Faculty Profiles - MURAMATSU, Hideki

Papers - MURAMATSU, Hideki

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Total body irradiation and melphalan as a conditioning regimen for children with hematological malignancies undergoing transplantation with stem cells from HLA-identical related donors Reviewed

Watanabe N., Takahashi Y., Matsumoto K., Horikoshi Y., Hama A., Muramatsu H., Yoshida N., Yagasaki H., Kudo K., Horibe K., Kato K., Kojima S.

Pediatric Transplantation Vol. 15 ( 6 ) page： 642 - 649 2011.9

Language：Japanese Publisher：Pediatric Transplantation

Although some studies have reported that TBI and MEL offer an effective conditioning regimen for autologous SCT in acute leukemia, little has been reported regarding outcomes of allogeneic SCT. We retrospectively evaluated outcomes for 50 pediatric patients who underwent allo-SCT conditioned with intravenous MEL (180-210 mg/m 2) and fractionated TBI (12-13.2 Gy) from HLA-identical related donors. Nineteen patients were in CR1, 18 were in CR2, and 13 showed advanced-stage disease (≤yen;CR3). Patients had received allo-SCT from HLA-identical siblings (n = 45) or phenotypically HLA-identical family donors (n = 5). Median duration of follow-up for all disease-free patients was 61 months (range, 8.8-177 months). At the time of analysis, 12 patients had died. Eleven of those died of relapse, and one died of TRM. DFS rates for all patients, patients with AML (n = 12), and patients with lymphoid malignancy (n = 38) were 61.4% and 82.1%, respectively. DFS rates for CR1, CR2, and ≤yen;CR3 cases were 89.2%, 88.1%, and 23.1%, respectively (p < 0.05). MEL/TBI for pediatric patients with hematological malignancies was associated with lower relapse rates and no increase in toxicity, resulting in better survival. © 2011 John Wiley & Sons A/S.

DOI： 10.1111/j.1399-3046.2011.01544.x

[Bone marrow findings of childhood aplastic anemia: analyses of 140 cases by central reviewers]. Reviewed

Hama A., Yoshimi A., Sakaguchi H., Doisaki S., Muramatsu H., Shimada A., Takahashi Y., Nozawa K., Ito M., Tsuchida M., Manabe A., Ohara A., Kojima S.

[Rinshō ketsueki] The Japanese journal of clinical hematology Vol. 52 ( 8 ) page： 653 - 658 2011.8

Language：Japanese Publisher：[Rinshō ketsueki] The Japanese journal of clinical hematology

The revised WHO classification proposed the term "refractory cytopenia of childhood (RCC)" for children with myelodysplastic syndrome (MDS) with a low blast count. The differential diagnosis between RCC and aplastic anemia (AA) is challenging, especially when bone marrow is hypoplastic and there is no detectable chromosomal abnormality. To reveal the difference between AA and RCC with respect to the clinical and biological features, we retrospectively reviewed the bone marrow smears of 140 patients registered for childhood AA-97 study, which were classified into three groups as follows; the AA group was defined as having no morphologically dysplastic changes; the AA-RCC borderline group was defined as having <10% dysplastic changes in the erythroid lineage only; and the RCC group was defined as having dysplastic changes in more than two cell lineages or >10% in a single cell lineage. The patients were classified into the AA group (n=96, 69%), AA-RCC borderline group (n=20, 14%) and RCC group (n=24, 17%). Most of the patients in the AA group were classified as having very severe disease, whereas most of the patients in the RCC group were classified as non-severe disease. Only 2 patients in the AA group developed acute myeloid leukemia. The response rate to immunosuppressive therapy did not differ among the 3 groups. To demonstrate whether the two diseases are truly different entities, it is necessary to compare molecular backgrounds between the AA and RCC groups.

CD20-negative Epstein-Barr virus-associated post-transplant lymphoproliferative disease refractory to rituximab in a patient with severe aplastic anemia Reviewed

Muramatsu H., Takahashi Y., Shimoyama Y., Doisaki S., Nishio N., Ito Y., Hama A., Shimada A., Yagasaki H., Ito M., Kojima S.

International Journal of Hematology Vol. 93 ( 6 ) page： 779 - 781 2011.6

Language：Japanese Publisher：International Journal of Hematology

Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV-PTLD) is a life-threatening complication following allogeneic hematopoietic stem cell transplantation (HSCT). Monitoring of EBV DNA in high-risk patients with subsequent pre-emptive rituximab treatment is highly effective, and can prevent EBV-associated disease following HSCT. Here, we report a 10-year-old girl with aplastic anemia who developed CD20 negative EBV-PTLD after unrelated bone marrow transplantation that was refractory to rituximab treatment. Similar to other types of lymphoma, the absence of CD20 antigen is likely to be characteristic of rituximab-refractory EBV-PTLD. © 2011 The Japanese Society of Hematology.

DOI： 10.1007/s12185-011-0870-3

Relapse of aplastic anemia in children after immunosuppressive therapy: A report from the Japan childhood aplastic anemia study group Reviewed

Kamio T., Ito E., Ohara A., Kosaka Y., Tsuchida M., Yagasaki H., Mugishima H., Yabe H., Morimoto A., Ohga S., Muramatsu H., Hama A., Kaneko T., Nagasawa M., Kikuta A., Osugi Y., Bessho F., Nakahata T., Tsukimoto I., Kojima S.

Haematologica Vol. 96 ( 6 ) page： 814 - 819 2011.6

Language：Japanese Publisher：Haematologica

Background Although the therapeutic outcome of acquired aplastic anemia has improved markedly with the introduction of immunosuppressive therapy using antithymocyte globulin and cyclosporine, a significant proportion of patients subsequently relapse and require second-line therapy. However, detailed analyses of relapses in aplastic anemia children are limited. Design and Methods We previously conducted two prospective multicenter trials of immunosuppressive therapy for children with aplastic anemia: AA-92 and AA-97, which began in 1992 and 1997, respectively. In this study, we assessed the relapse rate, risk factors for relapse, and the response to secondline treatment in children with aplastic anemia treated with antithymocyte globulin and cyclosporine. Results From 1992 to 2007, we treated 441 children with aplastic anemia with standard immunosuppressive therapy. Among the 264 patients who responded to immunosuppressive therapy, 42 (15.9%) relapsed. The cumulative incidence of relapse was 11.9% at 10 years. Multivariate analysis revealed that relapse risk was significantly associated with an immunosuppressive therapy regimen using danazol (relative risk, 3.15; P=0.001) and non-severe aplastic anemia (relative risk, 2.51; P=0.02). Seventeen relapsed patients received additional immunosuppressive therapy with antithymocyte globulin and cyclosporine. Eight patients responded within 6 months. Seven of nine non-responders to second immunosuppressive therapy received hematopoietic stem cell transplantation and five are alive. Eleven patients underwent hematopoietic stem cell transplantation directly and seven are alive. Conclusions In the present study, the cumulative incidence of relapse at 10 years was relatively low compared to that in other studies mainly involving adult patients. A multicenter prospective study is warranted to establish optimal therapy for children with aplastic anemia. ©2011 Ferrata Storti Foundation.

DOI： 10.3324/haematol.2010.035600

Prognostic Factors for Outcomes of Pediatric Patients with Refractory or Relapsed Acute Leukemia Undergoing Allogeneic Progenitor Cell Transplantation Reviewed

Watanabe N., Takahashi Y., Matsumoto K., Hama A., Muramatsu H., Doisaki S., Horibe K., Kato K., Kojima S.

Biology of Blood and Marrow Transplantation Vol. 17 ( 4 ) page： 516 - 523 2011.4

Language：Japanese Publisher：Biology of Blood and Marrow Transplantation

Allogeneic stem cell transplantation (SCT) is the only curative therapy for patients with refractory or relapsed acute leukemia, although the prognosis remains poor. Few reports have described outcomes of SCT in pediatric patients with refractory acute leukemia. To identify prognostic factors for these patients, we retrospectively evaluated SCT outcomes for advanced acute leukemia in 82 pediatric patients from 3 transplant units in Nagoya City between 1990 and 2008. Median age at transplantation was 8 years (range, 0.5-17 years). Transplantation was performed in the first refractory relapse for 53 patients (64.6%), in the second or subsequent relapse for 16 patients (19.5%), and during primary induction failure for 13 patients (15.9%). Only 4 patients (4.9%) underwent transplantation in the untreated first relapse, and 39 patients (47.6%) received unrelated donor progenitor cells. Of the 82 patients, 61 died (77.9%), with a median survival of 7.1 months (95% confidence interval [CI], 4.2-10.0 months). Median disease-free survival (DFS) was 4.7 months (95% CI, 2.6-6.9 months). In multivariate analysis, peripheral blood blasts, cord blood transplantation, and more than 3 courses of previous salvage chemotherapy were predictive of DFS. These results support the notion that allogeneic SCT offers only a small chance of cure for most pediatric patients with refractory or relapsed acute leukemia, and suggest that reduction of the leukemia burden and earlier optimal timing of transplantation are essential for long-term survival even in patients with refractory acute leukemia. © 2011 American Society for Blood and Marrow Transplantation.

DOI： 10.1016/j.bbmt.2010.07.019

Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation Reviewed

Takagi M., Shinoda K., Piao J., Mitsuiki N., Takagi M., Matsuda K., Muramatsu H., Doisaki S., Nagasawa M., Morio T., Kasahara Y., Koike K., Kojima S., Takao A., Mizutani S.

Blood Vol. 117 ( 10 ) page： 2887 - 2890 2011.3

Language：Japanese Publisher：Blood

Autoimmune lymphoproliferative syndrome (ALPS) is classically defined as a disease with defective FAS-mediated apoptosis (type I-III). Germline NRAS mutation was recently identified in type IV ALPS. We report 2 cases with ALPS-like disease with somatic KRAS mutation. Both cases were characterized by prominent autoimmune cytopenia and lymphoadenopathy/splenomegaly. These patients did not satisfy the diagnostic criteria for ALPS or juvenile myelomonocytic leukemia and are probably defined as a new disease entity of RAS-associated ALPS-like disease (RALD). © 2011 by The American Society of Hematology.

DOI： 10.1182/blood-2010-08-301515

Reduced-intensity conditioning for alternative donor hematopoietic stem cell transplantation in patients with dyskeratosis congenita Reviewed

Nishio N., Takahashi Y., Ohashi H., Doisaki S., Muramatsu H., Hama A., Shimada A., Yagasaki H., Kojima S.

Pediatric Transplantation Vol. 15 ( 2 ) page： 161 - 166 2011.3

Language：Japanese Publisher：Pediatric Transplantation

DC is an inherited bone marrow failure syndrome mainly characterized by nail dystrophy, abnormal skin pigmentation, and oral leukoplakia. Bone marrow failure is the most common cause of death in patients with DC. Because previous results of HSCT with a myeloablative regimen were disappointing, we used a reduced-intensity conditioning regimen for two patients with classic DC, and one patient with cryptic DC who harbored the TERT mutation. Graft sources included two mismatched-related bone marrow (BM) donors and one unrelated BM donor. Successful engraftment was achieved with few regimen-related toxicities in all patients. They were alive 10, 66, and 72 months after transplantation, respectively. Long-term follow-up is crucial to determine the late effects of our conditioning regimen. © 2010 John Wiley & Sons A/S.

DOI： 10.1111/j.1399-3046.2010.01431.x

Analysis of mutations and recombination activity in RAG-deficient patients Reviewed

Asai E., Wada T., Sakakibara Y., Toga A., Toma T., Shimizu T., Nampoothiri S., Imai K., Nonoyama S., Morio T., Muramatsu H., Kamachi Y., Ohara O., Yachie A.

Clinical Immunology Vol. 138 ( 2 ) page： 172 - 177 2011.2

Language：Japanese Publisher：Clinical Immunology

Mutations in the recombination activating genes (RAG1 or RAG2) can lead to a variety of immunodeficiencies. Herein, we report 5 cases of RAG deficiency from 5 families: 3 of Omenn syndrome, 1 of severe combined immunodeficiency, and 1 of combined immunodeficiency with oligoclonal TCRγδ+ T cells, autoimmunity and cytomegalovirus infection. The genetic defects were heterogeneous and included 6 novel RAG mutations. All missense mutations except for Met443Ile in RAG2 were located in active core regions of RAG1 or RAG2. V(D)J recombination activity of each mutant was variable, ranging from half of the wild type activity to none, however, a significant decrease in average recombination activity was demonstrated in each patient. The reduced recombination activity of Met443Ile in RAG2 may suggest a crucial role of the non-core region of RAG2 in V(D)J recombination. These findings suggest that functional evaluation together with molecular analysis contributes to our broader understanding of RAG deficiency. © 2010 Elsevier Inc.

DOI： 10.1016/j.clim.2010.11.005

Excellent outcomes of children with CML treated with imatinib mesylate compared to that in pre-imatinib era Reviewed

Muramatsu H., Takahashi Y., Sakaguchi H., Shimada A., Nishio N., Hama A., Doisaki S., Yagasaki H., Matsumoto K., Kato K., Kojima S.

International Journal of Hematology Vol. 93 ( 2 ) page： 186 - 191 2011.2

Language：Japanese Publisher：International Journal of Hematology

Allogeneic hematopoietic stem cell transplantation (HSCT) and tyrosine kinase inhibitor have revolutionized the treatment of patients with chronic myeloid leukemia (CML). In this study, the clinical impact of HSCT and imatinib mesylate (IM) was retrospectively analyzed in 28 children with CML treated in our institutes from 1984 to 2008. Twelve patients were given oral IM. At 36 months after initiation of IM therapy, the complete cytogenetic response rate was 90.9%, and the major molecular response rate was 36.4%. Sixteen children received allogeneic HSCT without administration of IM. The stage of disease at transplantation was: first chronic phase (n = 10), second chronic phase (n = 2), accelerated phase (n = 2), and blastic crisis (n = 2). The progression rate was significantly lower in patients treated with IM than in those treated without IM (0 vs. 28.6%, p = 0.006). In summary, the survival outcomes of pediatric patients with CML were dramatically improved by treatment with IM compared to HSCT. © 2011 The Japanese Society of Hematology.

DOI： 10.1007/s12185-010-0764-9

Danaparoid as the prophylaxis for hepatic veno-occlusive disease after allogeneic hematopoietic stem cell transplantation in childhood hematological malignancy Reviewed

Sakaguchi H., Watanabe N., Muramatsu H., Doisaki S., Yoshida N., Matsumoto K., Kato K.

Pediatric Blood and Cancer Vol. 55 ( 6 ) page： 1118 - 1125 2010.12

Language：Japanese Publisher：Pediatric Blood and Cancer

Background: Veno-occlusive disease (VOD) is a regimen-related toxicity that occurs in the early phase of hematopoietic stem cell transplantation (HSCT). Therapeutic modalities for established VOD are limited, and severe VOD characterized by multiple organ failure is associated with a fatal prognosis despite intensive supportive care. Procedure: We analyzed the data of 95 consecutive allogeneic HSCT for childhood hematological malignancies, and assessed the efficacy of our VOD prophylaxis regimen based on danaparoid (n = 48), comparing with historical control regimen based on dalteparin (n = 47). Results: Eight patients (danaparoid cohort in one; dalteparin cohort in seven) developed VOD on day +30 (median onset, day +22; range, day +11 to day +28) after HSCT. The probability of developing VOD for the danaparoid cohort was 2% (95% CI, 0-6%) and that of the dalteparin cohort was 15% (95% CI, 5-26%). In the Cox hazard proportional model, the danaparoid cohort had a significant advantage over the dalteparin cohort for the prophylaxis of VOD (hazard ratio (HR), 0.0; 95% CI, 0.0-0.3; P < 0.01) without increasing hemorrhagic events. Conclusions: Our findings suggest that danaparoid may have promise for the prophylaxis of VOD after allogeneic HSCT and further randomized studies are warranted. © 2010 Wiley-Liss, Inc.

DOI： 10.1002/pbc.22645

Comparison of matched-sibling donor BMT and unrelated donor BMT in children and adolescent with acquired severe aplastic anemia Reviewed

Yagasaki H., Takahashi Y., Hama A., Kudo K., Nishio N., Muramatsu H., Tanaka M., Yoshida N., Matsumoto K., Watanabe N., Kato K., Horibe K., Kojima S.

Bone Marrow Transplantation Vol. 45 ( 10 ) page： 1508 - 1513 2010.10

Language：Japanese Publisher：Bone Marrow Transplantation

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 MSDBMT 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). © 2010 Macmillan Publishers Limited All rights reserved.

DOI： 10.1038/bmt.2009.378

Relationship between tacrolimus blood concentrations and clinical outcome during the first 4 weeks after SCT in children Reviewed

Watanabe N., Matsumoto K., Muramatsu H., Horibe K., Matsuyama T., Kojima S., Kato K.

Bone Marrow Transplantation Vol. 45 ( 7 ) page： 1161 - 1166 2010.7

Language：Japanese Publisher：Bone Marrow Transplantation

The relationship between tacrolimus concentration and acute GVHD is not well known, with few published data available for lower target levels. We hypothesized that lower levels of tacrolimus would correlate with higher incidence of acute GVHD and poorer prognosis. Receiver operator characteristic curves (ROC) were used to quantify tacrolimus blood levels as predictors of grade II-IV acute GVHD. A total of 97 pediatric patients with hematological malignancies met the study criteria. On the ROC, a cutoff of 7 ng/ml provided the best balance between sensitivity and specificity (62.8 vs 68.2%, respectively). Cumulative incidence of acute GVHD was 65.9% (range 58.5-73.3%) in patients with mean tacrolimus concentration of 7 ng/ml and 34.8% (range 27.8-41.8%) in patients with mean tacrolimus concentration of 7 ng/ml (P0.002). Incidence of non-relapse mortality (NRM) was higher in patients with tacrolimus of 7 ng/ml (42.9%; range 35.6-50.2%) than in patients with tacrolimus of 7 ng/ml (28.3%; range 17.4-39.2%; P0.008). This translated into better EFS in patients with tacrolimus of 7 ng/ml (48.9%; range 39.8-58.0%) than in patients with tacrolimus of 7 ng/ml (31.8%; range 25.0-38.6%; P0.031). Multivariate analysis showed that tacrolimus concentration was significantly associated with clinical outcomes. Mean whole-blood level of tacrolimus as continuous infusion should be maintained at 7 ng/ml for pediatric patients. © 2010 Macmillan Publishers Limited All rights reserved.

DOI： 10.1038/bmt.2009.327

Spectrum of molecular defects in juvenile myelomonocytic leukaemia includes ASXL1 mutations: Short report Reviewed

Sugimoto Y., Muramatsu H., Makishima H., Prince C., Jankowska A.M., Yoshida N., Xu Y., Nishio N., Hama A., Yagasaki H., Takahashi Y., Kato K., Manabe A., Kojima S., MacIejewski J.P.

British Journal of Haematology Vol. 150 ( 1 ) page： 83 - 87 2010.7

Language：Japanese Publisher：British Journal of Haematology

Summary Mutations in NF1, PTPN11, NRAS, KRAS and CBL have been reported to play a pathogenetic role in juvenile myelomonocytic leukaemia (JMML), a rare myelodyplastic/myeloproliferative neoplasm occurring in children. Recently, mutations in ASXL1 were identified in chronic myelomonocytic leukaemia and other myeloid malignancies. We sequenced exon 12 of ASLX1 in 49 JMML patients, and found 2 novel heterozygous (nonsense and frameshift) mutations, one occurring as a sole lesion, the other was in conjunction with a PTPN11 mutation. ASXL1 cooperates with KDM1A in transcriptional repression and thereby ASXL1 mutations may synergize with or mimic other JMML-related mutations. © 2010 Blackwell Publishing Ltd.

DOI： 10.1111/j.1365-2141.2010.08196.x

Relapse of leukemia with loss of mismatched HLA resulting from uniparental disomy after haploidentical hematopoietic stem cell transplantation Reviewed

Villalobos I.B., Takahashi Y., Akatsuka Y., Muramatsu H., Nishio N., Hama A., Yagasaki H., Saji H., Kato M., Ogawa S., Kojima S.

Blood Vol. 115 ( 15 ) page： 3158 - 3161 2010.4

Language：Japanese Publisher：Blood

We investigated human leukocyte antigen (HLA) expression on leukemic cells derived from patients at diagnosis and relapse after hematopoietic stem cell transplantation (HSCT) using flow cytometry with locus-specific antibodies. Two of 3 patients who relapsed after HLA-haploidentical HSCT demonstrated loss of HLA alleles in leukemic cells at relapse; on the other hand, no loss of HLA alleles was seen in 6 patients who relapsed after HLA-identical HSCT. Single-nucleotide polymorphism array analyses of sorted leukemic cells further revealed the copy number-neutral loss of heterozygosity, namely, acquired uniparental disomy on the short arm of chromosome 6, resulting in the total loss of the mismatched HLA haplotype. These results suggest that the escape from immunosurveillance by the loss of mismatched HLA alleles may be a crucial mechanism of relapse after HLA-haploidentical HSCT. Accordingly, the status of mismatched HLA on relapsed leukemic cells should be checked before donor lymphocyte infusion. © 2010 by The American Society of Hematology.

DOI： 10.1182/blood-2009-11-254284

Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia Reviewed

Muramatsu H., Makishima H., Jankowska A.M., Cazzolli H., O'Keefe C., Yoshida N., Xu Y., Nishio N., Hama A., Yagasaki H., Takahashi Y., Kato K., Manabe A., Kojima S., Maciejewski J.P.

Blood Vol. 115 ( 10 ) page： 1969 - 1975 2010.3

Language：Japanese Publisher：Blood

Juvenile myelomonocytic leukemia (JMML) is a rare pediatric myeloid neoplasm characterized by excessive proliferation of myelomonocytic cells. When we investigated the presence of recurrent molecular lesions in a cohort of 49 children with JMML, neurofibromatosis phenotype (and thereby NF1 mutation) was present in 2 patients (4%), whereas previously described PTPN11, NRAS, and KRAS mutations were found in 53%, 4%, and 2% of cases, respectively. Consequently, a significant proportion of JMML patients without identifiable pathogenesis prompted our search for other molecular defects. When we applied single nucleotide polymorphism arrays to JMML patients, somatic uniparental disomy 11q was detected in 4 of 49 patients; all of these cases harbored RING finger domain c-Cbl mutations. In total, c-Cbl mutations were detected in 5 (10%) of 49 patients. No mutations were identified in Cbl-b and TET2. c-Cbl and RAS pathway mutations were mutually exclusive. Comparison of clinical phenotypesshowedearlier presentation and lower hemoglobin F levels in patients with c-Cbl mutations. Our results indicate that mutations in c-Cbl may represent key molecular lesions in JMML patients without RAS/PTPN11 lesions, suggesting analogous pathogenesis to those observed in chronic myelomonocytic leukemia (CMML) patients. © 2010 by The American Society of Hematology.

DOI： 10.1182/blood-2009-06-226340

Outcome of 125 Children with Chronic Myelogenous Leukemia Who Received Transplants from Unrelated Donors: The Japan Marrow Donor Program Reviewed

Muramatsu H., Kojima S., Yoshimi A., Atsuta Y., Kato K., Nagatoshi Y., Inoue M., Koike K., Kawase T., Ito M., Kurosawa H., Tanizawa A., Tono C., Hamamoto K., Hotta N., Watanabe A., Morishima Y., Kawa K., Shimada H.

Biology of Blood and Marrow Transplantation Vol. 16 ( 2 ) page： 231 - 238 2010.2

Language：Japanese Publisher：Biology of Blood and Marrow Transplantation

Because of a small number of patients, only a few studies have addressed the outcome of bone marrow transplantation (BMT) in children with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML), who receive graft from a volunteer-unrelated donor (VUD), especially after practical application of imatinib mesylate. The outcomes of BMT from a VUD in 125 children with Ph+ CML were retrospectively reviewed. Patients were identified through the Japan Marrow Donor Program as having undergone BMT between 1993 and 2005 and were aged 1-19 years at the time of transplant (median age, 14 years). The probabilities of 5-year overall survival (OS) and leukemia-free survival (LFS) were 59.3% and 55.5%, respectively. Multivariate analysis identified the following unfavorable survival factors: infused total nucleated cell dose < 314 × 106 /kg (relative risk [RR] = 2.43; 95% confidence interval [CI] = 1.33-4.44; P = .004), advanced phase (RR = 2.43; 95% CI = 1.37-4.31; P = .004), and no major cytogenetic response (MCyR) at the time of BMT (RR = 6.55; 95% CI = 1.98-21.6; P = .002). Of the 17 patients treated with imatinib, 15 (88%) achieved MCyR at the time of BMT, and this group had an excellent 5-year OS of 81.9%. Disease phase, infused total nucleated cell dose, and cytogenetic response were independent risk factors for survival of unrelated BMT. These findings provide important information for assessing the indications for and improving outcome in unrelated BMT for the treatment of pediatric CML. © 2010 American Society for Blood and Marrow Transplantation.

DOI： 10.1016/j.bbmt.2009.09.022

Mutations of E3 ubiquitin ligase Cbl family members constitute a novel common pathogenic lesion in myeloid malignancies Reviewed

Makishima H., Cazzolli H., Szpurka H., Dunbar A., Tiu R., Huh J., Muramatsu H., O'Keefe C., Hsi E., Paquette R.L., Kojima S., List A.F., Sekeres M.A., McDevitt M.A., Maciejewski J.P.

Journal of Clinical Oncology Vol. 27 ( 36 ) page： 6109 - 6116 2009.12

Language：Japanese Publisher：Journal of Clinical Oncology

Purpose: Acquired somatic uniparental disomy (UPD) is commonly observed in myelodysplastic syndromes (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), or secondary acute myelogenous leukemia (sAML) and may point toward genes harboring mutations. Recurrent UPD11q led to identification of homozygous mutations in c-Cbl, an E3 ubiquitin ligase involved in attenuation of proliferative signals transduced by activated receptor tyrosine kinases. We examined the role and frequency of Cbl gene family mutations in MPN and related conditions. Methods: We applied high-density SNP-A karyotyping to identify loss of heterozygosity of 11q in 442 patients with MDS, MDS/MPN, MPN, sAML evolved from these conditions, and primary AML. We sequenced c-Cbl, Cbl-b, and Cbl-c in patients with or without corresponding UPD or deletions and correlated mutational status with clinical features and outcomes. Results: We identified c-Cbl mutations in 5% and 9% of patients with chronic myelomonocytic leukemia (CMML) and sAML, and also in CML blast crisis and juvenile myelomonocytic leukemia (JMML). Most mutations were homozygous and affected c-Cbl; mutations in Cbl-b were also found in patients with similar clinical features. Patients with Cbl family mutations showed poor prognosis, with a median survival of 5 months. Pathomorphologic features included monocytosis, monocytoid blasts, aberrant expression of phosphoSTAT5, and c-kit overexpression. Serial studies showed acquisition of c-Cbl mutations during malignant evolution. Conclusion: Mutations in the Cbl family RING finger domain or linker sequence constitute important pathogenic lesions associated with not only preleukemic CMML, JMML, and other MPN, but also progression to AML, suggesting that impairment of degradation of activated tyrosine kinases constitutes an important cancer mechanism. © 2009 by American Society of Clinical Oncology.

DOI： 10.1200/JCO.2009.23.7503

Downregulation of GATA-2 and overexpression of adipogenic gene-PPARγ in mesenchymal stem cells from patients with aplastic anemia Reviewed

Xu Y., Takahashi Y., Wang Y., Hama A., Nishio N., Muramatsu H., Tanaka M., Yoshida N., Villalobos I.B., Yagasaki H., Kojima S.

Experimental Hematology Vol. 37 ( 12 ) page： 1393 - 1399 2009.12

Language：Japanese Publisher：Experimental Hematology

Aplastic anemia (AA) is characterized by a reduced number of hematopoietic stem cells and fatty replacement in the bone marrow. Transcriptional factor GATA-2 plays several important roles in both hematopoiesis and adipogenesis. Decreased levels of GATA-2 compromise the proliferation and survival of hematopoietic stem cells. GATA-2 suppresses adipocyte differentiation through direct inhibition of adipogenic factors, including peroxisome proliferator-activated receptor-γ (PPARγ). Previous studies have shown that expression of GATA-2 is decreased in marrow CD34-positive cells in AA. To elucidate the mechanisms of fatty marrow replacement, we evaluated the mRNA expression for GATA-2 and PPARγ in mesenchymal stem cells (MSCs) from patients with AA by quantitative real-time polymerase chain reaction. GATA-2 expression by MSCs from AA patients was significantly lower than in normal subjects. Conversely, expression of PPARγ was significantly higher in AA patients. Western blot analysis demonstrated that protein levels of GATA-2 were lower in AA patients than those in normal subjects. Moreover, incubation with interferon-γ induced downregulation of GATA-2 levels in MSCs from normal subjects. These findings indicate that fatty marrow replacement in AA patients can be explained by downregulation of GATA-2 and overexpression of PPARγ in MSCs. Decreased expression of GATA-2 might be responsible for the pathogenesis and development of the clinical features of the disease. © 2009 ISEH - Society for Hematology and Stem Cells.

DOI： 10.1016/j.exphem.2009.09.005

Tacrolimus/Methotrexate versus Cyclosporine/Methotrexate as Graft-versus-Host Disease Prophylaxis in Patients with Severe Aplastic Anemia Who Received Bone Marrow Transplantation from Unrelated Donors: Results of Matched Pair Analysis Reviewed

Yagasaki H., Kojima S., Yabe H., Kato K., Kigasawa H., Sakamaki H., Tsuchida M., Kato S., Kawase T., Muramatsu H., Morishima Y., Kodera Y.

Biology of Blood and Marrow Transplantation Vol. 15 ( 12 ) page： 1603 - 1608 2009.12

Language：Japanese Publisher：Biology of Blood and Marrow Transplantation

Tacrolimus (FK) and cyclosporine (CsA) have been shown to be effective in the prophylaxis of graft-versus-host disease (GVHD). However, no comparative studies have yet been conducted to examine the efficacy of FK/methotrexate (MTX) and CsA/MTX in patients with severe aplastic anemia (SAA) given unrelated donor bone marrow transplantation (U-BMT). We used matched-pair analysis to compare FK/MTX with CsA/MTX in patients with SAA who received U-BMT through the Japan Marrow Donor Program. Forty-seven pairs could be matched exactly for recipient age and conditioning regimens. Forty-five patients achieved engraftment in the FK group and 42 patients in the CsA group. The probability of grade II-IV acute GVHD (aGVHD) was 28.9% in the FK group and 32.6% in the CsA group (P = .558). The probability of chronic GVHD (cGVHD) was 13.3% in the FK group and 36.0% in the CsA group (P = .104). The 5-year survival rate was 82.8% in the FK group and 49.5% in the CsA group (P = .012). The study shows the superiority of FK/MTX over CsA/MTX in overall survival because of the lower incidence of transplantation-related deaths. A prospective randomized study comparing FK/MTX and CsA/MTX is warranted. © 2009 American Society for Blood and Marrow Transplantation.

DOI： 10.1016/j.bbmt.2009.08.012

Engraftment syndrome following allogeneic hematopoietic stem cell transplantation in children Reviewed

Nishio N., Yagasaki H., Takahashi Y., Hama A., Muramatsu H., Tanaka M., Yoshida N., Yoshimi A., Kudo K., Ito M., Kojima S.

Pediatric Transplantation Vol. 13 ( 7 ) page： 831 - 837 2009.11

Language：Japanese Publisher：Pediatric Transplantation

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. © 2008 John Wiley & Sons A/S.

DOI： 10.1111/j.1399-3046.2008.01068.x

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