAA. We reviewed the records of 70 children with acquired AA who were referred to our hospital between 1986 and 2006, and among them we found 22 patients who had transfusion-independent NSAA at diagnosis and were treated with supportive care alone until progression to transfusion-dependent AA. 22 patients were followed up for a median of 86 months (range, 11-198 months). The Kaplan-Meier estimates for progression-free survival were 62 +/- A 12 and 22 +/- A 13% at 60 and 120 months after diagnosis, respectively. None of the patients treated with supportive care alone improved hematologically. In conclusion, because the incidence of disease progression was high in patients with NSAA, a prospective randomized trial of early intervention with IST or observation alone until disease progression to SAA, followed by IST when the patients become transfusion-dependent is warranted.

CD4(+)/CD56(+) malignancies tire rare hematologic neoplasms, which have recently been shown to represent the malignant counterpart of plasmacytoid dendritic cells (pDC). A 5-year-old boy initially presented with multiple subcutaneous lesions oil his upper and lower extremities. Skin biopsy results showed large atypical lymphoid cells in the dermis. The blast cells were stained with CD4 and CD56. In the bone marrow aspirate, 20% of the blast cells were found. The patient wits diagnosed as acute unclassified leukemia and received chemotherapy designed for the treatment of acute myeloid leukemia. He achieved a complete remission that lasted for 8 months. However, multiple subcutaneous lesions recurred 1 month after the end of the therapy, with increasing blast cells in his blood. Immunophenotypically, the blast cells were positive for CD2, CD4, CD7, and CD56, and negative for CD3, CD13, CD19, CD33, and CD34 antigens. The blast cells were positive for CD123 (interleukin-3 receptor Of. chain) and blood dendritic cell antigen-2, which are expressed oil pDC. The patient was diagnosed as acute leukemia derived from pDC. The CD4(+), CD56(+), CD3(-), CD13(-), CD19(-), CD33(-) profile is highly suggestive of this disease, and the CD123 and blood dendritic cell antigen-2 markers are useful in helping to diagnose pDC leukemia.

Mutations in RAS, neurofibromatosis type 1 (NF1), and PTPN11, constituents of the granulocyte-macrophage colony-stimulating factor signaling pathway, have been recognized in patients with juvenile myelomonocytic leukemia (JMML). We assessed 71 children with JMML for NRAS, KRAS. and PTPN11 mutations and evaluated their clinical significance. Of the 71 patients, three had been clinically diagnosed with neurofibromatosis type 1, and PTPN11 and NRAS/KRAS mutations were found in 32 (45%) and 13 (18%) patients, respectively. No Simultaneous aberrations were found. Compared with patients with RAS Mutation or without any aberrations, patients with PTPN11 mutation were significantly older at diagnosis and had higher fetal Hb levels, both of which have been recognized as poor prognostic factors. As was expected, overall survival was lower for patients with the PTPN11 mutation than for those without (25 versus 64%; p = 0.0029). In an analysis of 48 patients who received hematopoietic stein cell transplantation, PTPN11 mutations were also associated with poor prognosis for survival. Mutation in PTPN11 was the only unfavorable factor for relapse after hematopoietic stem cell transplantation (p = 0.001). All patients who died after relapse had PTPN11 mutation. These results suggest that JMML with PTPN11 mutation might be a distinct subgroup with specific clinical characteristics and poor outcome.