[Aleukemic leukemia].
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
N Asou
Publications and source records attributed to N Asou.
Detection of the PEBP2beta/MYH11 fusion transcript in acute myelomonoblastic leukemia (M4Eo) supervening in a patient with adult T-cell leukemia.
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Aged↗
All-trans retinoic acid therapy for newly diagnosed acute promyelocytic leukemia: comparison with intensive chemotherapy. The Japan Adult Leukemia Study Group (JALSG).
We analyzed the results of treating patients with newly diagnosed acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) in the JALSG AML-92 study and compared them with those of the AML-87 and AML-89 studies, which consisted of standard chemotherapy. In the AML-92 study, patients were scheduled to receive 45 mg/ m2 oral ATRA daily until achievement of a complete remission (CR). If patients had initial leukocyte counts of > 3.0 x 10(9)/l, they received 40 mg/m2 daunorubicin (DNR) for 3 days and 200 mg/m2 behenoyl cytarabine (BHAC) for 5 days in addition to ATRA. During remission induction therapy, if the patients showed peripheral blood myeloblast and promyelocyte counts of > 1.0 x 10(9)/l, they received additional DNR and BHAC on the same schedule. After achievement of a CR, patients received three courses of consolidation and six courses of maintenance/intensification chemotherapy. Of 196 evaluable patients, 173 (88%) achieved a CR: 59 of 62 (95%) treated with ATRA alone, 41 of 49 (84%) treated with ATRA plus later chemotherapy, 63 of 73 (86%) treated with ATRA plus initial chemotherapy, and 10 of 12 (83%) treated with ATRA plus both initial and later chemotherapy. The CR rate in AML-92 was significantly higher than that in AML-89, but not than that achieved in AML-87. In addition, the early mortality and relapse rates in AML-92 were significantly lower than those in AML-89, but were not than those in AML-87. At a median follow-up of 36 months the predicted 4-year event-free survival (EFS) rate for 196 evaluable patients and the 4-year disease-free survival (DFS) rate for the CR cases were 54% and 62%, respectively. There was a significant difference in DFS between AML-92 and AML-87 (P = 0.0418) but not between AML-92 and AML-89 (P = 0.0687). In contrast, significant differences in EFS between AML-92 and both AML-87 (P = 0.0129) and AML-89 (P = 0.005) were observed. These results suggest that non-cross-resistant therapy combined with ATRA and intensive chemotherapy for APL contributes synergistically to the significant improvement in EFS.
Adolescent↗
Case-control study of leukemia and diagnostic radiation exposure.
A case-control study of leukemia and diagnostic X-ray exposure was conducted by a multi-institution co-operative study group. The subjects were 134 patients with acute myelogenous leukemia, 57 with chronic myelogenous leukemia, 56 with acute lymphocytic leukemia and 50 with myelodysplasia syndrome, who were between 15 and 79 years old, and diagnosed at one of 27 hospitals between September 1993 and August 1995. The controls were 479 first-visit patients seen at eight of these 27 hospitals. History of diagnostic X-ray tests between 1982 and 1991 was determined by an anonymous self-administered questionnaire. The total relative dose of radiation exposure was calculated by summing the products of given weights and frequencies of each test. The relative risk was 0.83 (95% confidence interval (C.I.), 0.58-1.19) for relative dose of 10-30 (equivalent to 4-11 times of UGI series), 0.76 (0.48-1.20) for relative dose of 30 or more (more than 12 times of UGI series), when compared with relative dose of 0-10 (0-3 times of UGI series). Analysis according to type of leukemia revealed that only acute myelogenous leukemia had an estimated relative risk above unity (1.08, 95% C.I. 0.69-1.69, for relative dose 10-30). This study did not support the hypothesis that diagnostic X-ray tests increases leukemia risk.
Adolescent↗
TEL/AML1 fusion gene resulting from a cryptic t(12;21) is uncommon in adult patients with B-cell lineage ALL and CML lymphoblastic transformation.
TEL is a new member of the ETS-like family on chromosome 12 and forms fusion genes with several partners in leukemia. Among these fusion genes, the TEL/AML1 translocation resulting from t(12;21) is found in approximately one quarter of the childhood B-cell lineage acute lymphoblastic leukemia (ALL) cases and its prognosis is excellent. We examined 42 adult patients with B-cell lineage ALL and 13 adult patients with lymphoblastic transformation of chronic myeloid leukemia (CML) to detect TEL/AML1 fusion genes using the reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern blotting, but no translocation was detected. These findings indicate that absence of the TEL/AML1 fusion transcript partly correlates with the poorer outcome of adult B-cell lineage ALL as compared with childhood ALL and the TEL/AML1 fusion transcript is specific for pediatric B-cell lineage ALL.
Adolescent↗
Morphological subtyping of acute myeloid leukemia with maturation (AML-M2): homogeneous pink-colored cytoplasm of mature neutrophils is most characteristic of AML-M2 with t(8;21).
Morphologic and cytochemical features of 30 acute myeloid leukemia subtype M2 (AML-M2) patients with t(8;21) were compared with those of 50 AML-M2 patients without t(8;21). It was disclosed that irregular nuclear shape, Auer bodies, and at least 90% myeloperoxidase positivity in blast cells, and pseudo-Pelger-Huët anomaly of the nuclei and homogeneous pink-colored cytoplasm of mature neutrophils were observed in 90-100% of the t(8;21)+ patients. The percentages of patients showing these features were significantly (P < 0.01) lower in the t(8;21)- group. Among these morphological features, homogeneous pink-colored cytoplasm of mature neutrophils is most characteristic of t(8;21)+ AML-M2, because it was seen in 90% of the t(8;21)+ patients but in only 2% of the t(8;21)- patients. Conversely, pale-colored cytoplasm without any granules in mature neutrophils or dyserythropoietic features was observed in 84% of the t(8;21)- patients, but in none of the t(8;21)+ patients. These data suggest that it is possible to subtype AML-M2 patients morphologically by the recognition of homogeneous pink-colored or pale-colored cytoplasm of mature neutrophils and dyserythropoietic features. Thus, the morphologic subtyping of AML-M2 can be utilized alone or in combination with chromosomal or molecular subtyping for biological and clinical studies of AML with maturation.
Adolescent↗
Myelomonoblastic leukaemia cells carrying the PEBP2beta/MYH11 fusion gene are CD34, c-KIT+ immature cells.
To clarify the aspects affected by the PEBP2beta/MYH11 fusion gene involved in the inv(16), we analysed immunophenotypes in myelomonoblastic leukaemias. We found high expressions of CD34 and c-KIT antigens in myelomonoblastic cells from all patients carrying this fusion gene, including two with M4 and one CML blastic phase, in contrast to those with M4 without the fusion gene. These findings indicate that immunophenotyping is useful for detecting a leukaemia with the fusion gene in myelomonoblastic leukaemias and that the PEBP2beta/MYH11 gene is involved in immature cells expressing CD34 and c-KIT antigens.
Antigens, CD34↗
Human urinary macrophage colony-stimulating factor reduces the incidence and duration of febrile neutropenia and shortens the period required to finish three courses of intensive consolidation therapy in acute myeloid leukemia: a double-blind controlled study.
PURPOSE: To determine whether macrophage colony-stimulating factor (M-CSF) reduces the incidence and duration of febrile neutropenia during three courses of intensive consolidation therapy and whether it shortens time to complete consolidation therapy. PATIENTS AND METHODS: In 198 adult patients with acute myeloid leukemia (AML) in complete remission (CR), M-CSF (8 x 10(6) U/d) or placebo was administered from 1 day after the end of each consolidation chemotherapy for 14 days. RESULTS: The duration and incidence of febrile neutropenia was significantly reduced by 34% (P = .00285) and 17% (P = .02065), respectively, in 88 assessable patients in the M-CSF group compared with those in 94 assessable patients in the placebo group. Patients in the M-CSF group had 565 days and 133 episodes of febrile neutropenia during 7,901 days at risk, while patients in the placebo group had 977 days and 185 episodes during 9,077 days at risk. The median period required to finish the three courses of consolidation therapy was 93 days in the M-CSF group, which was significantly shorter than 110 days in placebo group (P = .0050). In the M-CSF group, the recovery of neutrophils and platelets was significantly faster (P = .0348 and P = 0.0364, respectively), the administration of systemic antimicrobial agents tended to be less (P = .0839), and the frequency of platelet transfusion (P = .0259) and the total volume of transfused platelets (P = .0292) were significantly less. However, there was no significant difference in the disease-free survival. CONCLUSION: M-CSF significantly reduced the incidence and duration of febrile neutropenia during the intensive consolidation therapy, and shortened the time to complete consolidation chemotherapy in AML.
Acute Disease↗
Burkitt's type acute lymphoblastic transformation associated with t(8;14) in a case of B cell chronic lymphocytic leukemia.
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Aged↗
Molecular cloning of complex chromosomal translocation t(8;14;12)(q24.1;q32.3;q24.1) in a Burkitt lymphoma cell line defines a new gene (BCL7A) with homology to caldesmon.
Chromosome 12q24.1 is a recurrent breakpoint in high-grade B-cell non-Hodgkin lymphoma (B-NHL). To identify the genes involved at 12q24.1, molecular cloning of a three-way translocation t(8;14;12)(q24.1;q32.3;q24.1) in a Burkitt lymphoma cell line (Wien 133) was performed; all four translocation breakpoints were cloned and sequenced. Analysis of clones encompassing the der(12)(12;14)(q24.1;q32.3) breakpoint showed a CpG island from chromosome 12q24.1 juxtaposed in a tail-to-tail configuration with a productively rearranged Ig VH4-DH-JH5 gene. A total of 4.5 kb of genomic DNA including the CpG island was sequenced and analyzed using gene-identification programs; all three programs identified a potential 92-bp exon within the centromeric boundary of the CpG island. Using this as a probe, an RNA transcript of 3.8 kb, expressed at low levels in a wide variety of normal tissues, was detected. Overlapping cDNA clones were isolated and sequenced. The longest open-reading frame predicted a serine-rich protein of 231 amino acids. This protein, termed BCL7A, exhibited no recognizable protein motifs but showed homology with the actin-binding protein, caldesmon. In Wien 133, the BCL7A breakpoint occurred within the first intron and resulted in a MYC-BCL7A fusion transcript, with exon I of BCL7A being replaced by MYC exon I. The normal, untranslocated allele of BCL7A was also expressed without mutation. One of the 11 other B-NHL cell lines examined with 12q24.1 cytogenetic abnormalities, a mediastinal B-NHL cell line (Karpas 1106), showed biallelic rearrangement within the first intron of BCL7A, which was adjacent to the breakpoint observed in Wien 133. Disruption of the amino-terminus of BCL7A defines a new mechanism in the pathogenesis of a subset of high-grade B-NHL.
Amino Acid Sequence↗
Aggressive CD5-positive diffuse large B cell lymphoma showing c-myc rearrangements developed in a patient with autoimmune hemolytic anemia.
A case of CD5-positive diffuse large cell lymphoma in a patient with autoimmune hemolytic anemia (AIHA) is reported. The patient was diagnosed with AIHA in December 1988. Three and a half years later, the patient complained of fever and left sided flank pain. Abnormal lymphocytes appeared in the peripheral blood and were positive for HLA-DR, CD5, CD19, CD20, and surface immunoglobulin (mu, lambda). The pathological diagnosis of the cervical lymphnode was non-Hodgkin lymphoma; diffuse large cell type with a starry sky-like appearance. Although the 8q24 translocation was not detected by karyotypic analysis of the peripheral blood mononuclear cells (PBMNC), Southern blot analysis revealed that the c-myc rearrangements had occurred. This case showed two rearranged bands with Eco RI, Bam HI, or Bgl II digestion, and a germline band with Hin dIII digestion using a second exon fragment of the c-myc gene as a probe. Despite intensive chemotherapy, this patient died 6 months after being diagnosed with malignant lymphoma. We discuss the c-myc rearrangements in this aggressive CD5-positive diffuse large B cell lymphoma.
Anemia, Hemolytic, Autoimmune↗
Randomized trials between behenoyl cytarabine and cytarabine in combination induction and consolidation therapy, and with or without ubenimex after maintenance/intensification therapy in adult acute myeloid leukemia. The Japan Leukemia Study Group.
PURPOSE: We analyzed complete remission (CR), disease-free survival (DFS), and event-free survival (EFS) rates in two groups of patients treated with either N4-behenoyl-1-beta-D-arabinosylcytosine (BHAC) or cytarabine, and analyzed DFS with or without ubenimex, a biologic response modifier. PATIENTS AND METHODS: Newly diagnosed patients with acute myeloid leukemia (AML) were randomized to receive either BHAC or cytarabine as remission-induction combination chemotherapy and two courses of consolidation therapy. After maintenance/intensification therapy, patients in CR were randomized to receive either ubenimex and no drug. RESULTS: Of 341 patients registered, 326 were assessable. The age of assessable patients ranged from 15 to 82 years (median, 48). The overall CR rate was 77%: 72% in the BHAC group and 81% in the cytarabine group, and there was a significant difference between the two groups (P = .035, chi 2 test). The predicted 55-month EFS rate of all patients was 30%: 23% in the BHAC group and 35% in the cytarabine group, with a significant difference between groups (P = .0253). The predicted 55-month DFS rate of all CR patients was 38% and that of CR patients less than 50 years of age was 47%. There was no significant difference in DFS between the ubenimex group and the group that did not receive ubenimex. CONCLUSION: Analyses of our clinical trial showed that the use of BHAC in remission-induction therapy and in consolidation therapy resulted in poorer CR and EFS rates in adult AML patients compared with the use of cytarabine at the doses and schedules tested. Immunotherapy with ubenimex after the end of all chemotherapy did not improve DFS.
Acute Disease↗
A human T-cell lymphotropic virus type-I carrier with chronic renal failure, aplastic anemia, myelopathy, uveitis, Sjögren's syndrome and panniculitis.
A 53-year-old female infected with human T lymphotropic virus type-I (HTLV-I) suffered from chronic renal failure, aplastic anemia, myelopathy, uveitis, Sjögren's syndrome and Weber-Christian disease. Although HTLV-I antibody was negative in cerebrospinal fluid, she was diagnosed as HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) based on clinical and histological findings. Though to date there is no direct evidence, other complications have also been reported to be HTLV-I related diseases. This case provided the unique opportunity to observe various HTLV-I related diseases.
Anemia, Aplastic↗
[Detection of PEBP2 beta/MYH11 fusion mRNA in acute myelomonocytic leukemia without marrow eosinophilia].
We present a 15-year-old woman with acute myelomonocytic leukemia without marrow eosinophilia, M4 in the FAB classification. She was admitted to our hospital with nausea and headaches. Upon admission, the leukocyte count was 284,000/microliters with 95% leukemic cells. The bone marrow aspirate was hypercellular with 74.8% blasts and 0.2% eosinophils. Leukemic cells were positive for myeloperoxidase and esterase staining. Initially, the karyotype of the bone marrow cells on admission was considered to be normal. However, the PEBP2 beta/MYH11 fusion transcript was detected in the bone marrow mononuclear cells by using the reverse transcriptase-polymerase chain reaction (RT-PCR). Reevaluation of karyotypes showed a t(16;16) (p13;q22) in the bone marrow cells. After achieving complete remission, she was treated with low-dose etoposide. Chromosome analysis showed a normal karyotype and no amplified chimeric transcripts were observed. This case indicates that the molecular analysis of PEBP2 beta and MYH11 genes is a useful tool to detect inv (16) and t(16;16) which were often difficult to find, and that leukemic cells from some cases of M4 without marrow eosinophilia have these chromosome abnormalities.
Adolescent↗
Significant reduction of medical costs by differentiation therapy with all-trans retinoic acid during remission induction of newly diagnosed patients with acute promyelocytic leukemia. The Japan Adult Leukemia Study Group.
BACKGROUND: Differentiation therapy with all-trans retinoic acid (RA) induces more than 80% complete remission with the least complications in patients with acute promyelocytic leukemia (APL). The authors studied the cost-benefit of this new treatment modality compared with conventional chemotherapy in newly diagnosed patients with APL. METHODS: Costs were calculated retrospectively through the monthly bills of each patient to national health insurance and were compared between 36 patients treated with conventional chemotherapy in the AML-87 or AML-89 studies and 40 patients treated with all-trans RA alone or with all-trans RA plus low dose chemotherapy in the AML-92 study of the Japan Adult Leukemia Study Group who were treated at 22 university and cancer hospitals in Japan. RESULTS: Average medical costs except for antileukemic drugs during 2 months after admission were 4,164,026 yen (approximately US$46,300) in the chemotherapy group and 2,906,825 yen (approximately US$32,300) in the all-trans RA group (P < 0.0001). The difference resulted mainly from the costs of antibiotics and of platelet and erythrocyte transfusions. Average costs of antibiotics were 650,494 yen (approximately US$7,200) and 349,138 yen (approximately US$3,900), respectively (P < 0.0002), and those of platelet and erythrocyte transfusions were 1,016,190 yen (approximately US$11,300) and 633,444 yen (approximately US$7,000), respectively (P < 0.0020). CONCLUSION: During the remission induction therapy of newly diagnosed APL, all-trans RA significantly reduced medical costs. all-trans RA should be incorporated into the front-line therapy of patients with APL for medical and economic reasons.
Adult↗
All-trans retinoic acid for the treatment of newly diagnosed acute promyelocytic leukemia. Japan Adult Leukemia Study Group.
We conducted a multicenter trial of treatment with all-trans retinoic acid (ATRA) for newly diagnosed acute promyelocytic leukemia (APL) in the AML-92 study and compared it with our previous study with standard intensive chemotherapy, the AML-89 study, in the view of complete remission (CR) rate, incidence of early death, and event-free survival (EFS). Patients were scheduled to receive oral ATRA 45 mg/m2 daily until CR. If patients had leukocyte counts above 3 x 10(9)/L at the start of therapy, they received daunorubicine (DNR) 40 mg/m2 for 3 days and behenoyl cytosine arabinoside (BHAC) 200 mg/m2 for 5 days in addition to ATRA. During the ATRA therapy, if patients showed myeloblast plus promyelocyte counts higher than 1 x 10(9)/L in the peripheral blood, they received additional DNR and BHAC in the same schedule, as well. A total of 110 patients were entered into the study. Median age was 43 years (range, 16 to 74). Twenty-eight (26%) of 109 patients (one died before the start of therapy) received ATRA alone. Ninety-seven patients (89%) achieved CR; 48 of 49 (98%) aged less than 40 years, 44 of 52 (84%) aged between 40 and 69, and 5 of 8 (63%) aged above 70 achieved CR, respectively; 25 of 28 (89%) with ATRA alone, 46 of 51 (90%) with ATRA plus initial chemotherapy and 26 of 30 (87%) with ATRA plus later chemotherapy attained CR, respectively. Nine (8%) patients died within 28 days after the start of therapy. In contrast, 44 of 62 patients (71%) attained CR, and 13 (21%) died within 28 days in the AML-89 study with the combination of DNR, BHAC, 6-mercaptopurine and prednisolone. Seven developed retinoic acid syndrome and one died of it in the present study. Other toxicities associated with this drug included cheilitis, desquamation, muscle pain, and hypertriglyceridemia. Predicted 23 months EFS for all ATRA-treated patients and disease-free survival (DFS) in the CR cases were 75% and 81%, respectively, in a median follow-up period of 21 months. Compared to the AML-89 study, there was a highly significant difference in remission rate (P = .004), EFS (P = .0007), and also early mortality rate (P = .02). Present results demonstrated that ATRA with or without chemotherapy gives a statistical improvement in CR rate and early mortality rate, as well as superior survival in newly diagnosed APL.
Adolescent↗
Lack of the expression of EBNA-2 and LMP-1 in T-cell neoplasms possessing Epstein-Barr virus.
We investigated 34 cases of T-cell neoplasm [15 cases of T-cell granular lymphocytic leukemia (T-GLL), 10 cases of T-cell non-Hodgkin's lymphoma (T-NHL), six cases of T-cell chronic lymphocytic leukemia (T-CLL), and three cases of cutaneous T-cell lymphoma] to study their association with Epstein-Barr virus (EBV). In 4 (three T-NHL and one T-GLL) of 34 cases, EBV genome was detected in a single episomal form, while polyclonal EBV-DNA was detected in one (T-NHL) of the remaining cases. All three cases of T-NHL having monoclonal EBV episome showed histologically diffuse large-cell lymphoma and developed leukemic conversion. Phenotypic analysis showed that two of these four cases were CD4+, CD8-, and the remaining two cases were CD4-, CD8+. The cells from all four cases were confirmed to be in T-cell lineage by detecting the rearrangement of T-cell receptor (TCR) beta or gamma chain gene. By reverse transcription-polymerase chain reaction (RT-PCR), EBNA-1 was detected at low levels, and neither EBNA-2 nor LMP-1 were found in any of the three cases examined. Lack of the expression of EBNA-2 and LMP-1 was also confirmed by immunocytochemical staining. The cells of these four cases did not show rearrangement or overexpression of c-myc and bcl-2 genes by Southern and Northern blots, and the mutation of p53 gene was detected in only one patient. These results suggest that other latent gene products of EBV or other cellular oncogenes are involved in the development of Japanese T-cell neoplasm after EBV infection.
Antigens, Viral↗
Identification of two transcripts of AML1/ETO-fused gene in t(8;21) leukemic cells and expression of wild-type ETO gene in hematopoietic cells.
The t(8;21) is a common chromosomal abnormality, preferentially associated with acute leukemia showing features of myeloid differentiation. Recently, two genes--AML1, which has a unique runt domain, and ETO (MTG8)--have been isolated from the chromosomal breakpoint. In this study, we isolated and identified two fused transcripts from a leukemic cell line carrying t(8;21). AML1 and ETO were fused at the same position in these transcripts. One of the transcripts codes a unique domain, including two zinc finger domains and three proline- and one leucine-rich region. The other transcript codes only for one proline- and leucine-rich region but lacks zinc finger domains. We demonstrated by polymerase chain reaction (PCR) analysis that 1) these two transcripts are consistently expressed in leukemic cells with t(8;21) obtained from patients and 2) expression of AML1 was not restricted to the particular stage of hematopoietic differentiation but was present in all hematopoietic cells investigated. We also provide evidence that two wild types of ETO transcripts containing the region of the ETO gene in fused transcripts are expressed in hematopoietic cells from different lineages. The widespread expression of AML1 and ETO in hematopoietic cells suggests a fundamental role of these proteins in hematopoiesis. Furthermore, the differences in the carboxy termini of ETO may modulate the activity of fused proteins resulting from the chromosomal translocation t(8;21).
Acute Disease↗