aclarubicin and Leukemia--Myelomonocytic--Acute

To assess the efficacy and toxicity of HAA regimen (Homoharringtonine 4 mg/m(2)/day, days 1-3; cytarabine 150 mg/m(2)/day, days 1-7; aclarubicin 12 mg/m(2)/day, days 1-7) as a salvage therapy in the treatment of refractory and/or relapsed acute myeloid leukemia (AML), 46 patients with refractory and/or relapsed AML, median age 37 (16-65) years, participated in this clinical study. The median follow-up was 41 (10-86) months. Eighty percent of patients achieved complete remission (CR), and the first single course of re-induction HAA regimen resulted in CR rate of 76.1 %. The study protocol allowed two courses of induction. The CR rates of patients with favorable, intermediate and unfavorable cytogenetics were 90 %, 88.9 %, and 37.5 %, respectively. For all patients, the estimated 3-year overall survival (OS) rate was 42 %, and the estimated relapse free survival (RFS) at 3 years for the 36 CR cases was 49 %. The toxicities associated with HAA regimen were acceptable. HAA is a good choice in cases with refractory/relapsing AML for salvage chemotherapy, preferably with a high-efficacy and low-toxicity profile.

Topics: Aclarubicin; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Cytarabine; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Harringtonines; Heart Diseases; Homoharringtonine; Humans; Kaplan-Meier Estimate; Kidney Diseases; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Male; Middle Aged; Recurrence; Remission Induction; Salvage Therapy; Stem Cell Transplantation; Young Adult

Elderly patients (age > or = 60 years) with acute myeloid leukemia (AML) have unfavourable prognoses when polychemotherapy regimens are used, because therapy response is characterized by low remission rates, short remission duration and high toxicity.. A phase II trial in elderly AML patients was conducted to determine the efficacy of two induction courses of a moderately-dosed combination of aclarubicin (25 mg/m2, 30 min i.v., days 1-4), etoposide (100 mg/m2, 30 min i.v., days 1-3) and conventional-dose cytosine arabinoside (ara-C, 100 mg/m2, c.i.v., days 1-3 and 30 min i.v., q 12 hours, days 4-7) (AVA-7), followed by one consolidation treatment using a reduced-dose schedule over five days (AVA-5) after three months in CR.. Thirty-two AML patients with a median age of 66.2 years (range 60-76) were included in the study: three of them had histories of preexisting myelodysplasia and one of polycythemia vera. Following 1-2 courses of AVA-7 17 patients (53%) achieved CR, two PR (6%), and nine had resistant disease (28%); the overall response rate was thus 59%. Toxicity was significant but acceptable, with an overall treatment-related death rate of five of 32 patients (16%) after 63 courses of AVA. The median disease-free survival (DFS) was 12 months, and the median survival of all patients was 16.6 months.. These results indicate that the combination of aclarubicin, etoposide and conventional-dose ara-C is effective in elderly AML patients. The relatively brief remission duration requires new consolidation and maintenance therapy approaches.

Topics: Aclarubicin; Aged; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Disease-Free Survival; Etoposide; Female; Humans; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Male

The clinical efficacy of aclarubicin, an anthracycline antibiotic, was studied in 48 patients with leukemia. The antibiotic was used in the following combinations with cytarabine: "7 + 7", "5 + 5" and "7 & 3". A complete remission was stated in 14 (42.4 per cent) out of 33 patients with acute nonlymphoid leukemia, 6 (43 per cent) out of the 14 patients having relapses. The combined therapy was effective in 4 out of 5 pre-resistant patients. The "7 + 3" scheme was the most beneficial. The most common adverse reactions were nausea and vomiting.

Topics: Aclarubicin; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Cytarabine; Humans; Leukemia; Leukemia, Monocytic, Acute; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction

Topics: Aclarubicin; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Austria; Child; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Doxorubicin; Etoposide; Female; Humans; Hungary; Infant; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Life Tables; Male; Multicenter Studies as Topic; Prednisone; Prospective Studies; Remission Induction; Thioguanine; Vincristine

The selection of chemotherapy regimen for elderly patients with acute myeloid leukemia (AML) remains challenging. Here, we report that granulocyte colony-stimulating factor (G-CSF) upregulates the expression of microRNA (miR)-146a in a nuclear factor kappaB-dependent manner, leading to direct decreases in the expression of the target proteins CXCR4 and Smad4 in AML cells in vitro. The reduction in CXCR4 expression suppressed the migration abilities of leukemia cells. Downregulation of Smad4 promoted cell cycle entry in leukemia cells. Furthermore, an increase in apoptosis was observed when leukemia cells were treated sequentially with G-CSF and cytosine arabinoside in vitro. These findings suggest that G-CSF treatment may disrupt the protection of bone marrow niches from leukemia cells. In a review of data from 78 cases of primary AML, we found that a high miR-146a expression and/or upregulation of this miRNA during G-CSF priming chemotherapy was predictive of better clinical outcomes. Our findings suggest that miR-146a may be a novel biomarker for evaluating the clinical prognosis and treatment effects of a G-CSF priming protocol in elderly patients with AML.

Topics: Aclarubicin; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotaxis; Coculture Techniques; Cytarabine; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Leukemic; Granulocyte Colony-Stimulating Factor; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Male; MicroRNAs; Middle Aged; Neoplasm Proteins; NF-kappa B; Prognosis; Receptors, CXCR4; RNA Interference; RNA, Neoplasm; RNA, Small Interfering; Smad4 Protein; Stem Cell Niche; Tumor Microenvironment; Up-Regulation

In 145 adult patients diagnosed with non-M3 acute myeloid leukaemia (AML) the relevance of FAB-subtype and immunophenotype to in vitro cellular drug resistance towards the anthracyclines aclarubicin (Acla) and daunorubicin (Dau), and the nucleoside analogue cytarabine (Ara-C), as well as other antileukaemic drugs, was investigated using a 4-d MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. We demonstrate that high CD14 expression is highly significantly associated with high cellular Ara-C and Dau resistance in univariate as well as multivariate analyses. FAB subtypes with highest and lowest cellular Ara-C resistance were M4 and M5, respectively (P < 0.01, one-way anova), whereas FAB subtypes with highest and lowest cellular Dau resistance were M4 and M1, respectively (P < 0.01, one-way anova). By contrast, no significant differences in cellular drug resistance towards Acla could be demonstrated among FAB subtypes. Furthermore, in two cohorts of AML patients treated by two different regimens for remission induction over a period of 15 yr (1985-94, n = 159 and 1995-99, n = 76, respectively) we demonstrate in univariate analyses a significance of CD14 expression with respect to clinical outcome. With the exception of significance to probability of obtaining complete remission in the first cohort (P = 0.03, logistic regression), this significance was, however, lost in multivariate analyses. It was demonstrated that FAB-M4 patients were older than M5 patients and that high CD14 expression was associated with the presence of secondary AML and older age. We conclude that although cases with high blast cell CD14 expression (and FAB-M4 cases) were more resistant to Ara-C as well as Dau in vitro, the clinical and biological significance of this may be debatable because of interactions with major prognostic factors in AML.

Topics: Aclarubicin; Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Amsacrine; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Chromosome Aberrations; Cohort Studies; Cytarabine; Daunorubicin; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Etoposide; Female; Humans; Idarubicin; Leukemia, Myeloid; Leukemia, Myelomonocytic, Acute; Lipopolysaccharide Receptors; Male; Middle Aged; Mitoxantrone; Multivariate Analysis; Neoplastic Stem Cells; Thioguanine; Treatment Outcome

We report a patient with acute myelomonocytic leukemia (AMMoL) who showed two independent point mutations of the N-ras gene at codons 12 and 13. Longitudinal analysis revealed that one mutation at codon 13 was detectable throughout his disease course and the other at codon 12 emerged as a second mutation 14 months after the diagnosis was made, at the refractory stage. Cloning to vector and subsequent sequencing confirmed that these mutations occurred in different alleles. Chromosome findings showed a simple abnormal karyotype at presentation and further karyotypic aberrations during his disease course, concomitantly with the second mutation of the N-ras gene. These findings revealed a close relationship among the disease progression, karyotypic evolution and a newly-appearing N-ras mutation.

Topics: Aclarubicin; Alleles; Antineoplastic Combined Chemotherapy Protocols; Chromosome Deletion; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 9; Codon; Cytarabine; Daunorubicin; Disease Progression; Doxorubicin; Etoposide; Fatal Outcome; Genes, ras; Genetic Vectors; Humans; Karyotyping; Leukemia, Myelomonocytic, Acute; Male; Mercaptopurine; Middle Aged; Mitoxantrone; Point Mutation; Prednisolone; Vinblastine; Vincristine

A 44 year-old woman with acute myeloid leukemia (AML, FAB, M4E) developed heart failure during treatment with anthracyclines for AML. She had not experienced heart disease and her left ventricular ejection fraction (LVEF) was 59% at the end of a successful remission induction therapy. Because her LVEF decreased to 33% after early consolidation therapy, the chemotherapy for AML was discontinued. The cumulative dose of daunorubicin, aclarubicin and mitoxantrone was 486 mg/m2, 135 mg/m2 and 55 mg/m2, respectively. In October 1990, four months after the end of the chemotherapy, heart failure (class III, NYHA) developed and did not improve by treatment consisting of dobutamin, digoxin and diuretics. Anthracycline cardiomyopathy was histologically confirmed by endomyocardial biopsy. Then we administered selective beta 1-antagonist, metoprolol (Seloken), with an initial dose of 5 mg/day which was doubled 3 times every 4 or 8 weeks to 40 mg/day, according to the treatment schedule of dilated cardiomyopathy. She recuperated satisfactorily (Class I, NYHA), and was discharged on February '91. Her LVEF gradually improved and it has been maintained at above 50% on an outpatient basis. The patient has been in complete hematological remission during this period. It seems that low dose selective beta 1-antagonist therapy has a potential to improve myocardial function in some patients with anthracycline cardiomyopathy.

Topics: Aclarubicin; Adrenergic beta-Antagonists; Adult; Antibiotics, Antineoplastic; Cardiomyopathy, Hypertrophic; Chronic Disease; Daunorubicin; Drug Administration Schedule; Female; Heart Failure; Humans; Leukemia, Myelomonocytic, Acute; Metoprolol; Mitoxantrone

The following presents 6 cases of therapy related leukemia (TRL) along with discussion of their clinical features in comparison with those previously reported in Japan. Common primary malignancies were mammalian cancer, lung cancer and malignant lymphoma in both groups. It was observed that, 1) average age was higher (68 years), 2) average latent period from primary malignancy to leukemia was longer (10 years), particularly in patients treated solely with radiation, 3) in 4 out of 6 patients (67%) karyotype analysis of leukemia cells showed normal results, but in one case previously administered etoposide, translocation involving 15q+, 17q- was noted, and 4) the CR ratio in our cases was 83%; half the cases are still alive at 10 months of follow-up, while in previously reported cases the CR ratio was 41%, and the median survival time was 12 months according to Kaplan-Meier analysis. Although poor response to conventional chemotherapy has been reported in TRL patients, the present data indicated TRL in some cases to achieve complete response and long-term survival. Aggressive chemotherapy should be considered for such patients.

Topics: Aclarubicin; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Daunorubicin; Female; Humans; Leukemia, Myelomonocytic, Acute; Leukemia, Promyelocytic, Acute; Lung Neoplasms; Lymphoma; Male; Middle Aged; Neoplasms, Second Primary; Survival Rate