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Junichi Hara,
Yong-Dong Park,
Akira Yoshioka,
Keiko Yumura-Yagi,
Urara Koudera,
Gaku Hosoi, Masahiro Sako,
Yoshiyuki Kosaka,
Kimihiko Sano,
Hideo Misu,
Osamu Mabuchi,
Noriyuki Aoyagi,
Masuji Yamamoto,
Akio Tawa,
Hiroshi Miyata,
Haruki Tanaka,
Makiko Kikkawa,
Mutsuro Shimodera,
Keisei Kawa-Ha
[show abstract]
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ABSTRACT: Between April 1994 and March 1997, 143 children (age range, 1–15 years) with newly diagnosed acute lymphoblastic leukemia
(ALL), except for those patients with t(9;22), were treated according to protocol-94 of the Osaka Childhood Leukemia Study
Group. In this trial, the intensity of chemotherapy was enforced in the consolidation and reinduction phases by introducing
AML-type block therapies consisting of concentrated administration of 4 to 6 drugs during 5 or 6 days. For patients in the
higher risk groups, rotational combination chemotherapy was introduced following the early phase. A total of 124 children
with B-cell precursor ALL (B-pre ALL) were classified into 3 groups, the ultrahigh-risk group (UHRG) (15 patients), the high-risk
group (HRG) (61 patients), or the standard-risk group (SRG) (48 patients), based on age, leukocyte count, immunophenotype,
central nervous system leukemia, response to treatment, and selected chromosomal abnormalities. The complete remission rate
was 93%, and the 6-year event-free survival (EFS) rate was 79% ± 4%. EFS rates for the UHRG, HRG, and SRG groups were 67%
± 12%, 80% ± 6%, and 81% ± 6%, respectively. Nineteen patients with T-cell ALL were treated with the protocol for the UHRG.
Thirteen patients (68%) attained complete remission, and the 6-year EFS rate was 55% ± 12%. Thus, intensification of chemotherapy
improved the EFS rate and AML-type block therapies appeared to be effective as the consolidation and reinduction therapies
for B-pre ALL.
International Journal of Hematology 04/2012; 74(2):165-172. · 1.27 Impact Factor
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[show abstract]
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ABSTRACT: To assess the clinical significance of monitoring minimal residual disease in t(8;21)(q22;q22) AML, RT-PCR assay was conducted during the clinical course of 12 patients who had undergone BMT or conventional chemotherapy. Two cases relapsed after BMT and chimeric RNA was detected soon after BMT in their bone marrow cells. The other three cases, in whom chimeric RNA was not detected after BMT, are in CR at 21 to 33 months following BMT. Similarly, four out of 7 cases who showed negative chimeric RNA after completion of chemotherapy have been in CR at 11 to 34 monthsfollowing completion of chemotherapy. The present findings appear different from other studies which reported the detection of AMLI-ETO chimeric RNA in long-term CR patients.
08/2009; 26(1-2):141-152.
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Akira Shirahata,
Kohji Fujisawa,
Eiichi Ishii,
Shigeru Ohta, Masahiro Sako,
Yukihiro Takahashi,
Masashi Taki,
Jun-Ichi Mimaya,
Masaru Kubota,
Takuma Miura,
Junichi Kitazawa,
Michiko Kajiwara,
Fumio Bessho
[show abstract]
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ABSTRACT: We evaluated the clinical pictures, outcome for childhood idiopathic thrombocytopenic purpura (ITP) and the trends of the choice of management for childhood ITP in Japan.
Every year, questionnaires were sent to all institutions that employ the active members of the Japanese Society of Pediatric Hematology. The questionnaires included age, sex, date of diagnosis, platelet count at diagnosis, the presence or absence of antecedent infection, hemorrhagic symptoms, initial management, and the outcome of all patients newly diagnosed with ITP.
A total of 986 newly diagnosed as ITP patients were reported between January 2000 and December 2005. The occurrence of ITP peaked in boys less than 1 year of age, and at 1 year of age in girls. The male-to-female ratio was 1.24:1. Wet purpura was observed in more than half of the patients with platelet counts of <10,000/microL. The initial treatment varied among the patients with different platelet counts at diagnosis; most of the patients with platelet counts <20,000/microL received intravenous immunoglobulin or oral corticosteroids. Conversely, cases without any aggressive treatment increased to a larger degree in patients with > or =20,000/microL of platelet.
These findings indicate that overall compliance to the Japanese guideline is considered to be relatively good in Japan.
Journal of Pediatric Hematology/Oncology 01/2009; 31(1):27-32. · 1.16 Impact Factor
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ABSTRACT: Patients with infant acute myeloid leukemia (AML) who carry a t(7;12)(q36;p13) translocation have been reported to have a poor clinical outcome. MNX1-ETV6 fusion transcripts (previously HLXB9-ETV6) were rarely detected in AML patients having t(7;12)(q36;p13). A 23-month-old girl with acute megakaryoblastic leukemia (AMKL) exhibited chromosome abnormalities, including add(7)(q22), and del(12)(p12p13). Southern blot analysis of bone marrow cells showed an ETV6 gene rearrangement. Reverse transcriptase-polymerase chain reaction (RT-PCR) followed by sequence analysis revealed the presence of an MNX1-ETV6 fusion gene. The patient responded well to chemotherapy, achieved complete remission, and at writing had been in complete remission for 60 months. The MNX1 expression by RT-PCR was significantly more frequent in Epstein-Barr virus-transformed B-cell lines derived from normal adult lymphocytes than in leukemic cell lines. This represents a novel case of an AMKL patient with MNX1-ETV6 fusion transcripts who had a good prognosis.
Cancer genetics and cytogenetics 11/2008; 186(2):115-9. · 1.54 Impact Factor
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N Ishikawa,
S Okada,
M Miki,
K Shirao,
H Kihara,
M Tsumura,
K Nakamura,
H Kawaguchi,
M Ohtsubo,
S Yasunaga,
K Matsubara, M Sako,
J Hara,
M Shiohara,
S Kojima,
T Sato,
Y Takihara,
M Kobayashi
[show abstract]
[hide abstract]
ABSTRACT: Severe congenital neutropenia (SCN), also known as Kostmann syndrome (SCN3, OMIM 610738), includes a variety of haematological disorders caused by different genetic abnormalities. Mutations in ELA2 are most often the cause in autosomal dominant or sporadic forms. Recently, mutations in HAX1 have been identified as the cause of some autosomal recessive forms of SCN, including those present in the original pedigree first reported by Kostmann. We sought to determine the relationship between HAX1 gene mutations and the clinical characteristics of Japanese cases of SCN.
The genes implicated in SCN (ELA2, HAX1, Gfi-1, WAS, and P14) were analysed in 18 Japanese patients with SCN. The clinical features of these patients were obtained from medical records. Immunoblotting of HAX1 was performed on cell extracts from peripheral blood leucocytes from patients and/or their parents.
We found five patients with HAX1 deficiency and 11 patients with mutations in the ELA2 gene. In HAX1 deficiency, a homozygous single base pair substitution (256C>T), which causes the nonsense change R86X, was identified in three affected individuals. Two sibling patients showed a compound heterozygous mutation consisting of a single base pair substitution (256C>T) and a 59 bp deletion at nucleotides 376-434. There was no detectable phenotype in any heterozygous carrier. All patients with HAX1 deficiency had experienced developmental delay. Three patients carrying R86X also suffered from epileptic seizures. In contrast, no SCN patient with heterozygous mutations in the ELA2 gene suffered from any neurodevelopmental abnormality.
These findings suggest that the R86X mutation in the HAX1 gene is an abnormality in Japanese SCN patients with HAX1 deficiency and may lead to neurodevelopmental abnormalities and severe myelopoietic defects.
Journal of Medical Genetics 07/2008; 45(12):802-7. · 6.36 Impact Factor
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Miharu Yabe, Masahiro Sako,
Hiromasa Yabe,
Yuko Osugi,
Hidemitsu Kurosawa,
Taemi Nara,
Mika Tokuyama,
Souichi Adachi,
Chie Kobayashi,
Masakatsu Yanagimachi,
Yoshitoshi Ohtsuka,
Yozo Nakazawa,
Chitose Ogawa,
Atsushi Manabe,
Seiji Kojima,
Tatsutoshi Nakahata
[show abstract]
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ABSTRACT: A pilot study was undertaken using a myeloablative conditioning with fludarabine, busulfan, and melphalan to improve the outcome of HSCT in 10 children, aged six months to six yr, with JMML. All patients were conditioned with oral busulfan (560 mg/m(2)), fludarabine (120 mg/m(2)), and melphalan (180-210 mg/m(2)) prior to HSCT, and received stem cells from bone marrow in seven cases, and from cord blood in three cases. Engraftment was documented in eight patients, whereas graft failure occurred in two, one of whom had received HLA-mismatched cord blood and other had received bone marrow from HLA-mismatched mother. Three patients, including two in who graft failure had occurred, relapsed. Five patients developed acute GVHD and two developed chronic GVHD. Seven patients are alive and in remission 27-69 months after transplantation. Thus, our study showed that HSCT following conditioning with fludarabine, busulfan, and melphalan was well tolerated and appeared to be effective for JMML.
Pediatric Transplantation 05/2008; 12(8):862-7. · 1.48 Impact Factor
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ABSTRACT: Bruton's tyrosine kinase (BTK), which is defective in patients with X-linked agammaglobulinemia (XLA), is expressed not only in B cells but also in monocytes and dendritic cells (DCs). DCs play a crucial role in the innate immune response against infections by sensing pathogens through Toll-like receptors (TLRs). However, it is not known whether BTK deficiency in XLA might impair TLR-mediated signaling in DCs, which are susceptible to various infections. The phenotypic maturation and cytokine production mediated by TLRs were examined in monocyte-derived DC from XLA patients and normal controls. The TLR expression in DCs was analyzed by flow cytometry. TLR-mediated signaling in DCs was evaluated for the phenotypic maturation based on CD83 expression and production of cytokines, such as TNF-alpha, IL-6 and IL-12p70. TLR levels in DCs were similar between XLA and controls. TLR2, TLR4 and TLR7/8 ligands elicited less phenotypic maturation of DCs from XLA patients than normal controls based on CD83 expression. Stimulation with TLR2, TLR4 and TLR7/8 ligands, as well as TLR3 ligand, resulted in significantly lower production of TNF-alpha, but neither IL-6 nor IL-12p70, by DCs from XLA patients in comparison to normal controls. These findings suggest that BTK may thus be required for TLR signaling in DCs. The impaired TLR signaling in DCs may therefore be partly responsible for the occurrence of severe infections with bacteria and some viruses in XLA patients.
Clinical Immunology 03/2008; 126(2):148-54. · 4.05 Impact Factor
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Yuko Osugi,
Hiroshi Yagasaki, Masahiro Sako,
Yoshiyuki Kosaka,
Takashi Taga,
Tsuyoshi Ito,
Masuji Yamamoto,
Akira Ohara,
Takeyuki Sato,
Junichi Mimaya,
Ichiro Tsukimoto,
Seiji Kojima
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ABSTRACT: We analyzed the outcomes of 44 children with hepatitis associated aplastic anemia (HAA) who received immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine (CsA). Fourteen (31.8%) patients achieved complete response and 17 (38.6%) achieved partial response, for an overall response rate of 70.4% after 6 months. Seven non-responders received bone marrow transplantation from an HLA-matched unrelated donor and 6 out of 7 are alive. The probability of overall survival at 10 years was 88.3+/-4.9%, which supports the role of IST with ATG and CsA as treatment of choice for children with HAA without an HLA identical sibling donor.
Haematologica 01/2008; 92(12):1687-90. · 6.42 Impact Factor
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International Journal of Hematology 11/2007; 86(3):289-90. · 1.27 Impact Factor
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Akira Morimoto,
Satoshi Ikushima,
Naoko Kinugawa,
Eiichi Ishii,
Urara Kohdera, Masahiro Sako,
Junichiro Fujimoto,
Fumio Bessho,
Keizo Horibe,
Yukiko Tsunematsu,
Shinsaku Imashuku
[show abstract]
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ABSTRACT: The treatment outcome of multifocal childhood Langerhans cell histiocytosis (LCH) has not been satisfactory and has resulted in poor therapeutic responses with high mortality and a high incidence of reactivation with late sequelae. To overcome these issues, the Japan LCH Study Group-96 (JLSG-96) protocol was conducted prospectively from 1996 to 2001 in Japan.
Newly diagnosed children with multifocal LCH were classified into 2 groups: a single-system multisite (SS-m) group and a multisystem (MS) group. All patients initially were treated on Protocol A, which consisted of 6 weeks of induction therapy with combined cytosine arabinoside, vincristine (VCR), and prednisolone (PSL) followed by 6 months of maintenance therapy. Patients who had a poor response to the induction of Protocol A were switched to a salvage regimen (Protocol B), which consisted of an intensive combination of doxorubicin, cyclophosphamide, VCR, and PSL.
In total, 91 patients were treated, including 32 patients in the SS-m group and 59 patients in the MS group. At the median 5-year follow-up, 96.9% of patients in the SS-m group and 78.0% of patients in the MS group had good response status. Diabetes insipidus developed in 3.1% of patients in the SS-m group and in 8.9% of patients in the MS group. The overall survival rate at 5 years for the SS-m and MS groups was 100% and 94.4% +/- 3.2%, respectively.
The JLSG-96 protocol attained very low mortality for pediatric patients with multifocal LCH.
Cancer 09/2006; 107(3):613-9. · 4.77 Impact Factor
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Hiromasa Yabe,
Hiroyasu Inoue,
Masae Matsumoto,
Satoshi Hamanoue,
Takashi Koike,
Hiroyuki Ishiguro,
Hideki Koike,
Kazuo Suzuki,
Shunichi Kato,
Seiji Kojima,
Masahiro Tsuchida,
Tetsuya Mori,
Souichi Adachi,
Koichiro Tsuji,
Kenichi Koike,
Akira Morimoto, Masahiro Sako,
Miharu Yabe
[show abstract]
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ABSTRACT: A pilot study was undertaken using a fludarabine-based conditioning regimen to improve haematopoietic cell transplantation (HCT) from alternative donors in 27 Fanconi anaemia (FA) patients. Patients were conditioned with 150-180 mg/m2 of fludarabine, 40 mg/kg of cyclophosphamide, 5-10 mg/kg of antithymocyte globulin, and 300-450 cGy of thoracoabdominal/total body irradiation. One patient who received unrelated cord blood transplantation failed to engraft, another patient died of sepsis. The 1-year overall survival was 96.3% (95% CI, 89-100). This conditioning regimen exerted an immunosuppressive effect that enabled durable engraftment in alternative donor HCT without severe toxicity.
British Journal of Haematology 08/2006; 134(2):208-12. · 4.94 Impact Factor
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ABSTRACT: Most cases of nephrotic syndrome following stem cell transplantation (SCT) occur 6 months after SCT. The patients are treated with immunosuppressive therapies; however, in some cases treatment is not effective. We used enalapril, an angiotensin-converting enzyme inhibitor (ACEI) and candesartan, an angiotensin II receptor blocker (ARB), for the control of proteinuria in a case of immunosuppressive treatment (IST)-resistant nephrotic syndrome. A 15-year-old boy with acute lymphoblastic leukemia underwent allogeneic peripheral blood SCT from a completely HLA-matched sibling after completion of a conditioning regimen composed of 12-Gy doses of total-body irradiation, 600 mg/m2 thiotepa, and 140 mg/m2 melphalan. Twenty-eight months after SCT, minimal-change nephrotic syndrome was diagnosed on the basis of biopsy findings. Although neither cyclosporine (trough level, 100-150 ng/mL) nor corticosteroid was effective, proteinuria disappeared 2 months after the beginning of treatment with tacrolimus (trough level, 13-20 ng/mL), and remission was maintained for 23 months. Nephrotic syndrome recurred, however, and was resistant to tacrolimus. Findings at the second renal biopsy revealed membranous nephropathy. An ARB (candesartan, 4 mg/ day) in combination with an ACEI (enalapril, 5 mg/day) was started. Proteinuria improved within 2 weeks. We suggest that ARB combined with ACEI can be used to control proteinuria in patients with IST-resistant nephrotic syndrome after SCT.
International Journal of Hematology 07/2006; 83(5):454-8. · 1.27 Impact Factor
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ABSTRACT: Classification of familial hemophagocytic lymphohistiocytosis (FHL) into FHL2, FHL3, and other subtypes based on genetic abnormalities has recently become possible. We studied the phenotypic differences among these subtypes in Japan.
Forty patients clinically diagnosed with FHL were analyzed. Perforin abnormality was screened by flow cytometric analysis and/or DNA sequencing in these patients, and those without perforin abnormalities were further examined for the presence of mutations in the Munc13-4 gene by DNA sequencing. The correlation between clinical features and genetic subtypes was investigated.
Of the 40 HLH patients, 11 showed perforin gene mutations (classified as FHL2) and ten had Munc13-4 gene mutations (FHL3), but neither mutation was noted in 19 patients (non-FHL2/3). Although the majority of the patients developed the disease before the age of 1 year, the onset in three FHL2 patients with missense mutations was late (7, 11, and 12 years). Incidence of deficient natural killer cell activity was higher in FHL2 patients (9/9 FHL2, 4/9 FHL3, and 6/17 non-FHL2/3; P = 0.005). The serum levels of ferritin and soluble interleukin-2 receptor were significantly higher in FHL2 patients with nonsense perforin mutations compared to other subgroups (P < or = 0.05). Epstein-Barr virus infection was involved in 8 of the 40 HLH patients: one FHL2, one FHL3, and six non-FHL2/3.
Although clinical features of FHL3 appear to be homogeneous, the heterogeneous clinical features of FHL2 depend upon the nature of perforin gene mutations. Characterization of the non-FHL2/3 group with regard to FHL1 or other novel gene mutations remains to be conducted.
Pediatric Blood & Cancer 05/2006; 46(4):482-8. · 1.89 Impact Factor
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Akira Shirahata,
Eiichi Ishii,
Haruhiko Eguchi,
Hiroji Okawa,
Shigeru Ohta,
Takashi Kaneko,
Shozaburo Konishi, Masahiro Sako,
Isao Sekine,
Yukihiro Takahashi,
Masashi Taki,
Shigeru Tsuchiya,
Kohji Fujisawa,
Fumio Bessho,
Yasuo Horikoshi,
Junichi Mimaya,
Jun-Ichi Akatsuka,
Sumio Miyazaki
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ABSTRACT: A practice guideline aimed at standardizing the treatment for childhood idiopathic thrombocytopenic purpura (ITP) is presented. This consensus guideline is based on a survey carried out via a questionnaire prepared by the ITP Committee of the Japanese Society of Pediatric Hematology and sent to society members. The survey questionnaire included questions on the diagnosis of ITP submitted for the purpose of revising the ITP diagnostic guideline prepared in 1990 by the Research Group for Intractable Hematopoietic Disorders; a revised diagnostic guideline also is presented.
International Journal of Hematology 02/2006; 83(1):29-38. · 1.27 Impact Factor
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Ritsuro Suzuki,
Shigeo Nakamura,
Junji Suzumiya,
Koichi Ichimura,
Masako Ichikawa,
Kiyoyuki Ogata,
Yoshimasa Kura,
Keiko Aikawa,
Hirofumi Teshima, Masahiro Sako,
Hiroshi Kojima,
Mitsufumi Nishio,
Tadashi Yoshino,
Hiroki Sugimori,
Keisei Kawa,
Kazuo Oshimi
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ABSTRACT: Blastic natural killer (NK) cell lymphoma/leukemia (BNKL) is an immature CD56-positive neoplasm, which was recognized recently and characterized by systemic proliferation of tumor cells including skin, lymph node, and bone marrow.
The current study analyzed 47 patients with BNKL (27 had leukemias and 20 had lymphomas). Patient data were collected for the survey of the NK-Cell Tumor Study Group.
There were 33 males and 14 females, with a median age of 53 years (range, 3 months to 89 years). There were few clinicopathologic differences between the leukemia and lymphoma types. Cutaneous involvement was noted at diagnosis in 28 patients, who presented a tendency for older age of onset (median: 56 vs. 46 years, P = 0.11) than patients with noncutaneous BNKL. Cutaneous BNKL showed less frequent mediastinal involvement (4% vs. 53%, P = 0.0002) and less severe thrombocytopenia (P =0 .03). Phenotypic characteristics were also different, with cutaneous BNKL favoring CD4 and HLA-DR expression, and noncutaneous BNKL favoring CD16 and CD34 expression. Both groups responded well to chemotherapy for lymphoid malignancies, but disease recurrence was frequent. The prognosis of patients with noncutaneous BNKL was significantly poorer than that of patients with cutaneous BNKL (median survival: 15 vs. 25 months, P = 0.02). Multivariate analysis confirmed that cutaneous involvement was a significant and independent prognostic factor for BNKL, as were age of onset and leukocyte count.
These findings suggested that BNKL is a heterogeneous disease and contains at least two subtypes. Although further investigations are needed to settle a marker for distinction, the presence of cutaneous involvement is a useful prognostic factor.
Cancer 10/2005; 104(5):1022-31. · 4.77 Impact Factor
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ABSTRACT: We analysed data of 96 infants (under 1 year of age) with haemophagocytic lymphohistiocytosis (HLH) from the registry of an HLH study conducted during 1986-2002 in Japan. The cases were classified into five groups. The diagnosis of familial HLH (FHL) as group 1 (n = 27) was made with positive family history and/or recent molecular test for perforin and Munc13-4 mutations. Neonatal enterovirus- or herpes simplex virus-associated HLH as group 2a (n = 7), Epstein-Barr virus-associated HLH (n = 12) as group 2b, adenovirus- or cytomegalovirus-associated HLH as group 3 (n = 9) were mostly diagnosed by viral isolation or by the detection of viral genome. Juvenile rheumatoid arthritis-associated macrophage activation syndrome was classified as group 4 (n = 4) and the remaining without known triggers as group 5 (n = 37). The peak onset age was 1-2 months for group 1, 1-2 weeks for group 2a, 12 months for group 2b, none for group 3, 9 months for group 4 and 2 months for group 5. Future novel diagnostic measures are required to define the precise nature of HLH in group 5. CONCLUSION: These data may provide useful information for neonatologists/ paediatricians in the differential diagnosis of haemophagocytic lymphohistiocytosis in early infancy.
European Journal of Pediatrics 06/2005; 164(5):315-9. · 1.88 Impact Factor
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Eiichi Ishii,
Ikuyo Ueda,
Ryutaro Shirakawa,
Ken Yamamoto,
Hisanori Horiuchi,
Shouichi Ohga,
Kenji Furuno,
Akira Morimoto,
Miyoko Imayoshi,
Yoshiyasu Ogata,
Masafumi Zaitsu, Masahiro Sako,
Kenichi Koike,
Akifumi Sakata,
Hidetoshi Takada,
Toshiro Hara,
Shinsaku Imashuku,
Takehiko Sasazuki,
Masaki Yasukawa
[show abstract]
[hide abstract]
ABSTRACT: Mutations of the perforin (PRF1) and MUNC13-4 genes distinguish 2 forms of familial hemophagocytic lymphohistiocytosis (FHL2 and FHL3, respectively), but the clinical and biologic correlates of these genotypes remain in question. We studied the presenting features and cytotoxic T lymphocyte/natural killer (CTL/NK) cell functions of 35 patients for their relationship to distinct FHL subtypes. FHL2 (n = 11) had an earlier onset than either FHL3 (n = 8) or the non-FHL2/FHL3 subtype lacking a PRF1 or MUNC13-4 mutation (n = 16). Deficient NK cell activity persisted after chemotherapy in all cases of FHL2, whereas some patients with FHL3 or the non-FHL2/FHL3 subtype showed partial recovery of this activity during remission. Alloantigen-specific CTL-mediated cytotoxicity was deficient in FHL2 patients with PRF1 nonsense mutations, was very low in FHL3 patients, but was only moderately reduced in FHL2 patients with PRF1 missense mutations. These findings correlated well with Western blot analyses showing an absence of perforin in FHL2 cases with PRF1 nonsense mutations and of MUNC13-4 in FHL3 cases, whereas in FHL2 cases with PRF1 missense mutations, mature perforin was present in low amounts. These results suggest an association between the type of genetic mutation in FHL cases and the magnitude of CTL cytolytic activity and age at onset.
Blood 06/2005; 105(9):3442-8. · 9.90 Impact Factor
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Yoshiyuki Kosaka,
Katsuyoshi Koh,
Naoko Kinukawa,
Yoshihiro Wakazono,
Keiichi Isoyama,
Takanori Oda,
Yasuhide Hayashi,
Shigeru Ohta,
Hiroshi Moritake,
Megumi Oda,
Yoshihisa Nagatoshi,
Hisato Kigasawa,
Yasushi Ishida,
Akira Ohara,
Ryouji Hanada, Masahiro Sako,
Takeyuki Sato,
Shuki Mizutani,
Keizo Horibe,
Eiichi Ishii
[show abstract]
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ABSTRACT: Forty-four infants with acute lymphoblastic leukemia (ALL) characterized by MLL gene rearrangements were treated on a protocol of intensive chemotherapy followed by hematopoietic stem cell transplantation (HSCT) between November 1998 and June 2002. The remission induction rate was 91.0%, and the 3-year overall survival and event-free survival (EFS) rates, with 95% confidence intervals, were 58.2% (43.5%-72.9%) and 43.6% (28.5%-58.7%), respectively. Univariate analysis of EFS by presenting features indicated a poorer outcome in patients younger than 6 months of age with high white blood cell counts (>/= 100 x 10(9)/L; EFS rate, 9.4% versus 55.1% for all others, P = .0036) and in those with central nervous system invasion (EFS rate, 10.0% versus 56.9% for all others, P = .0073). The 3-year posttransplantation EFS rate for the 29 patients who underwent HSCT in first remission was 64.4% (46.4%-82.4%). In this subgroup, only the timing of HSCT (first remission versus others) was a significant risk factor by multivariate analysis (P < .0001). These results suggest that early introduction of HSCT, possibly with a less toxic conditioning regimen, may improve the prognosis for infants with MLL(+) ALL. Identification of subgroups or patients who respond well to intensified chemotherapy alone should have a high priority in future investigations.
Blood 12/2004; 104(12):3527-34. · 9.90 Impact Factor
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Hiromasa Yabe,
Hiroyasu Inoue,
Masae Matsumoto,
Satoshi Hamanoue,
Aiko Hiroi,
Takashi Koike, Masahiro Sako,
Mitsuhiro Fujiwara,
Yasunori Ueda,
Etsuko Maruya,
Hiroh Saji,
Shunichi Kato,
Miharu Yabe
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ABSTRACT: Fetomaternal microchimerism has been demonstrated, and immunologic tolerance to unshared HLA antigens between mother and offspring may be suggested. We used T-cell-repleted bone marrow transplantation (BMT) from their HLA-haploidentical mothers to treat 6 patients with fatal nonmalignant diseases. The number of mismatched HLA loci in the graft-versus-host disease (GVHD) direction was 3 in 4 patients and 2 in 2 patients. The number in the host-versus-graft direction was 3 in 4 patients, 2 in 1 patient, and 1 in 1 patient. Microchimerism of inherited paternal antigens was demonstrated in 5 donors, and microchimerism of noninherited maternal antigens was detected in 3 recipients. GVHD prophylaxis consisted of short-course methotrexate, tacrolimus, and mycophenolate mofetil (3 patients) or short-course methotrexate, tacrolimus, and methylprednisolone (1 patient). Engraftment was achieved in 5 patients who had received preconditioning, and T-cell engraftment was confirmed in 1 patient with severe combined immunodeficiency. Acute GVHD developed in 3 patients: grade 1 in 2 patients and grade 2 in 1 patient. Chronic GVHD was observed in 5 patients: localized type in 3 patients and extended type in 2 patients. Five patients were alive 11 to 30 months after BMT and 1 patient died of chronic GVHD. Unmanipulated haploidentical BMT from a maternal donor may be the treatment of choice of poor-prognosis nonmalignant diseases.
International Journal of Hematology 08/2004; 80(1):78-82. · 1.27 Impact Factor
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Takako Miyamura,
Naoki Sakata,
Takayuki Okamura,
Masahiro Yasui,
Masami Inoue,
Keiko Yagi, Masahiro Sako,
Yoshihiro Komada,
Takaharu Matsuyama,
Megumi Oda,
Yong-Dong Park,
Keisei Kawa
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ABSTRACT: Many studies have assessed the clinical significance of the detection of minimal residual disease (MRD) in acute leukemia. Thus far, many studies have suggested that MRD detection to evaluate the response to chemotherapy is useful for predicting the prognosis of childhood acute lymphoblastic leukemia (ALL). However, few studies have reported on the significance of MRD in childhood acute myeloid leukemia (AML), because of small numbers of patients and limited availability of MRD markers. Therefore, we monitored MRD using currently available markers at several points during the treatment for childhood AML and tried to intensify the treatment based on the results of MRD. Thirty-one patients (26 de novo cases and 5 other cases) were examined for MRD between February 1999 and May 2002. After the first consolidation therapy (consolidation 1), the expression of Wilms tumor gene (WT1) and/or leukemia-specific fusion genes such as AML1/MTG8, PML/RAR alpha, and MYH11/CBF beta were analyzed. Patients with positive MRD but in hematological remission at that point were recommended to undergo stem cell transplantation (SCT). Positive WT1 expression (more than 10(3) copies/microgram RNA) was detected in 18 of 31 patients (58.1%) at onset. After consolidation 1 therapy, the WT1 expression became negative in 14 of 18 patients. The AML1/MTG8 fusion gene was expressed in 8 patients, PML/RAR alpha was expressed in 3 patients, and MYH11/CBF beta was expressed in 1 patient. Four of the 8 patients with AML1/MTG8 expression and all 3 with PML/RAR alpha expression also demonstrated positive WT1 expression at onset. Eight (5 de novo cases and 3 other cases) of the 31 patients had no available MRD markers. Four patients who showed pesistently high expression of WT1 after consolidation 1 therapy underwent SCT, and only 1 patient remained in complete remission (CR). Among 14 patients who became negative for WT1 expression, 6 patients received SCT for various reasons. Among 8 patients with the AML1/MTG8 fusion gene, 2 became MRD negative and 6 continued to be positive. Four of these 6 patients underwent SCT, and all but one who underwent syngeneic SCT became MRD negative. On the other hand, 1 of the 2 patients who continued on chemotherapy continued to be MRD positive, suggesting a graft-versus-leukemia effect in allogeneic SCT. All patients with the PML/RAR alpha and MYH11/CBF beta fusion gene continued to be in CR. The 3-year event-free survival in de novo AML was 69.4% +/- 9.8% (n = 26), a result that is encouraging and superior to other reported outcomes. Thus, an MRD-based treatment strategy together with conventional risk factors appears to be required for further improving the outcomes of AML.
International Journal of Hematology 05/2004; 79(3):243-9. · 1.27 Impact Factor
