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Volume 36, Issue 6
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[in Japanese]1995 Volume 36 Issue 6 Pages 511-516
Published: 1995
Released on J-STAGE: April 25, 2009
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—Comparative Study of BMT and Chemotherapy in Patients with the First Remission State—Yasuo MORISHIMA, Mitsume TANIMOTO, Yoshihisa KODERA, Shuuichi MIYAWAKI ...1995 Volume 36 Issue 6 Pages 517-523
Published: 1995
Released on J-STAGE: April 25, 2009
JOURNAL RESTRICTED ACCESSThe indication of allogeneic bone marrow transplantation (BMT) from HLA identical siblings during the first remission of acute myeloblastic leukemia was discussed according to the results of BMT and chemotherapy study groups. The comparison of disease free survival between both groups was done, after selection biases such as risk factors and time of BMT were adjusted by multivariate analysis or matched-pair analysis. In conclusion, patients with more than one high risk factors for leukemia relapse, that is, high peripheral white blood cell count (PBC) (>20,000/cmm) at diagnosis or more than two remission induction courses should be considered for BMT, and the indication of treatments for patients with no high risk factors should be determined depending on situations of the disease and patient's intention.View full abstractDownload PDF (540K) -
Shinichiro OKAMOTO, Mine HARADA, Shunichi KATO, Yasuo MORISHIMA, Masah ...1995 Volume 36 Issue 6 Pages 524-529
Published: 1995
Released on J-STAGE: April 25, 2009
JOURNAL RESTRICTED ACCESSBetween January 1993 and June 1994, the JMDP facilitated marrow donations from unrelated donors for 171 patients with malignant and non-malignant disorders. The median age of the patients was 21 years. All patients received marrow from phenotypically HLA-A, -B, -DR identical donors. About half of the patients wrer treated with total body irradiation (TBI)-containing regimens and about 80% of the patients received short-coures methotrexate and cyclosporine for graft-versus-host disease (GVHD) prophylaxis. Eight out of 171 patients (4.7%) had graft failure and 63 out of 144 patients (44%), who survived for more than 30 days posttransplant, developed grade II to IV acute GVHD. The incidence of chronic GVHD was 47% (extensive form; 27%); most of them were progressive/quiscent type. The incidence of moderate to severe acute GVHD was higher than that observed in sibling transplants. On the other hand, the incidence of chronic GVHD was similar to that observed in sibling transplants. Overall survival at 1.5 years posttransplant was about 50% with no significant differences between diseases. The age correlated significantly with the survival in standard risk leukemia but not in high-risk leukemia. Despite the risk of graft failure and acute GVHD, this preliminary analysis demonstrates that transplantation of marow from unrelated donors can be an effective treatment for certain hematologic disorders.View full abstractDownload PDF (366K) -
—Current Status and Issues—Koji NAGAFUJI, Mine HARADA1995 Volume 36 Issue 6 Pages 530-537
Published: 1995
Released on J-STAGE: April 25, 2009
JOURNAL RESTRICTED ACCESSAutologous blood stem cell transplantation (ABSCT) has been increasingly used in the treatment of malignant diseases. With the use of hematopoietic cytokines, collection of peripheral blood stem cell (PBSC) has become easier. Contamination of PBSC with tumor cells is supposed to be reflceting the amount of residual tumor cells in the host. G-CSF combined conditioning regimen seems to be effective for ANLL in complete remission (CR) probably by in vivo purging of residual leukemic cells. From our preliminary results, ABSCT can be used as the treatment of choice for standard risk ANLL, and aggressive non-Hodgkin's lymphoma. To clarify the curative potential of ABSCT, prospective clinical trial consisting of remission induction, consolidation of CR, PBSC harvests, and marrow-ablative therapy for ABSCT will be required.View full abstractDownload PDF (429K) -
Shunichi KATO, Hiromasa YABE1995 Volume 36 Issue 6 Pages 538-542
Published: 1995
Released on J-STAGE: April 25, 2009
JOURNAL RESTRICTED ACCESSGraft-versus-host disease (GVHD) is one of major causes of mortality in allogeneic bone marrow transplantation (BMT). GVHD prophylaxis for HLA matched sibling BMT is widely done by methotrexate and/or cyclosporine. More intensive modalities are necessary for HLA mismatched related or HLA matched unrelated BMT; T cell depletion, ALG/ATG in preconditioning or following BMT and FK-506 with short term methotrexate are currently used with certain success. Moderate to severe GVHD may develop despite of these preventions, and standard to high dose of steroid with or without ALG/ATG is currently used as the first line therapy. GVHD, however, is an important component to cure malignant diseases through its anti-tumor effect called graft-versus-leukemia (GVL) effect. Several attempts have been made to induce mild to moderate GVHD both in allogeneic and in autologous BMT; low dose of cyclosporine, IL-2, ubenimex and donor buffy coat or peripheral lymphocyte transfusion are shown to be effective with some limitation.View full abstractDownload PDF (256K) -
[in Japanese], [in Japanese], [in Japanese], [in Japanese], [in Japane ...1995 Volume 36 Issue 6 Pages 543-546
Published: 1995
Released on J-STAGE: April 25, 2009
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Takashi SHIMAMOTO, Junko H. OHYASHIKI, Kazuma OHYASHIKI, Keisuke TOYAM ...1995 Volume 36 Issue 6 Pages 547-551
Published: 1995
Released on J-STAGE: April 25, 2009
JOURNAL RESTRICTED ACCESSWe have studied gene expression of GATA-1, GATA-2, and SCL, which are known as cell-specific transcription factors, in 110 various leukemias consisted of 76 patients with acute myeloid leukemia (AML), 19 with acute lymphoblastic leukemia (ALL), and 15 with chronic myeloid leukemia (CML) in blast crisis by the revearse transcription-polymerase chain reaction assay. Accordingly, we divided into three groups. Group I (GATA-1+SCL+): patients with AML exhibiting phenotypic characteristics of erythroid or megakaryocytic lineage and most of CML myeloid blast crisis were included. Group II (GATA-1+, SCL-): Not only CD7-positive and CD19-positive AML, but also a part of Ph+ALL demonstrated this pattern. Leukemia in this group is considered to have a capability to defferentiate into myeloid and lymphoid lineages. Group III (GATA-1-, SCL-): patients in this group consisted of leukemias which are differentiated into specific cell-lineages, either myeloid or lymphoid, when compared to groups I or II. Our data suggest that the expression pattern of transcription factors reflects lineage potential in leukemia cells, leading to classification of leukemias.View full abstractDownload PDF (342K) -
Kazushi INOUE, Haruo SUGIYAMA1995 Volume 36 Issue 6 Pages 552-558
Published: 1995
Released on J-STAGE: April 25, 2009
JOURNAL RESTRICTED ACCESSThe WT 1 gene has been isolated as a tumor suppressor gene of Wilms' tumor. Using reverse transcriptase-polymerase chain reaction (RT-PCR), relative levels of the WT 1 gene expression was examined in 87 patients with acute leukemia, 25 with chronic myelogenous leukemia (CML), and 24 with non-Hodgkin's lymphoma (NHL). Significant levels of the WT 1 gene were expressed in all leukemia patients, and for CML the levels increased as the clinical phase progressed. No point mutations were found in the WT 1 gene when samples from 15 acute leukemia patients were subjected to PCR single-strand conformation polymorphism analysis. In striking contrast to acute leukemia, the levels of WT 1 gene expression for NHL were significantly low or even undetectable. The levels of WT 1 gene expression inversely correlated with the prognosis of acute leukemia. The quantification of the WT 1 gene expression made it possible to detect minimal residual disease (MRD) in acute leukemia regardless of the presence or absence of tumor-specific DNA markers. Simultaneous monitoring of MRD by RT-PCR using primers for specific DNA markers in four patients (two AML-M3 with PML/RAR-α, one AML-M2 with AML1/ETO, and one CML with bcr/abl) detected MRD comparable to that obtained from quantitation of WT 1 gene expression. In a patient with acute promyelocytic leukemia, the limits of leukemic cell detection by RT-PCR using either WT 1 or PML/RAR-α gene primers were 10-3-10-4 and 10-4 for bone marrow, and 10-5 and 10-4 for peripheral blood, respectively. We conclude that WT 1 is a new prognostic factor as well as a marker for the detection of MRD in acute leukemia.View full abstractDownload PDF (422K) -
Hiroaki HONDA1995 Volume 36 Issue 6 Pages 559-566
Published: 1995
Released on J-STAGE: April 25, 2009
JOURNAL RESTRICTED ACCESSThe bcr/abl chimeric oncoprotein is considered to be implicated in the pathogenesis of Philadelphia chromosome-positive human leukemias. To investigate its biological function and the role in leukemogenesis in vivo, we generated transgenic mice expressing p210bcr/abl driven by the metallothionein promoter. Two of six founder mice and the transgenic progeny of one leukemic founder mouse developed leukemias several months after birth. Phenotypically, each leukemic mouse showed a thymic enlargement, a marked splenomegaly, and/or lymphnode swellings. Pathological examination revealed that leukemic cells were infiltrated in all tissues examined, especially in thymus, spleen, liver, and lymphnode. Expression of the p210bcr/abl transgene product and increased phosphorylation of cellular proteins in leukemic tissues were detected by the Western blot analysis. In addition, the expressed p210bcr/abl protein was demonstrated to possess an enhanced kinase activity by the in vitro immunecomplex kinase assay. These results indicate that hematopoietic precursor cells expressing the p210bcr/abl transgene product acquired a proliferative advantage and eventually developed leukemias in transgenic mice. The p210bcr/abl transgenic mice are considered to be an excellent animal model to investigate p210bcr/abl function and its role in leukemogenesis in vivo.View full abstractDownload PDF (1013K) -
Motoko YAMAGUCHI, Minoru MIZUTANI, Hiroshi MIWA, Kenkichi KITA1995 Volume 36 Issue 6 Pages 567-572
Published: 1995
Released on J-STAGE: April 25, 2009
JOURNAL RESTRICTED ACCESSTo clarify the common characteristics among P-glycoprotein (P-gp)-expressing hematological malignancies and whether chemotherapies could or could not induce P-gp expression, we analyzed P-gp/MDR1 expression in tumor cells from 200 Japanese patients (104 with acute myeloblastic leukemia [AML]; 30 with acute lymphoblastic leukemia [ALL]; 66 with mature lymphoid malignancies). Functional P-gp expression was examined by Rhodamine-123 efflux test, and estimated with the data by RT-PCR method. In mature lymphoid malignancies, the cells of T or natural killer (NK) cell malignancies frequently expressed P-gp/MDR1. In AML, frequent P-gp/MDR1 expression was associated with the expression of CD7 or c-kit and with 8;21 chromosomal translocation (p<0.01), which were thought to be the characteristics of the hematopoietic stem cell. Though the expression of P-gp/MDR1 was more frequent at onset than at relapse phase, the increase is thought to result from the expansion of blastic fraction expressing P-gp/MDR1. In ALL, P-gp/MDR1 expression was not frequent in B-cell precursor lineage (three of eighteen patients), but the incidence was high in CD7(+) surface CD3(-) cases (seven of the cases). These results indicate P-gp/MDR1 expression is more frequently in the tumor of T, NK cell and stem cell, reflecting the characteristics of its normal counterpart.View full abstractDownload PDF (341K) -
Kazunori IMADA, Akifumi TAKAORI-KONDO, Takashi UCHIYAMA1995 Volume 36 Issue 6 Pages 573-577
Published: 1995
Released on J-STAGE: April 25, 2009
JOURNAL RESTRICTED ACCESSWe made a model of in vivo cell proliferation of leukemic cells from adult T cell leukemia (ATL) patients using severe combined immunodeficient (SCID) mice. SCID mice injected with ATL cells from 6 of 8 ATL patients were found to have the tumor. DNA analysis revealed that the clone of the cells proliferating in mice was the same as that of the original leukemic cells. Histologic examination showed that the pattern of the infiltration of ATL cells in mice was similar to that of an ATL patient. Next, we examined the tumorigenicity of HTLV-I infected cell lines using SCID mice. Seven HTLV-I infected cell lines were injected into SCID mice and it was found that 4 of them were capable of proliferating in SCID mice. HTLV-I infected cell lines of non-leukemic cell origin could not engraft in SCID mice, indicating that these cells seemed not to have the enough genetic changes to acquire the tumorigenic potential. Analysis of gene expression suggested that neither IL-2 nor HTLV-I viral product was directly involved in the neoplastic cell growth of ATL. Furthermore, T cells immortalized by introduction of Tax could not engraft in SCID mice, indicating that the expression of tax gene seemed not to be sufficient for the neoplastic cell growth in vivo.View full abstractDownload PDF (376K) -
Arinobu TOJO, Yasuo OSHIMA1995 Volume 36 Issue 6 Pages 578-581
Published: 1995
Released on J-STAGE: April 25, 2009
JOURNAL RESTRICTED ACCESSA chimeric toxin in which the cell surface binding domain of Pseudomonas exotoxin was replaced with mature human granulocyte colony-stimulating factor (G-CSF) was produced in Escherichia coli, partially purified and tested for its biological activity on a G-CSF-dependent murine myeloid leukemia cell line, NFS60. This fusion protein, termed as G-CSF-PE40, can displace [125I] G-CSF binding to its receptor. After 48 hrs' incubation in the presence of G-CSF, G-CSF-PE40 inhibited protein synthesis and revealed cytotoxicity in NFS60 cells in a concentration dependent manner. The half maximal dose of G-CSF-PE40 for protein synthesis inhibition (ID50) in NFS60 cells was estimated at around 100pM. Additionally, relatively low concentration of G-CSF-PE40 stimulated DNA synthesis in NFS60 cells after 16 hrs' incubation in the absence of G-CSF, suggesting that G-CSF-PE40 also can transduce a transient mitogenic signal. Thus, G-CSF-PE40 may be useful in the selective elimination of myeloid cells expressing G-CSF receptors, especially in combination with chemotherapeutic agents like cytosine arabinoside.View full abstractDownload PDF (240K)
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—Combined Use of All-trans Retinoic Acid and Granulocyte Colony-Stimulating Factor—Hisashi TSURUMI, Toshiki YAMADA, Michio SAWADA, Noriaki NAKAMURA, Take ...1995 Volume 36 Issue 6 Pages 582-588
Published: 1995
Released on J-STAGE: April 25, 2009
JOURNAL RESTRICTED ACCESSWe evaluated the effect of treatment by all-trans retinoic acid (ATRA) in 9 patients with acute promyelocytic leukemia (APL). Of 6 patients who had circulating leukemic blasts before treatment, 3 initially received ATRA alone but died of respiratory failure due to retinoic acid syndrome (RAS). High dose steroid therapy did not rescue RAS in these patients. Another 3 who were given intensive chemotherapy followed by ATRA and/or granulocyte colony-stimulating factor (G-CSF) achieved complete remission (CR). Of 3 patients without peripheral leukemic blasts before treatment, 1 received intensive chemotherapy followed by G-CSF and reached CR, 1 who had been previously given ATRA did not respond to ATRA, and 1 did not initially respond sufficiently to ATRA alone but responded dramatically to ATRA plus G-CSF. In the treatment of APL, appropriate combination of ATRA, G-CSF and chemotherapy should always be taken into consideration. In addition, RAS have to be carefully avoided when applying ATRA therapy in patients who have circulating leukemic blasts before treatment.View full abstractDownload PDF (488K) -
Yukihiko KIMURA, Keisuke TOYAMA, Kunitake HIRASHIMA, Minoru OKUMA, Hid ...1995 Volume 36 Issue 6 Pages 589-596
Published: 1995
Released on J-STAGE: April 25, 2009
JOURNAL RESTRICTED ACCESSA clinical study to investigate the efficacy and safety of recombinant human G-CSF (rG·CSF) was performed in patients with acute myelogenous leukemia who had had protracted neutropenia. The drug was administered d.i.v. at a dose of 5 μg/kg. Sixty-four patients entered the study, of whom 61 patients were evaluable for safety and 58 patients evaluable for efficacy. The treatment produced an early recovery in neutrophil count in the patients who had had protracted neutropenia (<1,000/μl) of over 10 days. Among relapsed cases and cases showing >20% blasts in the bone marrow, many showed blast stimulation in response to rG·CSF, suggesting difficulty in attaining complete remission by subsequent chemotherapy in such cases. The present data indicates that it is desirable to use the drug in lower-blast-count states in order to attain safe and sufficient therapeutic effects in patients with acute myelogenous leukemia who have had protracted neutropenia.View full abstractDownload PDF (523K) -
Hideaki NAKAJIMA, Yasuo IKEDA, Kunitake HIRASHIMA, Keisuke TOYAMA, Min ...1995 Volume 36 Issue 6 Pages 597-605
Published: 1995
Released on J-STAGE: April 25, 2009
JOURNAL RESTRICTED ACCESSA randomized treated/non-treated study of rG·CSF (5 μg/kg/d, d.i.v.) in patients with acute myelogenous leukemia was conducted to assess its efficacy on fever (≥38°C) or documented infection after induction therapy. Of 95 patients enrolled, 46 patients were evaluable for safety and 43 for efficacy in the treated group of 47 patients while 37 of 48 patients were eligible for data analysis in the untreated group. Mare patients showed a recovery in the blood neutrophil count (to >1,000/μl) during rG·CSF treatment (14 days) than in the non-treated group (p=0.039) while the number of febrile patients and duration of fever did not significantly differ between the two groups. The treatment with rG·CSF enabled an early recovery in neutrophil count in the patients with neutropenia and overt signs of infection after induction therapy, but there was no hastened allevistion of symptoms of infection in these patients.View full abstractDownload PDF (584K) -
Akihiro TAKESHITA, Ryuzo OHNO, Kunitake HIRASHIMA, Keisuke TOYAMA, Min ...1995 Volume 36 Issue 6 Pages 606-614
Published: 1995
Released on J-STAGE: April 25, 2009
JOURNAL RESTRICTED ACCESSA multicenter, randomized, double-blind controlled study was performed to evaluate the efficacy and safety of recombinant human granulocyte colony-stimulating factor (rG·CSF) in reducing infectious morbidity and neutropenia induced by consolidation chemotherapy for acute myeloid leukemia (AML). One hundred and twenty-four eligible patients were randomized to receive either rG·CSF (5 μg/kg/d d.i.v.; 59 patients) or placebo (65 patients) for 14 days from the day after chemotherapy. All of them were included in the safety analysis, while 57 patients receiving rG·CSF and 64 patients receiving placebo were included in the efficacy analysis. The duration of neutropenia as well as the incidence of fever and febrile neutropenia, and frequency of antibiotic therapy required, were all significantly reduced in the rG·CSF group. No serious adverse reactions were encountered; there was no significant difference between the two groups in terms of incidence of adverse events. These results demonstrate that rG·CSF is beneficial to alleviate neutropenic episodes induced by consolidation chemotherapy in patients with AML.View full abstractDownload PDF (575K)
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Jun TAKIZAWA, Kenji KISHI, Yoshiaki MORIYAMA, Shigeo HASHIMOTO, Takao ...1995 Volume 36 Issue 6 Pages 615-620
Published: 1995
Released on J-STAGE: April 25, 2009
JOURNAL RESTRICTED ACCESSWe report a case of a 19-year-old male with congenital aplastic anemia and multiple abnormalities; short stature, hypoplastic thumb, skin pigmentation and mental retardation. He was admitted to our hospital because of severe pancytopenia. Bone marrow aspiration showed markedly hypocellular marrow with 42% myeloblasts. He was diagnosed as AML (M2) transformed from Fanconi's anemia and underwent allo-BMT from an HLA-identical father. The conditioning regimen consisted of high dose Ara-C, high dose etoposide and 12Gy fractionated total body irradiation. Severe toxicity associated with the conditioning regimen was not observed. Ciclosporin A and short-term methotrexate were administered for prophylaxis of acute GVHD. Neither acute nor chronic GVHD were observed. He is well and free of disease for 15 months since BMT. Very few cases of Fanconi's anemia with leukemic transformation treated by BMT have been reported. Long-term observation will be necessary to evaluate our conditioning regimen for Fanconi's anemia with leukemic transformation.View full abstractDownload PDF (533K) -
Kakushi MATSUSHITA, Tadashi MATSUMOTO, Naomichi ARIMA, Shiroh HIDAKA, ...1995 Volume 36 Issue 6 Pages 621-626
Published: 1995
Released on J-STAGE: April 25, 2009
JOURNAL RESTRICTED ACCESSWe demonstrate two conventional chemotherapy-resistant cases of acute promyelocytic leukemia (APL) who were successfully treated with macrophage-colony stimulating factor (M-CSF). Case no 1 was a 40-year-old woman who was made diagnosis of APL on June, 1992, and treated repeatedly with a conventional chemotherapy, BHAC-DMP regimen, resulting in complete remission on Octorber, 1992. After a couple of years, she had relapse with marked growth of APL cells in bone marrow. She was treated with BHAC-AMP and modified B-triple V but could not obtain remission. Case no 2 was a 36-vear-old-man with APL who was treated with BHAC-DMP and BHAC-AMP and modified B-triple V therapy. These three conventional chemotherapy regimen were not effective for him. Eight million units of human native M-CSF was administered interavenously for 14 days after the last BHAC-AMP therapy in case no 1, and for 5 days after the last modified B-triple V therapy in case no 2. After the therapy, APL cells in peripheral blood or bone marrow of both patients disappeared completely and normal hemopoietic cells increased, obtaining in complete remission in both cases. These successful cases treated with M-CSF combining chemotherapy may suggest a new therapeutic strategy for APL in addition to all-trans retinoic acid.View full abstractDownload PDF (385K)
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