研究者詳細 - 村松　秀城

論文 - 村松　秀城

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Correlation of rabbit antithymocyte globulin serum levels and clinical outcomes in children who received hematopoietic stem cell transplantation from an alternative donor 査読有り

Elmahdi S., Muramatsu H., Narita A., Torii Y., Ismael O., Kawashima N., Okuno Y., Sekiya Y., Xu Y., Wang X., Hama A., Ito Y., Takahashi Y., Kojima S.

Pediatric Transplantation 20 巻 ( 1 ) 頁： 105 - 113 2016年2月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Pediatric Transplantation

We analyzed the correlation between rabbit ATG (rATG) serum levels and clinical outcomes in 37 children who received rATG at a total dose of 10 or 15 mg/kg during HSCT conditioning from an alternative donor. Fourteen patients had advanced malignant diseases, 13 had severe AA, and 10 had inherited disorders. Complete engraftment was achieved in all patients, and no rejection occurred. The cumulative incidence of grades II-IV acute GVHD and extensive chronic GVHD was 27% (95% CI, 12.5-39.6%) and 8.1% (95% CI, 0-23.1%), respectively. Multivariate analysis identified lower rATG levels at week 4 as an independent risk factor in the development of grades II-IV acute GVHD (p = 0.037). Serious infections were not observed in any patient following HSCT. No correlation was found between EBV reactivation and rATG levels at week 2 and week 4 after HSCT. Furthermore, no correlation was found between relapse and rATG levels two and four wk post-transplantation. The probability of five-yr OS among patients was 70.3% (95% CI, 59.8-79.2%). Our results suggest that targeted rATG administration may protect patients from severe acute GVHD without increasing the risk of EBV reactivation or relapse.

DOI： 10.1111/petr.12620

Extrapulmonary tuberculosis mimicking Mendelian susceptibility to mycobacterial disease in a patient with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation 査読有り

Kataoka S., Muramatsu H., Okuno Y., Hayashi Y., Mizoguchi Y., Tsumura M., Okada S., Kobayashi M., Sano C., Sato H., Oh-Iwa I., Ito M., Kojima D., Hama A., Takahashi Y., Kojima S.

Journal of Allergy and Clinical Immunology 137 巻 ( 2 ) 頁： 619 - 622.e1 2016年2月

Abnormal urinalysis on day 7 in patients with IgA vasculitis (Henoch-Schönlein purpura) 査読有り

Kawashima N., Kawada J.I., Nishikado Y., Kitase Y., Ito S., Muramatsu H., Sato Y., Kato T., Natsume J., Kojima S.

Nagoya Journal of Medical Science 78 巻 ( 4 ) 頁： 359 - 367 2016年

記述言語：日本語出版者・発行元：Nagoya Journal of Medical Science

Rare progression to renal failure imposes a burden on children with IgA vasculitis (Henoch-Schönlein purpura, HSP). An abnormal urinalysis on day 7 (7d-UA) may be a surrogate marker for persistent nephritis, but this has not been established. We retrospectively analyzed the risk factors for persistent nephritis in a cohort of 138 children. Of 35 children with abnormal 7d-UA, 24 (69%) had an abnormal urinalysis 6 months after the diagnosis of HSP, which was significantly more than 6 of 103 children (6%) with normal 7d-UA (P < 0.0001). The negative predictive values for normal urinalysis and negative proteinuria 6 months after diagnosis were 0.94 (95% confidence interval [CI], 0.90-0.97) and 0.98 (95% CI, 0.95-0.99), respectively. When children with abnormal urinalysis 6 months after diagnosis were compared with those without, the following factors were significantly associated: age at diagnosis, abnormal urinalysis at diagnosis, abnormal 7d-UA, complement C3, steroid treatment, and presence of abdominal pain. However, multivariate analysis revealed that abnormal 7d-UA was the only significant risk factor for abnormal urinalysis 6 months after diagnosis (odds ratio 54.3, 95% CI 15.3-275, P = 1.89 × 10-6). Abnormal 7d-UA may be an independent risk factor for persistent nephritis, but this should be confirmed in a prospective study.

DOI： 10.18999/nagjms.78.4.359

Aberrant DNA methylation is associated with a poor outcome in Juvenile myelomonocytic leukemia 査読有り

Sakaguchi H., Muramatsu H., Okuno Y., Makishima H., Xu Y., Furukawa-Hibi Y., Wang X., Narita A., Yoshida K., Shiraishi Y., Doisaki S., Yoshida N., Hama A., Takahashi Y., Yamada K., Miyano S., Ogawa S., Maciejewski J.P., Kojima S.

PLoS ONE 10 巻 ( 12 ) 頁： e0145394 2015年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：PLoS ONE

Juvenile myelomonocytic leukemia (JMML), an overlap of myelodysplastic/myeloproliferative neoplasm, is an intractable pediatric myeloid neoplasm. Epigenetic regulation of transcription, particularly by CpG methylation, plays an important role in tumor progression, mainly by repressing tumor-suppressor genes. To clarify the clinical importance of aberrant DNA methylation, we studied the hypermethylation status of 16 target genes in the genomes of 92 patients with JMML by bisulfite conversion and the pryosequencing technique. Among 16 candidate genes, BMP4, CALCA, CDKN2A, and RARB exhibited significant hypermethylation in 72% (67/92) of patients. Based on the number of hypermethylated genes, patients were stratified into three cohorts based on an aberrant methylation score (AMS) of 0, 1-2, or 3-4. In the AMS 0 cohort, the 5-year overall survival (OS) and transplantation-free survival (TFS) were good (69% and 76%, respectively). In the AMS 1-2 cohort, the 5-year OS was comparable to that in the AMS 0 cohort (68%), whereas TFS was poor (6%). In the AMS 3-4 cohort, 5-year OS and TFS were markedly low (8% and 0%, respectively). Epigenetic analysis provides helpful information for clinicians to select treatment strategies for patients with JMML. For patients with AMS 3-4 in whom hematopoietic stem cell transplantation does not improve the prognosis, alternative therapies, including DNA methyltransferase inhibitors and new molecular-targeting agents, should be established as treatment options.

DOI： 10.1371/journal.pone.0145394

Fulminant adenovirus hepatitis after hematopoietic stem cell transplant: Retrospective real-time PCR analysis for adenovirus DNA in two cases 査読有り

Kawashima N., Muramatsu H., Okuno Y., Torii Y., Kawada J.i., Narita A., Nakanishi K., Hama A., Kitamura A., Asai N., Nakamura S., Takahashi Y., Ito Y., Kojima S.

Journal of Infection and Chemotherapy 21 巻 ( 12 ) 頁： 857 - 863 2015年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Infection and Chemotherapy

Background: Viral infection is one of the major causes of mortality in patients undergoing hematopoietic stem cell transplant (HSCT). Systemic infection of adenovirus (AdV) has emerged as a not uncommon viral infection with significant morbidity and mortality as with cytomegalovirus and Epstein-Barr virus infection. Routine surveillance for these viruses has become a clinical practice and subsequent preemptive therapy improves patients' outcomes; however, the effectiveness of preemptive therapy for AdV has not been fully investigated in patients with a lethal form of AdV infection. Methods: Sequential AdV loads were retrospectively analyzed in children with fulminant AdV hepatitis after HSCT. Results: The AdV DNA became detectable (1 × 104 copies/mL) as early as 2 weeks after HSCT. These levels reached >1 × 108 copies/mL at the onset of fulminant hepatitis. However, we determined that γ-glutamyltransferase levels were elevated to >100 IU/L at least 2 weeks before the diagnosis of hepatitis. Conclusions: Our observation raises the possibility that elevated γ-glutamyltransferase could be a sentinel marker for AdV hepatitis, which prompts elaborated monitoring of AdV load and targeted treatment.

DOI： 10.1016/j.jiac.2015.08.018

Serial investigation of PTPN11 mutation in nonhematopoietic tissues in a patient with juvenile myelomonocytic leukemia who was treated with unrelated cord blood transplantation 査読有り

Hiramoto R., Imamura T., Muramatsu H., Wang X., Kanayama T., Zuiki M., Yoshida H., Moroto M., Fujiki A., Chiyonobu T., Osone S., Ishida H., Kojima S., Hosoi H.

International Journal of Hematology 102 巻 ( 6 ) 頁： 719 - 722 2015年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Hematology

After allogeneic stem-cell transplantation, nonhematopoietic tissues contain donor-derived cells; however, whether cells from malignant hematological disease can also be found in nonhematopoietic tissues is unclear. This report describes a juvenile myelomonocytic leukemia (JMML) case with a typical PTPN11 mutation (p.E76K) at different allele frequencies in the bone marrow mononuclear cells, buccal smear cells, and fingernails at diagnosis, which was suggestive of PTPN11 somatic mosaicism; however, the PTPN11 mutation in the buccal smear cells and fingernails was lost after unrelated cord blood transplantation. These results suggest that JMML-derived cells may migrate into and reside in nonhematopoietic tissues and furthermore that these cells can be eradicated by cord blood transplantation.

DOI： 10.1007/s12185-015-1877-y

Comparison of long-term outcomes between children with aplastic anemia and refractory cytopenia of childhood who received immunosuppressive therapy with antithymocyte globulin and cyclosporine 査読有り

Hama A., Takahashi Y., Muramatsu H., Ito M., Narita A., Kosaka Y., Tsuchida M., Kobayashi R., Ito E., Yabe H., Ohga S., Ohara A., Kojima S.

Haematologica 100 巻 ( 11 ) 頁： 1426 - 1433 2015年10月

記述言語：日本語出版者・発行元：Haematologica

The 2008 World Health Organization classification proposed a new entity in childhood myelodysplastic syndrome, refractory cytopenia of childhood. However, it is unclear whether this morphological classification reflects clinical outcomes. We retrospectively reviewed bone marrow morphology in 186 children (median age 8 years; range 1-16 years) who were enrolled in the prospective study and received horse antithymocyte globulin and cyclosporine between July 1999 and November 2008. The median follow-up period was 87 months (range 1-146 months). Out of 186 patients, 62 (33%) were classified with aplastic anemia, 94 (49%) with refractory cytopenia of childhood, and 34 (18%) with refractory cytopenia with multilineage dysplasia. Aplastic anemia patients received granulocyte colony-stimulating factor more frequently and for longer durations than other patients (P<0.01). After six months, response rates to immunosuppressive therapy were not significantly different among the 3 groups. Acquisition of chromosomal abnormalities was observed in 5 patients with aplastic anemia, 4 patients with refractory cytopenia of childhood, and 3 patients with refractory cytopenia with multilineage dysplasia. Although the cumulative incidence of total clonal evolution at ten years was not significantly different among the 3 groups, the cumulative incidence of monosomy 7 development was significantly higher in aplastic anemia than in the other groups (P=0.02). Multivariate analysis revealed that only granulocyte colony-stimulating factor administration duration of 40 days or more was a significant risk factor for monosomy 7 development (P=0.02). These findings suggest that even the introduction of a strict morphological distinction from hypoplastic myelodysplastic syndrome cannot eradicate clonal evolution in children with aplastic anemia.

DOI： 10.3324/haematol.2015.128553

GATA2 and secondary mutations in familial myelodysplastic syndromes and pediatric myeloid malignancies 査読有り

Wang X., Muramatsu H., Okuno Y., Sakaguchi H., Yoshida K., Kawashima N., Xu Y., Shiraishi Y., Chiba K., Tanaka H., Saito S., Nakazawa Y., Masunari T., Hirose T., Elmahdi S., Narita A., Doisaki S., Ismael O., Makishima H., Hama A., Miyano S., Takahashi Y., Ogawa S., Kojima S.

Haematologica 100 巻 ( 10 ) 頁： e398 - e401 2015年10月

Second allogeneic hematopoietic stem cell transplantation in children with severe aplastic anemia 査読有り

Kudo K., Muramatsu H., Yoshida N., Kobayashi R., Yabe H., Tabuchi K., Kato K., Koh K., Takahashi Y., Hashii Y., Kawano Y., Inoue M., Cho Y., Sakamaki H., Kawa K., Kato K., Suzuki R., Kojima S.

Bone Marrow Transplantation 50 巻 ( 10 ) 頁： 1312 - 1315 2015年10月

記述言語：日本語出版者・発行元：Bone Marrow Transplantation

The outcome of 55 children with severe aplastic anemia (SAA) who received a second hematopoietic stem cell transplantation (HSCT) was retrospectively analyzed using the registration data of the Japanese Society for Hematopoietic Cell Transplantation. The 5-year overall survival (OS) and failure-free survival (FFS) after the second transplantation were 82.9% (95% confidence interval (CI), 69.7-90.8)) and 81.2% (95% CI, 67.8-89.4), respectively. FFS was significantly better when the interval between the first and second transplantation was >60 days (88.9%; 95% CI, 73.0-95.7) than when it was ≤60 days (61.4%; 95% CI, 33.3-80.5; P=0.026). All 12 patients who were conditioned with regimens containing fludarabine and melphalan were alive with hematopoietic recovery. These findings justify the recommendation of a second HSCT for children with SAA who have experienced graft failure after first HSCT.

DOI： 10.1038/bmt.2015.153

Late-Onset Combined Immunodeficiency with a Novel IL2RG Mutation and Probable Revertant Somatic Mosaicism 査読有り

Okuno Y., Hoshino A., Muramatsu H., Kawashima N., Wang X., Yoshida K., Wada T., Gunji M., Toma T., Kato T., Shiraishi Y., Iwata A., Hori T., Kitoh T., Chiba K., Tanaka H., Sanada M., Takahashi Y., Nonoyama S., Ito M., Miyano S., Ogawa S., Kojima S., Kanegane H.

Journal of Clinical Immunology 35 巻 ( 7 ) 頁： 610 - 614 2015年9月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Clinical Immunology

Primary immunodeficiency disease (PID) is caused by mutations of more than two hundred immunity-related genes. In addition to the heterogeneity of the diseases, the atypical presentation of each disease caused by hypomorphic mutations or somatic mosaicism makes genetic diagnosis challenging. Next-generation sequencing tests all genes simultaneously and has proven its innovative efficacy in genomics. We describe a male PID patient without any family history of immunodeficiency. This patient suffered from recurrent infections from 1 year of age. Laboratory analysis showed hypogammaglobulinemia. T, B, and NK cells were present, but the T cell proliferative response decreased. Whole-exome sequencing analysis identified an IL2RG p.P58T missense mutation. CD8+ and CD56+ cells showed revertant somatic mosaicism to the wild-type allele. A late-onset and atypical presentation of the X-linked severe combined immunodeficiency (X-SCID) phenotype might be associated with revertant somatic mosaicism in T and NK cells. This patient is the seventh reported case of X-SCID with revertant somatic mosaicism. His classical clinical management did not result in a molecular diagnosis because of the atypical presentation. The coverage that is provided by whole-exome sequencing of most PID genes effectively excluded differential diagnoses other than X-SCID. As next-generation sequencing becomes available in clinical practice, it will enhance our knowledge of PID and rescue currently undiagnosed patients.

DOI： 10.1007/s10875-015-0202-0

Clinical and genetic features of dyskeratosis congenita, cryptic dyskeratosis congenita, and Hoyeraal-Hreidarsson syndrome in Japan 査読有り

Yamaguchi H., Sakaguchi H., Yoshida K., Yabe M., Yabe H., Okuno Y., Muramatsu H., Takahashi Y., Yui S., Shiraishi Y., Chiba K., Tanaka H., Miyano S., Inokuchi K., Ito E., Ogawa S., Kojima S.

International Journal of Hematology 102 巻 ( 5 ) 頁： 544 - 552 2015年9月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Hematology

Dyskeratosis congenita (DKC) is an inherited bone marrow failure (BMF) syndrome typified by reticulated skin pigmentation, nail dystrophy, and mucosal leukoplakia. Hoyeraal-Hreidarsson syndrome (HHS) is considered to be a severe form of DKC. Unconventional forms of DKC, which develop slowly in adulthood but without the physical anomalies characteristic of DKC (cryptic DKC), have been reported. Clinical and genetic features of DKC have been investigated in Caucasian, Black, and Hispanic populations, but not in Asian populations. The present study aimed to determine the clinical and genetic features of DKC, HHS, and cryptic DKC among Japanese patients. We analyzed 16 patients diagnosed with DKC, three patients with HHS, and 15 patients with cryptic DKC. We found that platelet count was significantly more depressed than neutrophil count or hemoglobin value in DKC patients, and identified DKC patients with large deletions in the telomerase reverse transcriptase and cryptic DKC patients with RTEL1 mutations on both alleles. This led to some patients previously considered to have unclassifiable BMF being diagnosed with cDKC through identification of new gene mutations. It thus seems important from a clinical viewpoint to re-examine the clinical characteristics, frequency of genetic mutations, and treatment efficacy in DKC, HHS, and cDKC.

DOI： 10.1007/s12185-015-1861-6

Somatic Mosaicism for a NRAS Mutation Associates with Disparate Clinical Features in RAS-associated Leukoproliferative Disease: a Report of Two Cases 査読有り

Shiota M., Yang X., Kubokawa M., Morishima T., Tanaka K., Mikami M., Yoshida K., Kikuchi M., Izawa K., Nishikomori R., Okuno Y., Wang X., Sakaguchi H., Muramatsu H., Kojima S., Miyano S., Ogawa S., Takagi M., Hata D., Kanegane H.

Journal of Clinical Immunology 35 巻 ( 5 ) 頁： 454 - 458 2015年7月

記述言語：日本語出版者・発行元：Journal of Clinical Immunology

RAS-associated leukoproliferative disease (RALD) is a newly classified disease; thus its clinical features and management are not fully understood. The cases of two patients with characteristic features of RALD are described herein. Patient 1 was a 5-month-old female with clinical features typical of autoimmune lymphoproliferative syndrome (ALPS) and markedly elevated TCRαβ+CD4−CD8− T cell numbers. Genetic analyses failed to detect an ALPS-related gene mutation; however, whole exome sequencing and other genetic analyses revealed somatic mosaicism for the G13D NRAS mutation. These data were indivative of NRAS-associated RALD with highly elevated αβ-double-negative T cells. Patient 2 was a 12-month-old girl with recurrent fever who clearly met the diagnostic criteria for juvenile myelomonocytic leukemia (JMML). Genetic analyses revealed somatic mosaicism, again for the G13D NRAS mutation, suggesting RALD associated with somatic NRAS mosaicism. Notably, unlike most JMML cases, Patient 2 did not require steroids or hematopoietic stem cell transplantation. Genetic analysis of RAS should be performed in patients fulfilling the diagnostic criteria for ALPS in the absence of ALPS-related gene mutations if the patients have elevated αβ-double-negative-T cells and in JMML patients if autoimmunity is detected. These clinical and experimental data increase our understanding of RALD, ALPS, and JMML.

DOI： 10.1007/s10875-015-0163-3

A Female Patient with Incomplete Hemophagocytic Lymphohistiocytosis Caused by a Heterozygous XIAP Mutation Associated with Non-Random X-Chromosome Inactivation Skewed Towards the Wild-Type XIAP Allele 査読有り

Yang X., Hoshino A., Taga T., Kunitsu T., Ikeda Y., Yasumi T., Yoshida K., Wada T., Miyake K., Kubota T., Okuno Y., Muramatsu H., Adachi Y., Miyano S., Ogawa S., Kojima S., Kanegane H.

Journal of Clinical Immunology 35 巻 ( 3 ) 頁： 244 - 248 2015年3月

記述言語：日本語出版者・発行元：Journal of Clinical Immunology

X-linked lymphoproliferative disease (XLP) is a rare inherited immunodeficiency that often leads to hemophagocytic lymphohistiocytosis (HLH). XLP can be classified as XLP1 or XLP2, caused by mutations in SH2D1A and XIAP, respectively. In women, X-chromosome inactivation (XCI) of most X-linked genes occurs on one of the X chromosomes in each cell. The choice of which X chromosome remains activated is generally random, although genetic differences and selective advantage may cause one of the X chromosomes to be preferentially inactivated. Here we describe three patients with pancytopenia, including one female patient, in a Japanese family with a novel XIAP mutation. All three patients exhibited deficient XIAP protein expression, impaired NOD2/XIAP signaling, and augmented activation-induced cell death. In the female patient, the paternally derived X chromosome was non-randomly and exclusively inactivated in her peripheral blood and hair root cells. In contrast to asymptomatic females, this patient exhibied non-random XCI skewed towards the wild-type XIAP allele. This is the first report of a female patient with incomplete HLH resulting from a heterozygous XIAP mutation in association with non-random XCI.

DOI： 10.1007/s10875-015-0144-6

Germline mutation of CBL is associated with moyamoya disease in a child with juvenile myelomonocytic leukemia and Noonan syndrome-like disorder 査読有り

Hyakuna N., Muramatsu H., Higa T., Chinen Y., Wang X., Kojima S.

Pediatric Blood and Cancer 62 巻 ( 3 ) 頁： 542 - 544 2015年3月

記述言語：日本語出版者・発行元：Pediatric Blood and Cancer

Germline mutations in CBL have been identified in patients with Noonan syndrome-like phenotypes, while juvenile myelomonocytic leukemia (JMML) harbors duplication of a germline CBL, resulting in acquired isodisomy. The association between moyamoya disease and Noonan syndrome carrying a PTPN11 mutation has recently been reported. We present a patient with JMML who developed moyamoya disease and neovascular glaucoma. Our patient exhibited a Noonan syndrome-like phenotype. Genetic analysis revealed acquired isodisomy and a germline heterozygous mutation in CBL. This is a rare case of CBL mutation associated with moyamoya disease. Prolonged RAS pathway signaling may cause disruption of cerebrovascular development.

DOI： 10.1002/pbc.25271

Aldehyde dehydrogenase-2 polymorphism contributes to the progression of bone marrow failure in children with idiopathic aplastic anaemia 査読有り

Kawashima N., Narita A., Wang X., Xu Y., Sakaguchi H., Doisaki S., Muramatsu H., Hama A., Nakanishi K., Takahashi Y., Kojima S.

British Journal of Haematology 168 巻 ( 3 ) 頁： 460 - 463 2015年2月

Choreito Formula for BK Virus-associated Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation 査読有り

Kawashima N., Ito Y., Sekiya Y., Narita A., Okuno Y., Muramatsu H., Irie M., Hama A., Takahashi Y., Kojima S.

Biology of Blood and Marrow Transplantation 21 巻 ( 2 ) 頁： 319 - 325 2015年2月

記述言語：日本語出版者・発行元：Biology of Blood and Marrow Transplantation

Therapy for BK virus (BKV)-associated hemorrhagic cystitis (BKV-HC) is limited after hematopoietic stem cell transplantation (HSCT). We examined whether choreito, a formula from Japanese traditional Kampo medicine, is effective for treating BKV-HC. Among children who underwent allogeneic HSCT between October 2006 and March 2014, 14 were diagnosed with BKV-HC (median, 36 days; range, 14 to 330 days) after HSCT, and 6 consecutive children received pharmaceutical-grade choreito extract granules. The hematuria grade before treatment was significantly higher in the choreito group than in the nonchoreito group (. P=.018). The duration from therapy to complete resolution was significantly shorter in the choreito group (median, 9 days; range, 4 to 17 days) than in the nonchoreito group (median, 17 days; range, 15 to 66 days; P=.037). In 11 children with macroscopic hematuria, the duration from treatment to resolution of macroscopic hematuria was significantly shorter in the choreito group than in the nonchoreito group (median, 2 days versus 11 days; P=.0043). The BKV load in urine was significantly decreased 1 month after choreito administration. No adverse effects related to choreito administration were observed. Choreito may be a safe and considerably promising therapy for the hemostasis of BKV-HC after HSCT.

DOI： 10.1016/j.bbmt.2014.10.018

Paroxysmal nocturnal hemoglobinuria and telomere length predicts response to immunosuppressive therapy in pediatric aplastic anemia 査読有り

Narita A., Muramatsu H., Sekiya Y., Okuno Y., Sakaguchi H., Nishio N., Yoshida N., Wang X., Xu Y., Kawashima N., Doisaki S., Hama A., Takahashi Y., Kudo K., Moritake H., Kobayashi M., Kobayashi R., Ito E., Yabe H., Ohga S., Ohara A., Kojima S.

Haematologica 100 巻 ( 12 ) 頁： 1546 - 1552 2015年

記述言語：日本語出版者・発行元：Haematologica

Acquired aplastic anemia is an immune-mediated disease characterized by severe defects in stem cell number resulting in hypocellular marrow and peripheral blood cytopenias. Minor paroxysmal nocturnal hemoglobinuria populations and a short telomere length were identified as predictive biomarkers of immunosuppressive therapy responsiveness in aplastic anemia. We enrolled 113 aplastic anemia patients (63 boys and 50 girls) in this study to evaluate their response to immunosuppressive therapy. The paroxysmal nocturnal hemoglobinuria populations and telomere length were detected by flow cytometry. Forty-seven patients (42%) carried a minor paroxysmal nocturnal hemoglobinuria population. The median telomere length of aplastic anemia patients was −0.99 standard deviation (SD) (range −4.01–+3.01 SD). Overall, 60 patients (53%) responded to immunosuppressive therapy after six months. Multivariate logistic regression analysis identified the absence of a paroxysmal nocturnal hemoglobinuria population and a shorter telomere length as independent unfavorable predictors of immunosuppressive therapy response at six months. The cohort was stratified into a group of poor prognosis (paroxysmal nocturnal hemoglobinuria negative and shorter telomere length; 37 patients) and good prognosis (paroxysmal nocturnal hemoglobinuria positive and/or longer telomere length; 76 patients), respectively. The response rates of the poor prognosis and good prognosis groups at six months were 19% and 70%, respectively (P<0.001). The combined absence of a minor paroxysmal nocturnal hemoglobinuria population and a short telomere length is an efficient predictor of poor immunosuppressive therapy response, which should be considered while deciding treatment options: immunosuppressive therapy or first-line hematopoietic stem cell transplantation.

DOI： 10.3324/haematol.2015.132530

First-line treatment for severe aplastic anemia in children: Bone marrow transplantation from a matched family donor versus immunosuppressive therapy 査読有り

Yoshida N., Kobayashi R., Yabe H., Kosaka Y., Yagasaki H., Watanabe K.I., Kudo K., Morimoto A., Ohga S., Muramatsu H., Takahashi Y., Kato K., Suzuki R., Ohara A., Kojima S.

Haematologica 99 巻 ( 12 ) 頁： 1784 - 1791 2014年12月

記述言語：日本語出版者・発行元：Haematologica

The current treatment approach for severe aplastic anemia in children is based on studies performed in the 1980s, and updated evidence is required. We retrospectively compared the outcomes of children with acquired severe aplastic anemia who received immunosuppressive therapy within prospective trials conducted by the Japanese Childhood Aplastic Anemia Study Group or who underwent bone marrow transplantation from an HLA-matched family donor registered in the Japanese Society for Hematopoietic Cell Transplantation Registry. Between 1992 and 2009, 599 children (younger than 17 years) with severe aplastic anemia received a bone marrow transplant from an HLA-matched family donor (n=213) or immunosuppressive therapy (n=386) as first-line treatment. While the overall survival did not differ between patients treated with immunosuppressive therapy or bone marrow transplantation [88% (95% confidence interval: 86-90) versus 92% (90-94)], failure-free survival was significantly inferior in patients receiving immunosuppressive therapy than in those undergoing bone marrow transplantation [56% (54-59) versus 87% (85-90); P<0.0001]. There was no significant improvement in outcomes over the two time periods (1992-1999 versus 2000-2009). In multivariate analysis, age <10 years was identified as a favorable factor for overall survival (P=0.007), and choice of first-line immunosuppressive therapy was the only unfavorable factor for failure-free survival (P<0.0001). These support the current algorithm for treatment decisions, which recommends bone marrow transplantation when an HLA-matched family donor is available in pediatric severe aplastic anemia.

DOI： 10.3324/haematol.2014.109355

Clinical course of juvenile myelomonocytic leukemia in the blast crisis phase treated by acute myeloid leukemia-oriented chemotherapy and allogeneic hematopoietic stem cell transplantation 査読有り

Ueda S., Sakata N., Muramatsu H., Sakaguchi H., Wang X., Xu Y., Kojima S., Yamaguchi T., Higa T., Takemura T.

International Journal of Hematology 100 巻 ( 5 ) 頁： 502 - 506 2014年11月

記述言語：日本語出版者・発行元：International Journal of Hematology

Juvenile myelomonocytic leukemia (JMML) is a mixed myeloproliferative and myelodysplastic disorder that occurs in early childhood. The clinical course of JMML is highly variable. A third of patients follow a relatively indolent course, although approximately 15 % cases are thought to develop acute myeloid leukemia, referred to as blast crisis. The etiology and clinical characteristics of blast crisis remain unclear. We document the case of a 27-month-old boy who presented with hepatosplenomegaly, skin rash, and lymphadenopathy. An initial diagnosis of acute erythroid leukemia was made according to the French–American–British classification. Following estimation of hypersensitivity to GM-CSF and genetic analysis of PTPN11, he was diagnosed with JMML in the blast crisis phase. Although he had several poor prognostic factors, including monosomy 7 and high HbF percentage, he achieved partial remission after treatment with acute myeloid leukemia-oriented chemotherapy followed by allogeneic hematopoietic stem cell transplantation. He has been in complete remission for over 6 years.

DOI： 10.1007/s12185-014-1638-3

Peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood aplastic anemia 査読有り

Sakaguchi H., Nishio N., Hama A., Kawashima N., Wang X., Narita A., Doisaki S., Xu Y., Muramatsu H., Yoshida N., Takahashi Y., Kudo K., Moritake H., Nakamura K., Kobayashi R., Ito E., Yabe H., Ohga S., Ohara A., Kojima S.

Haematologica 99 巻 ( 8 ) 頁： 1312 - 1316 2014年8月

記述言語：日本語出版者・発行元：Haematologica

Predicting the response to immunosuppressive therapy could provide useful information to help the clinician define treatment strategies for patients with aplastic anemia. In our current study, we evaluated the relationship between telomere length of lymphocytes at diagnosis and the response to immunosuppressive therapy in 64 children with aplastic anemia, using flow fluorescence in situ hybridization. Median age of patients was ten years (range 1.5-16.2 years). Severity of the disease was classified as very severe in 23, severe in 21, and moderate in 20 patients. All patients were enrolled in multicenter studies using antithymocyte globulin and cyclosporine. The response rate to immunosuppressive therapy at six months was 52% (33 of 64). The probability of 5-year failure-free survival and overall survival were 56% (95% confidence interval (CI): 41-69%) and 97% (95%CI: 87-99%), respectively. Median telomere length in responders was -0.4 standard deviation (SD) (-2.7 to +3.0 SD) and -1.5 SD (-4.0 to +1.6 (SD)) in non-responders (P<0.001). Multivariate analysis showed that telomere length shorter than -1.0 SD (hazard ratio (HR): 22.0; 95%CI: 4.19-115; P<0.001), platelet count at diagnosis less than 25×109/L (HR: 13.9; 95%CI: 2.00-96.1; P=0.008), and interval from diagnosis to immunosuppressive therapy longer than 25 days (HR: 4.81; 95%CI: 1.15-20.1; P=0.031) were the significant variables for poor response to immunosuppressive therapy. Conversely to what has been found in adult patients, measurement of the telomere length of lymphocytes at diagnosis is a promising assay in predicting the response to immunosuppressive therapy in children with aplastic anemia. © 2014 Ferrata Storti Foundation.

DOI： 10.3324/haematol.2013.091165

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