thioguanine-anhydrous and Leukemia--Myeloid--Acute

The first multicenter treatment study for AML in childhood in Germany was performed from 1978 onwards. The therapy plan was designed similar to that for the acute lymphoblastic leukaemia (ALL). The drugs with the highest efficacy in AML, cytarabine cutting catara-bine and anthracyclines, were combined during induction and consolidation, followed by preventive cranial irradiation and maintenance therapy similar to that in ALL. The remission rate of the initial study was 80%, and the 5-year survival rate increased from less than 10% before 1970 to 40%. 5 subsequent trials have further increased the 5-year survival to now 70% and even 90% in the subgroup of core-binding factor leukaemias by using an intensified and optimised treatment schedule.The AML-BFM studies were the only prospective study sequence testing the benefit of cranial irradiation. Results from study -87 including the non-randomized patients showed an increased risk of CNS and/or bone marrow relapses in non-irradiated patients. Later on there was evidence that 12 Gy resulted in the same relapse rate as 18 Gy. The AML-BFM studies always used the experience from the previous study to optimize the next study. This approach was essential together with improved supportive treatment and experience of the medical staff for the step-wise and considerable increase of longterm survival within the 6 subsequent AML-BFM studies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Etoposide; Germany; Humans; Idarubicin; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Methotrexate; Multicenter Studies as Topic; Prednisone; Randomized Controlled Trials as Topic; Survival Rate; Thioguanine; Vincristine

Undertreatment of the older patients with AML can explain, in part, their inferior outcome when compared with that in younger patients. In analogy to the benefit of patients under the age of 60 years from high-dose AraC there are dosage related therapeutic effects in the patients over 60 years in particular for daunorubicin in the induction treatment, and for maintenance versus no maintenance in the post-remission treatment. Utilizing these effects can partly overcome the mostly unfavorable disease biology in older age AML, whereas the role of risk factors involved is not completely understood and the concept of dose-response needs to be requestioned. We recommend an adequate dosage of 60 mg/(m2day) daunorubicin for 3 days in a combination with standard dose AraC and 6-thioguanine given for induction and consolidation and followed by a prolonged monthly maintenance chemotherapy. Further improvements in supportive care may help delivering additional anti-leukemic cytotoxicity. As a novel approach, reduced toxicity preparative regimens may open up allogeneic transplantation for older patients with AML. Other new options like MDR modulators, antibody targeted therapies and tyrosine kinase inhibitors are under clinical investigation. A questionnaire study in patients with AML showed that according to patients' self-assessment intensive and prolonged treatment did not result in decreasing quality of life. This finding did not vary by age under or above 60 years. Given the actual median age in this disease being more than 60 years the adequate management of older age AML remains as the major challenge.

Topics: Adult; Age Factors; Aged; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Middle Aged; Protein Kinase Inhibitors; Remission Induction; Stem Cell Transplantation; Thioguanine; Transplantation, Homologous

We report a case of acute myeloid leukemia (AML) M1 showing a 48,XY,+13,+13 karyotype. Treatment was according to the Medical Research Council AML14 trial protocol with two courses of DAT chemotherapy. Postchemotherapy bone marrow examination failed to show complete remission or cytogenetic normalization. Despite having resistant disease, the patient initially remained clinically well although requiring regular blood transfusions for anemia. However his leukocyte count gradually increased and he became symptomatic. He was treated subsequently with FLAG but died approximately 2 weeks later, 6 months after first presenting. Tetrasomy 13 as the sole cytogenetic abnormality has not been reported previously in M1 AML and has only been reported in three other AML cases, all with an immature phenotype and poor outcome.

Topics: Aneuploidy; Antineoplastic Combined Chemotherapy Protocols; Chromosomes, Human, Pair 13; Cytarabine; Daunorubicin; Drug Resistance, Neoplasm; Fatal Outcome; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Thioguanine; Vidarabine

We present the case of an 11.5-year-old girl with M1 acute myelogenous leukemia (AML) who had isolated extramedullary relapse develop in both breasts 12 months after diagnosis and 7 months off chemotherapy. She received further chemotherapy, focal radiation therapy, then underwent a matched, unrelated bone marrow transplant and continues in remission 37 months later. Review of the literature revealed 10 cases in other children younger than 21-years-old with AML and breast involvement. These cases are summarized, and potential pathophysiologic mechanisms of spread are discussed. Breast involvement in AML is rare in children. However, regular breast examinations should be performed as part of routine follow-up in all girls with AML.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biopsy; Bone Marrow Transplantation; Breast; Child; Combined Modality Therapy; Cytarabine; Daunorubicin; Dexamethasone; Etoposide; Female; Graft vs Host Disease; Humans; Idarubicin; Immunologic Factors; Interleukin-2; Leukemia, Myeloid, Acute; Leukemic Infiltration; Radiotherapy, High-Energy; Recurrence; Salvage Therapy; Thioguanine; Transplantation Conditioning; Vidarabine

Topics: Adult; Anti-HIV Agents; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Cytarabine; Daunorubicin; Drug Therapy, Combination; HIV Infections; Humans; Leukemia, Myeloid, Acute; Male; Thioguanine; Zidovudine

Acute promyelocytic leukemia is characterized by bone marrow infiltration with hypergranular promyelocytes, often with Auer bodies. Clinically it is characterized by a hemorrhagic syndrome caused by a disseminated intravascular coagulation. Karyotypic studies have shown a frequent translocation t(15;17). Improved prognosis resulted from chemotherapy with DAT and treatment with heparin.

Topics: Acute Disease; Adolescent; Adult; Aged; Anemia; Antibiotics, Antineoplastic; Child; Child, Preschool; Cytarabine; Daunorubicin; Disseminated Intravascular Coagulation; Female; Heparin; Humans; Inclusion Bodies; Leukemia, Myeloid, Acute; Male; Middle Aged; Naphthacenes; Neoplastic Stem Cells; Thioguanine; Translocation, Genetic

An uncompromisingly optimistic approach must now be taken to the future of the treatment of acute myelogenous leukemia. This view can be justified on two grounds. First, understanding of the biology of the disease is increasing, resulting for example in the demonstration of the prognostic significance of the behavior of the leukemic blast cells in culture and their chromosomal pattern. It seems most likely that individualization of treatment will follow from such observations, with obvious benefit to the patients. Second it has been shown that a modest proportion of patients is cured with the manipulations of chemotherapy with or without radiotherapy and bone marrow transplantation practised in the mid-1970s. Selected results reflecting a personal bias have been presented allowing speculation that very intensive chemotherapy, possibly of short duration may be able to increase this proportion. At the same time, advances in the techniques of preparation of both patient and bone marrow for transplantation are being made and may increase the potential pool of patients who may benefit from the procedure. Even within the limitations of the treatment available now, it is possible that a flexible attitude to the precise manipulation of cytotoxic drugs, radiotherapy and transplantation may result in cure for the majority, rather than the minority, of patients.

Topics: Adolescent; Adult; Antibiotics, Antineoplastic; Bone Marrow; Cell Transformation, Neoplastic; Cytarabine; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Middle Aged; Naphthacenes; Prednisolone; Prognosis; Regression Analysis; Thioguanine; Time Factors; Vincristine

Cytarabine and thioguanine therapy for acute myelomonocytic leukemia initiated in the tenth week of pregnancy (with the addition of vincristine and rubidomycin at 17 weeks) led to a short complete remission of the leukemia in a 24-year-old primigravida. This is the first case to be reported in which cytarabine was administered in the first trimester and a prostaglandin termination of pregnancy performed at 20 weeks produced an apparently normal fetus. A review of the literature suggests a slightly less than 50% chance of producing a live healthy baby if acute myelogenous leukemia is diagnosed in the first half of pregnancy, with materna mortality approaching 100% by six months postpartum. Current therapy may improve these figures.

Topics: Abortion, Therapeutic; Antineoplastic Agents; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Infant Mortality; Infant, Newborn; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Trimester, First; Pregnancy Trimester, Second; Risk; Teratogens; Thioguanine; Vincristine

Topics: Adult; Alkaline Phosphatase; BCG Vaccine; Blood Transfusion; Bone Marrow Examination; Central Nervous System Diseases; Cytarabine; Daunorubicin; Diagnosis, Differential; Drug Combinations; Drug Therapy, Combination; Esterases; Humans; Immunotherapy; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphocyte Transfusion; Meningitis; Microscopy, Electron; Neutrophils; Staining and Labeling; Subarachnoid Hemorrhage; Thioguanine

Topics: Cytarabine; Evaluation Studies as Topic; Humans; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Methods; Muramidase; Neutrophils; Thioguanine

Topics: Child; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Synergism; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Meningitis; Mercaptopurine; Prednisone; Remission, Spontaneous; Thioguanine; Vincristine

AML-2003 study sought to compare the long-term efficacy and safety of IAT and IdAraC-Ida in induction chemotherapy of acute myeloid leukemia (AML) and introduce the results of an integrated genetic and clinical risk classification guided treatment strategy.. Patients were randomized to receive either IAT or IdAraC-Ida as the first induction treatment. Intensified postremission strategies were employed based on measurable residual disease (MRD) and risk classification. Structured questionnaire forms were used to gather data prospectively.. A total of 356 AML patients with a median age of 53 years participated in the study. Long-term overall survival (OS) and relapse-free survival (RFS) were both 49% at 10 years. The median follow-up was 114 months. No significant difference in remission rate, OS or RFS was observed between the two induction treatments. Risk classification according to the protocol, MRD after the first and the last consolidation treatment affected the OS and RFS significantly (p < .001).. Intensified cytarabine dose in the first induction treatment was not better than IAT in patients with AML. Intensification of postremission treatment in patients with clinical risk factors or MRD seems reasonable, but randomized controlled studies are warranted in the future.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Finland; Humans; Idarubicin; Leukemia, Myeloid, Acute; Middle Aged; Neoplasm, Residual; Prospective Studies; Remission Induction; Thioguanine

NPM1 mutations represent frequent genetic alterations in patients with acute myeloid leukemia (AML) associated with a favorable prognosis. Different types of NPM1 mutations have been described. The purpose of our study was to evaluate the relevance of different NPM1 mutation types with regard to clinical outcome. Our analyses were based on 349 NPM1-mutated AML patients treated in the AMLCG99 trial. Complete remission rates, overall survival and relapse-free survival were not significantly different between patients with NPM1 type A or rare type mutations. The NPM1 mutation type does not seem to play a role in risk stratification of cytogenetically normal AML.

Topics: Adult; Aged; Antineoplastic Agents; Cytarabine; Daunorubicin; Female; fms-Like Tyrosine Kinase 3; Gene Expression; Humans; Induction Chemotherapy; Karyotyping; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitoxantrone; Mutation; Nuclear Proteins; Nucleophosmin; Prognosis; Remission Induction; Risk Factors; Survival Analysis; Thioguanine; Treatment Outcome

Single cell network profiling (SCNP) is a multi-parameter flow cytometry technique for simultaneous interrogation of intracellular signalling pathways. Diagnostic paediatric acute myeloid leukaemia (AML) bone marrow samples were used to develop a classifier for response to induction therapy in 53 samples and validated in an independent set of 68 samples. The area under the curve of a receiver operating characteristic curve (AUC(ROC)) was calculated to be 0·85 in the training set and after exclusion of induction deaths, the AUC(ROC) of the classifier was 0·70 (P = 0·02) and 0·67 (P = 0·04) in the validation set when induction deaths (intent to treat) were included. The highest predictive accuracy was noted in the cytogenetic intermediate risk patients (AUC(ROC) 0·88, P = 0·002), a subgroup that lacks prognostic/predictive biomarkers for induction response. Only white blood cell count and cytogenetic risk were associated with response to induction therapy in the validation set. After controlling for these variables, the SCNP classifier score was associated with complete remission (P = 0·017), indicating that the classifier provides information independent of other clinical variables that were jointly associated with response. This is the first validation of an SCNP classifier to predict response to induction chemotherapy. Herein we demonstrate the usefulness of quantitative SCNP under modulated conditions to provide independent information on AML disease biology and induction response.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Daunorubicin; Female; Flow Cytometry; Humans; Infant; Intracellular Signaling Peptides and Proteins; Leukemia, Myeloid, Acute; Male; Neoadjuvant Therapy; Prognosis; Prospective Studies; Remission Induction; Retrospective Studies; Single-Cell Analysis; Thioguanine; Treatment Outcome

The Medical Research Council Acute Myeloid Leukaemia 12 (MRC AML12) trial (children) addressed the optimal anthracenedione/anthracycline in induction and the optimal number of courses of consolidation chemotherapy. 504 children (<16 years) with AML were randomized between mitoxantrone/cytarabine/etoposide or daunorubicin/cytarabine/etoposide as induction chemotherapy and 270 entered a second randomization between a total of four or five courses of treatment. Ten-year event-free (EFS) and overall survival (OS) was 54% and 63% respectively; the relapse rate was 35%. There was no difference in complete remission rate between the induction regimens, but there was a benefit for mitoxantrone with regard to relapse rate [32% vs. 39%; Hazard ratio (HR) 0·73; 95% confidence interval (CI) 0·54, 1·00] and disease-free survival (DFS; 63% vs. 55%; HR 0·72; 95% CI 0·54, 0·96). However, this did not translate into a better EFS or OS (HR 0·84; 95% CI 0·63, 1·12). Results of the second randomization did not show a survival benefit for a fifth course of treatment (HR 1·01; 95% CI 0·63, 1·62), suggesting a ceiling of benefit for conventional chemotherapy and demonstrating the need for new agents. EFS was superior compared to the preceding trial AML10, partly due to fewer deaths in remission, highlighting the importance of supportive care.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Consolidation Chemotherapy; Cytarabine; Daunorubicin; Disease-Free Survival; Etoposide; Female; Humans; Induction Chemotherapy; Infant; Leukemia, Myeloid, Acute; Male; Mitoxantrone; Prognosis; Survival Analysis; Thioguanine; Treatment Outcome

To optimize treatment for younger patients with acute myeloid leukemia and high-risk myelodysplastic syndrome by comparing induction options and the number of consolidation courses and whether consolidation should include transplantation.. We randomly assigned 1,658 patients younger than age 60 years to receive mitoxantrone/cytarabine/etoposide versus cytarabine/daunorubicin/etoposide and subsequently 1,193 patients to daunorubicin/cytarabine/thioguanine (DAT) where the cytarabine dose was standard (S-DAT) versus double the standard dose (H-DAT). Patients in this randomization were randomly assigned to all-trans-retinoic acid or not. In consolidation, 992 patients were randomly assigned between a total of four courses versus five courses, and 324 patients who were not good risk were randomly assigned to transplantation or chemotherapy as the final course.. Complete remission (CR) was achieved in 74% of patients and CR without recovery was achieved in an additional 11%; overall survival (OS) at 8 years was 38%. No differences in CR, relapse-free survival, relapse, or OS were seen between any of the induction randomizations except for a reduction in relapse risk (RR) on the mitoxantrone arm, which was offset by increased myelosuppression and deaths in CR. The addition of a fifth course did not improve OS and may be detrimental in older patients. Although transplantation reduced RR, it did not improve OS for the intermediate-risk group but was probably of benefit in high-risk patients.. Several chemotherapy schedules achieved similar remission rates and OS. Four courses of chemotherapy are adequate, but the addition of transplantation as a final course does not improve OS. New agents are required to enhance conventional chemotherapy.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Daunorubicin; Etoposide; Female; Humans; Infant; Infant, Newborn; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitoxantrone; Neoplasm Staging; Prognosis; Remission Induction; Survival Rate; Thioguanine; Treatment Outcome; Tretinoin; Young Adult

Despite advances in therapy, the majority of adult patients diagnosed with acute myeloid leukemia (AML) develop disease recurrence and die of their disease. Early intensification of treatment for AML using timed sequential therapy (TST) has been proposed as a means of improving the survival outcome in children. The Children's Cancer Group demonstrated that children with AML who were randomized to receive 2 courses of daunorubicin, cytarabine, thioguanine, etoposide, and dexamethasone (the DCTER regimen) given 10 days apart had an improved event-free survival (EFS) and disease-free survival (DFS) (42% ± 7% and 55% ± 9%, respectively, at 2 years). Reports have suggested an improved outcome in adult patients with AML using TST (at the cost of increased toxicity). The current study was conducted to evaluate the feasibility and effectiveness of the intensively timed DCTER regimen for non-core-binding factor AML in adult patients aged <50 years.. Between February 2004 and August 2005, 61 patients received this timed sequential induction regimen. Their outcomes were compared with matched historical patients treated with the combination of idarubicin and cytarabine (IA).. The median follow-up for surviving patients was 67 months (range, 35-85 months). The timed sequential DCTER regimen had a lower complete remission (CR) rate when compared with the IA combination,, (71% vs 80%, respectively), but this appeared to be counterbalanced by a higher long-term leukemia-free survival rate using the intensified regimen (48% vs 30%, respectively) in patients who achieved a CR (P = .06).. The intensively timed regimen of DCTER was found to induce durable remissions in adult patients with AML, including those patients with high-risk disease. The identification of patients who would potentially benefit from such an intensive regimen may justify the higher early risk of early treatment failure that was found to accompany the intensified DCTER regimen in selected patients.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Dexamethasone; Etoposide; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Remission Induction; Thioguanine

We studied the pharmacokinetics of 6-thioguanine (6TG) in 50 children treated for newly diagnosed acute myeloid leukemia, four of them with Down syndrome (DS). They received oral 6TG 100 mg/m2 body surface area twice daily for 4 days. Etoposide, 100 mg/m2/24 h, and cytarabine, 200 mg/m2/24 h, were administered concomitantly by intravenous infusion. On day 5, doxorubicin 75 mg/m2 was given as an 8-h infusion. The concentration of thioguanine nucleotides (TGN) in erythrocytes, the active metabolites of 6TG, was determined by high-performance liquid chromatography. The mean TGN concentration from 72, 95, and 106-h samples was used as a measure of drug exposure for each individual. The median TGN concentration in non-DS children above 2 years of age was 2.30 micromol/mmol Hb (range 0.57-25.3). The TGN concentrations varied widely (30-fold) also after dose normalization. We found no correlation with demographic, clinical, or biochemical parameters, and differences in bioavailability might be the most important explanation to interpatient variability. Children with high TGN concentration tended to have longer treatment interval to the next course, but we found no correlation with our predefined parameters for clinical response, that is, remission and relapse rate. Therefore, 6TG does not seem to be a candidate for therapeutic drug monitoring by TGN measurement, at least not in the setting of short multidrug treatment courses. Children with DS had significantly higher TGN concentrations, indicating that dose reduction might be considered to reach the same drug exposure as in non-DS children.

Topics: Administration, Oral; Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Down Syndrome; Doxorubicin; Drug Administration Schedule; Drug Monitoring; Erythrocytes; Etoposide; Female; Guanine Nucleotides; Humans; Infant; Infusions, Intravenous; Leukemia, Myeloid, Acute; Male; Registries; Scandinavian and Nordic Countries; Thioguanine; Thionucleotides; Treatment Outcome

Many elderly patients with newly diagnosed acute myeloid leukemia (AML) present with cardiac comorbidity precluding the use of anthracycline containing chemotherapy regimens. Amsacrine, a topoisomerase II inhibitor, has been proposed as possible alternative to anthracyclines. Here, we report about the combination of amsacrine (210 mg/m(2)), in replacement for daunorubicin (DNR), with standard dose cytarabine and thioguanine (TAA) to elderly patients (>or=60 years of age) with impaired cardiac function. The outcome of 16 patients with a median age of 66 years treated between 1997 and 2003 was compared with standard treatment regimens of the AMLCG study group in a matched-pair analysis. There were no statistically significant differences in response rate, relapse free survival or overall survival between TAA treated patients or standard therapy. In conclusion, replacing anthracyclines with amsacrine for induction therapy of AML patients with significant cardiac comorbidities represents a treatment option without compromising the potential curability of the disease.

Topics: Aged; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Administration Schedule; Drug Evaluation; Female; Heart Diseases; Humans; Leukemia, Myeloid, Acute; Male; Matched-Pair Analysis; Middle Aged; Thioguanine

A randomised multicentre study was conducted among patients over 65 yr of age with newly diagnosed acute myeloid leukaemia (AML) to compare oral treatment with etoposide 80 mg/m(2) and thioguanine 100 mg/m(2) twice daily on 5 d and idarubicin 15 mg/m(2) on 3 d (ETI) to a mainly i.v. combination of cytarabine 100 mg/m(2) twice daily on 5 d, idarubicin 12 mg/m(2) x 1, and thioguanine (TAI). Ninety-two patients were enrolled. Their median age was 72 yr, range 65-84 yr. Sixty-five patients had de novo AML, 21 AML subsequent to myelodysplastic syndrome, and six treatment-related AML. They received at first a 6-d i.v. treatment with cytarabine and idarubicin. After the first treatment, 68 patients were randomised to receive two cycles of ETI (n = 36) or TAI (n = 32) and thereafter maintenance with mercaptopurine and methotrexate. Of the 92 patients, 52 (57%) achieved remission at some stage. The median survival was 10 months. There were no significant differences between the patients randomised to ETI or TAI in the remission rate (67% vs. 72%), survival (12 months from randomisation in both arms), event-free survival or relapse rate. The patients randomised to receive ETI spent significantly fewer days at hospital during the two randomised cycles (20 vs. 41 d, P = 0.010), and they had fewer days with infusions, shorter neutropenias and thrombocytopenias and fewer and less severe infections. In conclusion, treatment with oral ETI resulted in a similar antileukaemic effect as obtained with mainly i.v. TAI, with less toxicity and reduced need for hospitalisation.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Disease-Free Survival; Etoposide; Female; Humans; Idarubicin; Injections, Intravenous; Leukemia, Myeloid, Acute; Male; Patient Selection; Recurrence; Statistics, Nonparametric; Survival Rate; Thioguanine; Time Factors

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid, Acute; Middle Aged; Mitoxantrone; Stem Cell Transplantation; Survival Analysis; Thioguanine

To examine the efficacy of prolonged maintenance chemotherapy versus intensified consolidation therapy for patients with acute myeloid leukemia (AML).. Eight hundred thirty-two patients (median age, 54 years; range, 16 to 82 years) with de novo AML were randomly assigned to receive 6-thioguanine, cytarabine, and daunorubicin (TAD) plus cytarabine and mitoxantrone (HAM; cytarabine 3 g/m2 [age < 60 years] or 1 g/m2 [age > or = 60 years] x 6) induction, TAD consolidation, and monthly modified TAD maintenance for 3 years, or TAD-HAM-TAD and one course of intensive consolidation with sequential HAM (S-HAM) with cytarabine 1 g/m2 (age < 60 years) or 0.5 g/m2 (age > or = 60 years) x 8 instead of maintenance.. A total of 69.2% patients went into complete remission (CR). Median relapse-free survival (RFS) was 19 months for patients on the maintenance arm, with 31.4% of patients relapse-free at 5 years, versus 12 months for patients on the S-HAM arm, with 24.7% of patients relapse-free at 5 years (P =.0118). RFS from maintenance was superior in patients with poor risk by unfavorable karyotype, age > or = 60 years, lactate dehydrogenase level greater than 700 U/L, or day 16 bone marrow blasts greater than 40% (P =.0061) but not in patients with good risk by complete absence of any poor risk factors. Although a survival benefit in the CR patients is not significant (P =.085), more surviving patients in the maintenance than in the S-HAM arm remain in first CR (P =.026).. We conclude that TAD-HAM-TAD-maintenance first-line treatment has a higher curative potential than TAD-HAM-TAD-S-HAM and improves prognosis even among patients with poor prognosis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitoxantrone; Prognosis; Proportional Hazards Models; Survival Analysis; Thioguanine

It is still controversial how to treat elderly patients with acute myeloid leukaemia (AML), and results have been poor with most regimens. We report the long-term results of a randomised study performed by the Leukaemia Group of Middle Sweden during 1984-88 comparing two intensive chemotherapeutic drug combinations. Ninety patients >or=60-yr old with untreated AML were randomly allocated to treatment with daunorubicin, cytosine arabinoside (ara-C), and thioguanine (TAD) (43 patients) or a combination in which aclarubicin was substituted for daunorubicin (TAA) (47 patients). Forty-four patients (49%) entered complete remission (CR), 22/43 (51%) in the TAD group and 22/47 (47%) in the TAA group (ns). The CR rate in patients 70 yr 14/48 (29%) (P<0.0001). Early death within 30 d after treatment initiation was more often seen in patients >70 yr than in patients or=10 yr after inclusion of the last patient, 5/90 patients (one in the TAD group and four in the TAA group, respectively) were still alive, four in continuous complete remission and one in second complete remission. Thus, both treatment regimens appear to have similar efficacy, with a relatively high complete remission rate, and a reasonable survival as compared to other studies including some long-term survivors. However, early deaths are still numerous, particularly in patients above 70 yr of age, and the relapse rate is substantial.

Topics: Aclarubicin; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Middle Aged; Survival Rate; Thioguanine; Time Factors

Timed sequential chemotherapy and high-dose cytarabine (cytosine arabinoside, Ara-C; HDAC) are both effective treatments for acute myeloid leukemia (AML). We review our institutional experience with timed sequential induction chemotherapy consisting of daunorubicin/Ara-C/-thioguanine (DAT) or idarubicin/Ara-C/-thioguanine (IAT) followed on day 14 by HDAC regardless of the degree of marrow aplasia for children with newly diagnosed AML.. Children presenting with newly diagnosed AML were treated with induction chemotherapy consisting of idarubicin (12 mg/m/day on days 1-3 or daunorubicin at 45 mg/m(2)/day for the first five patients), Ara-C (100 mg/m(2)/day by continuous infusion on days 1-7), and thioguanine (100 mg/m(2)/day on days 1-7). HDAC (1 g/m(2)/dose every 12 hr for 10 doses) was administered beginning on day 14, regardless of the results of bone marrow examination.. Thirteen children received timed sequential HDAC. Only one child received HDAC later than Day 18. Eleven of the children achieved a complete remission. All patients experienced grade 4 hematologic toxicity, and all had fever as well. There were 11 children with documented infections. Ten had grade 3 or 4 GI toxicity. One patient died of sepsis.. HDAC administered as a part of timed sequential therapy yields an excellent remission induction rate with manageable toxicity.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Daunorubicin; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Infant; Leukemia, Myeloid, Acute; Male; Remission Induction; Survival Rate; Thioguanine; Time Factors; Treatment Outcome

Debate and controversy remain as to the optimal post-remission therapy for younger patients with acute myelogenous leukaemia (AML). The aim of this study was to evaluate high-dose treatment (HDT) with autologous bone marrow support (ABMS) as consolidation of first complete remission (CR).. One hundred forty-four patients (AML-M3 excluded, median age 38 years, range 15-49 years) received remission induction therapy comprising: adriamycin 25 mg/m2, days 1-3, cytosine arabinoside (ara-C) and 6-thioguanine, both at 100 mg/m2 bid, days 1-7. Patients in whom CR was achieved received two further cycles of the same treatment prior to bone marrow being harvested and cryopreserved. HDT comprised ara-C: 1 g/m2 b.i.d. x six days and total body irradiation (TBI): 200 cGy b.i.d. for three days. Thawed autologous marrow was then re-infused.. Complete remission was achieved in 106 of 144 patients (73%) who were thus eligible to receive ara-C + TBI + ABMS; 61 actually received it. Following HDT, the median time to neutrophil recovery (> 0.5 x 10(9)/l) was 25 days (range 11-72 days) and to platelet recovery (> 20 x 10(9)/l), 42 days (range 15-159 days). There were eight treatment-related deaths. Analysis by 'intention to treat' shows both remission duration (log-rank, P = 0.001) and survival (log-rank, P = 0.004) to be significantly longer for the 106 patients eligible to receive HDT than for a historical control group (n = 133) who received identical remission induction and consolidation therapy but without ara-C + TBI + ABMS. With a median follow-up of 5.5 years, 39 of 106 patients remain in CR (37%) and 54 (51% of those in whom CR was achieved) remain alive, with a predicted actuarial survival of 52% at 5 years.. The addition of ara-C + TBI + ABMS to conventional consolidation therapy significantly improved remission duration and survival over those of a historical control group of patients with AML (aged < 50, AML-M3 excluded). HDT was, however, associated with significant treatment-related mortality and slow blood count recovery. The use of ara-C + TBI supported by peripheral blood progenitor cells should make the treatment safer and more widely applicable in AML.

Topics: Adolescent; Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Cytarabine; Doxorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Neutropenia; Prognosis; Survival Analysis; Thioguanine; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation

Early intensification of chemotherapy with high-dose cytarabine either in the postremission or remission induction phase has recently been shown to improve long-term relapse-free survival (RFS) in patients with acute myeloid leukemia (AML). Comparable results have been produced with the double induction strategy. The present trial evaluated the contribution of high-dose versus standard-dose cytarabine to this strategy. Between March 1985 and November 1992, 725 eligible patients 16 to 60 years of age with newly diagnosed primary AML entered the trial. Before treatment started, patients were randomized between two versions of double induction: 2 courses of standard-dose cytarabine (ara-C) with daunorubicin and 6-thioguanine (TAD) were compared with 1 course of TAD followed by high-dose cytarabine (3 g/m2 every 12 hours for 6 times) with mitoxantrone (HAM). Second courses started on day 21 before remission criteria were reached, regardless of the presence or absence of blast cells in the bone marrow. Patients in remission received consolidation by TAD and monthly maintenance with reduced TAD courses for 3 years. The complete remission (CR) rate in the TAD-TAD compared with the TAD-HAM arm was 65% versus 71% (not significant [NS]), and the early and hypoplastic death rate was 18% versus 14% (NS). The corresponding RFS after 5 years was 29% versus 35% (NS). An explorative analysis identified a subgroup of 286 patients with a poor prognosis representing 39% of the entire population; they included patients with more than 40% residual blasts in the day-16 bone marrow, patients with unfavorable karyotype, and those with high levels of serum lactate dehydrogenase. Their CR rate was 65% versus 49% (p =.004) in favor of TAD-HAM and was associated with a superior event-free survival (median, 7 v 3 months; 5 years, 17% v 12%; P =.012) and overall survival (median, 13 v 8 months; 5 years, 24% v 18%; P =.009). This suggests that the incorporation of high-dose cytarabine with mitoxantrone may contribute a specific benefit to poor-risk patients that, however, requires further substantiation. Double induction, followed by consolidation and maintenance, proved a safe and effective strategy and a new way of delivering early intensification treatment for AML.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Chromosome Aberrations; Cytarabine; Daunorubicin; Humans; Karyotyping; L-Lactate Dehydrogenase; Leukemia, Myeloid, Acute; Leukocyte Count; Middle Aged; Mitoxantrone; Prognosis; Remission Induction; Thioguanine; Treatment Outcome

A phase III clinical trial was designed to determine if more intensive induction and consolidation therapy for acute myeloblastic leukemia increases the remission rate and prolongs survival. A minor objective was to determine if the use of non-cross resistant drugs was more effective than the same drugs used for induction. Patients with untreated leukemia between the ages of 15 and 50 were given daunorubicin 45 mg/m2 for the first 3 days of a 10-day continuous infusion of cytosine arabinoside, initially at a dose of 2000 mg/m2 but reduced to 100 mg/m2 because of toxicity. Those under 36 achieving a complete remission and with an histocompatible donor were assigned to a transplant arm. The rest were randomized to receive one of three consolidation arms: A, cytosine arabinoside, 200 mg/m2 daily for 7 days and daunorubicin 45 mg/m2 daily for 3 days for three courses; B, one course as in Arm A followed by amsacrine, 120 mg/m2 daily for 5 days followed by a 5-day continuous infusion of azacytidine, 150 mg/m2/day; C, thioguanine and cytosine arabinoside, 100 mg/m2 every 12 h and daunorubicin 10 mg/m2 daily for 5 days for three courses followed by four maintenance courses of cytosine arabinoside, 100 mg/m2 daily for 5 days and daunorubicin, 45 mg/m2 for 2 days every 13 weeks. From 1981 to 1986, 398 eligible patients were enrolled and 219 achieved a complete remission. The initial induction dose of cytosine arabinoside was reduced after five of 29 patients exhibited fatal gastrointestinal toxicity. Only 11 patients were assigned to the transplant arm. There were no significant differences in the consolidation arms. The 5 year disease-free survivals were 38, 31 and 27% in arms A, B, and C respectively. Intensive consolidation therapy with the same or different drugs used in induction was as effective as lower dose consolidation followed by maintenance therapy.

Topics: Adolescent; Adult; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Cytarabine; Daunorubicin; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Patient Selection; Remission Induction; Thioguanine

Complex-binding of anthracyclines to DNA may increase their therapeutic efficacy. In a previous randomized trial patients with acute myelocytic leukaemia (AML) receiving combination chemotherapy including a DNA-bound doxorubicin preparation had a longer duration of first complete remission (CR) and survival than patients receiving free doxorubicin. In a parallel phase I/II study a combination of mitoxantrone, activity. In this randomized study of AML patients (15-60 years) induction treatment with MEA was compared to a combination of doxorubicin/DNA conjugate ara-C, thioguanine, vincristine and prednisolone (POCAL-DNA). The study was closed after an interim analysis of 86 patients. Thirty-five/42 (83%) and 20/44 (45%) patients entered CR in the MEA and POCAL-DNA groups, respectively (p < 0.001). With rescue therapy the corresponding figures were 88 and 64% (p < 0.02). Median survival was 27.8 and 13.1 months for MEA and POCAL-DNA patients, respectively (p < 0.03). In conclusion, the MEA regimen has a very high antileukaemic activity in good accordance with our previous experience. Since we could not reproduce our earlier clinical results using DNA-bound anthracyclines, the source and preparation of DNA seem to be of major importance.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; DNA Adducts; Doxorubicin; Etoposide; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitoxantrone; Prednisolone; Recurrence; Survival Analysis; Thioguanine; Vincristine

Acute myelogenous leukemia (AML) in the elderly continues to have a poor prognosis and new treatment approaches are needed. This Phase II trial was undertaken to evaluate the complete remission rate and toxicity of a chemotherapeutic regimen including etoposide and 6-thioguanine, combined with reduced doses of cytosine arabinoside and daunorubicin (V-TAD) in individuals greater than 50 years of age with AML. Thirty-five patients, ranging in age from 51 to 80 years (median, 66 years), were registered onto the study. Twenty-nine patients were entered at the first dose level (daunomycin 20 mg/m2 days 1 and 2, ara-C 75 mg/m2 days 1-5, 6-thioguanine 75 mg/m2 every 12 hr days 1-5, and etoposide 50 mg/m2 days 1, 2, and 3) and six patients underwent therapy at the second dose level (ara-C 75 mg/m2 days 1-7 with the remainder of the regimen unchanged). After achieving a complete remission, patients underwent two to three consolidation cycles of chemotherapy. Thirty-one patients were evaluable for response. Thirteen patients (ten of twenty-five at the first dose level and three of six at the second dose level) achieved a complete remission (42%). Median remission duration was 6 months (range 1-21 months). The current regimen, while tolerated, did not result in improved survival compared with prior treatment regimens because of a high incidence of resistant and recurrent leukemia.

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Etoposide; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Survival Analysis; Thioguanine; United States

Acute myeloid leukemia preceded by a myelodysplastic syndrome (MDS-AML) is generally regarded as a high-risk type of AML, where remissions are rare and of short duration. Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) is suggested to increase the sensitivity of leukemic cells to cycle-specific drugs. In this study 14 MDS-AML patients were given rhGM-CSF together with standard induction chemotherapy (TAD). rhGM-CSF was started 48 h prior to chemotherapy and given for up to 3 weeks. The results showed eight (58%) complete and two (14%) partial remissions, while another two (14%) patients had minor responses. One patient relapsed after 1 year, and then responded a second time. rhGM-CSF had to be stopped owing to local allergic reactions in two patients, both non-responders, but was otherwise well tolerated. Compared with our historical group of controls we found significantly higher remission rates, fewer early deaths, fewer fever days, and fewer days with both neutropenia and thrombocytopenia among the patients treated with rhGM-CSF and TAD. The estimated median over-all survival was 332 days. The severity of initial myelodysplastic changes did not correlate to the outcome of therapy but the degree of peripheral blood dysplasia decreased among responding patients. MDS-AML patients in this pilot study did respond better, and with minimal toxicity, when standard induction chemotherapy was given in combination with rhGM-CSF.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cytarabine; Daunorubicin; Female; Follow-Up Studies; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Middle Aged; Myelodysplastic Syndromes; Pilot Projects; Prognosis; Recombinant Proteins; Remission Induction; Thioguanine

This study was conducted to assess the comparative values of allogeneic bone marrow transplantation (BMT) and autologous bone marrow transplantation (ABMT) with sequential postremission chemotherapy (SPC) in children with acute myelogenous leukemia (AML) in first remission.. From March 1987 to March 1990, 161 assessable patients younger than 15 years of age with newly diagnosed AML were treated uniformly with two courses of daunorubicin and standard-dose cytarabine. After initial consolidation with a course of daunorubicin, cytarabine, and thioguanine (DAT), patients in complete remission (CR) were randomized to receive either ABMT or SPC, except for those with an HLA-matched sibling who were assigned to undergo BMT. SPC consisted of three additional courses of DAT, followed by three pairs of drugs administered sequentially for a total of six cycles.. Overall, 127 of 161 patients attained CR (79%). The estimated probabilities of survival and event-free survival (EFS) at 5 years for all patients were 42% and 25%, respectively (median follow-up, 28 months). For the 127 complete responders, the 5-year probability of disease-free survival (DFS) was 31%, with a cumulative risk of relapse of 64%. For the purpose of this study, all complete responders were evaluated for analysis of disease outcome according to the intent-to-treat principle, regardless of whether they actually received the intended therapy. The 5-year DFS was 51% for the BMT group (n = 24), significantly higher (P = .03) than that observed for the other cohorts: 21% for ABMT (n = 35), 27% for SPC (n = 37), and 34% for a group of 31 nonrandomized (NR) patients. Bone marrow relapse was the most frequent cause of postremission failure in all therapeutic subgroups, including the BMT cohort, in which no deaths attributable to the toxicity of the procedure were recorded.. The results of this study show that BMT is more effective than ABMT or SPC in preventing leukemia relapse and extending DFS duration in children with AML in first remission.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Daunorubicin; Female; Humans; Infant; Leukemia, Myeloid, Acute; Male; Prospective Studies; Remission Induction; Survival Rate; Thioguanine

Forty-eight patients with acute myelogenous leukemia (AML) not eligible for anthracycline or mitoxantrone treatment, mostly due to cardiac contraindications, were given aggressive therapy using m-amsacrine (AMSA) in combination with conventional or high-dose cytarabine for remission induction. Twenty-nine patients (60.4%) responded to treatment, and complete remission was attained in 19 (39.6%), partial remission in 4 (8.3%) and death in bone marrow aplasia without detectable blasts in 6 patients (12.5%). Median time to granulocyte recovery was 32 days, median duration of relapse-free survival 199 days. One patient experienced a serious cardiac adverse event; nausea and vomiting were observed in 73%, diarrhea in 44%, and hepatoxicity in 29% of patients. All potentially AMSA-related side effects were fully reversible, and a lethal complication did not occur. It is concluded that combination chemotherapy with AMSA and Ara-C is also effective and tolerable in leukemic patients in whom cardiotoxic drugs are contraindicated.

Topics: Adult; Aged; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Heart Diseases; Humans; Incidence; Infections; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Male; Middle Aged; Remission Induction; Survival Analysis; Thioguanine; Treatment Outcome

The paper presents the results of 2 year maintenance treatment of patients with acute myeloid leukemias using cyclic, rotating and intensive polychemotherapy. Complete remission (CR) was achieved in 22 out of 33 patients with doxorubicin (60 mg/m2; 1-3 days) and cytosine arabinoside (100 mg/m2; 1-7 days). All patients in CR entered into the authors' programme of intensification therapy consisting of two consecutive polychemotherapy cycles, using various combinations of amsacrine, doxorubicin, cytosine arabinoside, etoposide and 6-thioguanine repeated every 3-4 months. The mean survival so far is 18 months (range, 1-52 months). The projected 3-years survival rate in complete remission concerns 33% of the patients treated. Relapses occurred in 50% of the patients, within 10 months (range 1-35 mos.) after CR. Our results indicate that intensive cyclic polychemotherapy markedly prolongs the survival of AML patients. The high frequency of relapses during the first year after CR indicates the necessity to enhance the degree of aggressiveness of treatment shortly after a complete remission has been obtained.

Topics: Adolescent; Adult; Aged; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Doxorubicin; Etoposide; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Remission Induction; Thioguanine; Time Factors

The results of four consecutive trials designed by the GIMEMA group for the treatment of ANLL in elderly patients are reviewed. Complete remission (CR) has been achieved in 20.8% of patients older than 60 years treated with 5-day courses of ARA-C plus thioguanine, in 22.7% of patients treated with high dose ARA-C (HDARAC) plus Asparaginase, in 39.5% of patients aged 55 to 80 receiving either Idarubicin or Daunorubicin in combination with Cytarabine in a standard 3+7 protocol and in 51% of patients older than 60 years treated with intermediate dose ARA-A (IDARAC) plus Mitoxantrone. From 1988, patients ineligible for aggressive chemotherapy entered a study of palliative treatment with Thioguanine and ARA-C. This 18 year GIMEMA experience showed that: CR can be obtained only with regimens producing marrow aplasia, the inclusion of anthracyclines or Mitoxantrone improves the CR rate, without prohibitive toxicity, haematological toxicity is very high in elderly patients and account for the most frequent cause of treatment failure namely death in aplasia, palliative treatment does not improve the quality of life and prolongs median survival only slightly. When comparing the results of these trials, it appears that in the GIMEMA group the capability of offering effective treatment to elderly patients with ANLL has continuously improved and that IDARAC plus Mitoxantrone is so far the most active and best tolerated regimen. Death in aplasia remains a major problem and future trials will be aimed at exploiting the possibility of reducing the haematological toxicity by using recombinant colony stimulating factors.

Topics: Age Factors; Aged; Aged, 80 and over; Anemia, Aplastic; Antineoplastic Combined Chemotherapy Protocols; Cause of Death; Cytarabine; Daunorubicin; Drug Administration Schedule; Feasibility Studies; Humans; Idarubicin; Infusions, Intravenous; Italy; Leukemia, Myeloid, Acute; Middle Aged; Mitoxantrone; Remission Induction; Thioguanine

Between 1978 and 1988 (median follow up 5 1/2 years), 396 newly diagnosed adults with AML (age range 14-59 years, median 44) received STT comprising daily Adriamycin: 25mg/m2 for 3 days, Cytosine arabinoside (ara-C): 100mg/m2 bd and 6-thioguanine: 100mg/m2 bd, each for 7 days. A maximum of 6 cycles was administered with as short an intercycle time as possible. No further treatment was given. Complete remission (CR) was achieved in 243/396 patients (62%), 71 patients (18%) having resistant leukaemia and 82 (21%) dying within 6 weeks. Antecedent myelodysplasia and advanced age correlated unfavourably with achievement of CR (p = less than 0.001 and 0.005 respectively). Sixty nine patients continue in first remission between 2 1/2 and 12 years; the median duration of remission was 1 year. M3 morphology (p = 0.005) and absence of hepatosplenomegaly (p = 0.001) correlated favourably with duration of remission. Ninety one patients remain alive with an actuarial survival of 22% at 5 years. More recently, additional consolidation comprising high-dose ara-C and total body irradiation (TBI) with autologous bone marrow transplantation (ABMT) has been evaluated in an open study. CR has been achieved in 41/66 patients under the age of 50 but only 19/41 have proceeded to ara-C + TBI + ABMT. Twenty two have not (early recurrence 10, allogeneic BMT 4, debility 6, refusal 2). 11/19 who proceeded to ablative therapy continue in remission (4 treatment related deaths, 4 recurrences) as compared to 9/22 who did not. Currently the overall median duration of remission for the 41 patients intended to proceed is identical to that of age-matched historical controls illustrating the difficulties inherent in demonstrating benefit for the use of myeloablative therapy and ABMT in patients with AML in first remission.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Cytarabine; Doxorubicin; Humans; Leukemia, Myeloid, Acute; Middle Aged; Remission Induction; Survival Analysis; Thioguanine; Whole-Body Irradiation

Topics: Adolescent; Adult; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; DNA; DNA Adducts; Doxorubicin; Drug Administration Schedule; Humans; Leukemia, Myeloid, Acute; Mercaptopurine; Methotrexate; Middle Aged; Prednisolone; Prednisone; Survival Analysis; Thioguanine; Vincristine

The Italian Co-operative Group GIMEMA conducted a randomized trial in adult acute nonlymphocytic leukemia (ANLL) to assess the role of postconsolidation treatment. Of 448 evaluable patients entered into the study, 305 (68%) achieved a complete remission after a standard induction with daunorubicin and cytosine arabinoside (3 + 7; 2 + 5). Those in remission after a consolidation therapy including 4 courses of daunorubicin, cytosine arabinoside, and 6-thioguanine (DAT) were allocated to one of three arms: no treatment, conventional maintenance, or intensive postconsolidation therapy. The median disease-free survival (DFS) was 13 months, and the median survival was 14 months, with 26% surviving at 6.5 years. There was no difference in survival and in disease-free survival among the three postconsolidation arms. In conclusion our study, as others, suggests that the critical period of ANLL treatment is within the first 5-6 months.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cytarabine; Daunorubicin; Etoposide; Humans; Leukemia, Myeloid, Acute; Middle Aged; Remission Induction; Thioguanine; Time Factors

We studied the efficacy of ceftazidime as initial monotherapy in 82 adult patients with acute leukemia who developed 123 febrile episodes during induction chemotherapy. 88% of the patients survived their febrile episode(s), whereas 10% died of infection. When assessed at 72 h after initiation of treatment (early evaluation), 43/123 episodes (35%) had been successfully treated with ceftazidime. These 43 favourable responses were seen in 15/47 (32%) microbiologically documented infections, 20/46 (43%) clinically defined infections, and 8/30 (27%) fever of unknown origin (FUO). At the resolution of fever (late evaluation) 115 episodes were evaluable, and 48% had responded successfully to ceftazidime. Successful treatment was most frequently observed in FUO, 18/29 (62%). In contrast, only 19/44 (43%) microbiologically documented infections and 18/42 (43%) clinically defined infections were cured during ceftazidime treatment. In bacteremia the response rate was only 8/26 (31%). Thus, this study shows that although ceftazidime can be safely used for initial empirical monotherapy in neutropenic leukemia patients, the need for therapy modification is high and few patients with serious infections are cured with ceftazidime alone.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bacterial Infections; Ceftazidime; Cytarabine; Daunorubicin; Female; Fever; Fever of Unknown Origin; Humans; Leukemia; Leukemia, Myeloid, Acute; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Thioguanine

Since the differentiating effect of high-dose methylprednisolone (HDMP) on myeloid leukemic cells has been shown in one of our patients with acute myeloblastic leukemia (AML-M4), 27 previously untreated children with AML were given HDMP (20-30 mg/kg per day) combined with cytosine arabinoside (Ara-C; 3 mg/kg) for the first 2 weeks of induction therapy. Marked clinical improvement was observed in all patients with the exception of one who died within 24 hours of the treatment. Enlarged liver and spleen (greater than 5 cm) became nonpalpable in 3 (37%) out of 8 and 5 (100%) out of 5 patients, respectively, and bone marrow blasts decreased below 5% in 7 patients (27%) within 2 wk of HDMP and Ara-C treatment. Adriamycin (1 mg/kg) was added 2 wk after initiation of induction therapy. Twenty-two (84.6%) of the 26 patients achieved complete remission, 3 (11.5%) had partial remission and no response was obtained in one. Treatment was well tolerated. The addition of HDMP as a differentiating and/or cytolytic agent to conventional anti-leukemic chemotherapy increased the complete remission rate and prolonged the duration of remission of our AML patients.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Liver; Male; Methylprednisolone; Mitoxantrone; Remission Induction; Spleen; Thioguanine; Vincristine

Fifty seven patients entered the cooperative study AML II/87 of the working group "Pediatric Hematology and Oncology" of East Germany. Two patients with initial hyperleukocytosis died prior therapy. 13 patients died within the first 4 weeks of therapy, 3 patients did not respond to therapy, and one patient is not yet in remission. 38 patients (70%) attained a complete remission. 15 patients get a bone marrow transplantation in first CR (10 autologous BMT without purging, 5 allogenous BMT). 12 of them are living and well 3 to 34 months after BMT. 9 of the 23 patients under chemotherapy relapsed, one patient is lost to follow up. 13 patients are living in continuous complete remission. The life table probabilities 48 months after the start of the protocol are 0.43 for disease free survival (DFS) and 0.60 for event free interval (EFI). The respective results of the former protocol AML I/82 were 0.34 for DFS and 0.47 for EFI.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Survival Analysis; Thioguanine; Transplantation, Autologous; Transplantation, Homologous

255 patients with acute non-lymphoid leukaemia (ANLL), observed between October 1984 and June 1987, entered a chemotherapy regimen consisting of induction therapy with cytarabine in combination with idarubicin (IDA/ARA) or daunorubicin (DNR/ARA), followed by consolidation with four courses of IDA + ARA plus 6-thioguanine (6-TG) or DNR + ARA + 6-TG and a 6 month maintenance therapy with 6-TG and ARA. The median age was 62 years (range 55-78 years) and 33 were aged more than 70 years. The treatment groups were comparable for median age, FAB type, performance status and initial blood counts. 249 patients were randomised, 124 to the IDA/ARA arm and 125 to the DNR/ARA arm. Complete remission was achieved in 50 patients (40%) on the IDA/ARA treatment program and 49 patients (39%) on DNR/ARA. No definite differences were found between patients receiving IDA/ARA and those treated with DNR/ARA as far as complete response (CR), overall survival, failure free and relapse free survival are concerned. 74% of the complete responders in the IDA/ARA arm and 51% in the DNR/ARA arm achieved CR after a single course of treatment. Resistant leukaemia was observed in 13.7% of the patients in the IDA/ARA arm and in 31.2% in the DNR/ARA one, whereas hypoplastic death occurred in 29% and 14.4%, respectively. In conclusion, our data failed to show any advantage of idarubicin over daunorubicin even though there is some evidence that IDA, despite the higher toxicity, is more rapid in eradicating leukaemia as proved by the higher CR rate obtained after one course of induction.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Humans; Idarubicin; Leukemia, Myeloid, Acute; Male; Middle Aged; Remission Induction; Thioguanine

Two hundred fifty-six children with previously untreated acute nonlymphocytic leukemia (ANLL) were evaluated on a Pediatric Oncology Group (POG) phase III randomized trial of both induction and continuation chemotherapies. Induction therapy compared vincristine, cytarabine, and dexamethasone (VADx) with daunorubicin, cytarabine, and thioguanine (DAT). The complete remission (CR) rate using DAT was superior (82% v 61%, P = .02). Postremission therapy consisted of either "standard" two-cycle therapy or a more intensive four-cycle regimen given for 2 years. Overall, there was no difference in outcome for patients randomized to either continuation regimen. The overall complete continuous remission rate (CCR) for the "best" induction/continuation therapy combination at 2 years was .50 (SE = .06), at 3 years was .35 (.04), and at 4 years was .34 (.05). Analysis of selected clinical and laboratory parameters demonstrated differences in induction responses favoring DAT induction but did not impact eventual disease-free survival. There were two subgroups of patients who responded better to four-cycle continuation therapy. These were patients with French-American-British (FAB) M1/M2 (2-year CCR was .20 v .44, P = .01) and patients older than 10 years at diagnosis (.32 v .62, P = .004).

Topics: Agranulocytosis; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Child; Child, Preschool; Cytarabine; Daunorubicin; Dexamethasone; DNA Nucleotidylexotransferase; Female; Fever; Humans; Infant; Leukemia, Myeloid, Acute; Male; Multivariate Analysis; Random Allocation; Receptors, Glucocorticoid; Recurrence; Remission Induction; Retrospective Studies; Survival Rate; Thioguanine; Tumor Cells, Cultured; Vincristine

In a prospective study running between 1981 and 1983, a group of 156 adult (under 60 years of age) patients with de-novo acute myelogenous leukaemia were randomly assigned to receive a daunorubicin, cytosine arabinoside and thioguanine combination or a regimen containing lower dosages of these drugs but also containing etoposide and vindesine. Patients who entered complete remission received maintenance therapy for 2 years. The survival and remission duration curves of the two groups were exactly superimposable and for this long-term analysis all patients have been considered together. The follow-up times range between 84 and 104 months. Actual survival at 7 years is 15% (95% confidence intervals 9-20%), with a stable curve thereafter. Actual probability of continuous complete remission at 7 years is 22% (95% C.I. 13-31%) with a stable curve beyond that point. These findings, similar to those of the few other studies of chemotherapy with comparable follow-up times, suggest that only a small fraction of adult patients become long-term survivors, irrespective of the precise type or amount of antineoplastic agents administered.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Daunorubicin; Etoposide; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prospective Studies; Remission Induction; Thioguanine; Vindesine

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Etoposide; Germany, West; Humans; Leukemia, Myeloid, Acute; Methotrexate; Prednisone; Prognosis; Remission Induction; Thioguanine; Time Factors; Vincristine

Topics: Adolescent; Adult; Aged; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Dacarbazine; Daunorubicin; Doxorubicin; Drug Combinations; Etoposide; Humans; Leukemia, Myeloid, Acute; Middle Aged; Mitoxantrone; Multicenter Studies as Topic; Nimustine; Prednisone; Randomized Controlled Trials as Topic; Remission Induction; Survival Rate; Thioguanine; United Kingdom; Vincristine

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Etoposide; Humans; Infant; Leukemia, Myeloid, Acute; Multicenter Studies as Topic; Pilot Projects; Randomized Controlled Trials as Topic; Remission Induction; Thioguanine; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cross-Sectional Studies; Cytarabine; Down Syndrome; Doxorubicin; Humans; Iceland; Infant; Infant, Newborn; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Life Tables; Multicenter Studies as Topic; Preleukemia; Remission Induction; Scandinavian and Nordic Countries; Survival Rate; Thioguanine

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Daunorubicin; Doxorubicin; Etoposide; Germany, West; Humans; Infant; Leukemia, Myeloid, Acute; Life Tables; Multicenter Studies as Topic; Remission Induction; Thioguanine

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

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Etoposide; Humans; Italy; Leukemia, Myeloid, Acute; Life Tables; Middle Aged; Multicenter Studies as Topic; Prospective Studies; Randomized Controlled Trials as Topic; Remission Induction; Survival Rate; Thioguanine

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Daunorubicin; Germany, West; Humans; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Remission Induction; Thioguanine

Topics: Adolescent; Adult; Aged; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Thioguanine; United States

Previous investigations in animals and one retrospective study in man suggest that verapamil can prevent anthracycline-induced cardiomyopathy. In the following study, patients with acute myeloid leukemia (AML) treated with double induction and consolidation chemotherapy (AML COOP study 1986, [3]) were randomized in a group with and without accompanying low-dose oral verapamil treatment. Since July 1986, 64 patients have been included. Thirty patients have been evaluated for pre- and posttreatment cardiological investigations. So far, no significant difference in cardiotoxicity has been observed either between the verapamil and nonverapamil group or between the two induction chemotherapy regimens (TAD/TAD - TAD/HAM).

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cardiomyopathies; Cytarabine; Daunorubicin; Hemodynamics; Humans; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Middle Aged; Mitoxantrone; Multicenter Studies as Topic; Prospective Studies; Randomized Controlled Trials as Topic; Thioguanine; Verapamil

Topics: Adolescent; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Austria; Child; Cytarabine; Daunorubicin; Drug Resistance; Germany, West; Humans; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Middle Aged; Mitoxantrone; Multicenter Studies as Topic; Neoplasm Recurrence, Local; Prospective Studies; Randomized Controlled Trials as Topic; Thioguanine

We have prospectively compared the values of autologous BMT (auto-BMT) and allogeneic marrow transplantation (allo-BMT) in patients (age 15-60 years) with acute myeloid leukemia (AML) who attained complete remission (CR) following remission-induction therapy. In 90/117 cases CR was reached. In 32 of those complete responders auto-BMT was undertaken and in 21 eligible cases HLA-matched allo-BMT. AML relapse was the predominant cause of failure after auto-BMT (17/32). The incidence of relapse after allo-BMT was 6/21. Patients treated with auto-BMT and allo-BMT have an overall survival of 37% and 66% at 3 years posttransplant (P = 0.05). Survival of the nongrafted complete responders is less than 10%. Allo-BMT in adult patients with AML in first complete remission provides a superior outcome when directly compared with the results of auto-BMT.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Middle Aged; Multicenter Studies as Topic; Netherlands; Prospective Studies; Survival Rate; Thioguanine; Transplantation, Autologous; Transplantation, Homologous

The Children's Cancer Study Group instituted a pilot study to investigate the use of high doses of cytosine arabinoside (AraC) in the intensification phase of treatment for acute nonlymphocytic leukemia (ANLL). Patients achieving remission and not eligible for allogeneic bone marrow transplantation were treated with four doses of high-dose AraC and L-asparaginase. These drugs were repeated either on or after 28 days (q28 days), after recovery of hematologic parameters (for the first 49 patients entered onto this trial); or after 7 days (q7 days), despite dropping blood counts (for the last 53 patients enrolled). After completing an additional 3 months of intensification therapy, patients were then allocated by physician choice to either discontinue therapy or receive 18 28-day cycles of maintenance therapy, including the daily administration of 6-thioguanine. Despite three deaths associated with the toxicity of the aggressive (q7 days) AraC timing, patients receiving this approach demonstrated equal or better disease-free survival from the end of induction (55% versus 42% actuarially at 3 years [P = 0.52]). Maintenance therapy appeared to play no role in improving outcome for people who received the aggressive timing of AraC cycles. Fifty-nine percent were alive disease free actuarially at 3 years from the decision to not give maintenance therapy (n = 27) compared with 62% for those receiving maintenance therapy (n = 16; P = 0.49). On the other hand, patients who received the less aggressive AraC intensification timing (q28 days) had an improved survival rate if maintenance therapy was administered (n = 17) (65% versus 39% for patients not receiving maintenance therapy [n = 24] at 3 years [P = 0.07]). Maintenance therapy therefore may not improve outcome in patients receiving aggressive timing of high-dose AraC but may be important in less intensive postremission regimens in childhood ANLL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cytarabine; Daunorubicin; Dexamethasone; Drug Administration Schedule; Etoposide; Female; Humans; Infant; Infant, Newborn; Infusions, Intravenous; Leukemia, Myeloid, Acute; Male; Multicenter Studies as Topic; Pilot Projects; Random Allocation; Remission Induction; Thioguanine

In a randomized trial, 299 evaluable patients with acute myelogenous leukemia, age greater than or equal to 51, were initially randomized to cytosine arabinoside, 100 mg/m2/day, by continuous intravenous infusion for seven days, plus either daunorubicin 45 mg/m2/day x 3 (DA), or m-AMSA 200 mg/m2/day x 3 days (MA). Complete remission (CR) rates were not significantly different, 47% for DA and 42% for MA. Toxicities were similar except that severe hepatic toxicity, serum bilirubin greater than or equal to 7 mg/dl, was more frequent in patients receiving MA (10%) than in patients receiving DA (4%), p less than 0.05. Deaths during induction were significantly more frequent in patients receiving MA (38%) than in patients receiving DA (25%), p = 0.018. Patients achieving a CR received thioguanine, cytosine arabinoside, and daunorubicin (TAD) for three cycles as consolidation. Among evaluable patients, 82/102 (80%) stayed in CR during these three cycles. Patients were then randomized to either no maintenance or to DA every 13 weeks x 4 cycles, at a dose slightly lower than used for induction. Remission duration was similar for the two maintenance programs, 10.7 months for no maintenance and 8.5 months for DA. The percentage of patients evaluable for maintenance achieving three year relapse-free survival was similar for the two maintenance programs, 28% for no maintenance and 21% for DA. However, overall survival was significantly greater (40 vs 12 months, p = 0.007) for patients receiving no maintenance therapy, due to greater survival after recurrence in these patients. At each phase of the study there were substantial numbers of non-evaluable cases, often due to incomplete evaluation of remission status. Of the 379 patients initially entered into the trial, 35% obtained a complete remission. Of all the patients who achieved a complete remission, 61% were both evaluable and in remission upon completion of the maintenance phase. Of these patients who completed the maintenance phase in remission, 15% were relapse free survivors three years following initiation of maintenance therapy. Overall, only 3.2% of patients who entered the trial (35% x 61% x 15%) were continuous relapse-free survivors three years into the maintenance phase.

Topics: Aged; Aged, 80 and over; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Administration Schedule; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Remission Induction; Survival Rate; Thioguanine; United States

The Childrens Cancer Study Group conducted four therapeutic studies on a total of 1006 children with acute nonlymphocytic leukemia from 1972 to 1983. This report describes the therapeutic strategies of these studies and examines trends in induction rates and long-term outcome over this period. The remission induction rate has changed from 58% in 1972 to 1975 to 80% for the period 1980 to 1983, and the induction mortality dropped from 20% to 6%. Four-year survival probabilities from time of diagnosis have almost doubled from 19% to 36%. Few deaths occurred more than 5 years after diagnosis: children surviving in first remission beyond 5 years had a 92% survival rate and an 86% relapse-free survival rate over the next 5 years. In contrast, median survival after a marrow relapse was less than 6 months and the 6-year survival probability was 4%. The leukocyte count was a significant prognostic factor, and although the mortality for infants was high initially, long-term survival was not decreased.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Infant; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Prednisolone; Prognosis; Remission Induction; Thioguanine; Vincristine

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Clinical Trials as Topic; Cytarabine; Daunorubicin; Humans; Infant; Italy; Leukemia, Myeloid, Acute; Multicenter Studies as Topic; Remission Induction; Thioguanine

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Cytarabine; Daunorubicin; Drug Administration Schedule; Drug Evaluation; Humans; Italy; Leukemia, Myeloid, Acute; Multicenter Studies as Topic; Random Allocation; Remission Induction; Thioguanine

69 patients (median age 53 years, 19-79 years old) with untreated acute non-lymphoblastic leukemia (ANLL) were randomized to receive either a regimen of amsacrine, cytarabine, thioguanine (AAT) or daunorubicin, cytarabine, thioguanine (DAT). AAT consisted of amsacrine 200 mg/m2/day x 5, thioguanine 100 mg/m2/12 h p.o. x 10; DAT was daunorubicin 50 mg/m2/day x 3, cytarabine 200 mg/m2/day x 5, thioguanine 100 mg/m2/12 h p.o. x 10. After one or two induction courses the patients subsequently received 2 consolidation courses. 17 patients were not assessable for response to therapy due to exitus during induction treatment. Complete remission could be obtained in 14/24 (58%) of DAT patients respectively. Patients less than 60 years of age achieved CR in 63% (AAT) vs 65% (DAT), whereas patients greater than or equal to 60 years obtained a CR in 50% (AAT) vs 13% (DAT). Toxicity appears not to be increased significantly with amsacrine. These data indicate that amsacrine could replace daunorubicin in remission induction regimens of ANLL containing cytosin arabinoside and thioguanine without decreasing the response rate.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Middle Aged; Random Allocation; Thioguanine

Three hundred and seventy-one children below 16 years, with newly diagnosed acute myeloid leukaemia, were included in six consecutive GATLA/GLATHEM protocols, from November 1967 to December 1987. The study was divided in three periods: 1967 to 1975, 1976 to 1982, and 1983 to 1987. Three induction schedules were used during the first two periods, and different maintenance schemes alternating with monthly consolidations were explored; the value of immunotherapy with C. Parvum and androgen therapy with stanozolol was also tested. Protocol 3-AML-83, representing the third period, included a four-week induction phase with vincristine, adriamycin, cytosine-arabinoside, prednisone and 6-mercaptopurine, followed by a consolidation phase with cyclophosphamide, cytosine-arabinoside and 6-mercaptopurine for four weeks. Maintenance phase included daily, oral 6-mercaptopurine, and monthly cytosine-arabinoside, both during two years, and adriamycin every eighth week, for one year. Complete remission rates for the first two periods of therapy were 40% and 55%, whereas that of the last period was 74%. The overall results of the period 1967-1982, showed actuarial duration rates of complete remission, event-free survival and survival, at 60 months, between 2% and 6%, their median duration being of 9, 8 and 10 months respectively. No significant difference was observed between the first two periods or protocols. Protocol 3-AML-83, activated in March 1983, achieved actuarial rates of continuous complete remission, event-free survival, and survival of 51%, 37% and 39% respectively, at 48 months. The difference between the first two periods and the last one was highly significant (P less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Clinical Trials as Topic; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Evaluation Studies as Topic; Humans; Infant; Leukemia, Myeloid, Acute; Methotrexate; Prednisolone; Prednisone; Thioguanine; Vincristine

Ninety-six patients with de novo acute nonlymphocytic leukemia (ANLL) were randomized to receive either daunorubicin (50 mg/m2, IV) on days 1-3; cytarabine (Ara-C) (25 mg/m2, IV) bolus, followed by 160 mg/m2 as a continuous IV infusion daily for 5 days and 6-thioguanine (6-TG) (100 mg/m2 po) every 12 hr daily for 5 days (DAT); or amsacrine (190 mg/m2, IV) on days 1-3 with Ara-C and 6-TG at the above doses (AAT). Patients achieving complete remission (CR) then received two courses of consolidation therapy with the same combination that had induced remission but at slightly reduced total doses. Patients less than or equal to age 40 with an HLA-identical sibling donor underwent allogeneic transplantation, usually after consolidation therapy. The remaining patients were then randomized to receive either maintenance therapy (alternating cycles of vincristine/methotrexate, cyclophosphamide/6-TG, daunorubicin/hydroxyurea and Ara-C/6-TG) or no further treatment. Ninety-two patients were evaluable for response. Twenty-five of the 46 patients (54%) who received DAT and 32 of the 46 patients (70%) who received AAT achieved CR (p = 0.13). When patients were stratified by age, however, remission induction advantage with AAT became statistically significant (p = 0.03). Additionally, more patients achieved CR following one course of AAT than following one course of DAT (48% vs 28%, p = 0.03). Overall survival in the AAT group was improved as well (p = 0.01). Too few patients were randomized on the maintenance arm of the protocol to make interpretation meaningful. Non-hematologic toxicity was generally comparable in both arms. In conclusion, patients with de novo ANLL who received AAT had a higher remission incidence and slightly longer survival compared to patients who received DAT. Further investigation of this drug combination in untreated patients with ANLL is warranted.

Topics: Age Factors; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Administration Schedule; Humans; Leukemia, Myeloid, Acute; Prognosis; Thioguanine

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cytarabine; Humans; Leukemia, Myeloid, Acute; Remission Induction; Thioguanine

Topics: Adult; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Child; Clinical Trials as Topic; Cytarabine; Daunorubicin; Etoposide; Female; Humans; Leukemia, Myeloid, Acute; Male; Random Allocation; Remission Induction; Risk; Thioguanine; United Kingdom

Topics: Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Clinical Trials as Topic; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Combinations; England; Etoposide; Humans; Leukemia, Myeloid, Acute; Prednisone; Remission Induction; Thioguanine; Vincristine

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Remission Induction; Thioguanine

Major chemotherapeutic alternatives for AML have been implemented and compared in three multicenter studies, including a total of 877 adult patients of all ages. The results strongly suggest that myelosuppressive postinduction treatment is a prerequisite for the achievement of long-term remissions. In addition, it was possible to establish an important antileukemic effect of monthly maintenance chemotherapy. Initial results from an intensive two-course preremission therapy concept revealed good practicability and acceptable toxicity, as well as promising response and remission durations by this new approach.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cytarabine; Daunorubicin; Germany, West; Humans; Leukemia, Myeloid, Acute; Mitoxantrone; Random Allocation; Remission Induction; Thioguanine

Between July 1, 1981, and July 1, 1985, 167 patients with acute myelogeneous leukemia (AML) were treated with one or, if necessary, two courses of a modified TAD regimen (TAD9) for induction. 96 patients (58%) achieved a complete remission (CR); 62 achieved CR after one and 34 patients after two courses of TAD9. 29 patients (17%) were considered early deaths, and 42 patients (25%) nonresponders. For CR maintenance 64 patients were eligible according to protocol criteria; 33 patients were randomized to chemotherapy, only, (CT) by monthly courses of cytosine arabinoside (ARA-C) alternatingly combined with daunorubicin or thioguanine or cyclophosphamide, while 31 patients were randomized to receive immunotherapy in addition to chemotherapy (CIT) by intradermal injections of 10(10) neuraminidase-treated viable allogeneic blasts per immunization interspersed between the CT courses. Maintenance therapy was given for up to 3 years. The median survival in CT patients is 23 months, while in CIT patients the median has not been reached after 54 months; corresponding median relapse-free survival is 15 months for the CT patients as opposed to 40 months for the CIT group. The differences are not significant. Comparing CT with CIT, the survival data show a persistent trend in favor of CIT; under the conditions of the study, however, a substantial benefit of immunotherapy may be restricted to a certain subset of patients with low risk for early relapse.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Combined Modality Therapy; Cytarabine; Daunorubicin; Germany, West; Humans; Immunization; Leukemia, Myeloid, Acute; Neuraminidase; Prospective Studies; Random Allocation; Remission Induction; Thioguanine

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Clinical Trials as Topic; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Etoposide; Germany, West; Humans; Leukemia, Myeloid, Acute; Methotrexate; Prednisone; Prognosis; Remission Induction; Risk; Thioguanine; Vincristine

Eighty-seven children with acute nonlymphoblastic leukemia were treated with the AML protocol BFM 78 between June 1979 and February 1986 in a multicenter study in the GDR. Seventeen children (20%) died from early complications, eight did not respond to therapy. Fifty-eight patients (70%) achieved a complete remission. Twenty-three patients relapsed. The life table analysis revealed after 5 years a probability for event-free survival of 36% (SD = 6%) and an event-free interval of 51% (SD = 8%). Six patients were transplanted in first remission. Two of them died; one (M 1) on day + 19 from encephalopathy and one (M 4) on day + 60 from acute GVHD. The overall results are in good correlation with the original BFM study, but there are differences in the subtypes. Results are superior to other AML protocols in our group.

Topics: Actuarial Analysis; Antineoplastic Combined Chemotherapy Protocols; Child; Clinical Trials as Topic; Cyclophosphamide; Cytarabine; Doxorubicin; Germany, East; Humans; Leukemia, Myeloid, Acute; Methotrexate; Prednisone; Remission Induction; Thioguanine; Vincristine

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cytarabine; Doxorubicin; Humans; Leukemia, Myeloid, Acute; Middle Aged; Random Allocation; Thioguanine

This trial, which will probably accrue over 1,000 patients before it closes, has already demonstrated that high remission rates are attainable in large multicenter studies using 'conventional' doses of ara-C. The results in the group aged less than 40 are comparable with many single-center studies. There is, at the moment, only a borderline difference in the remission rates between the two forms of induction therapy but the more intensive regimen of DAT 3 + 10 achieves remission more quickly and requires less supportive care. Analysis of the reasons for failure to enter remission continues to show that inadequate supportive care remains an important reason why the remission rates are not higher. Drug-related deaths in remission, though decreasing gradually in this study, are a disturbing consequence of increasing the intensity of consolidation treatment.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Child; Cyclophosphamide; Cytarabine; Daunorubicin; Etoposide; Humans; Leukemia, Myeloid, Acute; Middle Aged; Prednisolone; Thioguanine; Vincristine

High-dose cytosine arabinoside (HDAra-C) has been used for remission induction, and in conventional doses for maintenance in a trial of single-agent therapy in 43 previously untreated patients with acute myelogenous leukemia (AML). Rationale for the trial was provided by the observed decrease in leukemic blast cell self-renewal in culture following exposure to Ara-C. Compared with a previous trial of 57 patients treated with multidrug therapy, single-drug Ara-C was associated with a significantly improved complete remission rate (P = .010), although the survival time was not increased. All patients with low self-renewal responded to HDAra-C in contrast to the previous trial where some patients with this phenotype failed remission induction. The clinical observations are consistent with the view that the antileukemic effect of Ara-C has some specificity for cellular events required for self-renewal of blast cells. Exposure in vivo to Ara-C was associated with an increase in blast stem cell renewal at relapse, indicating that maintenance with other drugs should be tested. The study demonstrates the importance of biological attributes in design and analysis of clinical trials.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Clinical Trials as Topic; Cytarabine; Doxorubicin; Drug Combinations; Humans; Leukemia, Myeloid, Acute; Middle Aged; Neoplastic Stem Cells; Phenotype; Remission Induction; Statistics as Topic; Sulfamethoxazole; Thioguanine; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Tumor Stem Cell Assay

Ninety-seven patients less than or equal to 70 years of age with previously untreated primary acute myeloblastic leukemia were randomly treated with either the DAT or TAD regimen: daunorubicin (70 mg/m2/day) administered on Days 1-3 (DAT) or 5-7 (TAD) of a 7-day sequence consisting of cytarabine (200 mg/m2/day) and 6-thioguanine (200 mg/m2/day). Complete responders received consolidation, maintenance, and final intensification over 14 months using mostly the same drugs as during induction and administered in the same sequence. The regimens did not significantly differ from each other with regard to toxicity or efficacy. Complete remission rate was 80% in the two groups, and median duration of complete remission was 549 days with DAT and 518 days with TAD.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cytarabine; Daunorubicin; Drug Administration Schedule; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Random Allocation; Statistics as Topic; Thioguanine

In a study of 272 consecutive patients with acute myeloblastic leukaemia admitted to 14 general hospitals in the Toronto region the complete remission rate ranged from 43.8% to 85.3% depending on the exclusion applied. The median duration of survival for all patients was 5 months, and for those who achieved complete remission it was 16.8 months. The first 130 patients received different treatments from the other 142, with the second group showing an improved remission rate. Differences in exclusion criteria might have affected considerably the comparison of these two consecutive groups. To aid in the comparative evaluation of drug regimens the population base from which the patients are drawn must be fully described. This would help haematologists explain prognosis to unselected and unreferred patients.

Topics: Administration, Oral; Clinical Trials as Topic; Cytarabine; Daunorubicin; Drug Administration Schedule; Evaluation Studies as Topic; Humans; Infusions, Parenteral; Injections, Subcutaneous; Leukemia, Myeloid, Acute; Prognosis; Random Allocation; Thioguanine

Between 1978 and 1983, 1127 patients with de-novo acute myeloid leukaemia (AML) were entered into the Medical Research Council (MRC)'s 8th AML trial. All received the same induction therapy consisting of daunorubicin, cytarabine, and 6-thioguanine--DAT (1 + 5). The 67% who entered complete remission were randomised to consolidation with two or six further courses of DAT. Adults under the age of 55 were randomised for central nervous system (CNS) prophylaxis with intrathecal cytarabine and methotrexate. Finally, those still in remission after 1 year of cytarabine and 6-thioguanine (AT) maintenance were randomised to receive either late intensification with cyclophosphamide, vincristine, cytarabine, and prednisolone (COAP) or continued AT. The median survival for the whole group was 12 months; the median duration of first remission was 15 months, with relapse-free survival at 5 years estimated at 18%. The factors most strongly associated with poor survival were performance status and age at presentation, but even among those over 60 years of age, half went into remission. Six courses of DAT consolidation gave a small advantage over two courses in reducing the number of late relapses but no significant survival advantage. Late intensification showed a marginally significant advantage over continued AT maintenance. The incidence of CNS relapse was low and unaffected by prophylaxis. The second remission rate varied from 10% when the first remission was shorter than 6 months to 61% when it had continued for more than 2 years. 40 patients received histocompatible allogeneic bone-marrow transplants in first remission. There was a high procedure-related death rate, particularly among patients over 30 years of age. Thus, initially at least, the transplanted group had shorter survival than a comparable group of chemotherapy-treated patients. Treatment specifications remained unchanged throughout the trial but those enrolled in the later half of the trial had a better (p = 0.003) survival.

Topics: Adolescent; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Central Nervous System Diseases; Child; Child, Preschool; Clinical Trials as Topic; Cytarabine; Daunorubicin; Drug Administration Schedule; Humans; Infant; Leukemia, Myeloid, Acute; Middle Aged; Neoplasm Recurrence, Local; Neoplasms; Prognosis; Random Allocation; Thioguanine

The analysis of the treatment results of the co-operative therapy studies BFM 78 and 83 for the treatment of acute myelogenous leukemia in children revealed the following risk factors: Death before the onset of therapy and early death occurred more frequently in children with acute monoblastic/monocytic leukemia and in children with initial WBC of greater than 100,000/microliters than in the other patient groups. The remission rate was lower in children with an initial WBC greater than 100,000/microliters (56%) than in children with an initial WBC less than 100,000/microliters (86%). In study BFM 78 the probability of a relapse free interval of 6 years is significantly lower in children with an initial WBC greater than 100,000/microliters (pCCR = 28%; SD 11%) than in children with an initial WBC less than 100,000/microliters (pCCR = 64%; SD 10%). The median follow up time is 4 3/4 years (range 2 3/4-6 3/4 years). The probability of an event free interval of 3 years was significantly lower in children with initial involvement of the CNS (pCCR = 24%, SD 12%) than in children without involvement of the CNS (pCCR = 50%; SD 5%).

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Clinical Trials as Topic; Combined Modality Therapy; Cytarabine; Daunorubicin; Etoposide; Female; Humans; Infant; Leukemia, Myeloid, Acute; Male; Prognosis; Risk; Thioguanine

Twenty-three European centers participated in a randomized clinical trial (AML-5) to study the effect of androgens and immunotherapy during maintenance in adult acute myelogenous leukemia. Induction treatment consisted of Adriamycin (doxorubicin) 50 mg/m2 day 1, vincristine VCR 1 mg/m2 day 2, and cytosine arabinoside 80 mg/m2 every 12 hours by push injection days 3-9. Patients in complete remission were randomized into four groups: (1) 6-mercaptopurine 70 mg/m2 days 1-14, methotrexate 15 mg/m2 twice weekly days 15-28, and reinduction with daunorubicin 35 mg/m2 and vincristine 1 mg/m2 day 29; (2) chemotherapy as in group 1 plus stanozolol 0.15 mg/kg/day; (3) 6-thioguanine 70 mg/m2 orally on 4 consecutive days and cytosine arabinoside 80 mg/m2 subcutaneously day 5 every week; and (4) chemotherapy as in Group 3 plus irradiated blast cells treated with neuraminidase. Three hundred forty-eight patients were eligible and 295 were evaluable. The median age was 45 yrs. A complete remission was achieved in 64% of the patients, with 158 complete remissions randomized. Patients not randomized and patients receiving bone marrow transplantation (BMT) were analyzed separately. There was no difference in disease-free survival (DFS) or survival in the four maintenance arms. For patients reaching complete remission, the median DFS was 40 weeks, and median survival was 22 months with 30% surviving at 4 years. The overall survival was 18% at 4 years. There was no beneficial effect for DFS or survival by adding either immunotherapy or androgens to chemotherapy during maintenance. However, patients receiving immunotherapy seemed to have a higher rate of responses to reinduction after relapse than those in the other treatment arms.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Child; Clinical Trials as Topic; Combined Modality Therapy; Cytarabine; Daunorubicin; Doxorubicin; Humans; Immunotherapy; Leukemia, Myeloid, Acute; Mercaptopurine; Methotrexate; Middle Aged; Prospective Studies; Random Allocation; Testosterone Congeners; Thioguanine; Time Factors; Vincristine

In a prospective controlled trial, the relative effectiveness of allogeneic bone marrow transplantation and postremission chemotherapy was assessed for adult patients with acute myelogenous leukemia in first complete remission. Twenty-three patients, 15 to 45 years of age, who had an HLA-identical sibling donor were designated to receive bone marrow transplantation. Forty-four patients who either lacked an HLA-identical sibling or were over 45 years of age were designated to receive intensive consolidation chemotherapy. The actuarial rate of leukemia relapse was significantly lower in the transplantation group than in the chemotherapy group (40 +/- 25% [95% confidence interval] compared with 71 +/- 14%, p = 0.01). Actuarial survival at greater than 4 years was not significantly different (40 +/- 21% compared with 27 +/- 14%, p greater than 0.4). These data show that bone marrow transplantation is more effective than consolidation chemotherapy in preventing leukemia relapse, but overall survival was not improved in this study.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Clinical Trials as Topic; Cytarabine; Daunorubicin; Female; HLA Antigens; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Recurrence; Thioguanine

The present study reports on the treatment of 44 patients with AML. 17 patients were male, 27 female. Mean age was 50.1 years. Treatment-regimen consisted of induction-therapy with daunorubicin 45 mg/m2 i.v. d 1-3, cytarabine 100 mg/m2 X 24 h continuous intravenous infusion (c.i.v.i.) d 1-7, 6 thioguanine 100 mg/m2 twice orally d 1-7. There were only two consolidation therapies with daunorubicin and cytarabine and no maintenance therapy. 30 patients (68%) achieved CR, 1 patient (2%) PR, 3 were non-responders (7%). There were 10 (23%) early deaths during or following induction therapy. Median disease-free survival was 6 months, median overall survival 7.5 months. We conclude, that the reported induction therapy is efficient though toxic. To improve long term results, consolidation and intensification therapy should be escalated.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Thioguanine

102 patients with AML (leukemia after preleukemia, 2nd neoplasia included) were treated for remission induction by a modified TAD regimen in Munster; 55 patients (54%) achieved a complete remission (CR). For CR maintenance 40 patients were eligible for randomization according to the study protocol: cyclic chemotherapy (CT) alone vs. chemoimmunotherapy (CIT: plus allogeneic Neuraminidase-treated blasts in high dosage). 5 CR patients, induced identically in Essen, were randomized additionally. Evaluating all patients randomized there is only a marginally beneficial effect of CIT (21 patients) compared to CT (24 patients) concerning median survival (1020+ vs. 612 days) and relapse-free survival (494 vs. 380 days) until now. For patients receiving more than 2 cycles of maintenance therapy, however, CIT prolongs relapse-free survival significantly (930+ vs. 409 days; p = 0,02); that is also true for remission duration. This suggests that only repeated application of blasts may induce an immune response leading to a biologically relevant antileukemic effect.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Administration Schedule; Humans; Immunotherapy; Leukemia, Myeloid, Acute; Prospective Studies; Random Allocation; Thioguanine

In two multicenter trials, a total of 576 patients with acute myeloid leukemia (AML) were treated and found to be evaluable. Two hundred forty-two patients were in a 1978 pilot study and 334 patients were in a 1982 randomized study. Ages were between 15 and 78 years (median, 48). The uniform remission induction therapy in both studies consisted of one to two courses of a 9-day combination of 6-thioguanine (TG) with cytosine arabinoside (ARA-C) and daunorubicin (DNR) [TAD9]. The timing and sequencing of TAD9 was designed according to cell kinetic effects of ARA-C. A complete remission (CR) was achieved in 65% (70% and 61%, respectively) of patients within a median of 33 days, and in 68% of responders after only one course. The CR rate in patients 60 to 78 years of age was 51% (66% and 39%, respectively). In the 1978 pilot study, different protocols of post-remission treatment were applied at the different centers: monthly 5-day maintenance, TAD9 consolidation, both consolidation and maintenance, or no further therapy. The group receiving treatment during CR showed 24% probability of remissions at 4 years v 0% probability of remissions in the untreated group. Between the different post-remission protocols, no significant differences were observed. Remission duration was not influenced by age, WBC, or morphologic cell type, but was longer in patients achieving CR within 30 days (P = .017). In the subsequent 1982 study, 145 patients in CR were randomized for TAD9 consolidation with or without monthly maintenance. The updated life-table analysis revealed a predicted rate of continuous remission at 2 1/2 years of 30% for the maintenance and 17% for the nonmaintenance arm (P = .003). These results of response and remission duration in adult patients of all ages support the validity of intensified induction therapy and of consequent myelosuppressive treatment in remission.

Topics: Actuarial Analysis; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cytarabine; Daunorubicin; Germany, West; Humans; Leukemia, Myeloid, Acute; Middle Aged; Pilot Projects; Random Allocation; Thioguanine; Time Factors

To investigate the value of maintenance chemotherapy after early consolidation treatment, an attempt was made to induce remission in 162 previously untreated patients, age-range 7-65 years (median 43). The 74 patients who were still in remission after early consolidation treatment (given for 3-5 months) were assigned to either maintenance chemotherapy every 8 weeks for 2 years or to observation only. After a median observation period of 44 months there was no difference between the groups in duration of remission or survival. Surprisingly, patients above 40 survived longer after early consolidation (median 4 years) than did patients aged 40 and below (median 1.6 years, p = 0.0002).

Topics: Adolescent; Adult; Aged; Agranulocytosis; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Child; Clinical Trials as Topic; Cytarabine; Evaluation Studies as Topic; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prednisone; Prognosis; Random Allocation; Thioguanine; Thrombocytopenia; Vincristine

The Southeastern Cancer Study Group conducted a post-remission induction randomized trial in adult acute myelogenous leukemia to assess the efficacy of alternate drug therapy during consolidation and of immunotherapy during maintenance. Of 508 evaluable patients entered into the study, 335 (66%) achieved a complete remission treated with a 7-day infusion of cytosine arabinoside at a dose of 100 mg/sq m/day and 3 days of daunorubicin at a dose of 45 mg/sq m/day. Those in remission were randomized to receive 3 courses of 1 of 3 consolidation regimens: (A) a continuous infusion of 5-azacytidine, 150 mg/sq m/day for 5 days; (B) 5-azacytidine plus beta-deoxythioguanosine, 300 mg/sq m/day for 5 days; or (C) cytosine arabinoside, 100 mg/sq m/day intravenously, and thioguanine, 100 mg/sq m orally every 12 hr, plus daunorubicin, 10 mg/sq m every 24 hr daily for 5 days. There was no difference in relapse rate among the 3 arms. Those completing consolidation and remaining in remission were randomized to 1 of 3 maintenance regimens: (D) chemotherapy, 5-day infusion of cytosine arabinoside and 2 days of daunorubicin (same doses as induction) given every 13 wk for 1 yr; (E) BCG given twice weekly for 1 mo and then monthly for 1 yr; or (F) the combination of regimens D and E. The median duration of remission was significantly better on regimen D (17.4 versus 9.4 and 9.5 mo), and median survival was 29 mo compared to 21 mo for the other regimens. Those given different drugs during consolidation than used for induction (regimens A and B) and subsequent chemotherapy for maintenance (regimen D) had the longest remission durations and survival. Immunotherapy was not as good as intensive chemotherapy for maintenance.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; BCG Vaccine; Clinical Trials as Topic; Combined Modality Therapy; Cytarabine; Daunorubicin; Deoxyguanosine; Female; Humans; Immunotherapy; Leukemia, Myeloid, Acute; Male; Middle Aged; Random Allocation; Thioguanine; Thionucleosides; United States

In a prospective study 100 AML cases were randomized in two groups and underwent remission induction treatment in 4 departments with "Ara-C c. inf. from the first to the eight day plus Adr. from the first to the third day" or "Ara-C + 6-TG + Adr., 6 + 6 + 2 days". The CR patients were divided into two subgroups. Subgroup A obtained maintenance therapy with 5 day course of Ara-C s.c. in addition to 6-TG, Vincristine plus Prednisone and Adriamycin sequentially, with each cycle repeated at 6 week intervals. Subgroup B obtained the calf thymus extract (TFX-Polfa) between the cycles additionally. The current results of remission induction treatment are similar to "8 + 3" and "6 + 6" regimens as measured by the CR rate (45% and 44%), survival curves (survival after 24 months - 23% and 28% respectively) and relapse rates (3.5%/pt.mo.obs. and 5.3%/pt.mo.obs.). It is still too early to evaluate the efficacy of this maintenance treatment, because the programme is still open to patient entries. At present 13 patients received maintenance regimen A and 12 patients received maintenance regimen B, with an average survival being equal to 14 and 13.5 months respectively.

Topics: Adult; Animals; Blood Transfusion; Cattle; Cytarabine; Doxorubicin; Granulocytes; Humans; Leukemia, Myeloid, Acute; Middle Aged; Platelet Transfusion; Poland; Prospective Studies; Random Allocation; Thioguanine; Thymus Gland; Tissue Extracts

Three sequential trials of treatment for acute myelogenous leukemia (AML) involving 173 patients were analyzed to identify clinical and myeloblast-cell progenitor properties in culture related to outcome. The latter, including self-renewal capacity expressed as plating efficiency (PE2) and drug sensitivity, were determined for a representative group of 45 patients. Despite increasingly intensive remission induction therapy, similar response rates were achieved in the three trials and no increase in the duration of survival was observed. Clinical attributes at presentation by multivariate analyses were not consistently predictable of outcome. Of the blast cell attributes, only PE2 was predictive of duration of survival (p less than 10(-6)). For patients in remission the relapse rate during the first year was 0.63 compared with 0.15 in subsequent years. The percentage marrow myeloblasts at presentation, a measure of disease activity, was significantly higher for the patients having remissions lasting less than one year. These studies demonstrate the importance of disease-related attributes on the outcome of patients with AML.

Topics: Actuarial Analysis; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Clinical Trials as Topic; Colony-Forming Units Assay; Cyclophosphamide; Cytarabine; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance; Humans; Leukemia, Myeloid, Acute; Middle Aged; Prognosis; Thioguanine; Time Factors; Vincristine

Short-term treatment with doxorubicin, cytarabine, and 6-thioguanine was given to 91 consecutive adults with acute myelogenous leukaemia. Fifty patients received high doses (regimen I) and 41 very high doses (regimen II). Where possible, six treatment cycles were given (total dose of doxorubicin 450 mg/m2) regardless of the number of cycles required to achieve complete remission. No additional treatment was given. The remission rate was significantly higher with regimen I than with regimen II (34/50 compared with 15/41, p less than 0.01), the latter, more intensive regimen being associated with a greater incidence of fatal infection (13/41 compared with 5/50, p less than 0.01). Duration of remission was, however, significantly longer with regimen II (p less than 0.05); the median has not yet been reached after a minimum follow-up of two years. Intensive short-term treatment is a feasible strategy for the treatment of acute myelogenous leukaemia.

Topics: Adolescent; Adult; Aged; Cytarabine; Doxorubicin; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Thioguanine

Topics: Adult; Aged; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Thioguanine

A trial of maintenance chemotherapy of nonlymphoblastic acute leukemia led to a comparison of two groups of patients in complete remission. Group 1 (14 patients) received only monthly reinduction chemotherapy. Group 2 (17 patients) received identical chemotherapy together with weekly immunotherapy combining BCG and irradiated leukemic cells. While the duration of the first complete remission was unmodified, the overall survival time and, above all, survival after the first relapse were prolonged in group 2 chemoimmunotherapy. These results were all the more marked when a homogeneous group of patients having received the same induction chemotherapy were considered.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Clinical Trials as Topic; Cytarabine; Daunorubicin; Female; Humans; Immunotherapy; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Leukocyte Count; Leukocytes; Male; Middle Aged; Mycobacterium bovis; Thioguanine

The effect of a synchronizing-recruiting drug schedule vs. myelotoxic therapy on remission rate and of Bacillus Calmette-Guerin on remission duration and survival of adults with acute myelogenous leukemia were studied in a prospective cooperative trial. After randomized remission induction with Arabinosyl Cytosine + vincristine + methotrexate + leucovorin (AVML), thioguanine + Ara-C + Daunorubin (TAD), or Daunorubicin + Ara-C (DA), complete remissions (CR) were consolidated with TAD or AVML. CRs were maintained with BCG vaccination (Tice strain) by the tine technique, or BCNU plus Ara-C (B/A), or no further therapy (NFT). Of 209 evaluable TAD patients, 105 (50%) achieved CR; of 187 DA, 97 (52%) achieved CR. AVML yielded only 15 CR among 59 patients (25%). The time to remission was significantly shorter with DA compared with TAD. Ninety-seven patients were randomized to maintenance therapy (35 B/A, 30 BCG, 32 NFT). There were no differences in remission duration (7, 8, 6 months) or survival (16, 22, 16 months, respectively). Manipulation of the cell cycle, as employed in this study, was not helpful. There may be a marginal effect of BCG, but our data fail to show a statistically significant benefit.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; BCG Vaccine; Clinical Trials as Topic; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Methotrexate; Middle Aged; Probability; Random Allocation; Thioguanine; Vincristine

Fifty-one adult patients with acute nonlymphocytic leukemia (excluding acute promyelocytic leukemia) were treated on the L-12 protocol. The L-12 differed from the preceding L-6 in that 2,2-anhydro-1-B-D-arabinofuranosyl-5-fluorocytosine (AAFC), replaced arabinosylcytosine (ara-C) together with 6-thioguanine (TG) for remission induction. Achievement of remission was followed by an extended 14-week multi-drug consolidation program. With this more intense regimen, an overall complete remission rate of 49% and a median remission duration of 23.7 months were achieved; these results were not significantly better than the 57% complete remission rate and 8.6 months median remission duration obtained with the L-6 regimen. Four year disease-free survival was 22% on the L-12 compared with 16% on the L-6 protocol. No relationship between prognosis and FAB classification was found on either the L-6 or the L-12 protocol.

Topics: Adolescent; Adult; Aged; Ancitabine; Antineoplastic Agents; Bacterial Vaccines; Cytarabine; Drug Therapy, Combination; Female; Humans; Leukemia; Leukemia, Myeloid, Acute; Male; Middle Aged; Prognosis; Pseudomonas aeruginosa; Random Allocation; Thioguanine

A complete remission rate of 82% was obtained in a group of 68 patients with acute myelogenous leukemia treated with a high-dose induction chemotherapy (TAD) consisting of 7-day courses of 6-thioguanine, cytarabine, and daunorubicin. The patients who achieved remission received intensive consolidation chemotherapy and were randomized to receive maintenance chemotherapy with or without immunotherapy. Median remission duration was 13 months and median survival, 21 months. Neither central nervous system prophylaxis nor the addition of immunotherapy to the maintenance regimen prolonged remissions or improved survival. Age, sex, and subclassification of acute myelogenous leukemia had no effect on the remission rate or survival. These data indicate that a large proportion of patients with acute myelogenous leukemia can achieve remission with intensive induction chemotherapy. Attempts to prolong remission have been less successful.

Topics: Adolescent; Adult; Age Factors; Aged; Antineoplastic Agents; Child; Cytarabine; Daunorubicin; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Sex Factors; Thioguanine

From 1976 until 1978, 136 adult patients with acute leukemia were treated in four hospitals in Berlin. A complete remission was achieved in 47 patients (35%). Twenty-six patients with non-lymphocytic acute leukemia, who had achieved a complete remission with induction chemotherapy consisting of daunorubicin (45 mg/m2/day, day 1, 2 and 3) and cytosine-arabinoside (100 mg/m2/day, continuous infusion, day 1 to day 7) were entered into a randomized trial. Thirteen patients were treated with an intermittent combination chemotherapy at 4-week intervals; the other group of patients received in addition a specific immunotherapy consisting of neuraminidase-modified allogeneic blast cells. The results revealed that the addition of this kind of immunotherapy did not increase the duration of first remission or survival.

Topics: Adolescent; Adult; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Immunotherapy; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Thioguanine; Vincristine

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Clinical Trials as Topic; Cytarabine; Drug Therapy, Combination; Humans; Infant; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Middle Aged; Prednisolone; Thioguanine

There has been substantial recent progress in the treatment of acute myelogenous leukemia (AML). Intensive induction chemotherapy with cytosine arabinoside and daunorubicin with or without 6-thioguanine will induce remission in over 70% of patients, with median remission of 1-2 years in most series. Attempts to prolong remissions with maintenance chemotherapy, immunotherapy, late intensification or central nervous system prophylaxis have been disappointing and there are no convincing data that these modalities are useful. Nevertheless, an increasing proportion of patients with AML have remissions of 3 or more years, and a small proportion may be cured.

Topics: Bone Marrow Transplantation; Clinical Trials as Topic; Cytarabine; Daunorubicin; Doxorubicin; Drug Administration Schedule; Drug Therapy, Combination; Graft vs Host Reaction; Humans; Immunotherapy; Leukemia, Myeloid, Acute; Middle Aged; Thioguanine; Time Factors

In order to determine whether the use of a sequence of chemotherapeutic regimens plus BCG could produce longer durations of remission in adult acute nonlymphocytic leukemia than maintenance therapy with cytosine arabinoside, 6-thioguanine, plus BCG, a randomized study was performed at Washington University. Upon achieving complete remissions with daunorubicin plus cytosine arabinoside, 14 patients were randomized to receive either: Regimen A--cytosine arabinoside, 6-thioguanine, plus BCG each month; or regimen B--sequential regimens consisting of: 1) azacytidine daily for five days; 2) cyclophosphamide plus cytosine arabinoside daily for four days, prednisone daily for five days, plus vincristine on the first day; 3) prednisone, 6-mercaptopurine, and methotrexate daily for five days plus vincristine on the first day; and 4) cytosine arabinoside, 6-thioguanine, plus BCG. Each of the sequential regimens was given during consecutive months, and the cycle was then repeated starting with the first regimen. Median duration of complete remission was 27 months for 8 patients randomized to receive Regimen A, compared to only seven months for 6 patients receiving Regimen B (P less than 0.05). The median survival time of patients on Regimen B was only 14 months, and has not yet been reached in Regimen A. At 40 months after diagnosis, 75% of patients on Regimen A remain alive (P less than 0.05). Toxicity was equal for the maintenance regimens. Therefore, maintenance therapy with cytosine arabinoside, 6-thioguanine, plus BCG may be superior to the sequence of chemotherapy regimens plus BCG which was employed.

Topics: Adolescent; Adult; BCG Vaccine; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Middle Aged; Prognosis; Thioguanine; Time Factors

These advances in chemotherapy and supportive care of the myeloid leukaemias offer substantially improved prospects for the future. At present the intensive treatment of acute and chronic myeloid leukaemia requires the resources of a specialist unit and as many patients as possible should now be referred for diagnostic classification and remission induction. Thereafter, courses of maintenance chemotherapy can be supervised jointly by the referring local physician and the specialist centre. This collaborative approach is to the mutual advantage of the patient, his local clinician, and the specialist centre.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Busulfan; Child; Clinical Trials as Topic; Cytarabine; Daunorubicin; Drug Administration Schedule; Drug Therapy, Combination; Humans; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Remission, Spontaneous; Thioguanine

194 adults with acute leukaemia were randomly allocated to be treated with a combination of daunorubicine, cytarabine and prednisone either with (RAP + T) or without (RAP) thioguanine. A remission was achieved in 37% of 101 patients treated with RAP and in 35% of 93 patients treated with RAP + T. The survival and length of remission were similar in both groups. Neither regimen was superior to the other in any type of leukaemia nor in any age group of patients. In 9 of the patients failing to remit with RAP treatment a remission was obtained with other chemotherapy, while none of the patients not responding to RAP + T achieved a remission with further chemotherapy.

Topics: Acute Disease; Adolescent; Adult; Aged; Cytarabine; Daunorubicin; Drug Administration Schedule; Drug Evaluation; Drug Therapy, Combination; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Middle Aged; Prednisone; Prognosis; Remission, Spontaneous; Thioguanine

Two hundred and fifty patients with acute myeloid leukaemia (AML) were randomized between 2 regimens of chemotherapy: TRAP and BARTS III. Overall, patients randomized to TRAP, which was the more intensive of the 2 regimens, fared slightly better (P = 0.06) than those on BARTS III. However, the improvement in survival associated with more intensive chemotherapy was substantial only for patients who had favourable prognostic features at presentation, such as a normal total leucocyte count, or absence of palpable liver, or, especially, age under 40. Indeed, for patients under 40, those allocated to the more intensive regimen (TRAP) lived considerably longer than those allocated to BARTS III (P less than 0.002) while for patients over 40 there was no material difference in survival between patients on the 2 protocols. It thus appears that intensive chemotherapy is likely to be more effective when favourable prognostic features are recorded.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Child; Child, Preschool; Clinical Trials as Topic; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Administration Schedule; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Mercaptopurine; Methotrexate; Middle Aged; Prednisolone; Random Allocation; Thioguanine; Vincristine

In this study 523 previously untreated patients with acute myelocytic leukemia were randomly allocated to induction therapy with daunorubicin 60 mg/M2 daily X 3, cytosine arabinoside and thioguanine 100 mg/M2 each every 12 hours until marrow hypoplasia was achieved, or a 5-day course of the three drugs with daunorubicin 100 mg/M2 given on dav 1 and cytosine arabinoside plus thioguanine each given at a dose of 100 mg/M2 every 12 hours for five days. All patients received cyclophosphamide 600 mg/M2 followed in 24 hours by hydroxyurea 500 mg/M2 every six hours for four doses monthly for maintenance therapy. Patients were randomized to receive one of three antimetabolite treatments beginning 24 hours after the last dose of hydroxyurea each month for seven days. One such treatment consisted of 6-mercaptopurine 100 mg/M2 daily, another group received 6-thioguanine at the same dose daily, and the third group received 50 mg/M2 of both antimetabolites daily. There were no significant differences in complete response rate, remission duration, or survival among the various treatment groups.

Topics: Adult; Age Factors; Aged; Antineoplastic Agents; Bone Marrow; Clinical Trials as Topic; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Administration Schedule; Drug Synergism; Drug Therapy, Combination; Female; Humans; Hydroxyurea; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Middle Aged; Remission, Spontaneous; Thioguanine

Treatment of older acute leukemia patients has been the subject of recent debate. We treated 101 acute leukemia patients in a prospective randomized trial. Fifty-seven per cent of the population was over 50. Half were treated with a mild induction program (VAMP) and half with a vigorous program (CAT). The older patients who received vigorous treatment did better than those who received mild treatment. We suggest that patients over 50 should be regarded as a separate category in design of treatment protocols in order to further maximize the benefits of therapy.

Topics: Age Factors; Aged; Antineoplastic Agents; Bone Marrow; Cytarabine; Depression, Chemical; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Mercaptopurine; Methotrexate; Middle Aged; Prednisone; Prognosis; Thioguanine; Time Factors; Vincristine

One hundred patients were entered in a cooperative study comparing the efficacy of two different regimens in the induction treatment of acute nonlymphocytic leukemia (ANLL). Patients were randomly allocated to receive either the DAT or VAT combination; half of the patients were also randomized to receive CNS prophylaxis including intrathecal methotrexate + prednisone and cranial irradiation. Consolidation and maintenance therapy were uniform in responding patients. Out of 82 evaluable patients 41 (50%) attained complete remission (CR) with no significant difference between the two regimens. Median remission duration was slightly longer in the DAT group (32.5 vs 22 weeks); median survival was 34 weeks for all evaluable patients with no difference between the two schedules. Meningeal relapse occurred only in two patients after 19 and 99 weeks of continuous remission. Fourteen patients are still alive after 61 to greater than or equal to 155 weeks, of whom seven are in their initial remission (six in the DAT and one in the VAT group). We conclude that 1) DAT and VAT are equally effective in inducing CR in a high proportion of ANLL patients; 2) until marrow remission can be prolonged significantly, preventing CNS leukemia will not have any significant impact of the course of ANLL.

Topics: Adolescent; Adult; Antineoplastic Agents; Child; Child, Preschool; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Meningeal Neoplasms; Methotrexate; Middle Aged; Prednisone; Remission, Spontaneous; Thioguanine; Time Factors; Vincristine

Sixty-six newly diagnosed patients with acute nonlymphocytic leukemia received either daunorubicin alone or a combination of daunorubicin, cytosine arabinoside, 6-thioguanine, and pyrimethamine for remission-induction therapy. The two treatment groups were comparable with respect to the two major prognostic factors in this disease, which were age and presence or absence of infection on admission. The two therapies produced similar results with respect to CR rate and median survival results. Single-agent therapy was associated with less frequent utilization of hospital inpatient facilities and fewer platelet transfusions. The four-drug combination did not decrease the incidence of meningeal leukemia. Patients who achieved CR were treated with two half-dose consolidation courses of the successful remission-induction regimen. Subsequently, all patients received cyclophosphamide and guanazole monthly for maintenance therapy. Median durations of remission for both induction-treatment groups were similar (6.8 and 5.6 mos). The therapeutic results with the single agent in this study were not inferior to those obtained with the drug combination tested, as well as most other previously reported combinations of antileukemic drugs.

Topics: Acute Disease; Aged; Antineoplastic Agents; Bone Marrow; Central Nervous System Diseases; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Guanazole; Humans; Leukemia; Leukemia, Myeloid, Acute; Male; Meninges; Middle Aged; Pyrimethamine; Remission, Spontaneous; Skin Tests; Thioguanine

Three hundred twenty-six patients with acute myelocytic leukemia were randomly and prospectively assigned to four therapeutic regimens: cytosine arabinoside either alone or in combination with daunorubicin, 6-mercaptopurine, or 6-thioguanine. The results in 231 qualified previously untreated patients were analyzed. The combination treatments produced a significantly greater frequency of complete or partial remission than single drug therapy. Treatment with cytosine arabinoside and thioguanine led to 48% age-adjusted complete and partial responses. The median sur survival from diagnosis of all 66 evaluable patients treated with these two drugs was 18 weeks, while the median survival for those who responded to this combination was 15 months.

Topics: Adult; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Middle Aged; Remission, Spontaneous; Thioguanine; Time Factors

Topics: Bone Marrow; Bone Marrow Cells; Cytarabine; Daunorubicin; DNA, Neoplasm; Drug Therapy, Combination; Humans; Kinetics; Leucovorin; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Methotrexate; Mitotic Index; Thioguanine

Topics: Administration, Oral; Adolescent; Adult; BCG Vaccine; Cyclophosphamide; Cytarabine; Daunorubicin; Humans; Immunotherapy; Injections, Intravenous; Leukemia, Myeloid, Acute; Methotrexate; Middle Aged; Remission, Spontaneous; Thioguanine; Time Factors; Vincristine

Topics: Bone Marrow Examination; Cytarabine; Daunorubicin; Drug Therapy, Combination; Guanidines; Humans; Intensive Care Units; Leukemia, Myeloid, Acute; Leukocyte Count; Mitoguazone; Remission, Spontaneous; Thioguanine; Time Factors

Topics: Adolescent; Adult; Age Factors; Aged; Asparaginase; Blood Platelets; Child; Clinical Trials as Topic; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Leukocyte Count; Lymphocytes; Male; Mercaptopurine; Middle Aged; Prednisone; Prognosis; Remission, Spontaneous; Thioguanine; Thrombocytopenia

Consecutive adult patients admitted to St. Bartholomew's Hospital with acute myelogenous leukaemia have been treated with a remission induction drug schedule consisting of daunorubicin and cytosine arabinoside. Intermittent five-day courses were used in 72 patients, and a complete remission was obtained in 39 patients (54%). An alternative drug schedule in 22 patients resulted in fewer remissions but this may have been due to age differences in the two groups. Age and initial platelet count were found to be important factors in determining the success of remission induction therapy; the older patients and those with low platelet counts responded less well.A series of 23 patients who achieved remissions was divided into two groups; one received intermittent combination chemotherapy as the only form of maintenance, and the other was given weekly immunotherapy in addition to the chemotherapy. The immunotherapy consisted of irradiated allogeneic leukaemic cells and B.C.G. Eight of the 10 patients on chemotherapy alone have already relapsed compared with five out of 13 patients in the immunotherapy group. It is hoped that these promising initial results with this form of maintenance will be confirmed as more patients enter the maintenance trials.

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aged; Antineoplastic Agents; BCG Vaccine; Blood Cell Count; Blood Platelets; Child; Cytarabine; Daunorubicin; Humans; Immunotherapy; Leukemia, Myeloid, Acute; Mercaptopurine; Methotrexate; Middle Aged; Remission, Spontaneous; Thioguanine

Topics: Adolescent; Adult; Aged; Amidines; Antineoplastic Agents; Child; Cytarabine; Daunorubicin; Drug Therapy, Combination; Evaluation Studies as Topic; Glyoxal; Humans; Hydrazones; Leukemia, Myeloid, Acute; Middle Aged; Remission, Spontaneous; Thioguanine

The prognosis of AML in elderly patients is poor and research into novel therapeutic approaches is urgently needed. This study examined the use of low-dose chemotherapy with cytarabine and thioguanine administered in repetitive cycles in 62 elderly patients with newly diagnosed or relapsed/refractory AML. The overall response rate was 58% in the total cohort. Response rates (CR/CRi) were significantly higher in patients with newly diagnosed AML (74%) compared to patients with relapsed/refractory disease (25%,

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Humans; Leukemia, Myeloid, Acute; Neoplasm Recurrence, Local; Remission Induction; Retrospective Studies; Thioguanine; Treatment Outcome

Topics: Adult; Aged; Aged, 80 and over; Alleles; Antineoplastic Combined Chemotherapy Protocols; Chromosome Aberrations; Cytarabine; Daunorubicin; Etoposide; Female; Gene Expression; Genetic Predisposition to Disease; Humans; Idarubicin; Leukemia, Myeloid, Acute; Male; Middle Aged; Polymorphism, Single Nucleotide; Prognosis; Retrospective Studies; Survival Analysis; Thioguanine; Tumor Suppressor Protein p53

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cytarabine; Cytogenetic Analysis; Etoposide; Female; fms-Like Tyrosine Kinase 3; Follow-Up Studies; Humans; Idarubicin; Leukemia, Myeloid, Acute; Male; Middle Aged; Mutation; Neoplasm Staging; Nuclear Proteins; Nucleophosmin; Prognosis; Survival Rate; Thioguanine; Young Adult

Clinical trials in pediatric acute myeloid leukemia (AML) determine induction regimen standards. However, these studies lack the data necessary to evaluate mortality trends over time and differences in resource utilization between induction regimens. Moreover, these trials likely underreport the clinical toxicities experienced by patients.. The Pediatric Health Information System database was used to identify children treated for presumed de novo AML between 1999 and 2010. Induction mortality, risk factors for induction mortality, and resource utilization by induction regimen were estimated using standard frequentist statistics, logistic regression, and Poisson regression, respectively.. A total of 1686 patients were identified with an overall induction case fatality rate of 5.4% that decreased from 9.8% in 2003 to 2.1% in 2009 (P = .0023). The case fatality rate was 9.0% in the intensively timed DCTER (dexamethasone, cytarabine, thioguanine, etoposide, and rubidomycin [daunomycin]/idarubicin) induction and 3.8% for ADE (cytarabine, daunomycin, and etoposide) induction (adjusted odds ratio = 2.2, 95% confidence interval = 1.1-4.5). Patients treated with intensively timed DCTER regimens had significantly greater antibiotic, red cell/platelet transfusion, analgesic, vasopressor, renal replacement therapy, and radiographic resource utilization than patients treated with ADE regimens. Resource utilization was substantially higher than reported in published pediatric AML clinical trials.. Induction mortality for children with AML decreased significantly as ADE use increased. In addition to higher associated mortality, intensively timed DCTER regimens had a correspondingly higher use of health care resources. Using resource utilization data as a proxy for adverse events, adverse event rates reported on clinical trials substantially underestimated the clinical toxicities of all pediatric AML induction regimens.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cohort Studies; Cytarabine; Daunorubicin; Dexamethasone; Etoposide; Female; Health Resources; Hospitals, Pediatric; Humans; Induction Chemotherapy; Infant; Leukemia, Myeloid, Acute; Logistic Models; Male; Odds Ratio; Poisson Distribution; Risk Assessment; Risk Factors; Thioguanine; Treatment Outcome; United States

Children with poor response acute myeloid leukaemia (AML) generally have a very poor outcome. Allogeneic stem cell transplantation (SCT) is often recommended for these children but the benefit is unclear. The aim of this study was to investigate survival for poor response AML patients treated with SCT.. Treatment was given according to the NOPHO-AML 2004 protocol. All patients received AIET (Cytarabine, Idarubicin, Etoposide, Thioguanine) and AM (Cytarabine, Mitoxantrone) as induction. We included poor response defined as > 15% blasts on day 15 after AIET (n = 17) or > 5% blasts after AM (n = 14, refractory disease). Poor response patients received intensively timed induction and proceeded to SCT when a donor was available.. Thirty-one of 267 evaluable patients (12%) had a poor response. SCT was performed in 25; using matched unrelated donors in 13, matched sibling donors in 6, cord blood donor in 4, and haploidentical donor in two. The median follow-up for the 31 poor responding patients was 2.6 years (range 0.4 - 8.1 years) and 3-year probability of survival 70% (95% CI 59-77%).. The poor responders in the NOPHO-AML 2004 protocol had a favourable prognosis treated with time-intensive induction followed by SCT.

Topics: Adolescent; Child; Child, Preschool; Cytarabine; Disease-Free Survival; Early Medical Intervention; Etoposide; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Histocompatibility Testing; Humans; Idarubicin; Induction Chemotherapy; Infant; Infant, Newborn; Leukemia, Myeloid, Acute; Male; Mitoxantrone; Myeloablative Agonists; Thioguanine; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome

Congenital leukemia is infrequent, occurring in <1% of pediatric leukemia patients, and mainly of myeloid lineage. Twenty-five to 30% of congenital leukemia cases present with cutaneous leukemic infiltrates. Rarely, infants will have aleukemic leukemia cutis, presenting with leukemic skin lesions but without systemic symptoms or bone marrow involvement. Few cases of congenital aleukemic leukemia cutis have been reported in the literature. The course of disease is variable as cases of spontaneous resolution have been described. Here we present the first report of siblings with progressive congenital aleukemic leukemia cutis, both treated successfully with myeloid leukemia chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Dexamethasone; Etoposide; Female; Humans; Infant, Newborn; Leukemia, Myeloid, Acute; Male; Siblings; Skin Neoplasms; Thioguanine

To evaluate the outcomes of acute myeloid leukemia patients who were older than 60 years of age at the time of diagnosis following the implementation of a treatment algorithm based on age, performance status, and cytogenetic results.. We retrospectively compared the results of 31 elderly acute myeloid leukemia patients (median age of 74 years) who were treated according to the new algorithm.. Fifteen patients with a good performance status and no unfavorable karyotypes were treated with either intensive cytotoxic chemotherapy (<70 years, nine cases) or adapted etoposide, 6-thioguanine and idarubicine (>70 years, six cases); 16 cases with a poor performance status or unfavorable cytogenetics received supportive care only. Six patients achieved a complete remission and two achieved a partial remission after chemotherapy. There were three toxic deaths during induction, two in the adapted etoposide, 6-thioguanine and idarubicine group and one in the intensive cytotoxic chemotherapy group. The overall median survival time was 2.96 months, 1.3 months in the supportive care group, and 4.6 months in the treatment group.. Our results illustrate the importance of treatment guidelines adapted to local resources in an attempt to improve the survival of elderly acute myeloid leukemia patients in developing countries.

Topics: Aged; Aged, 80 and over; Algorithms; Antineoplastic Combined Chemotherapy Protocols; Brazil; Cytogenetic Analysis; Etoposide; Female; Hospitals, University; Humans; Idarubicin; Leukemia, Myeloid, Acute; Male; Middle Aged; Palliative Care; Prognosis; Retrospective Studies; Thioguanine; Treatment Outcome

We investigated the outcome of idarubicin plus N(4)-behenoyl-1-beta-D-arabinofuranosyl cytosine (BHAC)-based chemotherapy (BHAC group, n=149) compared to idarubicin plus cytarabine-based chemotherapy (cytarabine group, n=191) for childhood acute myeloid leukemia (AML). Between January 1996 and December 2005, 340 children with AML from 5 university hospitals in Korea received the BHAC-based or cytarabine-based chemotherapy, with or without hematopoietic stem cell transplantation. After induction therapy, 264 (77.6%) of 340 children achieved a complete remission (CR) and 43 (12%) achieved a partial remission (PR). The CR rate in the BHAC group was higher than in the cytarabine group (85.2% vs. 71.7%, P=0.004). However, the overall response rate (CR+PR) was not different between the two groups (93.3% vs. 87.9%, P=0.139). The 5-yr estimates of overall survival (OS) of children in the two groups were similar (54.9% for the BHAC group vs. 52.4% for the cytarabine group, P=0.281). Although the results were analyzed according to the treatment type and cytogenetic risk, the OS showed no significant difference between the BHAC group and the cytarabine group. In the present study, the clinical outcomes of the BHAC-based chemotherapy, consisting of BHAC, idarubicin, and 6-TG, are comparable to that of the cytarabine-based chemotherapy for childhood AML.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Cytogenetics; Female; Hematopoietic Stem Cell Transplantation; Humans; Idarubicin; Infant; Infant, Newborn; Leukemia, Myeloid, Acute; Male; Republic of Korea; Retrospective Studies; Survival Analysis; Thioguanine; Young Adult

The purpose of this study was to assess the frequency of blood stream infections (BSIs) during neutropenia in different cycles of intensive chemotherapy treatment in acute myeloid leukemia (AML). The register data of 327 consecutive patients aged 16-66 years having de novo AML between September 1992 and December 2001 were prospectively gathered in five Finnish tertiary care leukemia centers. The patients had not received fluoroquinolone prophylaxis. Reported BSI rates were compared during neutropenia in four chemotherapy treatment cycles (C). There were 956 treatment episodes, with 456 (47.7%) positive blood cultures. BSI was monomicrobial in 327 episodes (71.7%) and polymicrobial in 129 (28.3%). The overall incidence rate (per 1,000 hospital days) for BSI was 13.2, varying from 6.8 in CI after idarubicin, conventional-dose cytarabine, and thioguanine to 15.6 in CII, 15.8 in CIII, and 17.6 in CIV. The distribution of monomicrobial gram-positive BSIs was as follows: CI, 71.7%; CII, 62.8%; CIII, 53.3%; CIV, 36.6%; and CI-IV together, 43.2%. The most common finding in the four different cycles was coagulase-negative staphylococci (38.3 to 30.6%). Viridans group streptococci were most commonly observed (in 20.4% of positive blood cultures) during CII after high-dose cytarabine and idarubicin treatments. The distribution of monomicrobial gram-negative BSIs was as follows: CI, 21.7%; CII, 36.3%; CIII, 45.7%; CIV, 46.9%; and CI-IV together, 37.9%. A great variation of incidence and types of microorganisms between AML chemotherapy cycles was found. It would be more reasonable to analyze chemotherapy cycle-based BSI results rather than the overall results.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Bacteria; Blood; Cytarabine; Female; Finland; Humans; Idarubicin; Incidence; Leukemia, Myeloid, Acute; Male; Middle Aged; Neutropenia; Prospective Studies; Sepsis; Thioguanine; Young Adult

Testicular relapse of acute myeloid leukemia without bone marrow involvement is a rare event. We describe a case of an 18-year-old male who had an isolated testicular relapse 86 months (7.2 years) from original diagnosis. He was treated with surgery only, without adjuvant therapy. The patient then developed central nervous system involvement 9 months later. Fluorescence in situ hybridization and immunohistochemistry were used to establish the diagnosis of a relapse rather than a new leukemic process. He was treated with intrathecal chemotherapy and systemic reinduction, followed by a stem cell transplant. This patient had a 7.2-year period between original diagnosis and the testicular relapse of acute myeloid leukemia.

Topics: Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Child; Cytarabine; Daunorubicin; Humans; Immunoenzyme Techniques; In Situ Hybridization, Fluorescence; Injections, Spinal; Leukemia, Myeloid, Acute; Male; Neoplasm Recurrence, Local; Testicular Neoplasms; Thioguanine; Treatment Outcome

Second malignant neoplasms (SMNs) have become a concern in survivors of childhood malignancy. Although there are many reports describing SMN in patients treated for childhood cancer, salivary gland tumors rarely appear in these reports. Radiotherapy is a well-known risk factor for the development of secondary salivary gland malignancies after the treatment of childhood cancer. However, it is not well known whether chemotherapy itself treatment increases the risk of salivary gland malignancies. We report a child case with mucoepidermoid carcinoma of the submandibular gland as a SMN after chemotherapy alone for acute myeloid leukemia.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Busulfan; Carcinoma, Mucoepidermoid; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Etoposide; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Image Processing, Computer-Assisted; Leukemia, Myeloid, Acute; Male; Neck Dissection; Neoplasms, Second Primary; Positron-Emission Tomography; Submandibular Gland Neoplasms; Thioguanine; Tomography, X-Ray Computed; Transplantation Conditioning

The association of acute leukemia and multiple myeloma (MM) has been usually described not only as a complication of chemotherapy but also in the absence of chemotherapy or together at the time of diagnosis. Such leukemias are typically acute myeloid leukemia (AML). The myelomonocytic subtype is particularly found.. We report a case of a 68-year-old female who developed AML 2 years after the diagnosis of light chain (kappa) myeloma. She had been treated with oral melphalan and prednisone for MM. The patient was treated with an anthracycline-lacking therapy consisting of etoposide 120 mg/m2, thioguanine 100 mg/m2 orally twice daily on 1-5 days, and cytarabine 40 mg/m2 subcutaneously on day 1 (ETC) because of poor cardiac performance.. Following ETC therapy our particular patient has been in complete hematologic remission for 29 months. This therapy might be a safe alternative in secondary leukemia especially for elderly patients.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Drug Administration Schedule; Etoposide; Female; Humans; Injections, Subcutaneous; Leukemia, Myeloid, Acute; Multiple Myeloma; Remission Induction; Thioguanine

Myelodysplastic syndromes (MDS) in childhood are rare hematologic diseases. MDS with t(3;5) (NPM/MLF1) is an unusual subtype without a well-defined clinical and prognostic pattern. A poor outcome has been reported, suggesting that hematopoietic transplantation is the only treatment option. Here in we described a 2-year-old child diagnosed with the disease, without a suitable hematopoietic donor, treated early in the disease with chemotherapy. He is alive and well 4 years after the end of treatment. This unusual MDS needs further studies to better understand the disease.

Topics: Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Chromosomes, Human, Pair 3; Chromosomes, Human, Pair 5; Cyclophosphamide; Cytarabine; Doxorubicin; Humans; Leukemia, Myeloid, Acute; Male; Methotrexate; Oncogene Proteins, Fusion; Prednisone; Thioguanine; Translocation, Genetic; Treatment Outcome; Vincristine

Acute Myelogenous Leukemia (AML) is a common disease in people aged>60 years. About 50% of the patients are not eligible for aggressive chemotherapy (CT) and are only managed with conservative approaches. Results in this subset of patients have not been reported so far.. We retrospectively evaluated 244 consecutive elderly AML patients (M/F 143/101, median age 72 years, range 60-90) diagnosed at our institution from January 1989 to December 1998 and not eligible for intensive CT. Eighty-nine patients (36.5%) had evolved from previous myelodysplasia (sAML). Fifty-three out of 192 (26.4%) patients with available bone marrow (BM) analysis had oligoblastic leukaemia (blasts<40% and WBC<15x10(9)/l).. Sixty-seven patients (27.5%) were managed with supportive treatment only. One hundred seventy-seven patients (72.5%), in order to control disease, received conservative CT, consisting of Hydroxyurea (HU) (127 patients, 71.7%), Cytarabine and 6-Thioguanine (39 patients, 22%) or low-dose cytarabine (11 patients, 6.3%). Median overall survival was 179 days (1-3278) with 50 patients (20.5%) surviving>12 months. Older age (>75 years), poor WHO PS (>2), lower PLT levels (<50x10(9)/l) and higher absolute peripheral blast count (>5x10(9)/l) showed a negative prognostic impact on survival in multivariate analysis.. Our data outline the great heterogeneity of elderly AML patients not eligible for intensive CT. A simple scoring system including easily evaluable parameters, which could distinguish subjects with different prognosis, is proposed. Moreover, randomized studies in order to establish best conservative approaches are warranted.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Cytarabine; Female; Health Services for the Aged; Humans; Hydroxyurea; Leukemia, Myeloid, Acute; Male; Middle Aged; Palliative Care; Quality of Life; Retrospective Studies; Survival Analysis; Thioguanine

We previously found that 8-oxo-7,8-dihydro-2'-deoxyguanosine (oh(8)dG) kills KG-1, a human myelocytic leukemic cell line with mutational loss of 8-oxoguanine glycosylase (OGG1) activity in vitro. This observation prompted us to investigate the cytotoxicity of oh(8)dG on KG-1 in vivo. This cytotoxicity was observed by administrating oh(8)dG (3.3-330mg/kgb.w./day) for 14 days into nude mice bearing a KG-1 myelosarcoma. The results were as follows; oh(8)dG inhibited the growth of KG-1 myelosarcoma dose-dependently in terms of tumor size and weight, but had no effect on the growth of myelosarcoma of U937, a human monocytic leukemic cell line possessing wild-type OGG1. 6-Thioguanine (6-TG), an anticancer drug inhibited the growths of KG-1 and U937 tumors. 2'-Deoxyguanosine (dG) had a statistically insignificant anti-growth effect on both tumors. The oh(8)dG-treated KG-1 tumor showed the increased expression of apoptosis-processing caspases 8, 9 and 3 together with DNA fragmentation, the increased expression of cell cycle inhibitors, p16 and p27, and the decreased expression of cell cycle accelerator, cyclins and cdks, indicating the nature of cytotoxicity is cell cycle arrest and apoptosis. The genomic DNA of oh(8)dG-treated KG-1 tumors showed an increase in OGG1 sensitive sites, which is consistent with an increase in the 8-oxo-7,8-dihydroguanine (oh(8)Gua) level in the DNA of KG-1 treated with oh(8)dG in vitro. Presumably an increased level of oh(8)Gua in DNA may trigger the cytotoxicity. These findings suggest that oh(8)dG is selectively cytotoxic to KG-1 or tumors that are OGG1-deficient.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Apoptosis; Blotting, Western; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Deoxyguanosine; Disease Models, Animal; DNA; Dose-Response Relationship, Drug; Humans; Leukemia, Myeloid, Acute; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Structure-Activity Relationship; Thioguanine; Time Factors; Transplantation, Heterologous; U937 Cells; Xenograft Model Antitumor Assays

Topics: Antineoplastic Combined Chemotherapy Protocols; Colitis; Colon; Cytarabine; Daunorubicin; Dexamethasone; Etoposide; Female; Gastrointestinal Hemorrhage; Humans; Immunohistochemistry; Infant; Leukemia, Myeloid, Acute; Leukemic Infiltration; Leukocyte Common Antigens; Peroxidase; Sigmoidoscopy; Thioguanine

Children with Down syndrome (DS) have an increased risk for leukemia. The prognosis for DS acute myeloid leukemia (AML) is better than for non-DS AML, but the clinical outcome of DS acute lymphoblastic leukemia (ALL) is equal to that of non-DS ALL. Differences in prognosis may reflect differences in cellular drug resistance. In vitro drug resistance profiles were successfully investigated on leukemic cells from 13 patients with DS AML and 9 patients with DS ALL and were compared with reference data from 151 non-DS AML and 430 non-DS B-cell precursor (BCP) ALL. DS AML cells were significantly more sensitive to cytarabine (median, 12-fold), the anthracyclines (2-7-fold), mitoxantrone (9-fold), amsacrine (16-fold), etoposide (20-fold), 6-thioguanine (3-fold), busulfan (5-fold), vincristine (23-fold), and prednisolone (more than 1.1-fold), than non-DS AML cells. Compared with DS ALL, DS AML cells were significantly more sensitive to cytarabine only (21-fold). After short-term exposure to methotrexate, DS AML cells were 21-fold more resistant than non-DS AML cells, but no difference was observed after continuous exposure. DS ALL cells and non-DS BCP-ALL cells were equally sensitive to all drugs, including methotrexate. Normal peripheral blood mononuclear cells from DS and non-DS children without leukemia showed highly resistant drug profiles. It was concluded that the better prognosis of DS AML might, at least partially, be explained by a specific, relatively sensitive drug-resistance profile, reflecting the unique biology of this disease. (Blood. 2002;99:245-251)

Topics: Amsacrine; Anthracyclines; Antineoplastic Agents; Busulfan; Cell Survival; Child; Child, Preschool; Cytarabine; Down Syndrome; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Etoposide; Female; Humans; Infant; Leukemia, Myeloid, Acute; Male; Mitoxantrone; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prognosis; Thioguanine; Vincristine

Three adult de novo acute myeloid leukemias (AML M1, M2, and M4) with an isochromosome 7p are presented. No additional abnormalities were detected by G-band and multicolor, using combined binary ratio labeling, fluorescence in situ hybridization (FISH) analyses, indicating that the i(7p) was the sole, i.e., the primary, chromosomal aberration. Although the patients were elderly--68, 72, and 78 years old--they all responded very well to chemotherapy, achieving complete remission lasting more than a year. Further FISH analyses, using painting, centromeric, as well as 7q11.2-specific YAC probes, revealed that the i(7p) contained two centromeres and that the breakpoints were located in 7q11.2. Thus, the abnormality should formally be designated idic(7)(q11.2). The detailed mapping disclosed a breakpoint heterogeneity, with the breaks in 7q11.2 varying among the cases, being at least 1,310 kb apart. Furthermore, the breakpoints also differed within one of the cases, being located on both the proximal and the distal side of the most centromeric probe used. Based on our three patients, as well as on a previously reported 82-year-old patient with AML M2 and idic(7)(q11) as the only chromosomal change, we suggest that this abnormality, as the sole anomaly, is associated with AML in elderly patients who display a good response to induction chemotherapy and, hence, have a favorable prognosis. Furthermore, the heterogeneous breakpoints in 7q11.2 suggest that the important functional outcome of the idic(7)(q11.2) is the genomic imbalance incurred, i.e., gain of 7p and loss of 7q material, rather than a rearrangement of a specific gene.

Topics: Aged; Aged, 80 and over; Aging; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chromosome Banding; Chromosomes, Human, Pair 7; Cytarabine; Female; Humans; Idarubicin; In Situ Hybridization, Fluorescence; Isochromosomes; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Male; Remission Induction; Thioguanine

Topics: Adult; Alleles; Antineoplastic Agents; Heterozygote; Humans; Leukemia, Myeloid, Acute; Male; Methyltransferases; Mutation; Thioguanine

We report on a 49 year old female with primary extra-medullary manifestation of a acute myeloid leukemia in the lungs without leukemic signs. The disease was diagnosed by detection of leukemic blast cells in bronchoalveolar lavage. Chemotherapy with the TAD-VP-scheme resulted in partial remission. The patient died in systemic early relapse. To our knowledge this is the first description of primary isolated extra-medullary manifestation of a acute myeloid leukemia in the lungs.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Bronchoalveolar Lavage Fluid; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Middle Aged; Prednisolone; Radiography; Thioguanine; Vincristine

Topics: Antineoplastic Agents; Blast Crisis; Cell Survival; Child; Cytarabine; Dexamethasone; Down Syndrome; Doxorubicin; Etoposide; Humans; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine; Treatment Outcome; Tumor Cells, Cultured

Severe infections are a major problem in patients suffering from acute nonlymphocytic leukemia (ANLL) undergoing myeloablative chemotherapy. Possible factors leading to infectious complications in these patients are suppressed immune defense mechanisms existing prior to therapy, including those involving the neutrophil granulocyte department. In this study we investigated whether neutrophil function as measured by oxidative burst and phagocytosis before the start of treatment correlates with the severity of infection after therapy. Forty-four patients were included, 27 men and 17 women. Their median age was 46 years (range 20-70 years). According to the development of infectious complications the patients were assigned retrospectively to group 1 (no or only mild infections, n = 29) or to group 2 (severe infection or death due to infection, n = 15). The phagocytic activity was significantly reduced in group 2 as compared with group 1 [113.7+/-13.7 (SEM) vs 170.0+/-19.2, mean channel fluorescence; p =0.04]. In contrast, the oxidative burst as measured by FMLP stimulation was pronounced but not significantly enhanced in group 2 (24.8+/-6.1 vs 14.5+/-3.4, mean channel fluorescence). In conclusion, patients with severe infections after chemotherapy might already have preactivated neutrophils with suppressed function prior to treatment. Thus, evaluating function parameters could help to estimate the individual risk of infection for a patient with ANLL.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Fever; Humans; Idarubicin; Immunocompromised Host; Infections; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Middle Aged; Mitoxantrone; N-Formylmethionine Leucyl-Phenylalanine; Neutropenia; Neutrophils; Phagocytosis; Respiratory Burst; Retrospective Studies; Risk Factors; Thioguanine; Vidarabine

Splenic rupture is a rare but well-recognized complication of hematological malignancies. Here, we present the case of a 22-year-old woman with the diagnosis of acute myeloid leukemia who was undergoing peripheral blood stem cell transplantation. On day + 10 she developed a hypovolemic shock due to rupture of her spleen and went to emergency laparotomy. This is the first report of splenic rupture during peripheral blood stem cell transplantation.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Combined Modality Therapy; Cytarabine; Doxorubicin; Fatal Outcome; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematoma; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Puerperal Disorders; Remission Induction; Rupture, Spontaneous; Shock; Splenic Rupture; Thioguanine

Activity of BCL-2 protein may be antagonised by BAX protein expression, thereby affecting cellular sensitivity to chemotherapeutic drugs. We analysed the BCL-2 protein expression of blast cells from 19 patients by flow cytometry and immunocytochemistry. This was compared to in vitro sensitivity to the anthracyclines and antimetabolites using the MTT assay. We found a significant correlation between BCL-2 expression and in vitro response to two antimetabolite drugs. One of 7 patients (14%) whose cells were sensitive to ara-C expressed BCL-2 compared to 4/4 patients (100%) whose cells were resistant to ara-C in vitro (p = 0.05). Furthermore, none of the three patients whose cells were sensitive to 6-TG expressed BCL-2 compared to 6/9 patients (67%) whose cells were resistant in vitro (p = 0.045). We found no other correlation between BCL-2 expression and any other chemotherapeutic drug analysed. The ratio of BCL-2 to BAX may be more relevant clinically, therefore cells from a further 9 patients were analysed for both proteins. Whilst there was no overall relationship between BCL-2/BAX ratios and sensitivity to ara-C and 6TG, individual patients could be identified whose blast cells were resistant to ara-C and had high BCL-2/BAX ratios. Further analysis of the significance of these ratios to drug resistance may be of future prognostic value.

Topics: Apoptosis; bcl-2-Associated X Protein; Blast Crisis; Bone Marrow Cells; Cytarabine; Flow Cytometry; Humans; Immunohistochemistry; Leukemia, Myeloid, Acute; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Thioguanine

Since May 1996 all Nordic countries have been participating in a study of childhood acute myeloid leukemia (AML). The aim is to correlate the in vitro sensitivity of leukemic cells and individual plasma concentrations of cytotoxic drugs with clinical effect. Blast cells from bone marrow and/or peripheral blood are tested against a panel of cytotoxic agents using the fluorometric microculture cytotoxicity assay (FMCA). Plasma concentrations of cytotoxic drugs are analysed during induction therapy. Bone marrow samples from the participating centres generally reached the analysing laboratory within 24 hours. 61 out of 71 (86%) samples were successfully analysed, 47 de novo AML and 14 relapses. Relapsing patients tended to have a more resistant test profile than newly diagnosed patients. Steady state plasma levels of doxorubicin, etoposide and 6-thioguanine nucleotide varied about 10-fold between patients. The intra-individual variation was much less, suggesting that dose adjustment based on pharmacokinetic data might be useful in the future.

Topics: Amsacrine; Antineoplastic Agents; Blast Crisis; Bone Marrow; Cell Survival; Child; Cytarabine; Doxorubicin; Drug Screening Assays, Antitumor; Erythrocytes; Etoposide; Humans; Leukemia, Myeloid, Acute; Recurrence; Scandinavian and Nordic Countries; Thioguanine

To evaluate the prognostic significance of CD7 expression in de novo acute myeloid leukemia (AML), we studied 63 patients with AML who had been admitted to our hospital between September 1989 and January 1996. Even of the patients were later eliminated from the study (9 due to insufficient surface marker analyses, and 2 due to early death). The remaining 52 patients (median age: 42.5 years) were evaluated for morphologic subtype, immunophenotypic classification, complete remission (CR), disease-free survival (DFS) and overall survival (OS). All 52 patients were grouped by the French-American-British classification system: 10 as M1, 16 as M2, 11 as M3, 8 as M4, 5 as M5, and 2 as M6. Ten of the patients expressed CD7 on their leukemia cells (positive rate > or = 25) and were classified as CD7(+)AML, with morphological subtypes as follows: 3 as M1, 6 as M2, and 1 as M3. Thirty-three of the 42 patients with CD7 + AML (78.6%) and 6 of the 10 patients with CD7 + AML (40%) achieved CR. DFS and OS rates for the patients with CD7(+)AML were 22.1% and 35.4%, respectively; those for the CD7(+)AML patients were 53.3% and 44.4%, respectively. No significant differences in gender hematological findings, clinical manifestations such as hepatosplenomegaly, lymphadenopathy, or incidence of central nervous system involvement, CR rate, and DFS distinguished patients with CD7(+)AML from those with CD7(+)AML. These suggest that CD7 expression is unlikely to be a prognostic factor in AML.

Topics: Adolescent; Adult; Aged; Antigens, CD7; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Child, Preschool; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Middle Aged; Prednisolone; Prognosis; Survival Rate; Thioguanine; Tretinoin

Topics: Adult; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Bone Marrow Purging; Bone Marrow Transplantation; Crohn Disease; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Thioguanine; Transplantation, Homologous

Bcl-2 over-expression has been shown to inhibit apoptosis induced by a variety of stimuli, whereas a predominance of Bax alpha to Bcl-2 accelerates apoptosis upon apoptotic stimuli. We sought to study the relevance of these apoptotic regulating gene products in leukaemia. In a panel of leukaemia and lymphoma cell lines (HL60, DoHH2, CEM C7, L1210 and S49), the Bax alpha-to-Bcl-2 ratio as assessed by Western-blot analysis correlated with sensitivity to dexamethasone treatment. In addition, in HAbax alpha-transfected CEM C7 clones, a similar correlation was found for dexamethasone and thapsigargin sensitivity. In bone-marrow aspirates from patients with childhood acute lymphoblastic or myelocytic leukaemia (ALL, n = 48; AML, n = 8), the Bcl-2 and Bax alpha levels were highly variable, but well within the range found in the Bax alpha transfectants and in the established cell lines. Bcl-2 levels were lower in T- than in B-lineage ALL, which could be ascribed to simultaneous inverse relation between Bcl-2 and WBC. By contrast, Bax alpha:Bcl-2 was independent of any presenting feature and was largely dependent on Bax alpha levels. Results suggest that Bax alpha:Bcl-2, rather than Bcl-2 alone is important for the survival of drug-induced apoptosis in leukemic cell lines and ALL.

Topics: Apoptosis; bcl-2-Associated X Protein; Child; Dexamethasone; Humans; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Thioguanine; Tumor Cells, Cultured

We have previously described a case of clonality switch in a female patient with acute myeloid leukemia (AML) by X-chromosome inactivation analysis. She presented with refractory anemia with excess blasts in transformation but soon progressed to overt AML. Following induction chemotherapy, she went into complete remission but later relapsed into a second myelodysplastic phase. Analysis of her X-linked DNA polymorphism patterns at presentation and relapse showed that hematopoiesis was clonal, but the genotypes of the two clones was different. She remains clinically well and has a virtually normal blood count more than 5 years from presentation. We now report an update of this unique case and discuss the implications of this finding within the context of a multicellular origin of leukemia.

Topics: Adult; Anemia, Refractory, with Excess of Blasts; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Bone Marrow; Clone Cells; Cyclophosphamide; Cytarabine; Daunorubicin; Disease Progression; Dosage Compensation, Genetic; Female; Hematopoiesis; Heterozygote; Humans; Leukemia, Myeloid, Acute; Neoplastic Stem Cells; Prednisolone; Remission Induction; Thioguanine; Vincristine

The current study was undertaken to determine the relevance of leukemic blast cell proliferative activity, cellular parameters of Ara-C metabolism and the in vitro sensitivity to GM-CSF in association with the clinical response to TAD-9 induction therapy in 66 patients with de novo acute myeloid leukemia (AML). Proliferative activity was assessed by 3H-thymidine (3H-TdR) incorporation and thymidine kinase (TK) activity, parameters of Ara-C metabolism comprised the activities of deoxycytidine kinase (DCK) and DNA polymerase alpha (poly alpha) as well as Ara-CTP concentrations and 3H-Ara-C uptake into DNA. GM-CSF sensitivity was determined by in vitro incubation of blasts for 48 h with or without GM-CSF (100 U/ml) followed by an additional 4 h concurrent exposure to GM-CSF and 3H-TdR (0.5 microCi/ml). The following results were obtained as expressed by median values and ranges: 3H-TdR incorporation: 1.07 pmol/10(5) cells (0.0-10.1), TK: 7.3 pmol/min/mg protein (1.3-56.0), DCK: 9.3 pmol/min/mg protein (0.77-47.1), poly alpha: 1.7 pmol/min/mg protein (0.00-28.9), Ara-CTP: 53.3 ng/10(7) cells (13.3-211.0), 3H-Ara-C uptake: 0.06 pmol/10(5) cells (0.0-0.57). 3H-Ara-C uptake was correlated with 3H-TdR incorporation (r = 0.74) and with the (S-phase dependent) activities of TK (r = 0.73) and poly alpha (r = 0.71, but not with DCK activity or intracellular Ara-CTP content. Blast cells of 37 from 55 analyzed patients were found to be sensitive to GM-CSF stimulation as defined by an increase in 3H-TdR incorporation > or = 1.5-fold over control values after the 48 h GM-CSF exposure. In vitro data were related with clinical response to TAD-9 induction therapy in 43 patients with newly diagnosed AML, taking the blast cell reduction at day 10 or 16 to < 5% or > or = 5% residual blasts as early parameter for adequate or inadequate response, respectively. While neither 3H-Ara-C uptake, nor intracellular Ara-CTP concentration, TK nor DCK activity were predictive for response, a high 3H-TdR incorporation and a high poly alpha activity were associated with adequate blast cell reduction. Median values of 3H-TdR incorporation were 2.26 pmol/10(5) cells for patients with adequate blast cell clearance and 0.80 pmol/10(5) cells for patients with inadequate blast cell clearance (P = 0.11), the respective values for poly alpha were 3.22 pmol/min/mg protein for responders and 1.1 pmol/min/mg protein for non-responders (P = 0.0085).(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Cells; Cell Division; Cells, Cultured; Cytarabine; Daunorubicin; DNA Polymerase II; DNA, Neoplasm; Drug Screening Assays, Antitumor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukemia, Myeloid, Acute; Thioguanine

Topics: Adolescent; Adult; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cause of Death; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Thioguanine; Treatment Outcome

Experience with the use of cytotoxic drugs in the first trimester of pregnancy is limited. We report on the clinical phenotype and infantile development of a girl born to a 36-year-old mother. Before recognition of pregnancy, the latter had been treated for acute myelocytic leukaemia receiving cytarabine, daunorubicin and doxorubicin at conception and cytarabine and thioguanine at about 35-37 days post conception. At delivery, there were severe brachycephaly, hypoplasia of the anterior cranial base and the midface as well as synostoses of both coronal and metopic sutures. Further findings included bilateral four-finger hands with hypoplastic thumbs and absent radii. This phenotype is reminiscent of the Baller-Gerold syndrome. The child, at present 15 months old, has had to undergo two operations for fronto-orbital advancement because of insufficient growth of the mid-face, nasal airway hypoplasia and increased intracranial pressure. Motor milestones are slightly retarded--neurodevelopment is otherwise normal. These findings are discussed in the context of the few previous reports and are particularly important for future genetic counselling.

Topics: Abnormalities, Drug-Induced; Adult; Antineoplastic Combined Chemotherapy Protocols; Arm; Craniosynostoses; Cytarabine; Daunorubicin; Doxorubicin; Female; Humans; Infant, Newborn; Leukemia, Myeloid, Acute; Phenotype; Pregnancy; Pregnancy Complications, Neoplastic; Thioguanine

Patients with trisomy 21 have an increased incidence of haematological disorders, including neonatal 'leukaemoid reaction' (transient myeloproliferative disorder [TMD]), and acute leukaemias. In the past it has been felt that patients with trisomy 21 and acute leukaemia do not tolerate, and hence may not warrant, therapy as intensive as those without the syndrome. The present authors' experience and the current literature do not support this view. Two cases are reported of acute myeloid leukaemia in children with trisomy 21, successfully treated with intensive chemotherapy and bone marrow transplantation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child, Preschool; Combined Modality Therapy; Cytosine; Daunorubicin; Down Syndrome; Female; Follow-Up Studies; Health Care Rationing; Humans; Infant; Leukemia, Myeloid, Acute; Male; Thioguanine; Treatment Outcome

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Remission Induction; Thioguanine; Vincristine

The main clinical, morphological, cytochemical, immunological features and therapy results of eleven patients diagnosed as acute myeloblastic leukemia M0 (AML-M0) are reported here. There were no clinical characteristics, abnormalities on physical examination or initial laboratory parameters that distinguished these eleven patients. Bone marrow aspirates were hypocellular in four patients. The leukemic cells were undifferentiated by light microscopy and myeloperoxidase (MPO) and/or Sudan Black B (SBB) stains were negative in all cases. Myeloid differentiation antigens were present on the leukemic cells of all eleven patients, whereas B and T cell markers were clearly negative except for CD4 and CD7 antigens. Whatever the treatment employed survival was very short. Eight of the eleven patients were treated and two achieved complete remission (CR) but only one of them is alive in continuous CR. Our results like those previously reported, suggest that AML-M0 patients have a very poor prognosis with standard induction therapies and should perhaps be considered for experimental therapeutic approaches.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow; Chromosome Banding; Cytarabine; Daunorubicin; Doxorubicin; Female; Humans; Immunophenotyping; Leukemia, Myeloid, Acute; Lymphocytes; Male; Middle Aged; Peroxidase; Remission Induction; Thioguanine; Treatment Outcome

Thirty-four children with diagnosed cases of acute leukemias and being treated with cytotoxic chemotherapy at St James' Hospital, Leeds, were followed for between 6 months and 1 year to determine the changes in their oral microflora. They were examined before treatment commenced and then at monthly intervals. Swabs were taken from the oral cavity to test for the presence or absence of bacteria and Candida. Saliva samples were also used to assess the levels of Streptococcus mutans in the mouth. Sensitivity tests were carried out to assess the effect of the cytotoxic agents on the oral flora. All children received prophylactic nystatin and chlorhexidine gluconate mouthrinses four times daily for the whole period of the study. There was significant difference (p < 0.0001) for counts of S. mutans at different treatment stages. Sensitivity tests showed that S. mutans was sensitive to the cytotoxic drug daunorubicin, and this drug was probably responsible for the fall in S. mutans counts. A significant difference was also found in the types of bacteria isolated between the study and reference groups, but there was no change in the composition of the flora in the study group during treatment. These bacteria were also found to mirror those cultured from routine blood samples in children with acute leukemia.

Topics: Adolescent; Analysis of Variance; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bacterial Infections; Candida albicans; Candidiasis, Oral; Chi-Square Distribution; Child; Child, Preschool; Chlorhexidine; Colony Count, Microbial; Cytarabine; Daunorubicin; Etoposide; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Infant; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Methotrexate; Mouth; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Streptococcus mutans; Thioguanine; Trimethoprim, Sulfamethoxazole Drug Combination; Vincristine

A 6-year-old Turkish boy with bilateral orbito-ocular granulocytic sarcoma and AML is described. Cytogenetic studies on peripheral blood disclosed an abnormal hyperdiploid population with a double Ph chromosome. Despite intensive chemotherapy, he achieved only partial remission. Repeated cytogenetic studies on bone marrow during relapse revealed the persistence of double Ph chromosome. The aggressive course and the short survival time of this patient, despite adequate chemo-radiotherapy, may be explained by the presence of the double Ph chromosome.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Combined Modality Therapy; Cytarabine; Dexamethasone; Doxorubicin; Etoposide; Eye Neoplasms; Humans; Karyotyping; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Male; Methotrexate; Multigene Family; Neoplasms, Multiple Primary; Orbital Neoplasms; Philadelphia Chromosome; Thioguanine

The study included 68 children aged from 1 to 16 years treated for acute leukemias and bone marrow aplasia. Cytomegalovirus antigen (CMV) was detected by immunofluorescence in urinary sediment cells and in cell cultures after their inoculation with CMV. Besides, the activity of IgG and IgM classes of antibodies against CMV was determined. Presence of one or more markers of CMV infection was demonstrated in 31 children, i.e., 45.5%. In eight children (11.7%) clinical manifestation of CMV infection were demonstrable with fever, hepatitis, pneumonia, rash. In all the children who completed the treatment with hyperimmune globulin, regression of clinical symptoms and signs of CMV infection with the elimination of virus antigen from urine was achieved.

Topics: Adolescent; Anemia, Aplastic; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Cytomegalovirus Infections; Daunorubicin; Female; gamma-Globulins; Humans; Immune Tolerance; Immunization, Passive; Infant; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Male; Methotrexate; Opportunistic Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Thioguanine; Vincristine

The collection efficiency (CE) of the Fenwall CS3000 continuous flow blood cell separator in the apheresis of peripheral blood stem cells during haemopoietic recovery following myelosuppressive chemotherapy was analysed. Ninety-three apheresis were performed in 19 patients using procedure 3 on the Fenwal CS3000. The overall CE was calculated from the pre-apheresis cell counts and the stated blood volume processed. Instantaneous CE was calculated from cell counts in the inlet and return lines. The overall mononuclear cell and granulocyte-macrophage colony forming unit CE were 64.0% and 55.8%, respectively, significantly lower than the instantaneous CEs of 94.5% and 95.4%, respectively (P = 0.0001, t test, for both comparisons). Three factors unrelated to machine performance contributed to the lower overall CE despite a high instantaneous CE: (1) A fall in the patient's mononuclear cell counts during apheresis leading to an overestimation of the cells available for collection, (2) dilution of blood by anti-coagulant, and (3) the operational dead space of the Fenwal CS3000. The overall CE corrected for these 3 factors approximated the instantaneous CE closely. Thus there is little room for further enhancement of machine performance because the Fenwal CS3000 is already operating with a very high instantaneous CE. To achieve major improvement in the yield of peripheral blood stem cell harvests, more effective mobilization protocols and better timing of apheresis are required.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Blood Cells; Blood Component Removal; Blood Transfusion, Autologous; Bone Marrow Diseases; Cyclophosphamide; Cytarabine; Daunorubicin; Evaluation Studies as Topic; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Neoplasms; Thioguanine

Thirty-eight adults including 24 males and 14 females with acute nonlymphocytic leukemia were treated with DATV (Daunorubicin, Cytarabine, 6-thioguaninum, Vincristine) regimen from December 1987 to May 1991. The median age was 31 years old (range 13-54). The DATV regimen consisted of DNR 60 mg/day IV for 3 days; Ara-C 100 mg by continuous infusion every 12 hours for 7 days; 6-TG 150 mg PO for 7 days and VCR 2mg IV on day 1.. Complete remission (CR) was achieved in thirty-three of 38 patients after 1-2 courses (mean 1.3) with CR rates 86.8%. Five patients had no response to the regimen. Twenty-four of 33 patients who achieved CR are still in CR for 1-41 months with a median follow-up of 10 months.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Administration Schedule; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prospective Studies; Remission Induction; Thioguanine; Vincristine

Ninety-one patients with acute myelogenous leukaemia (AML) aged 17-59 years were treated with a chemotherapy programme which could be completed within 30 weeks for patients who achieved complete remission (CR). Four courses included daunorubicin, cytarabine and thioguanine, while two courses included amsacrine, etoposide and cytarabine. Sixty-five patients obtained CR (71%), more often in patients below (82%) than above (60%) 40 years of age (P = 0.03). Five patients underwent allogenic bone-marrow transplantation, and one patient received an autologous bone-marrow transplant after relapse. Five patients developed central nervous system leukaemia. The overall actuarial 3- and 5-year survival was 29% and 21%, respectively; for patients who obtained CR the corresponding survival rates were 40% and 30%, respectively. Patients below 40 years of age appeared to fare better (5-year survival 26%) than older patients (5-year survival 16%). The estimated disease-free survival rate was 26% at 3 years and 22% at 5 years. The main advantage of this regimen is that results compare favourably with those obtained with other regimens were achieved, without exposing patients to long periods of maintenance therapy.

Topics: Actuarial Analysis; Adolescent; Adult; Age Factors; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Examination; Bone Marrow Transplantation; Cause of Death; Combined Modality Therapy; Cytarabine; Daunorubicin; Etoposide; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Leukocyte Count; Middle Aged; Norway; Recurrence; Remission Induction; Survival Analysis; Survival Rate; Thioguanine

Topics: Abnormalities, Multiple; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Down Syndrome; Humans; Infant; Leukemia, Myeloid, Acute; Male; Remission Induction; Tetralogy of Fallot; Thioguanine

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Liver; Liver Failure, Acute; Mitoxantrone; Necrosis; Recurrence; Thioguanine

The expression of glutathione transferase pi (GST pi) was studied in leukemic cells from 60 patients with acute nonlymphoblastic leukemia at diagnosis and at progressing stages of the disease. A polyclonal rabbit antibody to human placental GST pi coupled with peroxidase antiperoxidase staining was used for immunodetection of GST pi on sections of routinely fixed bone marrow clots. All patients had received induction therapy based on an anthracycline and a standard dose of ara-C. The expression of GST pi at diagnosis was significantly correlated with response to induction therapy, duration of first remission, and overall survival. Twenty-nine of 36 samples of bone marrow from patients that entered complete remission (CR) following primary induction therapy showed a low expression, whereas nine of 16 sections from patients with resistant disease showed a high expression of GST pi (P less than or equal to 0.03). Of 40 sections that showed a low expression of GST pi, 29 (73%) were taken from patients that achieved a CR, whereas 12 of 19 sections that showed a high expression of the enzyme were from patients with resistant disease or that entered CR only after additional therapy (P less than or equal to 0.02). The median duration of first CR was 18.2 mo for patients whose cells showed a low expression of GST pi compared with 6.7 mo for those that entered CR in spite of a high expression of the enzyme (P less than or equal to 0.005). Of cells from ten patients that at the time of study were in a continuous first CR, none expressed high concentrations of GST pi. The expression of GST pi remained rather constant in most patients as the disease progressed to clinical resistance. At relapse there was no significant correlation between the expression of GST pi and treatment results but, of ten patients that entered a second CR or achieved a partial remission, only one showed a high expression of the enzyme. We conclude that there was a significant correlation between the expression of GST pi at the time of diagnosis and the subsequent treatment results and that GST pi is a useful marker for clinical resistance to cytostatic drugs in acute nonlymphoblastic leukemia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Glutathione Transferase; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prognosis; Recurrence; Remission Induction; Thioguanine; Time Factors

Both intensification therapies with high-doses ARA-C and bone marrow transplant, allogeneic (BMT) or autologous (ABMT), have proved effective in relapse prevention in ANLL. The present study combines both treatments. METHODS. Remission induction treatment was DAE combination. The first intensification consisted of HD ARA-C and mitoxantrone and the second HD ARA-C and AMSA. CNS prophylaxis consisted of 6 doses of i.t. ARA-C and MTX. Later, patients in remission with HLA-compatible donor received BMT and those without it, ABMT with "ex vivo" treatment of the bone marrow with ASTA-Z. Pre-BMT treatment was the same in both cases: fractionated total body irradiation (TBI) and cyclophosphamide in patients over 3 years of age; in patients under 3 busulfan was given instead of TBI. PATIENTS. Between April 88 and March 90, 18 patients (age 3 months to 14 years) were included. FAB subtypes were M1 + M2: 4; M3: 2; M4: 4; M5: 5; M6: 1; M7: 2. Two patients died of cranial haemorrhage before the 10th day, 15 achieved complete remission (CR) after one or two induction treatments and 1 only attained CR after the first intensification.. 1 patient with M7 relapsed after the 2nd intensification. Of the remaining 15, five received BMT and ten ABMT. Average interval between CR and transplant was 4 months (3 to 8). Of the 5 with BMT, one died from progressive obliterating bronchiolitis at 9 months and the other four continued in CR for 6 to 28 months. Of the 10 with ABMT none died from complications, 2 suffered early relapse and 8 continued in CR for 6 to 28 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Daunorubicin; Etoposide; Evaluation Studies as Topic; Female; Humans; Infant; Leukemia, Myeloid, Acute; Life Tables; Male; Methotrexate; Mitoxantrone; Remission Induction; Survival Rate; Thioguanine; Transplantation, Autologous; Transplantation, Homologous

96 consecutive acute myelogenous leukemia (AML) patients were analyzed retrospectively with regard to the regimen used for remission induction. 35 patients received daunorubicin for 3 days, cytosine arabinoside and 6-thioguanine for 7 days. 61 were treated with the same regimen but 6-thioguanine was replaced by etoposide. Complete remission was achieved in 57 and 72% of patients, respectively (p = 0.06). In leukemias with monocytic phenotype (M4-M5), the remission rate was significantly higher with the etoposide-containing regimen (p = 0.02). Our findings suggest that the replacement of thioguanine by etoposide could be useful in induction therapy of AML.

Topics: Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Evaluation; Etoposide; Humans; Leukemia, Myeloid, Acute; Remission Induction; Retrospective Studies; Thioguanine; Time Factors

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytosine; Daunorubicin; Humans; Ileal Neoplasms; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Thioguanine

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colony-Stimulating Factors; Cytarabine; Daunorubicin; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Humans; Leukemia, Myeloid, Acute; Middle Aged; Survival Rate; Thioguanine

Differentiation induction therapy provides an alternative therapeutic approach for patients with acute myeloid leukaemia (AML) who are either unsuitable for or unresponsive to conventional cytotoxic chemotherapy. The effect of a triple combination of retinoic acid (RA) + 6-thioguanine (6-Th) + hexamethylene bisacetamide (HMBA) on differentiation of blasts from 24 AML patients was studied. Nonadherent mononuclear cells were seeded at a concentration of 5 x 10(5) cells/ml in 24-well tissue culture plates containing RPMI-1640 culture medium with 20% fetal calf serum and 10% 5637-conditioned medium and incubated with 10(-6) M retinoic acid, 1.5 X 10(-6) M 6-thioguanine and/or 2 mM hexamethylene bisacetamide for six days at 37 degrees C in a humidified incubator under 5% CO2. Morphological, cytochemical and functional differentiation into mature cells were induced in blasts from 22 out of the 24 AML patients following exposure to the triple combination of 10(-6) M RA + 1.5 X 10(-6) M 6-Th + 2 mM HMBA in primary culture. These effective results justify a clinical trial of such triple combination for AML patients who are either unsuitable for or unresponsive to conventional cytotoxic chemotherapy.

Topics: Acetamides; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cell Differentiation; Drug Screening Assays, Antitumor; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Thioguanine; Tretinoin; Tumor Cells, Cultured

Response to salvage therapy at first and second relapse was analyzed in 150 patients with acute myeloid leukemia (AML) to improve the characterization of relapsed AML and to deduce from this analysis a proposal for the definition of refractoriness against conventional therapy. Salvage treatment consisted of a repetition of the TAD 9 regimen which was already applied as induction protocol at initial diagnosis. All patients were recruited from the multicenter 1982 trial of the German AML Cooperative Group and had thus received a standardized first line treatment. Response at first relapse was significantly related to the duration of the first remission. From 38 patients relapsing within 6 months after successful induction therapy, only 11 (28%) achieved a second complete remission as compared to 58 of 98 (59%) cases with later occurring relapses (p less than 0.01). This difference was due to a significantly higher incidence of persistent leukemia in the former group and not biased by differences in early death rates. No other variable was found predictive for the response to salvage treatment including age, WBC, serum LDH, morphologic subtype, presence or absence of DNA aneuploidy as detected by flow cytometry or maintenance chemotherapy. A low remission rate of 28% was also obtained in the 14 patients at second relapse. These data indicate that patients with a duration of their first remission of more than 6 months cannot be considered as being refractory against standard chemotherapy while patients with early relapses and second recurrences have a response rate of less than 30% due to refractory disease. Hence, the following criteria are proposed for the definition of refractoriness against standard chemotherapy in advanced AML: (a) nonresponse to first-line induction therapy, (b) early relapse within 6 to 12 months of first remission, (c) relapse after 6 to 12 months of first remission and failure on a reinduction attempt with established regimens, (d) second and subsequent relapses. These criteria may provide a useful rationale for the selection of the most appropriate treatment at relapse. They may also serve as eligibility criteria for clinical phase I/II studies and will facilitate interstudy comparisons.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Resistance; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Recurrence; Survival Rate; Thioguanine

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Neoplastic Stem Cells; Thioguanine; Tumor Cells, Cultured

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Cytarabine; Daunorubicin; Drug Evaluation; Humans; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Life Tables; Middle Aged; Netherlands; Remission Induction; Survival Rate; Thioguanine

Topics: Adolescent; Adult; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Cytarabine; Doxorubicin; Drug Evaluation; Humans; Interferon Type I; Leukemia, Myeloid, Acute; Middle Aged; Mitoxantrone; Thioguanine; United Kingdom

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Evaluation; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Preleukemia; Remission Induction; Thioguanine

Topics: Agranulocytosis; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Depression, Chemical; Hematopoiesis; Humans; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Life Tables; Mitoxantrone; Mycoses; Thioguanine; Thrombocytopenia

Great strides have been made in the chemotherapy of adult acute myeloid leukaemia in the last two decades. This paper describes our experience in the treatment of adult acute myeloid leukaemia from 1980-88. About two thirds of patients achieve remission with a standard chemotherapy protocol. Early disease relapse and measures to prevent it are major problems. The majority of patients with adult myeloid leukaemia, presently, are not cured with chemotherapy alone.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Remission Induction; Thioguanine

91 patients with acute nonlymphoblastic leukemia (ANLL) were treated with Homoharringtonine, Cytosine arabinnoside, Thioguanine (HAT) and/or Daunorubicin, (Adriamycin) Cytosine arabinnoside, Thioguanine D(A) AT protocols. The total CR rate was 68.1% with a median remission duration of 20.3 months, and the expectant survival rate in 5 years (Kaplan-Meier method) was 39%. The CR rate and the CR duration projected by HAT and D (A) AT protocols were very similar. After 20 prognostic factors from both clinical and laboratory examinations prior to treatment had been analysed, we concluded that (1) The CR rate was improved by increasing the dose of induction chemotherapy; (2) The patients might have longer remission and survival if they obtained remission in 2 courses of treatment; (3) The remission durations were comparable between the individuals receiving and not receiving maintenance chemotherapy.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Doxorubicin; Female; Harringtonines; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prognosis; Survival Rate; Thioguanine

Between November 1982 and November 1986 31 patients with acute myeloid leukaemia underwent peripheral blood stem cell apheresis during haemopoietic regeneration following induction chemotherapy. A retrospective analysis of the factors affecting the efficacy of stem cell harvest and of the clinical outcome of these patients was performed. The mean number of myeloid progenitor cells (CFU-GM) collected was significantly higher in the complete remission group (n = 22) than in the partial remission group (n = 9). Fifty x 10(4) CFU-GM/kg body weight or more, which produced rapid, complete and sustained haemopoietic reconstitution after autografting in our patients, were collected from six of nine patients who underwent three or four 7-litre aphereses over 5-7 days using a lymphocyte collection procedure on the Fenwal CS3000 [Protocol B] but only from two of 12 patients who underwent three or four 5-litre aphereses over 3-5 days using the Aminco Celltrifuge [Protocol A] (p less than 0.05). No adverse effects on the rates of neutrophil, platelet and lymphocyte recovery after induction chemotherapy or on long-term disease-free survival for patients who achieved a complete remission could be attributed to apheresis when compared with a historical control group of 39 patients who achieved complete remission following the same induction chemotherapy but did not undergo apheresis. We conclude that sufficient numbers of peripheral blood stem cells to produce safe and rapid haemopoietic reconstitution can be collected from most patients who achieve complete remission using apheresis Protocol B without impairment of haemopoietic recovery or adversely affecting the length of complete remission.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Component Removal; Bone Marrow Diseases; Cell Count; Combined Modality Therapy; Cytarabine; Daunorubicin; Evaluation Studies as Topic; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Retrospective Studies; Thioguanine; Transplantation, Autologous

Eleven patients with acute myeloid leukaemia have been transplanted with autologous marrow grown in long-term bone marrow culture. In the high risk group (six patients who had all previously relapsed) the procedure induced a remission in two patients who were in florid relapse at the time of the transplant. Five patients were transplanted in first remission and they remain well and disease-free between 150 and 12 weeks after their autologous transplant.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Cells, Cultured; Combined Modality Therapy; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Pilot Projects; Remission Induction; Risk; Thioguanine; Transplantation, Autologous

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Combined Modality Therapy; Cytarabine; Doxorubicin; Evaluation Studies as Topic; Female; Humans; Leukemia, Myeloid, Acute; Male; Methods; Middle Aged; Myelodysplastic Syndromes; Thioguanine; Transplantation, Autologous

A total of nine adults with newly diagnosed acute myeloblastic leukaemia (AML) and seven with relapsed disease were treated with fractionated daunorubicin in combination with cytosine arabinoside and 6-thioguanine. Remissions were seen in 89% and 57%, respectively. The side effects associated with bolus injections of daunorubicin were much less severe with fractionated treatment, and there was no significant cardiotoxicity despite total doses of up to 1363 mg/m2 daunorubicin. These results show that fractionated anthracyclines are effective in the treatment of AML and that this mode of administration may permit an upward revision of the accepted dose limits for anthracyclines.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Pressure; Cytarabine; Daunorubicin; Drug Administration Schedule; Heart Ventricles; Humans; Infusions, Intravenous; Leukemia, Myeloid, Acute; Middle Aged; Thioguanine

Eight patients with acute non-lymphocytic leukemia in adults refractory to Daunomycin (DM)-based conventional regimens were treated with AMSA-based regimens. Complete remission (CR) was obtained in 4 (50%) and partial remission (PR) in 2 (25%). The median time to CR was 26.5 days and 3 cases achieved CR in the first cycle. The median duration of CR was 8.3 months. Hematologic toxicity was severe and the nadir (median) of leukocytes and platelets was 0.15 x 10(3)/microliters and 15.5 x 10(3)/microliters, respectively. Other adverse effects were mucositis, nausea.vomiting and hepatotoxicity which occurred over 50%, while cardiac toxicity was not observed. This study indicates that AMSA is clinically non-cross-resistant to DM and considered to be an active drug for salvage therapy.

Topics: Adolescent; Adult; Aged; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Evaluation; Drug Resistance; Female; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Leukopenia; Male; Middle Aged; Prednisolone; Remission Induction; Thioguanine; Thrombocytopenia

A case of necrotizing fasciitis of the vulva arising in a leukemic patient during a chemotherapy nadir is presented. The nature of the process was not recognized initially, and the patient was treated with intravenous antibiotics. After clinically evident necrosis developed, prompt surgical debridement was carried out. Clinical improvement followed and the wound healed well. This case suggests that chemotherapy with its attendant immunosuppression is a predisposing factor in the development of necrotizing fasciitis and warrants a high index of suspicion.

Topics: Adult; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Fasciitis; Female; Humans; Leukemia, Myeloid, Acute; Necrosis; Thioguanine; Vulva; Vulvar Diseases

Fibrinopeptide A (FPA) was systematically investigated in 74 patients with acute leukaemia at different stages of the disease (50 with non-lymphocytic leukaemia, ANLL; 24 with lymphocytic leukaemia, ALL). At diagnosis, 75% of the cases had high FPA levels (86% in ANLL and 54% in ALL) with significantly higher levels in ANLL than in ALL (13.4 vs 4.4 ng/ml; p less than 0.001). Patients with DIC (20 cases in ANLL and 1 case in ALL) had significantly higher levels (p less than 0.001). FPA levels were neither correlated with fibrinogen or FDP levels nor with blast cell count. During chemotherapy, median FPA did not show significant changes whereas, at the end of therapy, a return toward normality was generally observed both in ALL and ANLL apart from the group of patients with acute promyelocytic leukaemia. Among the 24 patients who entered post-remission follow-up (13 ANLL and 11 ALL), 10 cases out of the 11 relapsing (6/6 with ANLL and 4/5 with ALL) had increased FPA 1 to 2 months before the ascertainment of the relapse. However, 16% and 9% of the samples obtained on different occasions, respectively from ANLL and ALL cases in maintained first remission, showed FPA above the normal limit. This study demonstrates that subclinical activation of blood coagulation, as indicated by high FPA level, is common both in lymphocytic and non-lymphocytic leukemia and suggests that this phenomenon is related to disease activity.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Daunorubicin; Disseminated Intravascular Coagulation; Female; Fibrinogen; Fibrinopeptide A; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Longitudinal Studies; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Radioimmunoassay; Thioguanine; Time Factors

One hundred ninety-six patients with acute myelogenous leukemia (AML) were treated with intensive induction chemotherapy using similar daunorubicin/cytarabine/thioguanine regimens. Treatment results of 44 patients who had a documented preleukemic syndrome or cytopenia present for more than 2 months before developing over AML were compared with 152 patients with de novo AML. Eighteen (41%) patients with preleukemia evolving into AML achieved complete remission compared with 111 (73%) patients with de novo AML (P less than .01). Patients with preleukemia-AML had a significantly longer period to recovery of granulocytes. Multivariate analysis indicated that presence of a previous preleukemic syndrome and advancing age were independent poor prognostic indicators for achieving remission. For patients who achieved remission, disease-free survival and overall survival were also inferior for patients with previous preleukemia; disease-free survival was 17 +/- 17% at 3 years compared with 29 +/- 10% in patients with de novo AML (P = .02). These data indicate that intensive chemotherapy has limited efficacy in patients with AML following a preleukemic syndrome. Durable remissions may be achieved in some patients.

Topics: Age Factors; Anemia, Aplastic; Anemia, Refractory, with Excess of Blasts; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Multivariate Analysis; Neural Tube Defects; Preleukemia; Prognosis; Regression Analysis; Survival Rate; Thioguanine

Topics: Antineoplastic Combined Chemotherapy Protocols; Antithrombin III; Antithrombin III Deficiency; Cytarabine; Daunorubicin; Disseminated Intravascular Coagulation; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Leukemia, Myeloid, Acute; Thioguanine; Thrombin; Thrombophlebitis

Granulocytic maturation of HL-60 promyelocytic leukemia cells induced by dimethylsulfoxide has been shown to produce a decrease in cellular protein phosphotyrosine residues and increases in both tyrosine kinase and protein phosphotyrosine phosphatase activities (D. A. Frank and A. C. Sartorelli, Biochem. Biophys. Res. Commun., 140: 440-447, 1986). These changes have been shown to not be restricted to dimethylsulfoxide-induced differentiation, since similar changes occur in HL-60 cells initiated with retinoic acid and in HL-60 sublines resistant to dimethylsulfoxide-induced differentiation treated with the retinoid. These regulatory events are not directly coupled to growth arrest, which accompanies terminal maturation, since the anthracycline antibiotics aclacinomycin A and marcellomycin, which induce HL-60 differentiation, cause these changes in phosphotyrosine metabolism, while Adriamycin, at a level which produces an equivalent degree of growth inhibition but does not initiate the maturation of HL-60 cells, does not. Furthermore, an HL-60 subline deficient in hypoxanthine-guanine phosphoribosyltransferase, which differentiates in the presence of 6-thioguanine, produced a decrease in phosphotyrosine residues and increases in tyrosine kinase and phosphotyrosine phosphatase activities in response to the purine antimetabolite, while the parental HL-60 line, in which 6-thioguanine inhibits cellular proliferation but does not induce maturation, does not exhibit these changes. Finally, similar alterations in phosphotyrosine regulation were exhibited during anthracycline-induced differentiation of the murine myelomonocytic leukemia cell line WEHI-3B D+, supporting the concept that the phenomena measured represent a general response to inducers of the granulocytic differentiation of leukemia cells.

Topics: Aclarubicin; Anthracyclines; Antibiotics, Antineoplastic; Cell Differentiation; Dimethyl Sulfoxide; Humans; Leukemia, Myeloid, Acute; Naphthacenes; Phosphoprotein Phosphatases; Phosphorylation; Protein Tyrosine Phosphatases; Protein-Tyrosine Kinases; Thioguanine; Tumor Cells, Cultured; Tyrosine

Treatment of HL-60 leukemia cells with the inducers of differentiation dimethyl sulfoxide (DMSO) and 6-thioguanine (TG) reduces the proliferative capacity of the cells. DMSO acted in a serum-independent manner and reversibly inhibited competence to enter S phase after 24 h of treatment. Purified human granulocyte-macrophage colony-stimulating factor (GM-CSF) but not human CSF-1, restored S phase competence and growth of DMSO-treated cells over a 7-day period. GM-CSF had no effect on the saturation density of control cells, even under conditions of reduced growth. Furthermore, GM-CSF antagonized the growth inhibitory actions of TG associated with cytodifferentiation but not those associated solely with TG cytotoxicity. The number of high affinity, cell surface GM-CSF receptors doubled after treatment of HL-60 cells with DMSO for 24 h and reached a maximum 4- to 5-fold increase within 72 h of exposure. The Kd of GM-CSF binding, 240 pM, was comparable to the concentration required to elicit a mitogenic response in DMSO-treated cells. An HL-60 variant that had been selected for resistance to TG-induced growth inhibition and differentiation (R. E. Gallagher et al., Cancer Res., 44: 2642-2653, 1984) was found to have less than 20% of the cell surface GM-CSF receptors when compared to either wild type cells, or a variant line selected for resistance to TG cytotoxicity. These studies demonstrate that HL-60 cells undergoing differentiation simultaneously lose autonomous growth properties and acquire cell surface growth factor receptors and mitogenic responsiveness.

Topics: Blood Physiological Phenomena; Cell Differentiation; Cell Division; Colony-Stimulating Factors; Dimethyl Sulfoxide; DNA; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Humans; Leukemia, Myeloid, Acute; Receptors, Cell Surface; Receptors, Colony-Stimulating Factor; Thioguanine; Tumor Cells, Cultured

Five cases of 'painful red hands', following chemotherapy for leukaemia, are reported. All the patients were women who had received treatment with cytosine arabinoside, 6-thioguanine and adriamycin. Several days after courses of chemotherapy, painful erythematous swelling of the palms and soles developed. In all cases the reaction was self-limiting and did not adversely affect their prognosis. Physicians should be aware of this reaction in order to reassure their patients. No treatment is required and the chemotherapy need not be stopped or altered.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Doxorubicin; Drug Eruptions; Female; Foot Dermatoses; Hand Dermatoses; Humans; Leukemia, Myeloid, Acute; Middle Aged; Pain; Thioguanine

A pilot study was undertaken to determine the efficacy of remission induction therapy with 1000 mg/m2 high-dose cytosine-arabinoside (one i.v. push injection every 24 h, days 1-12), 65 mg/m2 6-thioguanine (orally, days 1-12), and 40 mg/m2 doxorubicin (i.v., days 13 and 14) without maintenance or consolidation therapy as a possible cure of childhood acute nonlymphocytic leukemia. Children in first remission with a suitable donor were offered the opportunity of allogeneic bone marrow transplantation (BMT). Between March 1980 and June 1981, 24 of 27 consecutive, newly diagnosed children entered the pilot study. Complete remission was achieved in 15 (71.4%) of 21 treated patients. Eleven children received no further therapy: 9 relapsed within 5 months (all hematologically), 2 have been in longstanding continuous complete remission (CCR) for 70+ and 77+ months. Four children underwent allogeneic BMT: 2 have been in CCR for 68+ and 75+ months, 1 child died of graft-versus-host disease, and 1 child relapsed 60 months after BMT. Although the remission rate (71.4%) was satisfactory, only a minority (18%) of the patients who received no further therapy seem to be cured.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Doxorubicin; Female; Humans; Infant; Leukemia, Myeloid, Acute; Male; Netherlands; Pilot Projects; Remission Induction; Thioguanine

The effects of guanine coadministration on the metabolism and biological activity of 6-thioguanine (6-TG) were studied in human promyelocytic leukemia cells (HL-60). Cell growth, cytotoxicity (cloning assay), and cell differentiation were measured, along with nucleotide metabolism. Guanine was efficiently salvaged by HL-60 cells; at 200 microM, guanine suppressed the formation of 6-TG mononucleotides and abolished 6-TG incorporation into nucleic acids. Similarly, guanine antagonized 6-TG cytotoxicity in a dose dependent fashion. Furthermore, guanine (200 microM) fully suppressed the 6-TG (10 microM) induced HL-60 cell differentiation, which suggests that cell differentiation at pharmacological 6-TG concentrations is dependent on the anabolism of the drug to active nucleotides. 6-TG given alone reduced GTP levels and DNA synthesis rates in HL-60 cells, while a major intracellular 6-TG metabolite, 6-thioguanosine 5'-monophosphate, accumulated to high levels (approximately 100 microM). It is suggested that accumulation of 6-thioguanosine 5'-monophosphate and a resultant partial block of the de novo biosynthesis of guanine nucleotides is responsible for 6-TG induced cell differentiation in HL-60 cells.

Topics: Biotransformation; Cell Differentiation; Cell Division; Cell Survival; Guanine; Guanine Nucleotides; Humans; Leukemia, Myeloid, Acute; Nucleic Acids; Phosphorylation; Thioguanine; Tumor Cells, Cultured

In a single-institution study, 23 consecutive children with acute myeloid leukemia (AML) have been treated with a protocol including doxorubicin, cytarabine and 6-thioguanine as induction therapy, followed by four courses of high-dose cytarabine as consolidation. Total duration of chemotherapy was 6-8 months from diagnosis. 21 out of the 23 children achieved complete remission. During remission, the children received 52 mumol (50,000 I.U.) retinol as retinyl palmitate per square meter daily. 14 of the 21 children are still in their first remission with a mean observation time of 36 months. In our study retinyl ester given in doses up to 30 times the recommended daily allowances has not caused any clinical or biochemical side effect for up to 4 yr of therapy.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Doxorubicin; Drug Administration Schedule; Female; Humans; Infant; Leukemia, Myeloid, Acute; Male; Remission Induction; Thioguanine; Vitamin A

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Remission Induction; Retrospective Studies; Thioguanine

A patient with acute myeloblastic leukaemia developed jaundice revealing peliosis hepatis after receiving 6-thioguanine for two months. Peliosis hepatis was severe and was associated with mild lesions of centrilobular veins. Withdrawal of 6-thioguanine was followed by a progressive improvement of liver dysfunction. This report shows that 6-thioguanine, a thiopurine already reported to be responsible for veno-occlusive disease of the liver, can induce peliosis hepatis. This suggests that some liver vascular disorders caused by thiopurines (6-thioguanine, azathioprine and 6-mercaptopurine), particularly peliosis hepatis, veno-occlusive disease, sinusoidal dilatation and perisinusoidal fibrosis, might be related syndromes caused by similar lesions at different sites.

Topics: Chemical and Drug Induced Liver Injury; Female; Humans; Leukemia, Myeloid, Acute; Middle Aged; Peliosis Hepatis; Thioguanine

A study was carried out to determine whether bone marrow biopsy performed on day 6 of induction therapy for acute myeloid leukaemia (AML) can identify those patients with resistant disease who would need an intensification of the first course of induction. Bone marrow biopsies were performed on day 6 of induction chemotherapy in 44 patients with AML treated with daunorubicin, cytosine arabinoside and thioguanine. Biopsies were assessed for blast count, trephine cellularity and leukaemic index. Discrimination between patients who went on to achieve remission and those with resistant disease was best achieved using the reduction in bone marrow cellularity from pretreatment marrow to day-6 marrow. However, this discriminator identified only 50% of the patients with resistant disease and included 13% of patients who achieved remission with the first course of chemotherapy. The other parameters of response were even less effective at discriminating between chemotherapy-resistant and chemotherapy-responsive disease.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biopsy; Bone Marrow; Bone Marrow Examination; Cytarabine; Daunorubicin; Drug Resistance; Humans; Leukemia, Myeloid, Acute; Remission Induction; Thioguanine

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Evaluation; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prednisolone; Remission Induction; Thioguanine

A form of liver injury characterized by bile ductule-like transformation of hepatocytes, prominent hemosiderin deposition and fibrosis, was occasionally encountered in autopsy cases we examined during the period from 1973 to 1981. It was found that this liver injury was irreversible and intimately related to combination chemotherapy with the DCMP regimen (daunorubicin, cytosine arabinoside, 6MP and prednisolone) for acute non-lymphocytic leukemia (ANLL). Its correlation was reconfirmed by the fact that this liver injury disappeared after withdrawal of the DCMP regimen in 1981. After 1978, the regimen of combination chemotherapy for adult ANLL was partly changed, 6-thioguanine being utilized (DCTP) instead of the 6MP in the DCMP regimen. The hepatic injury occurring after the change in the regimen was different from that produced with DCMP, showing reversible intrahepatic cholestasis. These facts indicated that substitution for one drug in a combination chemotherapy regimen could cause a different type of hepatic change.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Liver; Melphalan; Prednisolone; Prednisone; Thioguanine

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Daunorubicin; Doxorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prednisone; Remission Induction; Thioguanine; Vincristine

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Remission Induction; Thioguanine

In a clinical phase I/II study, high-dose cytosine arabinoside and mitoxantrone (HAM) were given in combination to 40 patients with refractory acute myeloid leukemia. All patients had received a 9-day combination of thioguanine, Ara-C, and daunorubicin (TAD-9) as standardized first-line treatment. Refractoriness was defined as (a) nonresponse against two TAD-9 induction cycles, (b) early relapse within the first 6 months on monthly maintenance or after TAD-9 consolidation, (c) relapse after 6 months with nonresponse against one additional TAD-9 cycle, and (d) second and subsequent relapses after successful TAD-9 therapy at the preceding relapse. Therapy consisted of HD-Ara-C 3 g/m2 every 12 hours on days 1 through 4; mitoxantrone was started at 12 mg/m2/day on days 3, 4, and 5 and was escalated to 4 and 5 doses of 10 mg/m2/day on days 2 through 5 and 2 through 6. Of the 40 patients, 21 achieved a complete remission (53%), 1 patient had a partial remission, and 5 patients were nonresponders. Thirteen patients died in aplasia due to infections (n = 11), pericardiac effusion, or acute cardiomyopathy. Nonhematologic side effects consisted predominantly of nausea and vomiting, mucositis, and diarrhea. Central nervous system (CNS) symptoms were observed during six treatment courses. Recovery of blood counts occurred at a median of 27 days from the onset of treatment; the median time to complete remission was 36 days. Two of the 21 responders underwent successful bone marrow transplantations. The median remission duration for the remaining 19 patients is 4.5 months, and the median survival time is 9 months. These data emphasize that HAM has high antileukemic activity in refractory AML and strongly suggest starting the combination at earlier stages in AML therapy.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Cytarabine; Daunorubicin; Drug Administration Schedule; Drug Evaluation; Drug Resistance; Heart Diseases; Humans; Leukemia, Myeloid, Acute; Middle Aged; Mitoxantrone; Prognosis; Thioguanine

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Prednisone; Pregnancy; Pregnancy Complications, Neoplastic; Thioguanine; Vincristine

A 67-year-old woman with acute myelomonocytic leukemia had a clinical course characterized by the initial appearance of leukemia cutis without bone marrow involvement. When marrow involvement subsequently occurred, induction chemotherapy cleared all manifestations of the illness. Shortly thereafter, while blood and bone marrow remained in remission, the skin lesions reappeared. The introduction of 6-thioguanine, as part of the maintenance treatment protocol, resulted in the rapid and permanent disappearance of the leukemic skin infiltrates.

Topics: Aged; Bone Marrow; Female; Humans; Leukemia; Leukemia, Myeloid, Acute; Skin Neoplasms; Thioguanine

A sensitive and rapid assay for the quantitation of thioinosine monophosphate and thioguanosine monophosphate, the major intracellular active metabolites of mercaptopurine and thioguanine, respectively, has been developed. Neoplastic cells are extracted with trichloracetic acid, and the neutralized acid extracts are analyzed by ion-pairing high-performance liquid chromatography with dual-channel uv-wavelength detection. This technique provides a lower limit of sensitivity of 30 pmol of thioinosine monophosphate and 10 pmol of thioguanosine monophosphate. The number of cells assayed per sample was 2 X 10(7). This assay makes it possible to detect and quantitate low levels of thioinosine monophosphate and thioguanosine monophosphate present in neoplastic cells obtained directly from patients receiving mercaptopurine or thioguanine chemotherapy.

Topics: Bone Marrow; Cell Line; Chromatography, High Pressure Liquid; Guanine Nucleotides; Humans; Inosine Monophosphate; Inosine Nucleotides; Leukemia, Myeloid, Acute; Lymphoma; Mercaptopurine; Thioguanine; Thionucleotides

In the present study 55 patients with refractory acute myeloid leukemia (AML) (n = 44) and acute lymphoblastic leukemia (ALL) (n = 11) were treated with high-dose cytosine arabinoside (HD-ara-C) and mitoxantrone (HAM) to assess the toxicity and antileukemic activity of the two-drug combination. All patients had received a standardized first-line therapy according to the corresponding multicenter trials of the German AML and ALL cooperative groups and were considered refractory to conventional treatment. Therapy consisted of HD-ara-C 3 g/m2 every 12 hours on days 1 to 4; mitoxantrone was started at 12 mg/m2/d on days 3, 4, and 5 and was escalated to four and five doses of 10 mg/m2/d on days 2 to 5 and 2 to 6. From the 44 patients with AML, 24 (54%) achieved a complete remission, two a partial remission, and five were nonresponders. Thirteen patients died of infections (n = 11), pericardiac effusion, or acute cardiomyopathy. In refractory ALL, seven of 11 patients (64%) went into a complete remission, one patient was resistant, and three patients were early deaths. Nonhematologic side effects consisted predominantly of nausea and vomiting, mucositis, and diarrhea. More severe CNS symptoms were encountered during five treatment courses. The median time to complete remission was 36 days. Excluding five patients who underwent bone marrow transplantations, the median remission duration was 4.5 months in AML and 2.3 months in ALL. The median survival time was three months for all patients and nine months for responders only. These data emphasize a high antileukemic activity of HAM in refractory AML and ALL and support the incorporation of the HAM regimen into first-line treatment.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Dose-Response Relationship, Drug; Female; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitoxantrone; Thioguanine

Topics: Antineoplastic Combined Chemotherapy Protocols; Arabinofuranosyluracil; Cytarabine; Daunorubicin; Humans; Kinetics; Leukemia, Myeloid, Acute; Mitoxantrone; Thioguanine

Topics: Antineoplastic Combined Chemotherapy Protocols; Colony-Forming Units Assay; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Remission Induction; Thioguanine; Tumor Stem Cell Assay

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Daunorubicin; Doxorubicin; Drug Administration Schedule; Female; Humans; Leukemia, Myeloid, Acute; Male; Prednisolone; Prognosis; Remission Induction; Thioguanine; Time Factors; Vincristine

One hundred thirty-three children with acute myelogenous leukemia (AML) entered the multicenter Pediatric Branch of the Italian Association Against Leukemia trial AIEOP/LAM 8204 between July 1982 and May 1986. Induction therapy consisted of two courses of daunomycin (DNM) plus cytosine arabinoside (Ara-C). Those patients who achieved remission were given four courses of consolidation with DNM, 6-thioguanine (6-TG) and escalated doses of Ara-C followed by six courses of sequential continuation therapy using monthly pairs: etoposide (VP-16)/Ara-C, Ara-C/6-TG, and DNM/Ara-C. Periodic intrathecal Ara-C was used for CNS prophylaxis. One hundred seven (80%) children achieved complete remission (CR). Kaplan-Meier estimates of 3-year disease-free survival (DFS) and event-free survival (EFS) are 41% and 33%, respectively. Relapses occurred in 34 patients after 5 to 97 weeks (32 marrow; 2 marrow plus CNS). Overall, 14 patients died of complications during treatment (nine during induction; five during the postremission phase), mostly from infection. Risk factor analysis showed that induction failures occurred predominantly in children with French-American-British (FAB) M5 and in those with elevated leukocyte counts; by step-up Cox analysis, only FAB subtype was predictive of remission success. None of the variables examined was significant for predicting the duration of remission. Hyperleukocytosis was predictive of a significantly worse EFS rate. These results are encouraging and further support the use of intensive chemotherapy programs for childhood AML.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Daunorubicin; Drug Administration Schedule; Etoposide; Female; Humans; Infant; Leukemia, Myeloid, Acute; Male; Remission Induction; Thioguanine

The feasibility of using retroviral gene therapy to overcome drug resistance was assessed by determining the efficiency by which a retrovirus containing the human HGPRT gene could sensitize hypoxanthine-guanine phosphoribosyltransferase (HGPRT) negative human promyelocytic leukemia cells to 6-thioguanine. A single three-hour exposure at a virus to cell ratio of 6 X 2:1 restored sensitivity to 70(+/- 18)% of the clonogenic cells. The efficacy varied as a function of virus concentration and duration of viral exposure; the time allowed for integration and expression between one and five days post-infection had little effect. Cells successfully sensitized contained a proviral insert and expressed HGPRT activity that ranged from 1 to 92% of that in the wild-type cells. The mutation rate of the inserted gene varied from the same as that of the endogenous HGPRT gene to 200-fold greater in different clones. Failure of sensitization following viral exposure was associated with absence of an integrated provirus, and clonogenic cells failing to be sensitized by one virus exposure were sensitized with approximately the same efficiency by a second viral exposure. These results demonstrate the feasibility of transferring a drug sensitivity gene to a human leukemia cell line.

Topics: Cell Line; Drug Resistance; Gene Expression Regulation; Genetic Engineering; Genetic Vectors; Humans; Hypoxanthine Phosphoribosyltransferase; In Vitro Techniques; Leukemia, Myeloid, Acute; Retroviridae; Thioguanine; Time Factors

Treatment of hypoxanthine-guanine phosphoribosyltransferase (HGPRT)-deficient human promyelocytic leukemia (HL-60) cells with 6-thioguanine results in growth inhibition and cell differentiation. 6-Thioguanine is a substrate for the tRNA modification enzyme tRNA-guanine ribosyltransferase, which normally catalyzes the exchange of queuine for guanine in position 1 of the anticodon of tRNAs for asparagine, aspartic acid, histidine, and tyrosine. During the early stages of HGPRT-deficient HL-60 cell differentiation induced by 6-thioguanine, there was a transient decrease in the queuine content of tRNA, and changes in the isoacceptor profiles of tRNA(His) indicate that 6-thioguanine was incorporated into the tRNA in place of queuine. Reversing this structural change in the tRNA anticodon by addition of excess exogenous queuine reversed the 6-thioguanine-induced growth inhibition and differentiation. Similar results were obtained when 8-azaguanine (another inhibitor of queuine modification of tRNA that can be incorporated into the anticodon) replaced 6-thioguanine as the inducing agent. The data suggest a primary role for the change in queuine modification of tRNA in mediating the differentiation of HGPRT-deficient HL-60 cells induced by guanine analogs.

Topics: Antibodies, Monoclonal; Antigens, Differentiation; Azaguanine; Cell Differentiation; Guanine; Humans; Hypoxanthine Phosphoribosyltransferase; Leukemia, Myeloid, Acute; Nitroblue Tetrazolium; RNA Processing, Post-Transcriptional; RNA, Transfer; Thioguanine; Tumor Cells, Cultured

DNA synthesis inhibitors and vincristine greatly enhance the response of leukaemic and dysplastic cells to differentiation inducing agents such as retinoic acid (RET). Differentiation induction therapy is an attractive therapeutic approach in myelodysplasia (MDS) and in acute myeloid leukaemia (AML) in the elderly, since it should be possible to increase the production of mature cells, at the expense of precursor cells, without incurring the complications of intensive cytotoxic therapy. Single agent differentiation therapy has, however, not been highly successful. We have therefore investigated the use of synergistic combinations of agents. We treated nine patients (6 with MDS, 3 with AML) with 13-cis-retinoic acid (up to 100 mg/m2/day) in combination with either 6-thioguanine (20-40 mg/day in 14-57 day courses) or with vincristine (1-2 mg as a single injection during a four-day course of RET). Seven patients responded with an increase in the mature cells of at least one haemopoietic lineage. A concomitant decrease in marrow blasts was observed in 3/4 responding patients. The retention of dysplastic and karyotypic abnormalities and lack of a hypoplastic phase all suggested that differentiation induction was occurring in vivo. Prior failure to respond to therapy with single agents (RET in two and cytosine arabinoside in five patients) suggests that the synergy observed in vitro operates in vivo. In-vitro studies on marrow cells from seven patients demonstrated synergistic differentiation induction in 6/7 samples. The seventh patient was one of the two who did not respond clinically. The second of these clinically unresponsive patients had cells which were relatively refractory to RET in vitro, suggesting that in-vivo and in-vitro responses may be related.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cell Differentiation; Cytarabine; Drug Synergism; Female; Humans; Karyotyping; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Thioguanine; Tretinoin; Tumor Cells, Cultured; Vincristine

Hematopoietic regeneration following chemotherapy was studied in serial bone marrow biopsy (BMB) specimens from 20 patients with acute myeloid leukemia (AML) who went into complete remission following therapy. Immediately after intensive chemotherapy, the marrow was extremely hypocellular and edematous and contained widely dilated sinuses. Subsequently, areas of large uniform unilocular fat cells developed from multilocular precursor fat cells. Early aggregates of regenerating hemopoietic cells were seen closely adjacent to bony trabeculae (BT) and appeared to grow out from the endosteum in a sequential progression suggesting an origin from their endosteal progenitors. During the early part of hemopoietic regeneration, individual precursor cells appeared to migrate from these hemopoietic aggregates towards the central intertrabecular marrow space where they formed colonies of various hematopoietic cells in close association with fat and marrow sinusoids. Later, as the normal hemopoiesis was restored due to the gradual enlargement and confluence of these hemopoietic colonies, this characteristic pattern of paratrabecular proliferation and migration of cells became less obvious. These observations suggest that hemopoietic regeneration in AML after therapy is a local phenomenon and is initiated by progenitors of endosteal cells.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cytarabine; Daunorubicin; Etoposide; Humans; Leukemia, Myeloid, Acute; Regeneration; Thioguanine

Four patients with acute promyelocytic leukemia (APL) and clinical and laboratory manifestations of disseminated intravascular coagulation (DIC) were treated during induction chemotherapy with Org 10172 (Organon International), a low molecular weight heparinoid preparation. Plasma anti-Xa levels were maintained between 0.60 and 0.80 U/ml and anticoagulant activities, determined with a diluted activated partial thromboplastin time assay, ranged from 0.00 to 0.20 U/ml. Bleeding symptoms ceased and fibrinogen levels improved in the first week in all patients. In the second week, two patients developed bleeding as a result of primary fibrinolysis. It is concluded that Org 10172 may be useful in the treatment of patients with DIC. In patients with APL, inhibition of DIC will be insufficient to control all bleeding, since primary fibrinolysis may also occur.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chondroitin Sulfates; Cytarabine; Daunorubicin; Dermatan Sulfate; Disseminated Intravascular Coagulation; Drug Evaluation; Glycosaminoglycans; Heparinoids; Heparitin Sulfate; Humans; Leukemia, Myeloid, Acute; Middle Aged; Thioguanine; Time Factors

Serum levels of lactoferrin, lysozyme and myeloperoxidase were measured sequentially after induction treatment in 30 patients with AML in order to test the hypothesis that these proteins may be used to monitor activity and different stages of myelopoiesis in the bone-marrow. The results showed that myeloperoxidase and lysozyme started to rise again 6-8 days after initiation of treatment as compared to 12 d for lactoferrin and 16 d for blood polymorphonuclear leukocytes. The rate of marrow regeneration was exponential and estimated to be 9-20% per d. The comparison between two different chemotherapy regimes showed that the initial reduction in lysozyme, in contrast to other measured variables, was significantly larger with the therapy that contained vincristine and glucocorticosteroids. This might reflect a reduction in lysozyme secretion in addition to the effects on the leukemic cell mass. We conclude that the measurements of lactoferrin, lysozyme and myeloperoxidase in serum under certain circumstances may be used to monitor the myelopoietic activity in the bone-marrow.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cytarabine; Daunorubicin; Doxorubicin; Hematopoiesis; Humans; Lactoferrin; Lactoglobulins; Leukemia, Myeloid, Acute; Leukocyte Count; Muramidase; Neutrophils; Peroxidase; Prednisolone; Thioguanine; Time Factors; Vincristine

2 patients with acute megakaryoblastic leukaemia (AMKBL) were successfully treated with a combination of aclarubicin hydrochloride (an anthracycline), enocitabine (a derivative of cytosine arabinoside) and 6-mercaptopurine (6-MP) or 6-thioguanine (6-TG). They achieved a complete remission following 1 or 2 courses. They remained well and in complete remission throughout 3 courses of consolidation therapy, a total of 9 weeks. The results of remission induction therapy of AMKBL have been reviewed in the literature. 4 of 7 adult patients, including our cases, treated with 3 drugs, anthracycline, cytosine arabinoside or its derivative and 6-TG or 6-MP, achieved a complete remission. AMKBL may not have so poor a prognosis as previously believed.

Topics: Aclarubicin; Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Cytarabine; Female; Humans; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Middle Aged; Naphthacenes; Thioguanine

Blood or bone marrow samples from 15 patients with newly diagnosed acute myeloblastic leukemia undergoing remission induction treatment with daunorubicin, cytosine-arabinoside and 6-thioguanine were tested in vitro. Leukemic cells were incubated for 24 h at 37 degrees C with or without the drugs alone or in combination. A 3-h pulse with labelled precursors of DNA synthesis (3H-thymidine) or protein synthesis (3H-leucine) was then given separately. In vitro growth, expressed as the percentage ratio between labeled precursor uptake in treated cells and in control cells, was compared with the clinical results obtained. Three patients were not considered evaluable (death occurred too early), 8 had a complete response (CR), and 4 were disease resistant to chemotherapy. Leukemic cells of resistant-disease patients showed a significantly lower growth inhibition than cells taken from CR patients, with each drug alone or in combination, when measured with thymidine. Inhibition of leucine uptake was not related to the clinical outcome.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; DNA; Drug Administration Schedule; Drug Evaluation, Preclinical; Humans; Leucine; Leukemia, Myeloid, Acute; Protein Biosynthesis; Thioguanine; Thymidine

After pretreatment with anthracyclines, a boy entered a second complete remission of an acute myeloid leukemia lasting already for 16 months following chemotherapy with Aclacinomycin A combined with Etoposide, Cytosine Arabinoside and Thioguanine. The newly developed Aclacinomycin A was well tolerated. Presumably there is no cross resistance between Aclacinomycin A and the anthracyclines, the latter being in use for the therapy of leukemias since some time.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Drug Administration Schedule; Etoposide; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Naphthacenes; Thioguanine

Thioguanine and mercaptopurine are clinically important agents in widespread use for the treatment of acute leukemia. In this study the effect of low, physiological concentrations of hypoxanthine on thiopurine cytotoxicity was examined in the HL-60 human acute promyelocytic leukemia cell line. Initially the effect of cell concentration on medium hypoxanthine levels was investigated. When 10(5) to 10(6) cells/ml were used, medium hypoxanthine concentrations fell to undetectable (less than 0.1 microM) levels by 24 h, due to cell utilization. However, when the cell density was reduced to 10(3) cells/ml, it was possible to maintain a medium hypoxanthine level as low as 0.5 microM for 24 h without significant hypoxanthine depletion. This allowed for the investigation of the extent to which physiological concentrations of hypoxanthine (1.0 to 10 microM) could modulate thiopurine cytotoxicity. HL-60 cells were incubated in medium containing from 1.0 to 100 microM hypoxanthine concentrations and varying levels of thioguanine or mercaptopurine for 24 h. Cells were then washed and cloned in soft agar. Physiological concentrations of hypoxanthine (1.0 to 10 microM) provided significant protection to HL-60 cells from the cytotoxic effects of both thioguanine and mercaptopurine. An increase in medium hypoxanthine level from 1.0 to 3.0 microM resulted in a 3-fold increase in the thiopurine concentration required to kill 50% of cells. There was a linear relationship between the thiopurine concentration required to reduce clonogenic survival by 50% and medium hypoxanthine level over the hypoxanthine concentrations studied. Although thioguanine was 200-fold more potent than mercaptopurine, and an analogue of guanine rather than hypoxanthine, there was a similar degree of modulation of the cytotoxicity of both agents by hypoxanthine. These results indicate that low, physiological hypoxanthine concentrations can significantly modulate thiopurine cytotoxicity and suggest that endogenous hypoxanthine pools may have an important effect on the clinical activity of thioguanine and mercaptopurine.

Topics: Cell Count; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Humans; Hypoxanthine; Hypoxanthines; Leukemia, Myeloid, Acute; Mercaptopurine; Thioguanine

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Combinations; Drug Evaluation; Female; Humans; Leukemia, Myeloid, Acute; Male; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Middle Aged; Mitoguazone; Prednisone; Thioguanine; Vincristine

Reiter's syndrome and other reactive arthritides have been described following infection with various organisms although they can occur in unusual circumstances without an obvious infectious precipitant. We have recently witnessed two attacks of reactive arthritis and keratoderma blenorrhagica occurring in an HLA B27 adult male following chemotherapy on two separate occasions with the same drugs for acute myeloid leukaemia. No attacks occurred before or following the cessation of these drugs. This supports the view that in Reiter's syndrome a common pathogenic pathway is triggered by an 'arthritogenic factor' which in this case appears to have been chemical.

Topics: Adult; Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Arthritis, Reactive; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Male; Thioguanine

175 patients with acute myeloid leukemia were treated between February 1980 and March 1985 with a TAD-induction therapy, three intensified consolidation cycles (COAP, COAP, AD), and a two-year mild maintenance therapy. The median age of the patients was 44 years, range 15-68 years. 62.3% of all patients attained complete remission and 13.7% partial remission. The median duration of remission was 10 months and the median survival time of patients in complete remission was 20 months. Patients older than 50 years had a higher early death rate (17.6) than younger patients (8.9%), but no difference was found in remission rates or in the median duration of remission and of survival. These results are in line with those of comparable studies.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Combinations; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Methotrexate; Middle Aged; Prednisolone; Prednisone; Thioguanine; Vincristine

In the cooperative study AML-IGCI-84 27 children with AML (FAB M1 7X, M2 4X, M3 1X, M4 6X and M5 8X; 1 megakaryocytic leukemia) have been treated. The median initial white blood cell count was 18.0 G/l (range 1.8-1,350.0 G/l). 1 or 2 courses of induction therapy were used: I1 (aclacinomycin-A (ACLA-A), VP-16 and ARA-C) and I2 (daunorubicin (DNR), VP-16, and ARA-C). I2 was used only if bone marrow contained greater than 5% blast cells on day 21. I2 and consolidation treatment were identical with the current AML-BFM-83 protocol. 3 deaths before day 21 occurred (2 cerebral hemorrhages, 1 septicemia). 24 patients were evaluable for response, 20 (83.3%) achieved CR, 16 (66.7%) by I1, 4 after I2. 4 patients never reached CR, 3 of them had a PR after I1. M5 patients did badly (2 early deaths, 2 PR, 4 CR). All patients without CR after I1 received the whole AML-BFM-83 protocol. Comparison of the results of the 2 studies revealed a similar CR rate for I1 (our patients) and I2 (BFM data): 80.0% vs. 82.2% (calculated for patients who ever reached CR). CR was reached before consolidation in all our CR patients compared to 82.2% of BFM patients. Early CR may be of long term prognostic significance. Cardiotoxicity of induction may be reduced by substitution of DNR by ACLA-A.

Topics: Aclarubicin; Adolescent; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Daunorubicin; Etoposide; Female; Follow-Up Studies; Humans; Infant; Infusions, Parenteral; Leukemia, Myeloid, Acute; Male; Naphthacenes; Thioguanine

In a retrospective study, three groups of patients with acute myeloid leukaemia were analyzed in respect to the outcome of remission induction therapy: group I (vincristine, daunorubicin and prednisone) was treated between 1970 and 1976, group II (daunorubicin and cytosine-arabinoside) between 1976 and 1980 and group III (daunorubicin, cytosine-arabinoside, 6-thioguanine and consolidation therapy with cyclophosphamide, vincristine, cytosine-arabinoside and prednisone) between 1980 and 1982. Complete remissions were achieved in 49% (group I), 46% (group II) and 65% (group III) of the patients (p greater than 0.05, chi-square test). The mortality rate of the remission induction therapy was significantly reduced from 27% in group I to 15% and 13% in group II and III, respectively (p less than 0.05, chi-square test). The median remission duration increased significantly from four months (group I) to nine months (group III) (p less than 0.05, log-rank test). The long term results were about the same in the three groups. After three years, the proportion of patients being still in first remission was less than 10% in group I and II 13% in group III.

Topics: Adolescent; Adult; Blood Transfusion; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Platelet Transfusion; Prednisone; Retrospective Studies; Thioguanine; Vincristine

Previous work has shown that 6-thioguanine (TGua) is an effective inducer of differentiation of Friend and HL-60 leukemia cells which lack hypoxanthine-guanine phosphoribosyltransferase but is at best only weakly active in inducing maturation in parental wild-type cells. Studies in wild-type and mutant HL-60 cells have provided evidence that the free-base TGua is the form of this drug that induces differentiation, while the formation of TGua nucleotides leads to cytotoxicity and inhibits differentiation. To attempt to increase the potential of TGua to serve as an inducer of parental HL-60 leukemia cells, physiological purine and pyrimidine nucleosides were tested for their ability to protect HL-60 cells against TGua-induced cytotoxicity. Adenosine, deoxyadenosine, inosine, and deoxyinosine completely prevented the toxic action of the purinethiol, while guanosine and deoxyguanosine were only partially effective. The capacity of adenosine and deoxyadenosine to prevent the cytotoxicity of TGua was abolished by the inhibitor of adenosine deaminase, deoxycoformycin, implying that inosine and deoxyinosine were the active forms of the protecting agents. The protective activities of inosine and deoxyinosine appeared to depend on phosphorolysis catalyzed by purine nucleoside phosphorylase, since exogenously added hypoxanthine was as effective as inosine in reducing the cytotoxicity of the purine antimetabolite. Accumulation of TGua nucleotides in the acid-soluble fraction of HL-60 cells treated with TGua was significantly decreased by the presence of inosine. Inosine also served under these circumstances as a D-ribose 1-phosphate donor to TGua, as evidenced by its increased conversion to 6-thioguanosine. The prevention of the cytotoxicity of TGua by the simultaneous administration of hypoxanthine or its nucleosides resulted in an expression of the differentiation-inducing properties of TGua in HL-60 cells, as measured by the accumulation of nitroblue tetrazolium-positive cells. These findings support the concept that the processes of cytotoxicity and differentiation are separable events produced by different metabolic forms of the purine antimetabolite.

Topics: Animals; Cell Differentiation; Cell Division; Cell Line; Deoxyribonucleosides; Drug Synergism; Humans; Hypoxanthine; Hypoxanthine Phosphoribosyltransferase; Hypoxanthines; Leukemia, Experimental; Leukemia, Myeloid, Acute; Mice; Ribonucleosides; Structure-Activity Relationship; Thioguanine

The human promyelocytic leukemia cell line known as HL-60 can be triggered to mature to functional granulocytes and/or macrophages after exposure to a variety of compounds. The findings have generated enthusiasm for possible therapy of leukemia using compounds that induce leukemic cell differentiation. We investigated whether five compounds known to trigger HL-60 differentiation to granulocytes could trigger the maturation of blast cells from 12 patients with myelogenous leukemia. Maturation was judged by morphology, superoxide production, phagocytosis, expression of Fc receptors, and development of alpha-napthyl acetate esterase activity. The blast cells from most patients showed little morphological, histological or functional maturation after exposure to the various compounds as compared to the blast cells cultured without the compounds. Actinomycin was able to induce significant maturation of leukemic cells of some patients when maturation was analyzed by several statistical methods. Our study suggests that many compounds which trigger differentiation of promyelocytic leukemia cells may not trigger differentiation of less mature myeloid leukemic cells.

Topics: Adult; Aged; Cell Differentiation; Cell Line; Dactinomycin; Dimethyl Sulfoxide; Humans; Hypoxanthine; Hypoxanthines; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Middle Aged; Nitroblue Tetrazolium; Phagocytosis; Thioguanine

A 42-year-old woman developed myxoedema during the course of acute myeloid leukaemia. The possible association with cytostatic treatment, especially thioguanine, and the role of levothyroxine for the growth of the leukaemic cell mass are discussed.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Myxedema; Thioguanine; Thyroxine

Sub-lines of the cultured human promyelocytic leukemia cell line HL-60 were individually selected for their ability to sustain exponential growth in the presence of 3 structurally-unrelated inducers of granulocytic differentiation - retinoic acid (RA), dimethylsulfoxide (DMSO), and 6-thioguanine (6TG). Selections were made by step-wise augmentation to final drug concentrations of 10(-3)mM RA, 169mM (1.2%) DMSO and 0.12mM (20 micrograms ml-1) 6TG. In addition to growth resistance, cells in each sub-line displayed variable cytodifferentiation resistance to each of the 3 selective agents, which was quantitated as the ratio of the concentration of drug required to induce differentiation in 50% of the cells in each resistant sub-line versus comparably-passaged wild-type HL-60 cells. The levels of resistance/cross-resistance were as follows: RA-resistant (res) sub-line greater than 2700-fold to RA, 1.3-fold to DMSO and greater than 1.5-fold to hypoxanthine (HXN; the noncytotoxic purine base inducer analogue of 6TG); DMSO-res sub-line 2.5-fold to DMSO, 137-fold to RA and greater than 1.5-fold to HXN; and 6TG-res sub-line greater than 1.5-fold to HXN, 9-fold to RA and 1.6-fold to DMSO. These sub-lines were not cross-resistant to sodium butyrate (NaBut), a monocyte inducer, or to 12-0-tetradecanoylphorbol 13-acetate (TPA), a macrophage inducer. HL-60 sub-lines selected by exposure to a single high concentration of 5-bromo-2'-deoxyuridine (BUdR; 3.3 X 10(-2)mM) or oubain (Ou; 5 X 10(-3)mM) were not or were slightly cross-resistant to either granulocyte or monocyte inducers. Although some variations in line/sub-line phenotype were observed, this was minor compared to the quantitative variations in response to individual inducing agents. The RA-res and 6TG-res sub-lines contained numerous double minute chromosomes (indicators of amplified genes) which were either absent or present in much smaller numbers in the parental wild-type cells or in the other drug-resistant sub-lines. There was little change or a decrease in the amplification level of the known amplified oncogene c-myc in the various drug-resistant sub-lines compared to wild-type HL-60 cells. These results (a) confirm that the neutrophilic granulocytic and monocytic/macrophagic differentiation programs in HL-60 cells are mechanistically different and separable; (b) suggest that both agent-specific and common quantitative alterations contribute to the mechanism(s) for resistance to granulocyte differentiation

Topics: Bromodeoxyuridine; Butyrates; Butyric Acid; Cell Count; Cell Differentiation; Cell Division; Cell Line; Dimethyl Sulfoxide; Dose-Response Relationship, Drug; Drug Resistance; Gene Amplification; Humans; Hypoxanthine; Hypoxanthines; Leukemia, Myeloid, Acute; Oncogenes; Ouabain; Phenotype; Tetradecanoylphorbol Acetate; Thioguanine; Tretinoin

In 13 patients with acute myeloid leukaemia (AML), plasma fibronectin (P-FN) was measured before, during and after chemotherapy. Pre-treatment concentrations of P-FN were within the reference range and significantly higher than the nadir value (p less than 0.05). A rise in body temperature by more than 1 degree C induced a significant fall in P-FN (p less than 0.05) and transfusion with freshly drawn blood products could prevent this fall. P-FN concentrations were significantly higher in patients obtaining complete haematological remission than in patients in whom remission could not be induced (p less than 0.001). This difference could not be attributed to transfusion or febrile episodes.

Topics: Adult; Aged; Blood Transfusion; Cytarabine; Daunorubicin; Female; Fibronectins; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Precipitin Tests; Thioguanine

Progress in the treatment of childhood AML has not equalled the advances obtained in the management of ALL. Two recent chemotherapy studies (i.e. VAPA and BFM 78), however, reported marked increase in the proportion of long-term remissions. The initial therapy of the cooperative study BFM 78 consisted of two 4-week phases of intensive induction/consolidation with 7 different drugs and cranial irradiation followed by maintenance with thioguanine and cytosine arabinoside for 2 years and additional adriamycin during the first year. A total of 151 children with AML were enrolled in the study from 30 centers. Of these 119 (79%) patients achieved complete remission. After a median observation time of 34 (14-57) months, there have been 46 relapses. CNS was involved in 6 of these relapses. Life table analyses revealed the following probabilities after 4 1/2 years: survival: 46%; disease-free survival: 41% (total group), 52% (remission group); disease-free interval 56% (remission group). The risk of relapse appears to decrease considerably after 2 1/2 years. No risk factors for the occurrence of relapse have been identified.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Doxorubicin; Humans; Leukemia, Myeloid, Acute; Methotrexate; Prednisolone; Prednisone; Risk; Thioguanine; Vincristine

Topics: Antineoplastic Agents; Cell Line; Colony-Forming Units Assay; Cytarabine; Dose-Response Relationship, Drug; Doxorubicin; Humans; Leukemia, Myeloid, Acute; Thioguanine; Tumor Stem Cell Assay

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Transplantation; Combined Modality Therapy; Cytarabine; Daunorubicin; Female; Graft vs Host Disease; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Middle Aged; Pulmonary Fibrosis; Recurrence; T-Lymphocytes; Thioguanine; Whole-Body Irradiation

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Female; Harringtonines; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prednisone; Thioguanine; Vincristine

Thirty patients with the 8;21 translocation and three with closely related variants have been studied. Ages ranged from 3 to 64 years (mean 28.3). Thirty-one were entered into the MRC's 8th Acute Myeloid Leukaemia Trial. Twenty-nine (88%) achieved complete remission. Marrow smears from most patients showed granulocytic maturation (M2, FAB classification) with characteristic abnormalities, but at least six showed predominantly myeloblastic (M1) morphology. The blast cells were markedly heterogeneous with regard to size and nuclear cytoplasmic ratio. Typical staining patterns were observed in the blast cells using Sudan black B and diaminobenzidine peroxidase stains, and to a lesser extent with periodic acid-Schiff and chloroacetate esterase. Butyrate esterase was negative in all cases. Auer rods were present in the granulocyte precursors in 31 cases and in eosinophil precursors in two cases. In most cases the existence of the translocation was predicted from the cytological and cytochemical findings. Seven patients developed solid leukaemic deposits, principally in the mastoid cavities, orbital cavities or thoracic spine (extradural).

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Child; Child, Preschool; Chromosomes, Human, 21-22 and Y; Chromosomes, Human, 6-12 and X; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Staining and Labeling; Thioguanine; Translocation, Genetic

46 adults with previously untreated acute myelogenous leukaemia who achieved complete remission with 6-thioguanine, cytarabine, and daunorubicin (TAD) received two courses of intensive consolidation chemotherapy. The first cycle consisted of 5-azacytidine and doxorubicin followed by a second consolidation cycle with TAD. Maintenance chemotherapy was not administered. Median remission duration was 14 months and 26% (95% confidence interval, 11%-41%) remained in continuous remission at 5 years. Actuarial 5 year survival was 31% (+/- 15%). Results were most favourable in patients who achieved complete remission within 60 days of chemotherapy being initiated. These data indicate that prolonged disease-free survival can be achieved in patients treated with intensive induction and consolidation treatment alone without maintenance chemotherapy.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Cytarabine; Daunorubicin; Drug Administration Schedule; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Recurrence; Thioguanine; Time Factors

Topics: Adult; Aminoacridines; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Daunorubicin; Delayed-Action Preparations; Doxorubicin; Drug Administration Schedule; Humans; Leukemia, Myeloid, Acute; Prednisone; Recurrence; Thioguanine; Vincristine

The clinical courses of 54 consecutive adult patients with acute myelogenous leukemia (AML) who underwent 67 courses of intensive remission induction therapy were analyzed to assess factors associated with development of serious fungal and bacterial infections. Fever developed in 65 of 67 remission induction attempts and was due to bacterial, bacterial-fungal, and fungal etiologies in 49%, 14%, and 9% of cases, respectively. No etiology of fever was found in 28% of cases. Bacteremia occurred in 54% of remission induction attempts. Invasive fungal disease (IFD) occurred in 22% of cases with an overall mortality of 60%, including 45% of the patients who died during treatment. Using multivariate logistic regression analysis, a mathematical model was constructed which correlated with the risk of IFD. Major factors associated with patients who ultimately develop IFD included the duration of chemotherapy, the number of sites colonized with fungi and the number of fungal species isolated on certain surveillance cultures, particularly Aspergillus species. These studies define characteristics of patients at high risk for development of IFD for whom early initiation of empiric antifungal therapy is strongly recommended.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mycoses; Risk; Sepsis; Statistics as Topic; Thioguanine

In 71 adult acute myelogenous leukaemia (AML) cases, the relationship between well-known prognostic features and complete remission (CR) rate and survival was studied. These features were: (i) bone marrow karyotype classified NN, AN, AA according to Sakurai & Sandberg (5); (ii) patients' age; (iii) clinical 'negative prognostic features' (NPF): previous history of preleukaemia, septicaemia or pneumonia, hyperleucocytosis, associated pathology (diabetes, obesity, renal insufficiency etc.). 59 years of age was found to be a frontier between 2 homogeneous groups having quite different prognosis. The NN/AN/AA classification had good prognostic value (CR rate and survival) in patients under 59 years, but not in older patients. In those patients over 59, a significant difference in CR rate and survival appeared between cases with NPF and those without. For each feature having an established relationship to survival, a panel of prognostic points was determined as follows: age over 59 (1 point), AA karyotype in patients under 59 (2 points), NPF in patients over 59 (1 point). Using this stage classification, it was possible to classify every case into 1 of 3 groups (i.e.: 0 points, 1 point, 2 points). The life-table analysis of these 3 groups showed very significant differences. The median survival times were 18.5 months, 5.2 months and 1.3 month, for the 0-point group (26 cases), the 1-point group (19 cases) and the 2-point group (26 cases), respectively.

Topics: Adolescent; Adult; Age Factors; Aged; Bone Marrow Cells; Cytarabine; Daunorubicin; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Karyotyping; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasm Staging; Prognosis; Thioguanine

As an experimental strategy for potentially dissociating and studying the cytotoxic and cytodifferentiative antileukemic effects of 6-thioguanine (6-TG), cultured human promyelocytic leukemia cells (HL-60) were serially selected for growth in increasing concentrations of 6-TG (0.5 to 50 micrograms/ml). Three acquired characteristics, cytotoxic resistance, cytodifferentiative resistance, and double minute chromosomes (DM), were monitored at successive 6-TG selection levels. Approximately 200-fold resistance to the cytotoxic effect of 6-TG was acquired at the first selection step, and it neither increased at higher 6-TG selection levels nor reverted to greater sensitivity in cells subcultured off of drug. This was due to the irreversible loss of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity. In contrast, a lesser, not completely quantifiable, degree of resistance developed to the cytodifferentiative effects of the purine nucleobases hypoxanthine and 6-TG which varied as a function of 6-TG selection pressure. Numerous DM, not observed in the parental wild-type HL-60 cells, appeared at 6-TG (0.5 micrograms/ml) selection which varied substantially in parallel with 6-TG selection pressure up to 6-TG (20 micrograms/ml). At higher selection levels (50 micrograms/ml or prolonged culture on 20 micrograms/ml), a marked decrease in DM occurred which was associated with the acquisition of new marker chromosomes. The most consistent marker was a chromosome 6 with additional material in the short arm (6p+); this was noted as a single copy in the basal 6-TG/20 subline but as two copies (trisomy 6; 2p+) in independently selected higher 6-TG-resistant subcultures. These cytogenetic findings suggest the presence of amplified genes which increased in number and shifted from a predominance in extra-chromosomal DM to intrachromosomal sites as a function of 6-TG selection. Among the 6-TG-resistant sublines, there was no change or a decrease in the amplification level of the known amplified oncogene c-myc from that demonstrated in parental HL-60 cells. Although proof requires detailed analyses with specific gene probes, the overall results imply that: (a) the cytotoxic component of the resistance is due to an invariant loss of HPRT which, therefore, is not likely to be related to amplified genes; (b) the cytodifferentiative component of the resistance is due to a positively selectable mechanism which could be directly or indirectly related to 6-TG-selected ampli

Topics: Animals; Cell Differentiation; Cell Line; Cell Survival; Chromosome Aberrations; Chromosome Disorders; Clone Cells; Drug Resistance; Guinea Pigs; Humans; Hypoxanthine; Hypoxanthine Phosphoribosyltransferase; Hypoxanthines; Karyotyping; Leukemia, Myeloid, Acute; Mutation; Thioguanine

A novel mechanism of resistance to the antileukemic agent 6-thioguanine (TGua) was demonstrated in a clone (TGuo-30-2) derived from HL-60 human acute promyelocytic leukemia cells. The clone was isolated by prescreening mutagenized HL-60 cells in hypoxanthine-amethopterin-thymidine medium, followed by selection with 6-thioguanosine. TGuo-30-2 cells were cross-resistant to TGua and beta-2'-deoxythioguanosine. TGuo-30-2 cells exhibited a marked decrease in the capacity to accumulate intracellular TGua nucleotides after treatment with TGua. The decrease in accumulation was not caused by a defect in transport, a lack or alteration of hypoxanthine-guanine phosphoribosyltransferase activity, or enhanced degradation of TGua nucleotides but appeared to be due to the maintenance of a lowered level of 5-phosphoribosyl 1-pyrophosphate (PRPP) in the resistant variant, which corresponded to 20% of the parental concentration. Despite the decrease in PRPP levels, incorporation of glycine into purine nucleotides was greater in TGuo-30-2 than in parental cells. Measurement of PRPP amidotransferase activity using cell homogenates revealed altered kinetics for the enzyme from TGuo-30-2 cells, which included significant loss of sensitivity to feedback inhibition by 6-thioguanosine 5'-phosphate and greater catalytic activity at low concentrations of PRPP.

Topics: Amidophosphoribosyltransferase; Biological Transport; Biotransformation; Cell Line; Cell Survival; Humans; Kinetics; Leukemia, Myeloid, Acute; Pentosyltransferases; Thioguanine

Delayed growth arrest was observed in HL-60 acute promyelocytic leukemia cells after exposure to 6-thioguanine (TG). This growth arrest occurred in both wild-type HL-60 cells exposed to 2 microM TG and an HL-60 clone lacking hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity at a 500-fold higher concentration of drug. Both cell lines continued replication during an initial 4-day period of exposure to TG; however, upon removal of the purine antimetabolite and reincubation in fresh medium in the absence of drug, no further increase in cell number was observed over the next 4 days. Extensive differentiation, as measured by the reduction of nitroblue tetrazolium, occurred in TG-treated, HL-60 HGPRT-negative cells, whereas no significant increase in the number of nitroblue tetrazolium-positive cells was observed in wild-type HL-60 cells exposed to the purinethiol. Thus, termination of proliferation in wild-type cells appeared to be an expression of cytotoxicity, while in the HGPRT-negative clone, cell replication was apparently terminated by conversion of cells to end-stage forms with a mature phenotype. In support of this conclusion, differences occurred in the stage of the cell cycle arrest, determined on Day 6 after exposure to TG. Approximately 85% of parental HL-60 cells treated with TG were present in the S and G2 + M phases of the cell cycle, with the greatest proportional change from untreated controls being in the G2-M phase (i.e., a 63% increase over untreated controls). In contrast, HL-60 HGPRT-negative cells treated with TG accumulated in G1, with 68% of the population located in this phase (i.e., an 80% increase compared to controls), as might be expected for a differentiated population. Dimethyl sulfoxide, which produced differentiation in both parental HL-60 and HL-60 HGPRT-negative cells, was used as a positive control. Both cell lines responded identically to dimethyl sulfoxide, with growth arrest being due at least in part to differentiation, which corresponded to an increase in G1 cells.

Topics: Cell Cycle; Cell Differentiation; Cell Division; Cell Line; Flow Cytometry; Humans; Kinetics; Leukemia, Myeloid, Acute; Thioguanine

Twenty-two patients with acute myeloid leukemia were studied for in vitro drug sensitivity of the leukemic clonogenic cells in agar. The cells were preincubated for 1 hr with 1-beta-D-arabinofuranosylcytosine (ara-C; 0.15, 0.3, 0.6, 1.2, and 2.4 micrograms/ml) or daunorubicin (0.018, 0.037, 0.075, 0.15, and 0.30 micrograms/ml), washed, and plated in agar, and cluster/colonies were counted after 10 days of incubation. Survival curves were constructed and used for calculation of the surviving fraction of clonogenic cells. In 18 patients treated with thioguanine-daunorubicin-1-beta-D-arabinofuranosylcytosine-prednisone, the in vitro drug sensitivities could be correlated to the in vivo response to therapy. Patients who entered remission (12 of 18) were significantly more sensitive to ara-C (p less than 0.005) and to daunorubicin (p less than 0.02) than patients who did not enter remission (six of 18). All patients who entered remission, except two, had normal or increased sensitivity to both drugs, and all patients who did not enter remission, with one exception, had decreased sensitivity to one or both drugs. Comparison of the cytostatic effect of [3H]thymidine and ara-C suggested that, in some cases, ara-C killed more clonogenic cells than those in S phase, and in some cases, the cells seemed to be metabolically resistant to ara-C. We conclude that in vitro drug sensitivity tests on leukemic clonogenic cells reflect the patient's in vivo response to the tested drugs and may be used to study the biological properties of leukemic stem cells that determine their drug sensitivity.

Topics: Acute Disease; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cell Survival; Cells, Cultured; Colony-Forming Units Assay; Cytarabine; Daunorubicin; DNA Replication; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prednisolone; Thioguanine

A consecutive series of patients (1978-1981) comprising all patients with acute leukaemia from a population of 475000 inhabitants was reviewed. Thus, 94 patients were diagnosed as having acute leukaemia. No patients were lost from follow-up. The incidence figures of ALL and AML differed significantly from those of Sweden as a whole. 9 patients were less than 15 years old. The median age of adult patients was 64 years, 60.8% being greater than or equal to 60 years old. Of adult patients with AML, 20% had a preleukaemic history (chronic myeloproliferative disorders, myelodysplastic syndromes and others). None of 6 patients with leukaemia as a metamorphosis of a chronic myeloproliferative disorder achieved a complete remission. The overall remission rate of the remaining adult patients was 25%. Treated patients, 15-39 years old, with AML without any preleukaemic history, had a complete remission rate of 80% compared to 12% for patients greater than or equal to 60 years old with the same diagnosis. Of 60 patients with 'primary' AML, 14 were not treated, mainly because of advanced age and complicating diseases. Most of these patients died within a week of admission.

Topics: Adolescent; Adult; Age Factors; Aged; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Middle Aged; Prednisolone; Preleukemia; Sweden; Thioguanine; Vincristine

The relationship between cell growth inhibitory effects and terminal differentiation-inducing effects of nine clinically active chemotherapeutic agents was evaluated using HL-60, a human acute myelogenous leukemia cell line. Continuous exposure to HL-60 cells of adriamycin, daunorubicin, mitoxantrone, m-AMSA, cytosine arabinoside, 6-thioguanine (6-TG), actinomycin-D (Act-D) and vincristine resulted in percentage increase of morphologically differentiated cells and phagocytic cells. Hydrocortisone at a concentration of up to 10(-4) M failed to produce this effect. Examination of actual numbers per flask of morphologically differentiated cells and phagocytic cells revealed, however, that all these agents except Act-D and 6-TG failed to produce a numerical increase in differentiated cells in comparison with those of control groups at day 6. Only Act-D and 6-TG were able to produce increases in the percentage, as well as actual number, of differentiated cells. These data indicate that the percentage increase in terminal differentiation-induced cells by certain chemotherapeutic agents is due not to their ability to increase differentiated cells but to their ability to inhibit the growth of primitive cells preferentially.

Topics: Anthraquinones; Antineoplastic Agents; Cell Differentiation; Cell Division; Cell Line; Cell Survival; Cytarabine; Dactinomycin; Daunorubicin; Doxorubicin; Humans; Leukemia, Myeloid, Acute; Mitoxantrone; Phagocytes; Thioguanine; Vincristine

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Thioguanine

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Doxorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prednisolone; Prednisone; Thioguanine; Vincristine

HL-60 human acute promyelocytic leukemia cells that lack hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity have been developed by mutagenization and selection. These cells exhibited markedly decreased sensitivity to the cytotoxic action of 6-thioguanine (TG) and, in contrast to parental HL-60 cells, had the capacity to undergo terminal granulocytic differentiation after treatment with this purine antimetabolite. Analysis of extracellular and intracellular metabolites of TG revealed negligible metabolism of TG in these HGPRT- HL-60 cells. These findings are consistent with the concept that inhibition of cellular replication requires generation of analog nucleotide and suggest that TG itself is capable of initiation of differentiation. 6-Thioguanosine (TGuo) had limited activity, while beta-2'-deoxythioguanosine (dTGuo) was inactive, as an inducer of maturation of HGPRT- HL-60 cells. These cells converted relatively large amounts of the nucleosides to the free base TG; the simultaneous exposure of cells to 8-aminoguanosine (AGuo), an inhibitor of purine nucleoside phosphorylase activity, decreased the degradation of TGuo and dTGuo to TG and promoted the intracellular accumulation of TG nucleotides, presumably through the action of nucleoside kinase activities. In a double mutant deficient in both HGPRT and deoxycytidine kinase (DCK) activities, dTGuo was devoid of cytotoxicity and was an effective inducer of maturation. The potency of dTGuo as an inducer in this system was not significantly affected by the presence of AGuo. These results suggested that dTGuo itself was also an active initiator of maturation. Thus, induction of differentiation appeared to be due to the free base, TG, as well as its deoxynucleoside form, dTGuo, whereas the formation of TG nucleotides appeared to antagonize maturation and produce cytotoxicity.

Topics: Cell Differentiation; Cell Division; Cell Line; Cell Survival; Clone Cells; Deoxycytidine Kinase; Humans; Hypoxanthine Phosphoribosyltransferase; Kinetics; Leukemia, Myeloid, Acute; Mutation; Thioguanine

Hepatotoxicity is regarded as a rare side effect of amphotericin B therapy. A patient with acute myelogenous leukemia who had normal liver function was treated with amphotericin B for fungal pneumonia. While he was receiving the drug at high dosages asymptomatic elevation of the levels of alkaline phosphatase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, lactic dehydrogenase and bilirubin was noted. The levels returned to normal when the drug was discontinued. Rechallenge with a lower dosage prompted a rapid rise in the levels, with subsequent return to normal when the medication was withdrawn.

Topics: Amphotericin B; Chemical and Drug Induced Liver Injury; Cytarabine; Humans; Leukemia, Myeloid, Acute; Liver; Male; Middle Aged; Mycoses; Pneumonia; Thioguanine

Bone marrow fibre content was studied in 34 patients with acute myeloid leukaemia at presentation and subsequently after chemotherapy and at complete remission. The findings indicate that: some degree of marrow fibrosis is present in about one third of the patients with acute myeloid leukaemia at presentation; effective antileukaemia treatment may result in reversal of marrow fibrosis; and increase in marrow fibre content at diagnosis does not affect haemopoietic regeneration after treatment and achievement of complete remission.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Collagen; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Podophyllotoxin; Primary Myelofibrosis; Reticulin; Thioguanine

Twenty-six patients with acute myeloid leukemia, acute lymphoid leukemia and chronic granulocytic leukemia in blast crisis were studied by means of multiple biopsies during a polychemotherapeutic or autologous bone marrow transplant protocol. Following chemotherapy, 3 main phases were observed: leukemic cellular depletion, stromal bone marrow reconstruction, and bone marrow hemopoietic restoration. Following intensive chemotherapy (in 2 patients after cyclophosphamide and total body irradiation) and autologous bone marrow transplantation, the 3 phases appeared to be shorter. A focal or diffuse increase in marrow fibrosis was a common finding in leukemia. An effective antileukemic therapy resulted in a decrease in fibrosis, whereas in some cases a further increase was a precocious sign of leukemia relapse.

Topics: Adolescent; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Bone Marrow; Bone Marrow Transplantation; Child; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Male; Middle Aged; Prednisolone; Thioguanine; Time Factors; Transplantation, Autologous; Vincristine; Whole-Body Irradiation

Colony formation in vitro from bone marrow haemopoietic progenitors was studied in a group of patients with acute myeloblastic leukaemia and acute lymphoblastic leukaemia at presentation of the disease and, in a few cases, during complete remission. Both granulocytic-macrophagic (CFU-GM) and erythropoietic (CFU-E) colonies were studied. A sharp contrast was observed between CFU-GM and CFU-E formation at presentation of the disease: while the former was markedly depressed, with considerable increase of the cluster colony ratio, CFU-E production was not significantly affected, with only a reduced sensitivity to low-dose erythropoietin. CFU-GM formation returned to normal in the early stages of complete remission, but showed a progressive decline in the course of time; the process of cell differentiation was not significantly impaired, although minor changes were observed. It appears that the leukaemic process has much greater impact altogether on CFU-GM than on CFU-E colony formation, the latter being only marginally affected, even in the presence of a high proportion of blast cells.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colony-Forming Units Assay; Cytarabine; Daunorubicin; Drug Therapy, Combination; Erythrocytes; Female; Granulocytes; Hematopoietic Stem Cells; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Macrophages; Thioguanine; Time Factors

A longitudinal observation of a patient with idiopathic refractory sideroachrestic anemia (IRSA) progressing to acute mixed lymphoblastic-myelomonoblastic leukemia is reported. The leukemia was characterized by morphology, immunological cell markers, and dissociated clinical responsiveness to vincristine/prednisone and arabinosylcytosine/6-thioguanine. Attention is paid to the hematological changes prior to leukemia development. Acute leukemia was best heralded in this patient by a severe deterioration of dyserythropoiesis and by an increase of blasts in the marrow to more than 5%. The observed preleukemic features are compared to those described in the literature.

Topics: Aged; Anemia, Sideroblastic; Bone Marrow Examination; Cerebrospinal Fluid; Cytarabine; Female; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Pneumonia; Prednisone; Thioguanine; Tuberculosis, Miliary; Vincristine

Topics: Adult; Cerebral Hemorrhage; Cytarabine; Daunorubicin; Female; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Lung; Thioguanine

Cytochemical stains and morphologic characteristics were essential in making the correct diagnosis in a dog with acute myelomonocytic leukemia, which initially was diagnosed as lymphoblastic leukemia. Response to a treatment regimen of cytosine arabinoside, thioguanine, vincristine, and doxorubicin, besides accomplishing complete remission, helped revise the initial diagnosis to acute myelomonocytic leukemia. After remission was achieved, the dog died of a fulminating viral infection.

Topics: Animals; Antineoplastic Agents; Cytarabine; Dog Diseases; Dogs; Doxorubicin; Drug Therapy, Combination; Female; Leukemia, Myeloid, Acute; Thioguanine; Vincristine

Plasma fibronectin was determined using a laser nephelometric method in 10 patients with acute myeloid leukaemia undergoing chemotherapy. There was a continuous fall during the first 3 weeks to about 50% of the normal level. The decrease of fibronectin may contribute to the lowered resistance against infection characteristic of these patients.

Topics: Adult; Aged; Bronchopneumonia; Cytarabine; Daunorubicin; Female; Fever; Fibronectins; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Thioguanine

A case of acute nonlymphocytic leukemia presenting as pericarditis is reported in a five-year-old boy. Initially, a clinical diagnosis of viral pericarditis was made, because the child did not demonstrate hematologic or clinical manifestations of leukemia. Acute undifferentiated or lymphocytic leukemia. Acute undifferentiated or lymphocytic leukemia was diagnosed one week after admission when his peripheral blood count became abnormal. The patient did not respond to vincristine and prednisone. When cytochemical evaluation indicated acute myelomonocytic leukemia, employment of cytosine arabinoside and 6-thioguanine was instituted and the child began to improve. Currently, he is still in good remission and has no evidence of recurrence of pericarditis, 1 1/2 years after his initial presentation. In reviewing the literature, we found 17 patients who had leukemic pericardial effusion with cardiac tamponade. There are three reported cases of young children with pericardial effusion as the initial manifestation of acute lymphocytic leukemia, but no reported cases due to nonlymphocytic leukemia, as in this child.

Topics: Acute Disease; Child, Preschool; Cytarabine; Diagnosis, Differential; Humans; Leukemia; Leukemia, Myeloid, Acute; Male; Pericarditis; Thioguanine

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aged; Antineoplastic Agents; Asparaginase; Cyclophosphamide; Cytarabine; Dexamethasone; Doxorubicin; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Middle Aged; Patient Isolation; Prednisolone; Thioguanine; Vincristine

Refractory dysmyelopoietic anemia (RDA) is a myeloproliferative disorder usually of elderly patients which often evolves into acute myelogenous leukemia (AML). AML in such patients is usually considered untreatable with standard aggressive chemotherapy in part because these patients are often elderly, but primarily because of the concern that the bone marrow of these patients no longer has a residual stem cell to repopulate the bone marrow following chemotherapy-induced aplasia. The authors treated three patients (ages 72, 69, and 62 years, respectively) with intensive chemotherapy after RDA evolved into AML. Each patient had been pancytopenic for 3 to 15 months prior to their transition to AML. At the onset of therapy for AML, all were severely pancytopenic with greater than 50% myeloblasts in the bone marrow. All patients had bone marrow aplasia by day 14 after chemotherapy with a complete bone marrow remission and normal peripheral counts by day 26. These data suggest that intensive chemotherapy of AML with prior RDA may result in complete bone marrow remission.

Topics: Age Factors; Aged; Anemia, Hemolytic; Bone Marrow; Cytarabine; Doxorubicin; Drug Therapy, Combination; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Pancytopenia; Thioguanine

A system for the prediction of clinical response in acute myelocytic leukaemia (AML), based on inhibition of growth of colony forming cells (CFC) was studied. If the product of initial drug concentration and time of exposure (C X T) was constant, the response to adriamycin (Adr) was constant, at T values less than 48 h. No constancy of response to the phase-specific agents cytosine arabinoside (Ara-C) and 6-thioguanine (6TG) was demonstrated with constant C X T (T value range 0.25-48 h). Hence in the predictive test, a 1 h incubation with Adr was employed whilst a continuous exposure to Ara-C and 6TG, with these drugs incorporated in the agar medium, was used. The in vitro sensitivity to Adr, Ara-C and 6TG of 19 AML patients and the predictive value of several parameters of sensitivity were evaluated. 6TG sensitivity was not useful for prediction of remission. Adr sensitivity in vitro made a greater contribution to prediction of remission than did Ara-C sensitivity. Seventy-nine percent of patients were correctly classified if Adr data alone were considered. A multivariate function including Adr and Ara-C results was obtained which resulted in 84% of patients correctly classified as sensitive or resistant to the agents received in remission-induction therapy.

Topics: Adolescent; Adult; Antineoplastic Agents; Child; Child, Preschool; Colony-Forming Units Assay; Cytarabine; Dose-Response Relationship, Drug; Doxorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplastic Stem Cells; Thioguanine; Time Factors; Tumor Stem Cell Assay

Three children developed acute veno-occlusive disease of the liver following combination chemotherapy for acute myelocytic leukemia. The clinical presentation was similar in all three, with acute onset of hepatomegaly and thrombocytopenia in the absence of significant transaminasemia or icterus. In all three patients, radionuclide imaging with technetium-99m sulfur colloid showed hepatosplenomegaly, decreased liver uptake, and increased splenic activity. The results of liver biopsy established the diagnosis, revealing marked centrilobular congestion with hemorrhage into the spaces of Disse, atrophy of central hepatic cords, and edema of the walls of the central and sublobular veins. Each patient showed marked improvement following temporary cessation of chemotherapy. The diagnosis of veno-occlusive disease is suggested by the triad of: (1) clinical signs and symptoms; (2) scintigraphic findings; and (3) temporal relationship to chemotherapy.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Budd-Chiari Syndrome; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Daunorubicin; Drug Therapy, Combination; Female; Hepatic Veins; Humans; Leukemia, Myeloid, Acute; Liver Diseases; Male; Radionuclide Imaging; Thioguanine

We describe 3 cases of acute graft-versus-host (GVH) disease in patients with acute myeloid leukaemia following transfusions taken from non-HLA-identical healthy donors. The leucocyte transfusions were given because of severe bone marrow aplasia and granulocytopenia following leukaemia induction treatment. The first patient had an acute GVH reaction with an erythrodermia-like skin reaction all over and associated with severe abdominal cramping, enlarged liver and pathological liver function tests. The second patient had a relatively mild skin reaction and enlarged liver. Both died of severe pulmonary infection. The third patient also had a mild skin reaction and enlarged liver. He died of pulmonary embolism. The diagnosis of GVH of the latter 2 cases was made on skin biopsy. The autopsy samples revealed in all cases a heavy lymphocytic infiltration of the kidneys and liver portal area. Until more precise guidelines can be established, irradiation of blood cell products given to patients with neutropenia due to leukaemia induction treatment should be considered.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Daunorubicin; Graft vs Host Disease; Humans; Leukemia, Myeloid, Acute; Leukocytes; Male; Methotrexate; Middle Aged; Neutropenia; Prednisolone; Prednisone; Thioguanine; Transfusion Reaction; Vincristine

Topics: Cell Differentiation; Cell Line; Chromosomes, Human; Drug Resistance; Humans; Leukemia, Myeloid, Acute; Mutation; Thioguanine

Topics: Adolescent; Adult; Age Factors; Aged; Antineoplastic Agents; Child; Child, Preschool; Cytarabine; Daunorubicin; Doxorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Retrospective Studies; Thioguanine

Complete remission was achieved in 11 of 22 children with acute myeloid leukaemia using at least two courses of a 24 hour infusion of cytosine arabinoside (Ara-C) 10 mg/kg, followed by push injections of daunorubicin (DNR) 45 mg/m2, and adriamycin (ADR) 45 mg/m2. Consolidation therapy consisted of three courses of Ara-C and 6-thioguanine (Tg) and one course of cyclophosphamide (CPA) and ADR. Central nervous system prophylaxis with intrathecal Ara-C was given in all patients and cranial irradiation of five. Maintenance therapy consisted of 5 day courses of Ara-C and Tg given 4 weekly with immunotherapy (BCG) vaccine and subcutaneous leukaemic cells) between courses. Median length of first complete remission was 99+ weeks, and median survival of all patients was 44 weeks. Median survival of remitters was 195+ weeks and non-remitters, 28 weeks. Two patients developed central nervous system disease, one at presentation and the other 46 weeks from presentation. Five patients have ceased therapy and remain in remission from 32 to 142 weeks after ceasing treatment.

Topics: Adolescent; Antineoplastic Agents; Brain Neoplasms; Child; Child, Preschool; Cytarabine; Daunorubicin; Doxorubicin; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Infant; Leukemia, Myeloid, Acute; Male; Thioguanine

A patient with relapse of acute granulocytic leukemia developed an Aspergillus infection along the subcutaneous tract of a silicone rubber indwelling central venous catheter. The infection invaded the brachial plexus resulting in paralysis of the right upper extremity and subsequently invaded a major artery of the arm resulting in the demise of the patient. Both an infectious brachial plexus neuritis and fatal hemorrhage secondary to a Hickman catheter are apparently rare.

Topics: Antineoplastic Agents; Aspergillosis; Brachial Plexus; Catheters, Indwelling; Cytarabine; Female; Hemorrhage; Humans; Leukemia, Myeloid, Acute; Middle Aged; Neuritis; Thioguanine

A case of acute myelomonocytic leukaemia in pregnancy with successful outcome is reported. Aspects of management are reviewed, especially with regard to expected complications following cytostatic therapy and the effects on both mother and fetus. The need to determine the optimal time for elective delivery is emphasized. The seasons for formation of an international tumour registry are outlined. The disease can no longer be regarded as invariably fatal for mother and child.

Topics: Adult; Cytarabine; Female; Humans; Leukemia, Myeloid, Acute; Pregnancy; Pregnancy Complications, Hematologic; Thioguanine

Discriminant and regression analyses were employed to determine the influence of a large number of clinical and laboratory indices on outcome of treatment in a series of 158 adults presenting with acute leukaemia between 1970 and 1977. Induction therapy had been most commonly cytosine arabinoside plus daunorubicin, vincristine and prednisolone. This induced complete remission in 42% of non-lymphoblastic, and in 58% of lymphoblastic plus undifferentiated leukaemias. Some induction failures who had non-lymphoblastic leukaemia were treated with cytosine arabinoside plus 6-thioguanine, which induced remissions in 46%. Advanced age was the factor most strongly associated with failure either to achieve or to sustain complete remission. Thrombocytopenia, promyelocytic leukaemia, high percentage of marrow blasts, and absence of metaphases in marrow cytogenetic preparations were also associated with poor survival. A number of other factors which appeared to be associated with poor prognosis were found by the analysis to lack significance as independent variables.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Karyotyping; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Middle Aged; Prednisolone; Prognosis; Regression Analysis; Retrospective Studies; Thioguanine; Vincristine

Lesions of hepatic veno-occlusive disease were found in the needle biopsy specimen of one patient suffering from chronic granulocytic leukaemia and in the liver at necropsy of a second patient suffering from acute myeloid leukaemia. The treatment included administration of 6-thioguanine which was the only relevant compound used in the first patient and which was combined with cytosine arabinoside in the second patient.

Topics: Adult; Chemical and Drug Induced Liver Injury; Constriction, Pathologic; Female; Hepatic Veins; Humans; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Liver; Liver Diseases; Male; Thioguanine; Vascular Diseases

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Cytarabine; Doxorubicin; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Thioguanine

The most effective schedule of cytosine arabinoside (Ara-C) administration remains controversial and is further confused by the use of combination chemotherapy. Two remission induction regimens comprising adriamycin, Ara-C, and 6-thioguanine have been compared in patients with acute myelogenous leukemia. Administration of Ara-C by continuous intravenous infusion resulted in faster clearing of leukemic blasts from the peripheral blood and bone marrow than after administration of the same dose by twice daily intravenous injection. Myelosuppression and gastrointestinal toxicity were, however, more pronounced when Ara-C was given by infusion. The complete remission rate was higher in the patients treated with intravenous infusions. It is too early to assess the duration of remission in the infusion study; however, despite the relatively low remission rate, 80% of patients under the age of 60 in the intravenous bolus study remain in remission with a minimum follow-up of two years.

Topics: Adult; Bone Marrow; Cytarabine; Digestive System; Doxorubicin; Drug Administration Schedule; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Leukocyte Count; Thioguanine

The treatment of acute myelocytic leukemia in childhood and young adults has lagged behind that for acute lymphocytic leukemia. The studies described here were directed towards evaluating the role of intensive chemotherapy in the treatment of this illness. Intensive remission induction therapy combining cytosine arabinoside with an anthracycline antibiotic produced a complete remission rate comparable to that achieved in acute lymphocytic leukemia (45 of 49 patients or 92%). Intensive consolidation chemotherapy produced a median duration of complete remission of 160 weeks with 40% of patients projected to be in remission at 4 years. By contrast, the median duration of remission for patients treated with moderate consolidation/maintenance therapy was 23 weeks with only 10% of patients in remission at 4 years. These studies demonstrate that intensive chemotherapy can be administered to pediatric patients and young adults and that this approach to therapy produces a high remission rate with a 3 year median duration of remission.

Topics: Adolescent; Adult; Age Factors; Antineoplastic Agents; Cytarabine; Daunorubicin; Doxorubicin; Drug Combinations; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Sulfamethoxazole; Thioguanine; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Antineoplastic Agents; Cytarabine; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Middle Aged; Thioguanine; Vincristine

Topics: Cytarabine; Daunorubicin; Doxorubicin; Drug Therapy, Combination; Female; Humans; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Male; Thioguanine

One-hundred and seven patients with acute myelogenous leukemia (AML) ranging in age from 15 to 82 yr who were previously untreated, received a 70 day high-dose remission induction regimen consisting of daunorubicin, cytarabine, and thioguanine (TAD). Identical complete remission rates of 65% were observed for 33 patients 60 yr of age and older and for 74 patients age 15-59 yr. Median remission duration and survival were 14 mo and 22 mo for patients 60 yr and older, and 16 mo and 22 mo for patients 15-59 yr. These differences are not significant. These data indicate that older patients respond to intensive chemotherapy in a similar manner to younger patients with this disease.

Topics: Adolescent; Adult; Aged; Cytarabine; Daunorubicin; Female; Granulocytes; Humans; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Middle Aged; Platelet Count; Platelet Transfusion; Thioguanine; Time Factors

Although thioguanine has been in clinical use for over 20 years, few data are yet available on the clinical pharmacology of thioguanine administered orally. We have studied the plasma thioguanine levels in acute myelogenous leukemia patients during remission induction (daunomycin 60 mg/m2 on day 1, arabinosylcytosine 200 mg/m 2. day for 7 days by infusion, thioguanine 100 mg/m2 PO every 12 h for 7 days) and remission maintenance (arabinosylcytosine 200 mg/m2 . day for 4 days by infusion, thioguanine 100 mg/m2 PO every 12 h for 4 days). Hourly blood samples were taken after thioguanine administration, and plasma thioguanine levels were measured by high-performance liquid chromatography with an anion-exchange column. Prior to the chromatography the thioguanine was oxidized by alkaline potassium permanganate to the corresponding 6-sulfonate, which was monitored by means of fluorescence detection. Peak plasma levels of thioguanine were observed 2-4 h after administration and varied from 0.03-0.94 microM. Plasma levels of thioguanine were markedly lower in patients with severe nausea and emesis. Food intake at the same time as thioguanine administration also tended to lower plasma drug levels. The 30-fold range in thioguanine plasma levels observed in this study suggests that intermittent IV administration may provide a better means of standardizing the dosage of thioguanine.

Topics: Chromatography, Ion Exchange; Humans; Leukemia, Myeloid, Acute; Thioguanine; Time Factors

A study of over 300 adult patients with acute myeloid leukemia has been completed by member institutions of the Eastern Cooperative Oncology Group. A complete remission rate of 51% was achieved. The FAB classification was used with an overall concordance of 61% between investigators and the repository center. Acute monocytic leukemia (M5) and acute erythroleukemia (M6) accounted for 12% of the cases accessioned and had the worst median survival with no patients surviving 2 years. The longest response duration occurred in hypergranular promyelocytic leukemia (M3).

Topics: Adult; Cytarabine; Daunorubicin; Histocytochemistry; Humans; Leukemia, Myeloid, Acute; Nervous System Neoplasms; Prognosis; Thioguanine; Vincristine

Topics: Animals; Cytarabine; Dog Diseases; Dogs; Female; Leukemia; Leukemia, Myeloid, Acute; Meningitis; Thioguanine

Topics: Cell Line; Cells, Cultured; Dimethyl Sulfoxide; Dimethylformamide; Humans; Hypoxanthines; Karyotyping; Leukemia, Myeloid, Acute; Thioguanine

We evaluated retrospectively the clinical outcome of 47 patients with acute myelogenous leukemia who entered an intensive chemoimmunotherapy treatment protocol between January 1975 and July 1978. Remission duration and survival were substantially longer in patients in whom hepatitis developed.

Topics: Adolescent; Adult; Aspartate Aminotransferases; Child; Child, Preschool; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Hepatitis B; Humans; Infant; Leukemia, Myeloid, Acute; Liver Function Tests; Male; Middle Aged; Prognosis; Retrospective Studies; Thioguanine

Twenty-eight patients with acute non-lymphoblastic leukemia (ANLL) were started on induction chemotherapy consisting of Cytosine Arbinoside (Ara C) and 6 thioguanine (TG). Daunorubicin (DNR) was used selectively in 20 of 28 patients who failed to respond by day 14 to the Ara C and TG combination. Seven patients, or 25%, achieved complete remission (CR) without requiring DNR during remission induction. The overall response rate was 89% (64% CR and 25% PR). The median duration of survival for the CR group was 578 days. 189 days for the partial remission (PR) group (P = .02). Patients in the age groups of 18--40 years and with acute myelomonocytic leukemia subtype had the best response rate. There was no difference in the survival of the DNR treated group of complete responders as compared to DNR non-treated group. These results suggest that even though the majority of patients do require DNR for the remission induction, a significant number, perhaps as high as 25% of previously untreated patients, will achieve remission without the use of DNR. A significant minority of patients, therefore, be spared the toxicity of DNR early in the course of their disease.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Infant; Leukemia, Myeloid, Acute; Male; Middle Aged; Remission, Spontaneous; Thioguanine

Topics: Adult; Aged; Asparaginase; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Methotrexate; Middle Aged; Prednisone; Thioguanine; Vincristine

The management of acute leukemia during pregnancy is difficult. We induced remission in a 23-year-old woman with thioguanine and cytarabine therapy during the 27th week of pregnancy. There were no apparent drug-related, long-term effects on the newborn.

Topics: Adult; Cytarabine; Drug Administration Schedule; Female; Humans; Infant, Newborn; Leukemia, Myeloid, Acute; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Trimester, Second; Thioguanine

Topics: Adult; Age Factors; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Thioguanine

The antineoplastic agent, 6-thioguanine, was found to be a highly potent inducer of differentiation of HL60 human leukemia cells in vitro, producing cells with predominantly myeloid characteristics, as judged by morphological, functional, and cytochemical criteria. Maturation of HL60 was attainable without significant cytotoxicity as measured by cell number; moreover, maximal differentiation occurred at a level of the purine antimetabolite below that producing 50% growth inhibition. The 6-thioguanine-induced differentiated cells had distinctive granulocytic morphology, and were capable of generating superoxide anion during the respiratory burst typical of mature phagocytic cells.

Topics: Cell Differentiation; Cell Line; Dimethyl Sulfoxide; Humans; Leukemia, Myeloid, Acute; Thioguanine

Topics: Adolescent; Adult; Antineoplastic Agents; Asparaginase; Aziridines; Bone Marrow Transplantation; Carubicin; Cyclophosphamide; Drug Therapy, Combination; Graft Survival; Humans; Immunosuppressive Agents; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Mercaptopurine; Methotrexate; Middle Aged; Organophosphorus Compounds; Prednisolone; Purines; Thioguanine; Transplantation, Homologous; Vincristine

15 patients with acute myeloblastic leukaemia (AML) in remission were given immunotherapy and 17 similar patients were given immunotherapy plus chemotherapy with the drugs used to induce remission. Median remission length was 245 days for both groups and median survival was 465 days for patients given chemoimmunotherapy and 476 days for patients given only immunotherapy. The failure of remission chemotherapy in AML cannot be attributed to induced resistance because the same drugs induced a second remission in 60% of the patients. From laboratory studies with human AML cells it is suggested that in AML the residual leukaemic cells mature after induction chemotherapy and are then refractory to further drug treatment. Relapse occurs when the leukaemic population proliferates and the environment permits dedifferentiation into frank blast cells.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; BCG Vaccine; Bone Marrow; Bone Marrow Transplantation; Cytarabine; Daunorubicin; Doxorubicin; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prognosis; Remission, Spontaneous; Thioguanine; Transplantation, Homologous

Cell kinetic changes induced in the marrow blasts by treatment with a triple cytotoxic regimen including daunorubicin, cytosine arabinoside and 6-thioguanine (DAT) were investigated in 6 previously untreated acute nonlymphocytic leukemia patients. A decrease in the labeling and mitotic indices was consistently observed 24 h after administration of daunorubicin, suggesting a G2 block and a preferential lytic effect on the S-phase cells operated by the drug. Conversely, cytosine arabinoside and 6-thioguanine in combination induced a series of kinetic perturbations variable from case to case; however, three principal patterns of kinetic response were recogized and discussed in detail. Useful information for the planning of a more rational antileukemic therapy can be drawn from a systematic study of the kinetic effects induced by drug combinations.

Topics: Adolescent; Adult; Bone Marrow; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitotic Index; Thioguanine

Sequential studies in acute myeloid leukemia of bone marrow cells in agar culture showed striking fluctuations of colony and cluster formation during induction of remission. These oscillations may be initiated by recruitment of resting leukemic and normal cells upon chemotherapeutic perturbation. Striking oscillations of the colony and cluster formation occurred also during remission with or without maintenance therapy, but with a longer periodicity as compared sto the phase of induction of remission. Oscillations of the marrow growth capacity during remission may reflect potential relapses where the outcome depends on proliferative advantages of the normal or leukemic cell clone.

Topics: Adult; Bone Marrow; Colony-Forming Units Assay; Culture Techniques; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prednisone; Thioguanine

Topics: Adult; Animals; Antineoplastic Agents; Child; Drug Resistance; Drug Therapy, Combination; Humans; Immunosuppression Therapy; In Vitro Techniques; Kinetics; Leukemia; Leukemia L1210; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Middle Aged; Neoplasms, Experimental; Thioguanine

Tn polyagglutination (persistent mixed-field polyagglutination) was detected in the blood of a 66-yr-old male laborer at the time of a splenectomy for life-threatening thrombocytopenia. Confirmation that the polyagglutination was caused by Tn activation was established by the use of lectins, by failure of the patient's red cells to react with sera from other patients with Tn polyagglutination, by weak aggregation with polybrene, by low red cell sialic acid levels, and by the persistence of polyagglutination over several years of testing. Two years after the discovery of the Tn polyagglutination, the patient developed acute myelomonocytic leukemia. Vigorous chemotherapy regimens resulted in clinical remission of the leukemia and the Tn polyagglutination. This report describes the first known case of Tn polyagglutination preceding the development of acute myelogenous leukemia.

Topics: Aged; Cytarabine; Daunorubicin; Hemagglutination; Humans; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Splenectomy; Thioguanine; Thrombocytopenia

Between October 1974 and October 1978 23 children with acute myelocytic leucemia (AML) received intensive therapy in the Univ.-Kinderklinik Münster: 4 children were treated according to the ALGB-protocol consisting of 5-7 day courses of ARA-C-infusion and 3 DNR-injections. 19 patients received the West-Berlin-protocol: The first 7 the original ALL protocol, 11 the modified form of AML, which will be presented here as AML-therapy-study BFM 78. 4 of the 23 patients died with early acute cerebral bleeding. 2 patients were nonresponders. 17 children went into remission. One girl died in remission of septicemic aspergillosis. 4 children had a relapse. In November 1978 there were still 12 patients in continuous complete remission, 3 of them already without therapy. 13 of the 19 patients, who were treated with the West-Berlin-protocol went into remission. 1 had a relapse. At present there are 11 patients in continuous complete remission. The above results and those found in the literature could signify that the long term prognosis of children with AML will be improved. To coordinate efforts toward this goal a cooperative AML-therapy-study in the "Deutsche Arbeitsgemeinschaft für Leukämieforschung" (BFM-group) using the here presented therapy protocol was formed in November 1978.

Topics: Adolescent; Child; Child, Preschool; Cytarabine; Daunorubicin; Female; Humans; Infant; Leukemia, Myeloid, Acute; Male; Prognosis; Thioguanine

Combination cytotoxic chemotherapy was used to treat a case of acute myeloid leukaemia presenting in the 25th week of pregnancy with a sustained complete remission of the leukaemia and the successful delivery of a normal infant. The management of leukaemia presenting in pregnancy is discussed.

Topics: Adult; Blood Transfusion; Cytarabine; Drug Therapy, Combination; Female; Humans; Infant, Newborn; Leukemia, Myeloid, Acute; Platelet Transfusion; Pregnancy; Pregnancy Complications; Thioguanine

A 28-year-old woman with acute myeloblastic leukaemia was effectively treated with cytosine arabinoside and 6-thioguanine during the third trimester of pregnancy and a complete remission achieved. A normal infant was delivered at term. The patient survived for 27 months and the baby is now 2 1/2 years old with normal physical and mental development. The literature on management of acute non-lymphocytic leukaemia during the second and third trimester of pregnancy is reviewed and it is concluded that effective combination chemotherapy improves fetal survival.

Topics: Adult; Cytarabine; Female; Humans; Infant; Infant, Newborn; Leukemia, Myeloid, Acute; Pregnancy; Pregnancy Complications; Pregnancy Trimester, Third; Thioguanine

Topics: Antineoplastic Agents; Bacterial Infections; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Neutropenia; Prednisone; Thioguanine

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Child; Child, Preschool; Cytarabine; Daunorubicin; Drug Administration Schedule; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Middle Aged; Platinum; Thioguanine

A modification of the protocol of cytarabine and thioguanine was used for remission induction in patients with acute nonlymphocytic leukemia. First, synchronization of the mitotically active leukemia cells was attempted by administering cytarabine alone in a dose of 5 mg/kg of body weight 24 hours prior to initiating daily therapy with both drugs. Second, in order to recover dormant leukemic cells into the proliferative pool, both drugs were continued without interruption and without regard to the suppression of the circulating leukocyte and platelet count until bone marrow aspirates, repeated daily if necessary, were free of leukemic blast cells. This usually resulted in severe but reversible bone marrow hypoplasia, and 16 of 21 patients (76%) so treated achieved complete hematologic remission.

Topics: Adolescent; Adult; Aged; Cytarabine; Female; Humans; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Middle Aged; Platelet Count; Thioguanine

Patients with acute myelogenous leukemia in remission have pronounced deficiency in antibody-dependent cellular cytotoxicity (ADCC) and mitogen-induced cellular cytotoxicity. The deficiency in ADCC was partly explained by reduction in the number of circulating effector cells (Fc receptor-bearing cells) demonstrable at a time when white blood cell and platelet counts were normal. These cytotoxic functions, as well as the circulating numbers of T-cells and Fc receptor-bearing cells were further decreased by the administration of monthly cycles of combination chemotherapy with 1-beta-D-arabinofuranosylcytosine and 6-thioguanine. Following each cycle of chemotherapy, progressive recovery of these functions occurs during the third and fourth weeks with occasional increases above base line in patients in whom chemotherapy is withheld for longer than five weeks. In selected patients recovery of one cytotoxic function preceded the other, indicating that these functions are mediated by different effector cells. Administration of a single dose of daunomycin i.v. had no effect in either of these cytotoxic functions or in the circulating numbers of lymphocytes. The decrease in ADCC effector cell function induced by phase cycle-specific agents correlated with the level of reactivity exhibited by patients after achieving bone marrow and clinical remission. Patients showing low levels of reactivity postremission experienced highest degree of depression. In two patients, complete abrogation of ADCC effector function was demonstrated with minimal recovery even six weeks after stopping chemotherapy. These findings indicate that effector cells in ADCC and mitogen-induced cellular cytotoxicity are highly susceptible to phase cycle-specific agents, and their recovery takes longer that of other lymphoid and nonlymphoid populations.

Topics: Adult; Aged; Antibody-Dependent Cell Cytotoxicity; Antineoplastic Agents; Cytarabine; Cytotoxicity, Immunologic; Daunorubicin; Drug Therapy, Combination; Humans; Immunity, Cellular; Immunoglobulin Fc Fragments; Immunosuppression Therapy; Leukemia, Myeloid, Acute; Middle Aged; Phytohemagglutinins; Remission, Spontaneous; T-Lymphocytes; Thioguanine; Time Factors

Topics: Aged; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Remission, Spontaneous; Thioguanine

391 children received complex chemotherapy according to uniform treatment schedules, proposed by the Hungarian Study Group for Childhood Leukaemia, which was established in 1971. Survival among the patients showed an increasing tendency: more than 50% of patients with ALL are stille alive 3 years after the beginning of treatment. One patient is in complete remission 9 3/4 years after the establishment of the diagnosis. Two types of maintenance therapy were investigated among the patients entered for this study in 1974. "Pulses" with Vincristine-Prednisolone every second month were found to be more optimal than monthly "pulses".

Topics: Age Factors; Child; Cytarabine; Daunorubicin; Humans; Hungary; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Mercaptopurine; Prednisolone; Thioguanine; Vincristine

The need for prophylactic therapy of the central nervous system in adult acute nonlymphoblastic leukemia has been suggested but no proven. Over a 4-year period from January 1973, to December 1976, we have maintained 40 patients achieving complete remission on a regimen consisting of monthly courses of Cytosine Arabinoside and 6-thioguanine. Twenty patients remain in remission with a predicted median remission duration for the entire group of 14.5 months. Thirty nine of the patients did not have central nervous system leukemia at diagnosis, and only one of these patients (2.6%) has had remission tenance regimen there is little need for central nervous system prophylaxis in adult acute nonlymphoblastic leukemia.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Brain Neoplasms; Cytarabine; Drug Therapy, Combination; Female; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Middle Aged; Remission, Spontaneous; Thioguanine

A new non-radioisotopic technique is described for measuring rates of intracellular formation by human leukemic blasts of 6-thioguanine nucleotide metabolites, obligatory intermediates in the antineoplastic action of both 6-mercaptopurine and 6-thioguanine itself. The method is both specific and sensitive, and involves combined high-performance liquid chromatography and flow fluormetric detection of oxidized 6-thioquanine nucleotides in alkaline permanganate-treated cell extracts. Non-metabolized 6-thioguanine and 6-thioxanthine are also separated and quantitated in this system, permitting complementary in vivo pharmacokinetic analysis. The assay may be applied to detect resistant disease at an early stage in therapy, and thereby provides the opportunity for alternative treatments to be instituted.

Topics: Body Fluids; Chromatography, High Pressure Liquid; Fluorometry; Humans; Intracellular Fluid; Leukemia, Myeloid, Acute; Mercaptopurine; Thioguanine; Thionucleotides

The most important advances achieved during the past 5 years in the diagnosis and treatment of acute leukemia are presented. It is now possible to achieve complete remission in about 60% of all patients with acute myelocytic leukemia (AML) using optimal polychemotherapy. This significant advance is in part due to improved supportive measures such as transfusions and isolation etc., which are frequently necessary during the induction phase of treatment. Unfortunately, such remissions are still of relatively short duration and seldom exceed 1 year. The treatment of relapses remains less successful. The first attempts to include immunotherapy in the treatment of AML have also been rather disappointing. Today remissions are obtained in 70% of patients with acute lymphocytic leukemia (ALL) which last, on the average, almost 1 1/2 years. These results, however, do not approach those in childhood ALL. Finally, the therapeutic possibilities for the treatment of blastic crisis in chronic myelocytic leukemia (CML) are discussed.

Topics: Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Mercaptopurine; Prednisone; Remission, Spontaneous; Thioguanine; Vincristine

Fifteen newly diagnosed unselected adult patients with acute nonlymphocytic leukemia were treated in a pilot study of the combination of vincristine, cytosine arabinoside, 6-thioguanine, and daunorubicin (VAT-D) for remission induction therapy. Eleven of fifteen (75%) achieved a remission bone marrow. Median duration of remission was seven months in all responders (11 patients). The 11 patients achieving initial remission reached a median survival of 14 months. Twelve of seventeen attempts at reinduction of remission with VAT-D were successful. The total amount of daunorubicin required for induction was less than that required in the majority of reported acute leukemia treatment regimens utilizing daunorubicin.

Topics: Adolescent; Adult; Cytarabine; Daunorubicin; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Pilot Projects; Remission, Spontaneous; Thioguanine; Vincristine

Daunorubicin, thioguanine and cytosine arabinoside were administered from the 17th to 34th weeks of pregnancy in a 23-year-old patient with acute myeloid leukaemia. The patient went into remission of her leukaemia, and a normal male infant was born after labour was induced in the 40th week. This experience supports the view that modern regimens of anti-leukaemic drugs may be administered during the second and third trimesters of pregnancy without harmful effects on the foetus.

Topics: Adult; Cytosine; Daunorubicin; Female; Fetus; Humans; Infant, Newborn; Labor, Induced; Leukemia, Myeloid, Acute; Male; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Thioguanine

Topics: Adult; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Mercaptopurine; Methotrexate; Prednisone; Thioguanine; Vincristine

Topics: Adult; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Ifosfamide; Leukemia, Myeloid, Acute; Middle Aged; Thioguanine

Topics: Aged; Antineoplastic Agents; B-Lymphocytes; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Immunoglobulin G; Immunosuppression Therapy; Leukemia, Myeloid, Acute; Lymphocyte Cooperation; Middle Aged; T-Lymphocytes; Thioguanine

Topics: Adolescent; Adult; Antineoplastic Agents; Bone Marrow Transplantation; Cyclophosphamide; Cytarabine; Drug Therapy, Combination; Female; Hematopoiesis; Humans; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Lomustine; Male; Middle Aged; Neoplasms; Remission, Spontaneous; Thioguanine; Transplantation, Autologous

Fifteen patients with acute leukemia resistant to standard chemotherapy were treated by bone marrow transplantation from HLA-matched siblings after conditioning with a new combination chemotherapy/radiation therapy regimen--SCARI. SCARI consists of 5 days of high-dose cytosine arabinoside and 6-thioguanine followed by 3 days of daunorubicin. After a rest period, cyclophosphamide and total-body irradiation are given sequentially. This regimen had acceptable morbidity. Median survival was 169 days. Overall survival and disease-free survival was 27% at over 11 months. Relapse rate was 13% of the entire group and 30% by actuarial projection. Relapses were late and initially extramedullary. Deaths from causes other than leukemia occurred early secondary to fungal infection and late secondary to interstitial pneumonia (frequently cytomegalovirus). Graft-versus-host disease and graft rejection were not causes of mortality. In these patients conditioned with SCARI, leukemic recurrences were infrequent but infectious complications were a major hazard.

Topics: Adolescent; Adult; Bone Marrow Cells; Bone Marrow Transplantation; Child; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Graft vs Host Reaction; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Middle Aged; Thioguanine; Time Factors; Transplantation, Homologous

28 adult patients with acute myeloid leukaemia (A.M.L.) received T.A.D., a high-dose sequential chemotherapeutic remission-induction regimen consisting of 7-day courses of cytosine arabinoside, 6-thioguanine, and daunorubicin. Overall response-rate was 82%. 22 patients (79%) achieved complete remission, and 1 had a partial remission. Median remission duration was 280 days and median survival 375 days. 10 patients remain in remission. These induction results are superior to those reported in most studies and indicate that disease remission can be achieved in a high proportion of patients with A.M.L. treated with an intensive multi-agent chemotherapeutic regimen, provided support facilities are adequate.

Topics: Administration, Oral; Adult; Age Factors; Aged; Cytarabine; Daunorubicin; Drug Administration Schedule; Drug Evaluation; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Injections, Intravenous; Leukemia, Myeloid, Acute; Male; Middle Aged; Remission, Spontaneous; Thioguanine; Time Factors

Maintenance chemotherapy consisting of weekly oral 6-thioguanine and intramuscular cytosine arabinoside was administered to 24 adult patients with acute non-lymphocytic leukaemia in complete remission. The median duration of complete remission was 16-5 months, with 9 patients (38%) still in their first remission after 18--56 months. 33% of the patients have been in continuous remission for over 2 yr, 21% for over 3 yr, and 12-5% for over 4 yr. Median survival so far is 22-5 months. This maintenance regimen is well tolerated, is easily administered on an outpatient basis, and produces substantial numbers of long-term remissions.

Topics: Administration, Oral; Adolescent; Adult; Aged; Cytarabine; Drug Administration Schedule; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Injections, Intramuscular; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Middle Aged; Remission, Spontaneous; Thioguanine; Time Factors

The therapeutic regimens for acute myelogenous leukemia in 2 different periods of time will be described with comparison of their results. A. 28 adults were treated with cytosine arabinoside and 6-thioguanine only. Thereby, 28% complete and 16% partial remissions were achieved. The mean duration of the complete remissions was 23 weeks. The mean survival time of the patients with complete remission amounted to 53 weeks B. 46% complete and 12% partial remissions were obtained in 37 patients treated with cytosine arabinoside and 6-thioguanine doubling the dosage of the above mentioned regimen followed by 3 cycles of TRAP (and COAP). Using a maintenance therapy with modified TRAP, COAP, and POMP cycles the complete remissions lasted 47 weeks at an average. The mean survival time of patients with complete remission was 87 weeks after start of treatment.

Topics: Adult; Aged; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Prednisone; Remission, Spontaneous; Thioguanine; Time Factors; Vincristine

Because no conclusive evidence as to the efficacy of maintenance chemotherapy in acute myelogenous leukemia (AML) existed, a study to obtain such information was done. Twenty-six adult patients with AML in whom complete remission had been achieved following induction chemotherapy were randomly assigned to receive either maintenance chemotherapy consisting of cytarabine and 6-thioguanine for two days each month or to receive no maintenance therapy. The data showed a significant difference in remission duration between the two groups, with median remission lengths for the maintained and unmaintained groups being 10.3 and 6.7 months, respectively (p<.05). In 46 percent of the maintained patients there were remissions lasting longer than 11 months, whereas in none of the unmaintained patients was there such a prolonged remission. No significant drug-induced toxicity was observed. That the prolonged exposure to these chemotherapeutic agents, which were also used in our induction program, did not adversely affect the rate of successful reinduction therapy was shown by identical 50 percent complete remission rates for second inductions in both groups. In patients with palpable splenomegaly at the time of diagnosis, there was no prolongation of remission with maintenance therapy. These data indicate the potential utility of maintenance chemotherapy for prolonging remission duration in acute myelogenous leukemia.

Topics: Adolescent; Adult; Aged; Cytarabine; Humans; Leukemia, Myeloid, Acute; Middle Aged; Remission, Spontaneous; Thioguanine

A combination of eight cytotoxic drugs, administered simultaneously, has been used in 86 cases of acute leukemia. The regimen, designated TRAMPCOL, incorporated thioguanine, rubidomycin, (daunorubicin), cytosine arabinoside, methotrexate, prednisolone, cyclophosphamide, vincristine, and usually L-asparaginase. Treatment was administered in five-day pulses with treatment-free intervals varying from nine to 23 days. Subjective and objective toxic effects were not more severe than those seen with two- and four-drug regimens previously employed. Substantial clinical and hematologic improvement occurred in 8/19 patients with chronic granulocytic leukemia (CGL) in acute transformation. Complete clinical and hematologic remission (CR) was achieved in 3/7 patients with untreated acute myeloid leukemia (AML), 5/19 patients with AML who had failed to achieve CR with other therapy, and 4/18 patients with AML in relapse after CR obtained with regimens other than TRAMPCOL. CR occurred in 15/17 patients with acute lymphocytic leukemia (ALL), most of whom had had multiple previous relapses. CR was not achieved in four patients with AML superimposed on pre-existing myeloproliferative disorders. The TRAMPCOL regimen merits further evaluation in CGL after acute transformation, as a primary treatment for AML, and as therapy for ALL 1) in relapse, 2) in adults, 3) in children with adverse prognostic features, and 4) in T-cell ALL.

Topics: Adolescent; Asparaginase; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Male; Methotrexate; Prednisolone; Remission, Spontaneous; Thioguanine; Vincristine

Twenty-five patients with acute myeloid leukaemia were treated with three quadruple drug combinations in predetermined rotation: TRAP (thioguanine, daunorubicin, cytarabine, prednisolone); COAP (cyclophosphamide, vincristine, cytarabine, prednisolone); and POMP (prednisolone, vincristine, methotrexate, mercaptopurine). Fifteen patients (60%) achieved complete remission and five (20%) partial remission. For maintenance, five-day courses of drugs were administered every 14 to 21 days and doses were increased to tolerance. The median length of complete remission was 66 weeks. In eight patients remission maintenance treatment was discontinued and some remained in complete remission for over two years. In this series the remission induction rate was comparable with that reported for other regimens and complete remission lasted longer with this intensive maintenance regimen than with others. Nevertheless, the TRAP programme must still be regarded as only palliative treatment for acute myeloid leukaemia.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Prednisolone; Remission, Spontaneous; Thioguanine; Vincristine

Twenty children with acute myeloblastic leukemia were given induction and maintenance regimens combining cytosine arabinoside (ARA-C) and 6-thioguanine (TG). Two died before completing induction therapy and were considered unevaluable. Of the 18 remaining patients, 3 died shortly after induction, 2 had no response, 1 had a partial response and 12 (66%) had a complete remission (CR) lasting 4 to 68 months. Six still survive: two in their initial CR and four who relapsed but were reinduced to CR. Although no prophylactic central nervous system (CNS) therapy was given, only one patient has developed CNS involvement after diagnosis. Two girls became pregnant while on maintenance therapy. One delivered a normal, full-term infant; both she and the child are well 24 months later.

Topics: Adolescent; Brain Neoplasms; Child; Child, Preschool; Cytarabine; Drug Therapy, Combination; Female; Humans; Infant; Leukemia, Myeloid, Acute; Male; Pregnancy; Pregnancy Complications, Hematologic; Prospective Studies; Recurrence; Remission, Spontaneous; Thioguanine; Time Factors

Topics: Adolescent; Adult; Aged; Cytarabine; Daunorubicin; Doxorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Life Expectancy; Male; Middle Aged; Remission, Spontaneous; Thioguanine; Vincristine

Topics: Adolescent; Adult; Antineoplastic Agents; Child; Cyclophosphamide; Cytarabine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Semustine; Thioguanine

Twenty patients with acute myeloid leukaemia (AML) were treated with a combination of chemotherapy which included daunorubicin, cytosine arabino-side and 6-thioguanine (DAT). The complete remission rate was 85% and was achieved, in responsive cases, after an average of 2 courses of therapy. Patients remained in hospital for an average of 37.5 days during remission-induction therapy and 3.7 days per month thereafter. The median remission period was 48 weeks and median survival was 70 weeks. A disappointing feature was the high relapse rate. This feature of the results re-affirms the need for a more effective form of remission therapy.

Topics: Adolescent; Adult; Aged; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prognosis; Remission, Spontaneous; Thioguanine

The results of treatment of 57 patients suffering from acute non-lymphoid leukemia by two protocols are compared. The more aggressive Coap protocol rendered a higher remission rate (57.1%), than the mild Guyer protocol where the remission rate has been 25%. The best results have been achieved in the former group in the younger population; in the latter group there has been no age-effect relationship. Although the remission rate differed in both protocols there has been no statistically significant difference in survival.

Topics: Cyclophosphamide; Cytarabine; Drug Therapy, Combination; Female; Humans; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Male; Middle Aged; Prednisone; Prognosis; Thioguanine; Vincristine

Topics: Adult; Bone Marrow Transplantation; Cyclophosphamide; Cytosine; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Lomustine; Male; Thioguanine; Transplantation, Autologous

Topics: ABO Blood-Group System; Adolescent; Adult; Bone Marrow Cells; Bone Marrow Transplantation; Candidiasis; Child; Cyclophosphamide; Cytarabine; Cytomegalovirus Infections; Daunorubicin; Graft vs Host Reaction; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Middle Aged; Radiation Chimera; Thioguanine; Transplantation, Homologous

Topics: Adult; Azacitidine; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Phosphates; Prednisone; Pregnancy; Pregnancy Complications; Thioguanine; Vincristine

Topics: Asparaginase; Child; Cyclophosphamide; Cytosine; Daunorubicin; Doxorubicin; Drug Therapy, Combination; Hodgkin Disease; Humans; Infant; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphoma; Melphalan; Mercaptopurine; Methotrexate; Neoplasms; Nitrogen Mustard Compounds; Osteosarcoma; Prednisone; Procarbazine; Prognosis; Remission, Spontaneous; Rhabdomyosarcoma; Teniposide; Thioguanine; Vincristine; Wilms Tumor

Topics: Aged; Anemia; Blood Cell Count; Bone Marrow Examination; Cytarabine; Diagnosis, Differential; Female; Humans; Leukemia, Myeloid, Acute; Primary Myelofibrosis; Thioguanine

Based on our previous mathematical model of the acute myeloblastic leukemic (AML) state in man, we superimpose a chemotherapeutic drug treatment regimen. Our calculations suggest that small changes in the protocol can have significant effects on the result of treatment. Thus, the optimal period between drug doses is the S-phase interval of the leukemic cells--about 20h--and the greater the number of doses administered in a given course treatment, the longer the rest interval should be before the next course is administered. For a patient with a "slow" growing AML cell population, remission can be achieved with one or two courses of treatment, and further suppression of the leukemic population can be achieved with continued courses of treatment. However, for patients with a "fast" growing AML cell population, a similar aggressive treatment regimen succeeds in achieving remission status only at the cost of very great toxic effects on the normal neutrophil population and its precursors.

Topics: Cytarabine; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Mathematics; Models, Biological; Thioguanine

Two adult male patients with acute leukemia developed a fatal Budd-Chiari-like illness while receiving 6-thioguanine. Both had previously received cytosine arabinoside. Antemortem and postmortem specimens of liver showed changes characteristic of toxic veno-occlusive disease. Similar findings have been described after ingestion of certain plant alkaloids and after treatment with arsphenamine, urethane, and ionizing radiation to the liver. We are unaware of any published reports of veno-occlusive disease of the liver after treatment with either 6-thioguanine or cytosine arabinoside. Although 6-thioguanine was most likely responsible for this syndrome, it is not possible to eliminate cytosine arabinoside as the causative agent. Since both drugs are occasionally used for benign conditions, physicians should be aware of this possible complication.

Topics: Acute Disease; Adolescent; Aged; Budd-Chiari Syndrome; Chemical and Drug Induced Liver Injury; Cytarabine; Hepatic Veins; Humans; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Liver; Male; Thioguanine

Of 30 adult patients with acute myeloblastic leukemia, 14 achieved complete remission. Eight of these were given chemoimmunotherapy for maintenance. The immunotherapy consisted of intradermal pooled allogeneic leukemic cells (snap-frozen irradiated) and BCG vaccine given by Heaf gun, given twice in 4 weeks. The chemotherapy was given for 1 week in 4 weeks. The median duration of remission in these eight patients was 115+ weeks and the median duration of survival was 147+ weeks. The other six patients who were given chemotherapy only for maintenance had a median duration of remission of 15 weeks and a median survival of 52 weeks. The two groups cannot be compared properly, however, as allocation of patients was not random, and the chemotherapy differed significantly.

Topics: Adolescent; Adult; Aged; Antigens, Neoplasm; BCG Vaccine; Cytarabine; Daunorubicin; Female; Humans; Immunotherapy; Leukemia, Myeloid, Acute; Male; Middle Aged; Remission, Spontaneous; Thioguanine; Time Factors

Topics: Adolescent; Adult; Age Factors; Blood Transfusion; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Immunotherapy; Infant; Leukemia, Myeloid, Acute; Lomustine; Meningitis; Middle Aged; Prognosis; Thioguanine

Fifteen patients with acute myeloic leukemia in the first relapse following initial therapy were treated with a combination of adriamycin, vincristine, 6-thioguanine and the new podophyllotoxin derivative VP 16-213. Complete remission was obtained in 3 cases and partial remission in 3 further patients. The combination was generally well tolerated. These preliminary results are compared with those available in the relatively meagre literature. The study is being continued.

Topics: Cytarabine; Daunorubicin; Doxorubicin; Drug Therapy, Combination; Etoposide; Humans; Leukemia, Myeloid, Acute; Podophyllotoxin; Thioguanine; Vincristine

The results of treatment of 84 acute leukaemia patients during a 15-year period are reported. Sixty-three of the patients suffered from acute myeloid leukaemia, 14 had blastic crisis of chronic leukaemia and 7 had acute myelomonocytic leukaemia. Administration of prednisolone + purinethol, prednisolone + vincristine, and prednisolone + vincristine + purinethol combinations resulted in partial remission. The best results were achieved with the combination ARA-C + thioguanine + prednisolone, which produced complete remission in 2 out of 8 cases. One patient was refractory to this treatment.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Child; Cytarabine; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Mercaptopurine; Middle Aged; Prednisolone; Remission, Spontaneous; Thioguanine; Vincristine

The proliferation patterns of normal and leukaemic bone-marrow were studied by measuring the D.N.A. content of large numbers of cells by pulse cytophotometry (P.C.P.). In nineteen normal bone-marrow samples an average of 66-3% of the bone-marrow cells were in the G1 phase (2n D.N.A.), 26-1% in the S phase (2n smaller than D.N.A. smaller than 4n), and 7-5% in G2+M phase (4n D.N.A.). The percentages of S-phase cells determined by autoradiography and P.C.P. correlated well, both in normal and in leukaemic bone-marrow. In 25 patients with untreated acute myeloblastic leukaemia (A.M.L.) lower percentages of cells were found in S and G2+M phases, indicating a smaller proliferating pool compared with normal bone-marrow. The likelihood of a complete remission being attained in A.M.L. with the first treatment course was correlated with the percentage of S-phase cells present before treatment. At remission in A.M.L. the proliferation pattern was restored to normal.

Topics: Autoradiography; Bone Marrow; Bone Marrow Cells; Cell Count; Cell Division; Cytarabine; Daunorubicin; DNA, Neoplasm; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Photometry; Remission, Spontaneous; Thioguanine; Tritium

A 19-yr-old boy has been in continuous complete remission from acute myelogenous leukemia for 3 yr after allogeneic bone marrow transplantation prepared with combination chemotherapy. During the first year post-transplant, however, the patient developed near-fatal graft-versus-host reaction followed by 11 severe viral and bacterial infections. Immune evaluation during this period revealed multiple defects which were not present prior to transplantation, nor present in the transplant donor: diminution of lymphoid tissue, decline of all immunoglobulin subtypes, deletion of secretory immunoglobulin, disappearance of isohemagglutinins, loss of antibody to diptheria and tetanus toxoids, cessation of cutaneous hypersensitivity to mumps antigen, and inhibition of serum opsonizing activity. The patient was also unable to develop normal humoral or cellular reactivity to brucella antigen, keyhole limpet hemocyanin, or dinitrochlorobenzene. This patient's course illustrates the severity and chronicity of immunoincompetence associated with allogeneic marrow grafting, the importance of early detection and rigorous treatment of infectious disease in these patients, and the need for improved immunologic reconstitution in human marrow transplantation. It also indicates that complete recovery from the immune defects is possible, and that long-term remission from acute myelogenous leukemia can be achieved with allogeneic marrow transplantation.

Topics: ABO Blood-Group System; Adolescent; Adult; Anti-Bacterial Agents; Antilymphocyte Serum; B-Lymphocytes; Bacterial Infections; Blood Group Incompatibility; Bone Marrow Cells; Bone Marrow Transplantation; Candidiasis; Cyclophosphamide; Cytarabine; Graft vs Host Reaction; Histocompatibility Antigens; Humans; Immunity, Maternally-Acquired; Immunologic Deficiency Syndromes; Leukemia, Myeloid, Acute; Male; Nitrosourea Compounds; Opsonin Proteins; T-Lymphocytes; Thioguanine; Transplantation, Homologous; Virus Diseases

Although definite improvement in the treatment of acute myelogenous leukemia has taken place, the outlook for patients remains grim. The current aggressive approach to treatment, entailing a program of chemotherapy which almost invariably produces bone marrow aplasia and considerable toxicity, has been the subject of some controversy. Selected aspects of management are discussed.

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Antineoplastic Agents; Blood Transfusion; Cell Division; Cyclophosphamide; Cytarabine; Drug Evaluation; Drug Synergism; Drug Therapy, Combination; Humans; Infection Control; Kinetics; Leukemia, Myeloid, Acute; Mercaptopurine; Methotrexate; Mycoses; Prednisone; Pseudomonas Infections; Remission, Spontaneous; Thioguanine; Vincristine

Intensive care units for hematology or oncology patients consist of rooms free from pathogenic germs and low in microbe content. The units are staffed by doctors and nurses checked to be non carriers of pathogenic germs, and platelet and granulocyte transfusions are available. The first of these rooms, the Unit Fred-Siguier at the Hospital Paul-Brousse (Villejuif), was created for patients receiving bone marrow transplantation. Several units now exist in Europe. Results from two cooperative chemotherapy trials conducted at a European level showed that the number of remissions was double in services equipped with such rooms when compared with other hospital services. The study thus provides further evidence of the great need for such intensive care units.

Topics: Antineoplastic Agents; Blood Transfusion; Bone Marrow Cells; Bone Marrow Transplantation; Cross Infection; Cytarabine; Daunorubicin; Hemorrhage; Humans; Immunosuppression Therapy; Infection Control; Intensive Care Units; Leukemia, Myeloid, Acute; Patient Isolators; Thioguanine

16 courses of an 8-drug regimen including daunomycin, vincristine, cytosinearabinoside, thioguanine, methotrexate, cyclophosphamide, prednisolone and hydroxyurea, and 12 courses of a 7-drug regimen including the same drugs minus hydroxyurea were administered in 16 otherwise therapy-resistant cases of acute myeloid leukaemia. In spite of a significant and rapid reduction of the leukaemic cell-mass in all the cases treated, only two brief minimal remissions were obtained. The main toxic effect was myelosuppression. However, the treatment was associated with a high frequency of mucosal ulcerations of the oesophagus and stomach, and it cannot be excluded that the latter complication may be drug-related.

Topics: Adolescent; Adult; Aged; Candidiasis; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Resistance; Drug Therapy, Combination; Esophagitis, Peptic; Female; Humans; Hydroxyurea; Leukemia, Myeloid, Acute; Leukocyte Count; Leukopenia; Male; Mercaptopurine; Methotrexate; Middle Aged; Prednisolone; Stomach Ulcer; Thioguanine; Vincristine

Topics: Adult; Antineoplastic Agents; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Retrospective Studies; Thioguanine

Cytarabine is an effective agent in the treatment of acute leukemia. Since its approval by The Food and Drug Administration in 1969, the clinical effectiveness of this drug has increased as knowledge of its pharmacologic and biologic properties has been translated into clinical trials. A complete remission rate of greater than 50% can be achieved when cytarabine is used in combination with other agents in the treatment of adult acute myeloblastic leukemia. Remissions occur only after the development of significant bone-marrow hypoplasia, and the care of patients through this period of pancytopenia requires elaborate supportive techniques and facilities. The role of cytarabine in the treatment of acute lymphoblastic leukemia and lymphoma is still under clinical investigation and appears promising. Because the clinical effectiveness of cytarabine in the treatment of nonmalignant diseases has not been proved, its use in these disorders must be considered investigational and weighed against the serious bone-marrow suppression and potential long-term hazards of this drug.

Topics: Acute Disease; Adult; Animals; Bone Marrow Diseases; Central Nervous System Diseases; Cyclophosphamide; Cytarabine; Daunorubicin; DNA, Neoplasm; Drug Therapy, Combination; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphoma; Prednisone; Remission, Spontaneous; Thioguanine; Vincristine; Virus Diseases

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Body Weight; Child; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Middle Aged; Remission, Spontaneous; Thioguanine; Vincristine

Topics: Asparaginase; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Prednisone; Thioguanine; Vincristine

Improvement in the management of acute leukemia in adults has not progressed nearly so rapidly as has the treatment of childhood leukemia. One important difference is that most adults have myeloblastic or related forms of the disease (AML), whereas the majority of children have lymphoblastic leukemia (ALL). However, even adults with ALL fail to respond as well to a similar regimen as do children with the same type of leukemia. In a recent series of patients with ALL who were treated with the complex multiple drug "L-2" protocol, the incidence of complete remission in adults was 78% vs. 99% in children, and the median duration of remission was only 24 months in the adults, whereas it has not yet been reached in the children and is projected to be over 4 years. In AML and the related nonlymphoblastic forms of acute leukemia, therapy is still unsatisfactory in both adults and children. With the best current drug treatment schedules, the incidence of complete remission is now better than 50%, but it is often difficult to compare the exact remission rates in different series because of differences in reporting results. In adults treated with the multiple drug "L-6" protocol, the incidence of remission in previously untreated patients was 56% and the median duration of remission was 10 months. The median survival of all patients (responders and non-responders) was 1 year whereas that of responders only was 2 years. It is encouraging that a significant proportion of those patients with AML who have complete remissions now remain in remission for extended periods; about 45% of patients responding to the "L-6" protocol remained in remission over 1 year, and 18% have been in continuous remission for 2 to over 4 years. Even after discontinuing treatment, some patients with AML stay in remission for long periods, and it is possible that some of them may have been cured. If this proves to be true, it becomes of great importance to determine what is different about the patients who do exceptionally well as compared to the majority who continue to die within a year. However, no consistent nor distinctive favorable prognostic features have yet been identified.

Topics: Adolescent; Adult; Aged; Asparaginase; Carmustine; Child; Cytarabine; Daunorubicin; Female; Humans; Hydroxyurea; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Methotrexate; Middle Aged; Remission, Spontaneous; Thioguanine; Vincristine

Implications and course of fever were evaluated during hospitalization of 24 patients with acute myelogenous leukemia. Forty-five febrile episodes were identified. Fever present at admission was usually associated with a diagnosable and treatable infection; fever shortly after induction was self-limited; and fever during granulocytopenia was more likely to be associated with bacteremia. Bacteremia and pneumonia were the most common types of infection. Only Gram-negative bacteria and Candida were identified as causes of infection during life, with Pseudomonas and Klebsiella the most frequently isolated pathogens. Invasive candidiasis was a major postmortem finding. A delay in initiation of empirical treatment beyond the third day of fever was associated with an increase in mortality as was continuation of treatment for longer than 14 days.

Topics: Agranulocytosis; Anti-Bacterial Agents; Candidiasis; Cytarabine; Daunorubicin; Fever; Humans; Klebsiella Infections; Leukemia, Myeloid, Acute; Pseudomonas Infections; Thioguanine

Cytarabine and thioguanine therapy for acute myelocytic leukemia, initiated during the 26th week of pregnancy, led to complete remission of the leukemia in a 22-year-old woman, and allowed for delivery of a normal infant at term. No chromosomal abnormalities were detected in the infant. Cytarabine and thioguanine in combination are effective agents in the treatment of acute leukemia in adults. Their use appears warranted in pregnant patients after the first trimester.

Topics: Adult; Cytarabine; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Trimester, Second; Thioguanine

The presenting features and clinical course of 89 adults and 15 children with acute myeloblastic leukaemia (AML) presenting to a Regional Leukaemia Centre has been analysed. Remission rate was related to age, being 40% for the total adult group and 60% for all children. Young adults and children had a particularly high remission rate, whilst elderly patients faired badly. Survival diminished with increasing age and patients who entered complete remission survived for a significantly longer time (P less than 0.001) than those who did not. Adult AML differs from childhood AML, the adults having a lower remission rate, a significantly shorter survival (P less than 0.005) and almost complete absence of second remissions. Adults showed no correlation between complete remission and initial WBC or initial blast cell count, but in children there was a significant correlation (P less than 0.05) between initial total WBC and complete remission. A significant correlation between initial platelet count and complete remission could not be demonstrated in either group. Although the numbers of children are small, preadolescent children may represent a favourable sub-group, particularly those between 7 and 8 years of age.

Topics: Adolescent; Adult; Age Factors; Aged; Blood Cell Count; Blood Platelets; Bone Marrow Cells; Child; Child, Preschool; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Infant; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Middle Aged; Prednisone; Remission, Spontaneous; Thioguanine; Vincristine

Topics: Doxorubicin; Drug Therapy, Combination; Etoposide; Humans; Leukemia, Myeloid, Acute; Podophyllotoxin; Thioguanine; Vincristine

Eighteen children with acute myeloid leukemia have been treated with a four-drug protocol using cytosine arabinoside, daunorubicin, prednisolone, and mercaptopurine or thioguanine. The initial remission rate overall was 78%. Of 15 children who completed a week's treatment, i.e. one complete cycle, 14 entered complete remission (93%). The median survival was 7 months, and the median survival for those entering remission was 12 1/2 months.

Topics: Antineoplastic Agents; Child; Child, Preschool; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Infant; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Prednisolone; Remission, Spontaneous; Thioguanine

In 21 patients with acute leukaemia not or no longer responsive to conventional chemotherapy, and in four patients with chronic myeloid leukaemia in the blast phase, intensive combination treatment was started with thioguanine, daunomycine, cytarabine, methotrexate, prednisone, cyclophosphamide, and vincristine. Six patients with acute leukaemia went into complete remission, three into partial remission. The mean duration of remission was relatively short at 11 weeks. Of the four patients in the blast phase of chronic myeloid leukaemia two had objective and subjective remission. The toxicity of the combined treatment was not marked and subjective tolerance good. Such combined treatment is a realistic means of managing treatment-resistant acute leukaemia and chronic myeloid leukaemia in the blast phase.

Topics: Acute Disease; Adolescent; Adult; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia; Leukemia, Myeloid, Acute; Methotrexate; Middle Aged; Prednisone; Remission, Spontaneous; Thioguanine; Time Factors; Vincristine

Topics: Adolescent; Adult; Asparaginase; Bone Marrow; Bone Marrow Cells; Cell Division; Cells, Cultured; Child; Cytarabine; DNA, Neoplasm; Female; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphocytes; Male; Thioguanine; Thymidine

Topics: Adult; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Thioguanine

In the last few years tremendous progress has been made in the treatment of acute myelogenous leukemia: remissions have been observed more frequently and they last longer. Present-day therapy is described. It has become so complex that induction therapy must be carried out by oncologic departments. Maintenance treatment can however be conducted by the family physician, acting in close cooperation with the oncology unit.

Topics: Cyclophosphamide; Cytarabine; Daunorubicin; Drug Administration Schedule; Humans; Leukemia, Myeloid, Acute; Lomustine; Thioguanine

Topics: Adult; Aged; Cytarabine; Drug Therapy, Combination; Female; Humans; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Middle Aged; Thioguanine

The combination of arabinosyl cytosine and 6-thioguanine has been effective for the treatment of acute leukemia. Three schedules of this combination were studied to determine which was most effective, especially in patients who had prior exposure to either or both of these drugs. Sequential and simultaneous 5-day courses of the combination were ineffective. A regimen consisting of a 5-day course of arabinosyl cytosine followed by a 5-day course of 6-thioguanine and another 5-day course of arabinosyl cytosine produced responses in 36% of 25 patients. Seven of the nine patients who responded were refractory to prior therapy with arabinosyl cytosine and 5 were refractory tp prior therapy with 6-mercaptopurine. However, the median duration of response was only six weeks. Four patients developed central nervous system complications and three of these patients died while in complete remission. Major toxicity from all three regiments was myelosuppression. This regimen was about as effective as most other regimens used as secondary therapy in patients with acute myelogenous leukemia, but its toxicity was too great for routine usage.

Topics: Adolescent; Adult; Aged; Bone Marrow; Cytarabine; DNA; Drug Therapy, Combination; Female; Hematopoietic Stem Cells; Humans; Injections, Intravenous; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Male; Middle Aged; Remission, Spontaneous; Thioguanine

Topics: Antibodies, Neoplasm; Antibody Formation; Antigen-Antibody Complex; Antigens, Neoplasm; BCG Vaccine; Cell Transformation, Neoplastic; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Immunologic Deficiency Syndromes; Immunotherapy; Leukemia, Myeloid, Acute; Remission, Spontaneous; Thioguanine

Seventy-eight adult patients with acute leukaemia were classified cytologically into 3 categories: acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML) or acute undifferentiated leukaemia (AUL). The periodic acid-Schiff stain was of little value in differentiating the 3 groups. The treatment response in each group was different: 94% of patients with ALL (16/17) achieved complete remission with prednisone, vincristine and other drugs in standard use in childhood ALL; 59% of patients with AML (27/46) achieved complete remission with cytosine arabinoside and daunorubicin (22 patients), or 6-thioguanine and cyclophosphamide (2 patients), 6-thioguanine, cyclophosphamide and Adriamycin (1 patient), and cytosine and Adriamycin (1 patient); only 2 out of 14 patients (14%) with acute undifferentiated leukaemia achieved complete remission using cytosine and daunorubicin after an initial trial of prednisone and vincristine had failed. Prednisone and vincristine would seem to be of no value in acute undifferentiated leukaemia. It would seem also that no benefit is obtained by classifying all patients with acute leukaemia over 20 years of age as "adult acute leukaemia" and treating them with the same polypharmaceutical regimen. The problems posed by each disease are different and such a policy serves only to obscure them.

Topics: Acute Disease; Administration, Oral; Adult; Aged; Antineoplastic Agents; Cyclophosphamide; Cytarabine; Cytosine; Daunorubicin; Doxorubicin; Drug Therapy, Combination; Humans; Injections, Intravenous; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Middle Aged; Prednisone; Remission, Spontaneous; Staining and Labeling; Thioguanine; Vincristine

Topics: Adolescent; Adult; Antineoplastic Agents; Blood Transfusion; Bloodletting; Cell Count; Cyclophosphamide; Cytosine; Daunorubicin; Drug Therapy, Combination; Graft vs Host Reaction; Humans; Leukemia, Myeloid, Acute; Leukocytes; Life Expectancy; Middle Aged; Mitosis; Prednisolone; Prednisone; Remission, Spontaneous; Thioguanine; Vincristine

Topics: Adolescent; Adult; Asparaginase; Child; Child, Preschool; Cytarabine; Female; Humans; Immune Sera; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Leukocytes; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Lymphocytes; Male; Mercaptopurine; Methotrexate; Middle Aged; Nitrosourea Compounds; Prednisolone; Prognosis; Thioguanine; Vincristine

Topics: Adolescent; Adult; Aged; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Remission, Spontaneous; Thioguanine

Topics: Age Factors; Aged; Antineoplastic Agents; Connecticut; Cytarabine; Drug Combinations; Hospitals, Community; Hospitals, Special; Hospitals, Teaching; Humans; Leukemia, Myeloid, Acute; Middle Aged; Neoplasms; New York City; Prognosis; Remission, Spontaneous; Thioguanine

Topics: Age Factors; Bone Marrow Examination; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Hydroxyurea; Leukemia, Myeloid, Acute; Mercaptopurine; Nitrosourea Compounds; Prednisone; Remission, Spontaneous; Thioguanine; Vincristine

Topics: Anemia, Pernicious; Blood Cell Count; Bone Marrow Cells; Cytarabine; Cytoplasm; Follow-Up Studies; Hematologic Diseases; Humans; In Vitro Techniques; Leukemia, Erythroblastic, Acute; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Megakaryocytes; Mercaptopurine; Plasmacytoma; Polycythemia; Thioguanine; Thrombocytopenia

Topics: Aged; Anemia, Myelophthisic; Anemia, Sideroblastic; Bone Marrow Examination; Cells, Cultured; Chromosomes, Human, 6-12 and X; Cytarabine; Daunorubicin; Female; Folic Acid; Humans; Karyotyping; Lectins; Leukemia, Myeloid, Acute; Leukocytes; Middle Aged; Prednisolone; Pyridoxal Phosphate; Pyridoxine; Thioguanine; Trisomy

Topics: Adolescent; Adult; Aminosalicylic Acids; Asparaginase; Blood Cells; Bone Marrow; Bone Marrow Cells; Daunorubicin; Diagnosis, Differential; Doxorubicin; Esterases; Histocytochemistry; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Methotrexate; Middle Aged; Peroxidases; Prednisolone; Thioguanine; Vincristine

Topics: Age Factors; Aged; Cytarabine; Humans; Leukemia, Myeloid, Acute; Thioguanine

Topics: Adult; Age Factors; Aged; Antineoplastic Agents; Bone Marrow Cells; Carmustine; Chromosome Aberrations; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitosis; Nitrosourea Compounds; Prednisone; Prognosis; Thioguanine; Time Factors; Vincristine

Topics: Adult; Aged; Blood Cell Count; Bone Marrow; Bone Marrow Cells; Cell Division; Clone Cells; Cytarabine; DNA; Doxorubicin; Female; Glycoproteins; Hematopoiesis; Humans; Leukemia, Myeloid, Acute; Lymphoma; Male; Mitosis; Muramidase; Thioguanine; Thymidine; Tritium

Topics: Amyloidosis; Blood Cell Count; Blood Platelets; Blood Transfusion; Bone Marrow Examination; Cephalothin; Cytarabine; Erythrocytes; Gentamicins; Hemoglobins; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Proteinuria; Thioguanine

Topics: Acute Disease; Adult; Age Factors; Antineoplastic Agents; Child; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Middle Aged; Prednisolone; Prognosis; Remission, Spontaneous; Thioguanine; Vincristine

Topics: Adult; Bronchopulmonary Sequestration; Cytarabine; Hemorrhage; Humans; Leukemia, Myeloid, Acute; Lung Diseases; Male; Pneumonectomy; Thioguanine

Topics: Antineoplastic Agents; Busulfan; Child; Child, Preschool; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Infant; Infant, Newborn; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Methotrexate; Thioguanine; Vincristine

Topics: Administration, Oral; Adolescent; Adult; Age Factors; Aged; Anemia; Child; Cytarabine; DNA, Neoplasm; Female; Humans; Injections, Intravenous; Leukemia, Myeloid, Acute; Leukocytes; Male; Middle Aged; Muramidase; Nausea; Remission, Spontaneous; Sex Factors; Thioguanine; Thrombocytopenia; Time Factors; Vomiting

Topics: Adjuvants, Immunologic; Antigens, Bacterial; Antigens, Neoplasm; BCG Vaccine; Cytarabine; Daunorubicin; Freezing; Humans; Immunization; Immunotherapy; Leukemia, Myeloid, Acute; Leukocytes; Mycobacterium bovis; Neoplasm Transplantation; Radiation Effects; Remission, Spontaneous; Thioguanine; Time Factors; Transplantation, Homologous

Topics: Adult; Azathioprine; Blood Cell Count; Blood Platelets; Bone Marrow; Bone Marrow Cells; Cytarabine; Daunorubicin; Graft Rejection; Hepatitis; Humans; Immunosuppression Therapy; Kidney Transplantation; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Prednisone; Thioguanine; Transplantation, Homologous

Topics: Cell Division; Cells, Cultured; Cytarabine; DNA Nucleotidyltransferases; Folic Acid; Humans; In Vitro Techniques; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukocytes; Methionine; Methyltransferases; Prednisolone; Tetrahydrofolates; Thioguanine; Thymidine Kinase; Vincristine

Topics: Antineoplastic Agents; Asparaginase; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Drug Synergism; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Mercaptopurine; Methotrexate; Prednisone; Prognosis; Remission, Spontaneous; Thioguanine; Vincristine

Topics: Adult; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Male; Methylprednisolone; Phosphorus Isotopes; Polycythemia Vera; Remission, Spontaneous; Thioguanine; Vincristine

Sera from 16 of 20 patients with AML at some stage of the disease inhibited the in vitro PHA transformation of normal lymphocytes assessed by measuring the rate of DNA synthesis after 67-70 hours; 42% of pretreatment sera were inhibitory. Inhibitory activity was overcome at PHA concentrations 2-3 times greater than the concentration which allowed maximum discrimination between NHS and leukaemia sera.PHA transformation of washed lymphocytes obtained from AML patients before treatment and when receiving induction or consolidation (cytoreductive) chemotherapy was reduced only when cultures contained a high proportion of primitive cells. Even in primitive cell contaminated cultures significant responses to PHA could be measured if conditions were modified to prevent increasing acidity.Reports of reduced in vitro immunological reactions in pretreatment and poor prognosis patients may therefore be due to the presence of primitive cells in culture, and in treated patients to the failure of chemotherapy to reduce the circulating primitive cell count. Serum inhibitory factors may have a significant immunosuppressive effect in vivo, but the accurate assessment of the role of immune mechanisms in AML should attempt the measurement of specific immunity.

Topics: Culture Techniques; Cyclophosphamide; Deoxyuridine; DNA, Neoplasm; Humans; Immune Sera; Immunity, Cellular; Iodine Isotopes; Lectins; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphocyte Activation; Lymphocytes; Thioguanine

Topics: Acute Disease; Adult; Child; Cyclophosphamide; Cytarabine; Humans; Hydroxyurea; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Mercaptopurine; Methotrexate; Prednisolone; Thioguanine; Vincristine

Topics: Adenine; Adolescent; Adult; Aged; Antimetabolites; Drug Resistance; Female; Guanine; Humans; Hypoxanthines; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukocytes; Male; Mercaptopurine; Mutation; Pentosyltransferases; Remission, Spontaneous; Thioguanine

A preliminary report is given of a trial of the T.R.A.P. regimen (thioguanine, rubidomycin, cytosine arabinoside, and prednisolone) for the treatment of acute myeloid leukaemia. Out of 27 patients treated 13 (48.1%) obtained complete remission. The treatment was well tolerated and produced especially good results in elderly patients.

Topics: Adolescent; Adult; Age Factors; Aged; Child; Cytarabine; Daunorubicin; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid; Leukemia, Myeloid, Acute; London; Middle Aged; Prednisolone; Remission, Spontaneous; Thioguanine

Topics: Adolescent; Adult; Bone Marrow Cells; Bone Marrow Examination; Cell Count; Cell Division; Child; Clone Cells; Culture Techniques; Cytarabine; Daunorubicin; Drug Therapy, Combination; Embryo, Mammalian; Female; Humans; Kidney; Leukemia, Myeloid, Acute; Leukocytes; Male; Mercaptopurine; Methotrexate; Middle Aged; Prednisolone; Remission, Spontaneous; Thioguanine; Vincristine

Topics: Adrenal Cortex Hormones; Asparaginase; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Drug Therapy, Combination; Humans; Hydroxyurea; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Mercaptopurine; Methotrexate; Thioguanine; Vincristine

Topics: Administration, Oral; Adult; Bone Marrow Examination; Cytarabine; DNA; Drug Therapy, Combination; Humans; Injections, Intravenous; Leukemia, Myeloid, Acute; Mitosis; Remission, Spontaneous; Thioguanine

Topics: Adult; Aged; Antineoplastic Agents; Bone Marrow; Bone Marrow Cells; Cell Differentiation; Cell Division; Cell Survival; Cytarabine; Daunorubicin; Depression, Chemical; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Humans; Infant; Leukemia, Myeloid, Acute; Leukocyte Count; Lymphocyte Activation; Male; Middle Aged; Prognosis; Stimulation, Chemical; Thioguanine; Vincristine

Topics: Adult; Cytarabine; Drug Therapy, Combination; Female; Humans; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Middle Aged; Thioguanine

Topics: Antineoplastic Agents; Asparaginase; Carmustine; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Hydroxyurea; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Meningitis; Methotrexate; Prednisone; Thioguanine; Vincristine

Topics: Adult; Antineoplastic Agents; Asparaginase; Child; Cytarabine; Daunorubicin; Doxorubicin; Drug Therapy, Combination; Humans; Immunotherapy; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Prednisone; Remission, Spontaneous; Thioguanine; Time Factors; Vincristine

Topics: Age Factors; Bone Marrow Examination; Cytarabine; Daunorubicin; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Remission, Spontaneous; Thioguanine

Topics: Adult; Blood Cell Count; Bone Marrow Cells; Bone Marrow Examination; Chromosome Aberrations; Cytarabine; Cytogenetics; Daunorubicin; Humans; Hydroxyurea; Leukemia, Myeloid, Acute; Male; Prednisone; Thioguanine; Vincristine

Topics: Acute Disease; Adolescent; Adult; Aged; Bone Marrow; Cytarabine; Drug Synergism; Female; Humans; Hydroxyurea; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Male; Middle Aged; Nausea; Remission, Spontaneous; Thioguanine; Vomiting

Topics: Adult; Age Factors; Aged; Cytarabine; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prognosis; Thioguanine; Time Factors

Topics: Adult; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Synergism; Humans; Leukemia, Myeloid, Acute; Prednisone; Remission, Spontaneous; Thioguanine; Time Factors; Vincristine

Topics: Adolescent; Adult; Asparaginase; Child; Child, Preschool; Cytarabine; Drug Synergism; Female; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Prednisone; Recurrence; Thioguanine; Vincristine

Topics: Adult; Aged; Blood Cell Count; Bone Marrow Cells; Bone Marrow Examination; Child; Cytarabine; Densitometry; Female; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Middle Aged; Muramidase; Remission, Spontaneous; Thioguanine; Vincristine

Topics: Acute Disease; Adolescent; Adult; Aged; Bacterial Infections; Cytarabine; Drug Combinations; Female; Hemorrhage; Humans; Hydroxyurea; Length of Stay; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Middle Aged; Patient Isolators; Prednisone; Remission, Spontaneous; Thioguanine

Topics: Adult; Age Factors; Antineoplastic Agents; Cell Transformation, Neoplastic; Cytarabine; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Prognosis; Remission, Spontaneous; Thioguanine; United States

Topics: Aged; Anemia, Aplastic; Arsenic; Arsenic Poisoning; Autopsy; Biopsy; Bone Marrow Cells; Cytarabine; Environmental Exposure; Humans; Klebsiella Infections; Leukemia, Myeloid, Acute; Male; Oxymetholone; Penicillamine; Pesticides; Poisoning; Prednisone; Recurrence; Sepsis; Thioguanine

Topics: Acute Disease; Cytarabine; Female; Humans; Infant, Newborn; Leukemia, Myeloid, Acute; Pregnancy; Pregnancy Complications, Hematologic; Thioguanine

Topics: Adjuvants, Immunologic; Asparaginase; Bacterial Vaccines; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Synergism; Female; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Methotrexate; Mycobacterium bovis; Prednisone; Remission, Spontaneous; Thioguanine; Vincristine

Topics: Adult; Birth Weight; Cytarabine; Female; Fetus; Gestational Age; Humans; Leukemia, Myeloid, Acute; Pregnancy; Pregnancy Complications, Hematologic; Thioguanine; Vincristine

Topics: Acute Disease; Amino Sugars; Anemia; Antibiotics, Antineoplastic; Antineoplastic Agents; Blood Cell Count; Cyclophosphamide; Cytarabine; Glycosides; Humans; Injections, Intravenous; Injections, Subcutaneous; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukopenia; Lymphoma; Prednisone; Remission, Spontaneous; Thioguanine; Thrombocytopenia; Vincristine

Topics: Adult; Aged; Antibodies; Antigens; Cyclophosphamide; Cytarabine; Female; Hemocyanins; Humans; Hypersensitivity, Delayed; Immunity, Cellular; Immunologic Deficiency Syndromes; Immunosuppression Therapy; Lectins; Leukemia, Myeloid, Acute; Leukocyte Count; Lymphocyte Activation; Lymphocytes; Male; Mercaptopurine; Methotrexate; Prednisone; Prognosis; Remission, Spontaneous; Skin Tests; Thioguanine; Vincristine

Topics: Bone Marrow; Chromatography, Paper; DNA, Neoplasm; Leukemia, Myeloid, Acute; Neoplasms; RNA, Neoplasm; Sulfur Isotopes; Thioguanine

Topics: Abnormalities, Drug-Induced; Abortion, Therapeutic; Adult; Chromosome Aberrations; Chromosome Disorders; Chromosomes, Human, 6-12 and X; Cytarabine; Female; Humans; Leukemia, Myeloid, Acute; Mosaicism; Pregnancy; Pregnancy Complications, Hematologic; Thioguanine; Trisomy

Topics: Adult; Bronchopneumonia; Cytarabine; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Multiple Myeloma; Plasmacytoma; Thioguanine

Topics: Adolescent; Adult; Aged; Allopurinol; Anaphylaxis; Asparaginase; Blood Coagulation Disorders; Cytarabine; Daunorubicin; Drug Hypersensitivity; Female; Fever; Gastrointestinal Hemorrhage; Hallucinations; Humans; Hyperglycemia; Injections, Intravenous; Jaundice; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Liver; Male; Mercaptopurine; Methotrexate; Middle Aged; Oral Hemorrhage; Prednisone; Thioguanine; Uremia; Vincristine; Vomiting

Topics: Anemia, Aplastic; Bone Marrow Examination; Cell Nucleus; Child; Cytarabine; Erythrocytes; Erythropoiesis; Humans; Leukemia, Myeloid, Acute; Male; Megakaryocytes; Methotrexate; Mitosis; Reticulocytes; Thioguanine

Topics: Adolescent; Adult; Aged; Cytarabine; Dosage Forms; Female; Humans; Injections, Intravenous; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Middle Aged; Thioguanine

Topics: Adolescent; Adult; Age Factors; Aged; Antineoplastic Agents; Burkitt Lymphoma; Child; Child, Preschool; Cytarabine; Daunorubicin; Female; Humans; Infant; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Prednisone; Prognosis; Thioguanine; Time Factors; Vincristine