thioguanine-anhydrous and Leukemia--Myeloid

The majority of patients with acute myeloid leukemia (AML) are over 60 years of age at diagnosis. Unlike treatment options for younger adults, those for older patients are limited to non-myeloablative therapy, and many patients are not treatable because of poor performance status. In those who are treatable, long-term survival can be achieved using intensive induction and consolidation chemotherapy. Such curative treatment can be administered in about 70% of elderly patients with AML. In responding patients (up to 60%) the disease-free survival may be almost comparable to that of younger adults. However, treatment-related toxicity results in a higher mortality rate in the elderly patients. Moreover, aggressive chemotherapy cannot be used for 30% of the patients, due to their poor performance status. Currently, palliative cytoreductive treatment and supportive care are considered appropriate for these patients. Recently, however, targeting antileukemic antibodies and inhibitors of signal transduction have been introduced as promising new treatment options. The therapeutic efficiency and toxicity-profiles of these novel drugs are currently under investigation in clinical trials.

Topics: Acute Disease; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Disease-Free Survival; Etoposide; Follow-Up Studies; Forecasting; Humans; Idarubicin; Leukemia, Myeloid; Middle Aged; Palliative Care; Patient Selection; Randomized Controlled Trials as Topic; Thioguanine; Time Factors

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid; Remission Induction; Thioguanine

Most drugs available for cancer chemotherapy exert their effects through cytodestruction. Although significant advances have been attained with these cytotoxic agents in several malignant diseases, response is often accompanied by significant morbidity and many common malignant tumours respond poorly to existing cytotoxic therapy. Development of chemotherapeutic agents with non-cytodestructive actions appears desirable. Considerable evidence exists which indicates that (a) the malignant state is not irreversible and represents a disease of altered maturation, and (b) some experimental tumour systems can be induced by chemical agents to differentiate to mature end-stage cells with no proliferative potential. Thus, it is conceivable that therapeutic agents can be developed which convert cancer cells to benign forms. To study the phenomenon of blocked maturation, squamous carcinoma SqCC/Y1 cells were employed in culture. Using this system it was possible to demonstrate that physiological levels of retinoic acid and epidermal growth factor were capable of preventing the differentiation of these malignant keratinocytes into a mature tissue-like structure. The terminal differentiation caused by certain antineoplastic agents was investigated in HL-60 promyelocytic leukaemia cells to provide information on the mechanism by which chemotherapeutic agents induce cells to by-pass a maturation block. The anthracyclines aclacinomycin A and marcellomycin were potent inhibitors of N-glycosidically linked glycoprotein biosynthesis and transferrin receptor activity, and active inducers of maturation; temporal studies suggested that the biochemical effects were associated with the differentiation process. 6-Thioguanine produced cytotoxicity in parental cells by forming analog nucleotide. In hypoxanthine-guanine phosphoribosyltransferase negative HL-60 cells the 6-thiopurine initiated maturation; this action was due to the free base (and possibly the deoxyribonucleoside), a finding which separated termination of proliferation due to cytotoxicity from that caused by maturation.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Differentiation; Cell Division; Cell Line; Cell Survival; Cell Transformation, Neoplastic; Epidermal Growth Factor; Humans; Leukemia, Myeloid; Models, Biological; Naphthacenes; Thioguanine; Tretinoin

This article reviews the definition, etiology, epidemiology, cytogenetics, and diagnosis of chronic granulocytic leukemia (CGL). There is detailed consideration of clinical and laboratory findings, the natural history of CGL, and the selection of therapy at different stages of the disease. The roles of bone marrow transplantation and of newer experimental therapeutic approaches are discussed.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow Transplantation; Busulfan; Chromosomes, Human, 21-22 and Y; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Hydroxyurea; Leukapheresis; Leukemia, Myeloid; Male; Methotrexate; Middle Aged; Palliative Care; Prednisolone; Prednisone; Thioguanine; Vincristine

To detect karyotype changes during the chronic phase of CML, 31 mostly Ph1-positive patients were followed cytogenetically over a period of 3 years. Newly emerging abnormalities, e.g. second Ph1-chromosome, iso17q, trisomy 8, could be correlated with clinical and hematological characteristics of the course of the disease if they constituted the first additional chromosomal change. In 54 patients with suspected or established blast crisis, TdT determinations were performed. Out of 27 patients with verified blast crisis, 6 showed markedly elevated enzyme activities in the leukemic blast cells. These patients proved to be very sensitive to cytostatic therapy with prednisone and vincristine. The continuous observation of TdT levels enabled us to initiate a controlled and, with respect to the quality of life, a less toxic therapy. Our data indicate that serial chromosomal analyses and TdT determinations are of great value in predicting prognosis and therapeutic responsiveness in CML.

Topics: Busulfan; Chromosome Aberrations; Cytarabine; DNA Nucleotidylexotransferase; DNA Nucleotidyltransferases; Humans; Hydroxyurea; Karyotyping; Leukemia, Myeloid; Prednisone; Prognosis; Thioguanine; 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

The treatment of acute leukemia in adults, while not yet as successful as that in children with regard to either remission rate or prolongation of life, can now regularly result in at least 50% responses in acute myelocytic leukemia and 70-80% in acute lymphocytic leukemia. Intensive specific chemotherapy and supportive therapy throughout the resultant period of myelo and immuno-suppression are necessary to achieve these remission rates. Further investigations aimed at both prolonging the remissions so obtained and at improving the response rate further are essential.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Blood Transfusion; Cytarabine; Daunorubicin; Drug Therapy, Combination; Hematopoietic Stem Cells; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Middle Aged; Prognosis; Remission, Spontaneous; Thioguanine; Thrombocytopenia; Time Factors

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

Children who are treated for myeloid leukemia associated with Down syndrome (DS) experience superior survival compared with children who have myeloid leukemia without DS. To maintain excellent outcomes while avoiding toxicity, the Children's Oncology Group (COG) conducted the phase 3 trial COG A2971, the first trial solely designed to provide uniform treatment of myeloid leukemia in North American children with DS. A2971 eliminated 2 induction drugs and 3 months of maintenance therapy from the standard-timing regimen of dexamethasone, cytarabine, 6-thioguanine, etoposide, and rubidomycin/daunomycin (DCTER) used in the previous study (Children's Cancer Group [CCG] 2891).. COG A2971 was a multi-institutional, nonrandomized, clinical trial that enrolled 132 patients who had DS with either acute myeloid leukemia (n = 91) or myelodysplastic syndrome (n = 41).. The median follow-up was 4.8 years (range, 0.8-8.6 years), the median age at diagnosis was 1.7 years (range, 0.3-13.6 years), and the median white blood cell count was 6200/μL (range, 900-164,900/μL). The remission rate (92.7% ± 6%) was similar to that reported in the CCG 2891 study (91.3% ± 5%; P = .679). The 5-year event free survival (EFS) rate was 79% ± 7% (vs 77% ± 7% in CCG 2891; P = .589), the disease-free survival (DFS) rate was 89% ± 6% (vs 85% ± 6% in CCG 2891; P = .337), and the overall survival rate was 84% ± 6% (vs 79% ± 7% in CCG 2891; P = .302). Induction day-14 bone marrow response trended toward a more favorable outcome (EFS: P = .12). Age >4 years was an adverse risk factor (5-year EFS rate: 33% ± 38% for children aged >4 years [median, 8.5 years; n = 6] vs 81% ± 7% for children ages 0-4 years [median, 1.7 years; n = 126]; P = .001).. The COG A2971 trial reduced the chemotherapy dose and maintained survival to that achieved by the CCG 2891 trial in children who had myeloid leukemia associated with DS.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Down Syndrome; Drug Administration Schedule; Etoposide; Female; Humans; Infant; Kaplan-Meier Estimate; Leukemia, Myeloid; Male; Thioguanine; Treatment Outcome

The outcome of 45 AML1-ETO-positive acute myeloid leukemia (AML) patients was analyzed with special emphasis on the quality of molecular response to therapy. Patients received double induction therapy, either 6-thioguanine, cytarabine, and daunorubicin (TAD9)/high-dose cytosine arabinoside plus mitoxantrone (HAM) or HAM/HAM, followed by consolidation therapy (TAD9) according to the AML-Cooperative group 92 trial (AMLCG92) and AML-Cooperative group 99 trial (AMLCG99). All cases underwent cytomorphological, cytogenetical and molecular genetic analyses. AML1-ETO transcript levels were quantitatively assessed at diagnosis and during follow-up by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). The median reduction of initial AML1-ETO expression level was 4 log (range 0-5) after both induction and consolidation therapies. The quality of molecular response after induction as well as consolidation therapies had significant impact on the cumulative incidence of relapse (P=0.021 and P=0.001, respectively), event free survival (EFS: P=0.001 and P=0.001, respectively) and overall survival (OS: P=0.013 and P=0.014, respectively). HAM/HAM improved the molecular response to induction therapy (P=0.042) but after consolidation, no differences in molecular response were detectable between TAD9/HAM and HAM/HAM. Patient- or disease-related factors had no impact on the molecular response to induction or consolidation therapy. The current study demonstrates that quantification of AML1-ETO transcript levels is a powerful tool for prediction of prognosis that is independent of pretreatment risk factors, and may be helpful for directing therapeutic decisions in the future.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Core Binding Factor Alpha 2 Subunit; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid; Male; Middle Aged; Mitoxantrone; Oncogene Proteins, Fusion; Prognosis; Remission Induction; Risk Factors; RNA, Messenger; RUNX1 Translocation Partner 1 Protein; Thioguanine

Systematization of the results of 20-year multicenter randomized trial of the efficacy of treatment of acute myeloid leukemia (AML) of adults; presentation of the design of the study of the strategy of consolidation and maintenance therapy after high-dose consolidation initiated in 2007.. Treatment outcomes on the protocol AML-01.01 are presented for 354 AML patients from 29 hematological centers located in 22 towns of Russia and 2 towns of Ukraine. The patients were randomized into 3 groups by variant of therapy: 124 patients (62 males and 62 females; age median 42 years) received 4 courses of 7+3+VP-16 and 5 courses of maintenance therapy (7+3 with thioguanin); 130 patients (65 males and 65 females, age median 41 year) received 2 courses of 7+3+VP-16, 2 courses 7+3, maintenance--5 courses 7+3 with thioguanin; 126 patients (57 males and 68 females, age median 40 years) were given 2 courses of 7+3+VP-16, 2 HAD courses, treatment discontinuation.. A complete remission after the first course of 7+3+VP-16 was achieved in 55% patients, after the second course--in 30% after the course 7+3+VP-16 or 7+3 with mitoxantron, in 70%--after NAM. Overall and recurrence-free survival were 18 and 35%; 30 and 20%; 36 and 30%, respectively. There was no significant difference in efficacy of the treatment scheme.. The multivariate analysis has shown that a leading factor having impact on treatment results was the number of randomized patients: the less patients were randomized, the worse were the results.

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Humans; Leukemia, Myeloid; Male; Mitoxantrone; Recurrence; Thioguanine; Treatment Outcome

Down syndrome (DS) children are at an increased risk of developing myelodysplasia and acute myeloid leukaemia (AML). We retrospectively analysed the population-based data on 81 children with myeloid leukaemia of Down syndrome (ML-DS) from the UK National Registry of Childhood Tumours and experience in the Medical Research Council (MRC) AML 10 and AML 12 trials, which enrolled 46 children with ML-DS from 1988 to 2002. Eight per cent of UK children with AML had DS, but DS children comprised only 5% of children registered in MRC trials. The unique clinical characteristics of ML-DS were confirmed. Overall survival (OS) of ML-DS at 5 years increased from 47% in UK children diagnosed from 1988 to 1995 to 75% in children diagnosed from 1996 to 2002. OS for DS children registered in AML 10 and AML 12 was 74% in 5 years and improved from AML 10 to AML 12 (56% vs. 83%) There was no significant difference in OS between DS and non-DS children (OS: 74% vs. 62%, P = 0.4) in the trials, but this result masked a significant increase in early death amongst DS children, with a significant reduction in mortality later on. Relapse was significantly reduced (3% vs. 39%, P = 0.0003), leading to the improved disease-free survival (83% vs. 56%, P = 0.02). Given the increased number of early treatment-related deaths, future treatment protocols should aim to reduce chemotherapy dosage or intensity whilst maintaining low rates of resistant and recurrent disease.

Topics: Adolescent; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Cytogenetic Analysis; Daunorubicin; Down Syndrome; Drug Administration Schedule; Etoposide; Female; Humans; Infant; Leukemia, Myeloid; Leukocyte Count; Male; Mitoxantrone; Thioguanine; Treatment Outcome; United Kingdom

Elevated levels of nucleosomal DNA fragments can be detected in plasma and sera of patients with malignant diseases.. We investigated the course of nucleosomal DNA, thymidine kinase, lactate dehydrogenase and leukocytes in sera of 25 patients with acute myeloid leukemia during the first cycle of induction chemotherapy and tested their power to distinguish between patients with complete remission and those with no remission.. Almost all patients showed strongly decreasing levels of nucleosomal DNA during the first week, in some cases after initial peaks. In overall analysis of variance, DNA levels could clearly distinguish between patients with complete remission, who had higher DNA values, and those with insufficient response (p = 0.017). The area under the curve of DNA values of days 2-4 after start of therapy (AUC 2-4) discriminated between both groups with a sensitivity of 56% at a specificity of 100%. Further, pretherapeutic levels and AUC 2-4 of nucleosomal DNA correlated significantly with blast reduction after 16 days. A tendency to higher levels in patients with complete response was also found for thymidine kinase, lactate dehydrogenase and leukocytes, however the difference did not reach the level of significance (p = 0.542, p = 0.260, and p = 0.144, respectively).. Our results indicate that nucleosomal DNA fragments are valuable markers for the early prediction of therapeutic efficacy in patients with acute myeloid leukemia.

Topics: Acute Disease; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cytarabine; Daunorubicin; DNA Fragmentation; Female; Humans; L-Lactate Dehydrogenase; Leukemia, Myeloid; Leukocytes; Male; Middle Aged; Mitoxantrone; Nucleosomes; Predictive Value of Tests; Prognosis; Thioguanine; Thymidine Kinase; Treatment Outcome

As the response to chemotherapy in patients with acute myeloid leukaemia (AML) may still not be accurately determined by known prognostic factors, such as karyotype, the ex vivo chemosensitivity profile may help to predict the individual response. The predictive accuracy of an ex vivo assay should be assessed by correlation of assay results with both response rate and survival. We prospectively investigated the prognostic relevance of pre-therapeutic ex vivo chemosensitivity testing in primary cell cultures from adult AML patients by applying a new evaluation methodology, designated the chemosensitivity index, C(i). This C(i) was designed as a prognostic index by taking the area under the curve as an exact measure of the total dose-response relationship. We found an overall predictive accuracy of 98.2% concerning treatment response, which compares favourably with previously published data ranging from 75% to 92%. Moreover, the C(i) proved to be the strongest prognostic factor for overall survival in a multivariate Cox regression analysis including karyotype grouping and age (P < 0.001), and enabled the evaluation of response to combination therapies and selection of possible treatment alternatives. Our data suggest that ex vivo chemosensitivity testing evaluated by the C(i) could serve as a powerful tool for assay-directed therapy strategies in AML.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Screening Assays, Antitumor; Female; Humans; Leukemia, Myeloid; Male; Middle Aged; Mitoxantrone; Predictive Value of Tests; Prospective Studies; Sensitivity and Specificity; Survival Analysis; Thioguanine; Treatment Outcome; Tumor Cells, Cultured

Randomized comparisons of idarubicin (IDA) with daunorubicin (DNR) show that in adults with acute myeloid leukemia (AML), IDA achieves higher remission rates and longer remission durations. In Children's Cancer Group Pilot Study CCG-2941, we assessed toxicity and feasibility of substituting 4 mg of DNR with 1 mg of IDA in intensive-timing daunorubicin-based induction therapy (DNR/DNR) used in CCG-2891.. On days 1 through 3 and 10 through 14, patients received two courses of dexamethasone, cytarabine, 6-thioguanine, etoposide, and IDA (IDA/IDA). After enrollment of 65 patients, toxicity prompted replacement of IDA with DNR (IDA/DNR) on days 10 through 14 for the remaining 28 patients. Outcomes were compared with those of intensive timing in CCG-2891.. Treatment-related mortality after two courses of induction was not significantly different among the three regimens: 14% with IDA/IDA, 7% with IDA/DNR, and 9% with DNR/DNR. In course 1 of CCG-2941 IDA/IDA, 11% of patients withdrew compared with 1.5% in CCG-2891 (P <.001) and 5% in CCG-2941 IDA/DNR (P = not significant). Compared with CCG-2891 DNR/DRN, CCG-2941 IDA/IDA increased days in hospital (43 v 36 days; P =.007), mean duration of course 1 by a week (P =.002), and risk of grade 3 or 4 hyperbilirubinemia (18% v 5%; P =.02). Toxicity of IDA/DNR was not different from that of DNR/DNR in CCG-2891. The mean day 7 marrow blast percentage was 11.4% in CCG-2941 versus 21.1% in CCG-2891 (P =.004). Remission induction, survival, and event-free survival rates were not significantly different from those of CCG-2891.. In CCG-2941, excessive toxicity and withdrawals outweighed potential benefits of early response with IDA.

Topics: Acute Disease; Adolescent; Adult; Antibiotics, Antineoplastic; Child; Child, Preschool; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Drug Administration Schedule; Etoposide; Female; Humans; Idarubicin; Infant; Infant, Newborn; Leukemia, Myeloid; Male; Thioguanine; Treatment Outcome

The feasibility of combining gemtuzumab ozogamicin (GO) with intensive chemotherapy as first-line treatment of acute myeloid leukemia (AML) was assessed in 72 patients, aged 17 to 59 years, as a prelude to the United Kingdom Medical Research Council (MRC) AML15 trial. Sixty-four patients received induction chemotherapy (DAT [daunorubicin, ara-C, thioguanine], DA [daunorubicin, ara-C], or FLAG-Ida [fludarabine, ara-C, G-CSF, idarubicin]) with GO on day 1. It was possible to give GO 3 mg/m2 with course 1, but 6 mg/m2 with course 1 or GO in a dose of 3 mg/m2 with consecutive courses was not feasible because of hepatotoxicity and delayed hematopoietic recovery. Thirty-one patients who were treated in consolidation with MACE (amsacrine, ara-C, etoposide) or HidAC (HidAC) and GO (3 mg/m2), and 23 in induction and consolidation, tolerated GO (3 mg/m2) well. Grade 4 liver toxicity and sinusoidal obstructive syndrome was more common in thioguanine-containing schedules (P =.007). Remission with course 1 was seen in 86% of patients. DA or FLAG-Ida with GO in induction achieved complete remission in 91% of patients and 78% of these patients are in continuous complete remission at 8 months. GO given with induction (DA or FLAG-Ida) and consolidation (MACE or HidAC) was well tolerated. These schedules are now being compared in the MRC AML15 trial in patients younger than 60 years.

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aminoglycosides; Amsacrine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Cohort Studies; Cytarabine; Doxorubicin; Etoposide; Feasibility Studies; Gemtuzumab; Granulocyte Colony-Stimulating Factor; Humans; Idarubicin; Leukemia, Myeloid; Middle Aged; Pilot Projects; Remission Induction; Thioguanine; Vidarabine

In this prospective randomized multicenter trial 93 patients, median age 72 years, with RAEB-t (n=25) and myelodysplastic syndrome (MDS)-AML (n=68) were allocated to a standard induction chemotherapy regimen (TAD 2+7) with or without addition of granulocyte-macrophage-CSF (GM-CSF). The overall complete remission (CR) rate was 43% with no difference between the arms. Median survival times for all patients, CR patients, and non-CR patients were 280, 550, and 100 days, respectively, with no difference between the arms. Response rates were significantly better in patients with serum lactate dehydrogenase (S-LDH) levels

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Anemia, Refractory, with Excess of Blasts; Antineoplastic Combined Chemotherapy Protocols; Cell Transformation, Neoplastic; Cytarabine; Daunorubicin; Female; Follow-Up Studies; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukemia, Myeloid; Male; Middle Aged; Myelodysplastic Syndromes; Prospective Studies; Remission Induction; Survival Rate; Thioguanine

To determine whether granulocyte colony-stimulating factor (G-CSF) administered during acute myelogenous leukemia (AML) induction affects hematopoietic and nonhematopoietic toxicity, length and outcome of induction therapy, event-free survival, overall survival, and prognostic significance of the day 7 bone marrow.. In Children's Cancer Group study 2891, patients were given intensively timed induction with G-CSF (n = 254) after accrual for the regimen without G-CSF (n = 258) was met.. Time to neutropenic recovery after induction courses 1 and 2 was significantly shorter for patients who received G-CSF. Times to platelet recovery were similar regardless of G-CSF use. Effects on incidence of grades 3 and 4 toxicities, infections, or fatal infections were not observed. Use of G-CSF reduced the median length of induction by 9 days and hospital stay by 6 days. Induction remission rates, overall survival, and event-free survival were similar with and without G-CSF. Day 7 bone marrow was prognostic of better long-term outcome. Patients with hypercellular day 7 marrow who received G-CSF had a higher remission rate and event-free survival than patients who did not receive G-CSF.. The incidence of severe toxic event and infection, induction remission rate, overall survival, and event-free survival were comparable regardless of G-CSF use. Use of G-CSF decreased neutropenia duration, hospital stay, and length of induction. Patients with hypercellular day 7 bone marrow who received G-CSF had an induction remission rate and event-free survival superior to those of patients who did not receive G-CSF.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Child; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Etoposide; Female; Filgrastim; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Hyperbilirubinemia; Infection Control; Length of Stay; Leukemia, Myeloid; Male; Neutropenia; Prospective Studies; Recombinant Proteins; Remission Induction; Survival Analysis; Thioguanine; Thrombocytosis; Treatment Outcome

The clinical significance of complex chromosome aberrations for adults with acute myeloid leukaemia (AML) was assessed in 920 patients with de novo AML who were karyotyped and treated within the German AML Cooperative Group (AMLCG) trials. Complex chromosome aberrations were defined as three or more numerical and/or structural chromosome aberrations excluding translocations t(8;21)(q22;q22), t(15;17)(q22;q11-q12) and inv(16)(p13q22). Complex chromosome anomalies were detected in 10% of all cases with a significantly higher incidence in patients > or = 60 years of age (17.8% vs. 7.8%, P < 0.0001). Clinical follow-up data were available for 90 patients. Forty-five patients were < 60 years of age and were randomly assigned to double induction therapy with either TAD-TAD [thioguanine, daunorubicin, cytosine arabinoside (AraC)] or TAD-HAM (high-dose AraC, mitoxantrone). Twenty-one patients achieved complete remission (CR) (47%), 20 patients (44%) were non-responders and 9% of patients died during aplasia (early death). The median overall survival (OS) was 7 months and the OS rate at 3 years was 12%. Patients receiving TAD-HAM showed a significantly higher CR rate than patients receiving TAD-TAD (56% vs. 23%, P = 0.04). Median event-free survival was less than 1 month in the TAD-TAD group and 2 months in the TAD-HAM group, respectively (P = 0.04), with a median OS of 4.5 months vs. 7.6 months (P = 0.13) and an OS after 3 years of 7.6% vs. 19.6%. Forty-five patients were > or = 60 years of age: 28 of these patient were treated for induction using one or two TAD courses and 17 cases received TAD-HAM with an age-adjusted reduction of the AraC dose. The CR rate was 44%, 38% were non-responders and 18% experienced early death. The median OS was 8 months and the OS rate at 3 years was 6%. In conclusion, complex chromosome aberrations in de novo AML predicted a dismal outcome, even when patients were treated with intensive chemotherapy. Patients under the age of 60 years with complex aberrant karyotypes may benefit from HAM treatment during induction. However, long-term survival rates are low and alternative treatment strategies for remission induction and consolidation are urgently needed.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Chromosome Aberrations; Cytarabine; Cytogenetic Analysis; Daunorubicin; Disease-Free Survival; Female; Follow-Up Studies; Humans; Leukemia, Myeloid; Male; Middle Aged; Mitoxantrone; Prognosis; Remission Induction; Thioguanine

In an attempt to improve induction chemotherapy for older patients with acute myeloid leukemia (AML),1314 patients were randomized to 1 of 3 induction treatments for 2 courses of DAT (daunorubicin, cytarabine, and thioguanine) 3 + 10, ADE (daunorubicin, cytarabine, and etoposide) 10 + 3 + 5, or MAC (mitoxantrone-cytarabine). The remission rate in the DAT arm was significantly better than ADE (62% vs 50%; P =.002) or MAC (62% vs 55%; P =.04). This benefit was seen in patients younger and older than 70 years. There were no differences between the induction schedules with respect to overall survival at 5 years (12% vs 8% vs 10%). A total of 226 patients were randomized to receive granulocyte colony-stimulating factor (G-CSF) or placebo as supportive care from day 8 after the end of treatment course 1. The remission rate or survival were not improved by G-CSF, although the median number of days to recover neutrophils to 1.0 x 10(9)/L was reduced by 5 days. Patients who entered remission (n = 371) were randomized to stop after a third course (DAT 2 + 7) or after 6 courses, ie, a subsequent COAP (cyclophosphamide, vincristine, cytarabine, and prednisolone), DAT 2 + 5, and COAP. The relapse risk (81% vs 73%), disease-free survival (16% vs 23%), and overall survival at 5 years (23% vs 22%) did not differ between the 3-course or 6-course arms. In addition to a treatment duration randomization, 362 patients were randomized to receive 12-month maintenance treatment with low-dose interferon, but no benefit was seen with respect to relapse risk, disease-free survival, or overall survival.

Topics: Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; Drug Administration Schedule; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Humans; Immunologic Factors; Interferon-alpha; Lenograstim; Leukemia, Myeloid; Male; Middle Aged; Mitoxantrone; Prednisone; Recombinant Proteins; Remission Induction; Survival Analysis; Thioguanine; Treatment Outcome; United Kingdom; Vincristine

Acute myeloid leukemia (AML) in older adults carries a poor prognosis, and the optimum treatment remains to be determined. In younger patients, treatment stratification is frequently based upon diagnostic karyotype, which was the most important prognostic factor in the UK Medical Research Council (MRC) AML10 trial. Considered here is whether karyotype is also predictive in older adults; this is done by studying 1065 cases from MRC AML11 (median age, 66 years). Three prognostic groups were distinguished on the basis of response to induction therapy and overall survival (OS). Those with t(15;17), t(8;21), or inv(16) composed the favorable risk group. Overall, these abnormalities predicted a superior complete remission (CR) rate (72%), reflecting relatively low levels of resistant disease (RD) (8%), and lower relapse risk (RR) (56%) associated with superior OS (34% at 5 years). Normal karyotype (CR, 63%; RD, 17%; RR, 78%; OS, 15%) and other noncomplex abnormalities (CR, 53%; RD, 32%; RR, 85%; OS, 10%) composed the intermediate group; while complex karyotype predicted an extremely poor prognosis (CR, 26%; RD, 56%; RR, 91%; OS, 2%). Combining MRC AML10 and AML11 (n = 2677) revealed that the most favorable changes were rarer in older patients (younger than 55 years, 24%; 55 years or older, 7%), while complex abnormalities were more common (6% vs 13%). This study suggests that hierarchical cytogenetic classification identifies biologically distinct subsets of AML that are represented in all age groups. Furthermore, it highlights the importance of karyotype as a critical independent determinant of outcome in older patients with AML, providing a potential framework for stratified treatment approaches.

Topics: Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Chromosome Aberrations; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; Drug Administration Schedule; Etoposide; Female; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Immunologic Factors; Interferon-alpha; Karyotyping; Lenograstim; Leukemia, Myeloid; Life Tables; Male; Middle Aged; Predictive Value of Tests; Prednisone; Prognosis; Recombinant Proteins; Remission Induction; Survival Analysis; Thioguanine; Treatment Outcome; United Kingdom; Vincristine

Intensification of treatment for acute myeloid leukemia (AML) in adult patients resulted in a substantial improvement in long-term prognosis. Therefore, the assessment of quality of life (QL) of patients undergoing treatment is of growing interest. This study was designed to evaluate QL in patients with AML treated according to the protocol of the German AML-Cooperative Group (Münster, Germany). The EORTC QLQ-C 30 questionnaire was used to analyze QL throughout therapy, evaluating defined specific parameters at 12 different time-points. Sixty-one patients were recruited within the first 30 months of the study. Those 28 patients who have completed the course of inpatient treatment (n=28) are evaluated for changes in the conceptually distinct QL domains: Physical Functioning (P<0.001), Role Functioning (P=0.001), Emotional Functioning (P < 0.001) and Social Functioning (P=0.007) improve significantly from beginning of chemotherapy to the end of inpatient treatment. Individual assessment of Global Health Status and Subjective QL improves significantly over the same time (P< 0.001). At the end of inpatient treatment patients suffer significantly less from fatigue, nausea/emesis, loss of appetite and sleep disturbance (P < 0.001). Although most patients with AML eventually relapse, the evaluation of QL in patients undergoing treatment shows that subjective benefit outweighs the adverse effects of antileukemic therapy.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid; Longitudinal Studies; Male; Middle Aged; Mitoxantrone; Quality of Life; Thioguanine

359 eligible children with acute myeloid leukaemia (AML) entered the MRC AML 10 trial between May 1988 and March 1995. Patients received four courses of intensive induction and consolidation chemotherapy, with or without subsequent autologous (A-BMT) or allogeneic (allo-BMT) bone marrow transplant. There were randomized comparisons of thioguanine versus etoposide in induction and of A-BMT versus not. Allo-BMT was recommended for patients with a HLA-matched sibling and was evaluated by donor versus no donor comparison. The complete remission rate was 92%. In first remission there were 20 deaths during consolidation chemotherapy and 11 after BMT (8/61 allo-BMTs. 1/60 A-BMTs and 2/4 matched unrelated donor transplants). The relapse rate was low, decreasing from 26% in the first year to 2% in the fourth. Long-term outcome was excellent with survival at 7 years from entry of 56% and event-free survival of 48%. There were no significant differences between thioguanine and etoposide, whereas both A-BMT and allo-BMT reduced relapse risk but did not produce a significant survival benefit. It appears that over half the children entered into AML 10 are cured, a result which compares favourably with other reported series. We conclude that four courses of intensive chemotherapy are an effective approach to the treatment of paediatric AML, which avoids the acute toxicity and long-term side-effects of BMT and also avoids the need for prolonged maintenance therapy or cranial irradiation.

Topics: Acute Disease; Adolescent; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Cytarabine; Daunorubicin; Disease-Free Survival; Etoposide; Female; Humans; Infant; Infant, Newborn; Leukemia, Myeloid; Male; Mitoxantrone; Patient Compliance; Recurrence; Remission Induction; Survival Rate; Thioguanine; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome

The relative efficacy and toxicity of the chemotherapeutic agents thioguanine (6TG) and etoposide (VP16) were assessed by a randomized comparison of the DAT (daunorubicin, cytarabine, thioguanine) versus ADE (daunorubicin, cytarabine, etoposide) regimens in the Medical Research Council's 10th acute myeloid leukaemia trial (MRC AML 10), which was open to patient entry from May 1988 to April 1995. In this, the largest reported trial of AML therapy to date, 1,857 eligible patients, mostly less than 56 years old, were randomized: 929 (including 143 children under 15 years old) were allocated to DAT and 928 (143 children) to ADE. The two groups were well matched for presentation features. The complete remission (CR) rate was 81% with DAT and 83% with ADE (P = .3). The percentages of remitters achieving remission after 1, 2, or more than 2 courses were 70%, 22%, and 8% for DAT and 74%, 21%, and 5% for ADE. The percentages failing to achieve a CR due to resistant disease were 11% with DAT versus 9% with ADE (P = .07). There was a slightly higher death rate in CR during consolidation chemotherapy with ADE (9%) than with DAT (6%) (P = .06). Patients receiving DAT took slightly but significantly longer to recover from neutropenia and thrombocytopenia but the median number of days in hospital were similar in each group. ADE patients experienced slightly more severe nonhematologic toxicity. There was also no significant difference between the groups in the longer-term measures of efficacy: disease-free survival at 6 years from CR was 42% (+/-4) for DAT and 43% (+/-4) for ADE (P = .8); relapse rate at 6 years was 50% (+/-4) for DAT and 49% (+/-5) for ADE (P = .6); survival at 6 years was 40% (+/-4) for both DAT and ADE (P = .9). Subgroup analysis failed to show any benefit for etoposide in patients with monocytic or myelomonocytic disease, or in any other diagnostic subgroup. In conclusion, DAT and ADE both achieve high remission rates and good long-term survival, and are equally effective chemotherapy regimens for the treatment of AML patients aged up to 55 years.

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Daunorubicin; Disease-Free Survival; Etoposide; Female; Humans; Hydrocortisone; Infant; Leukemia, Myeloid; Life Tables; Male; Methotrexate; Middle Aged; Myelodysplastic Syndromes; Patient Compliance; Remission Induction; Survival Analysis; Thioguanine; Treatment Outcome

The objective of this study was to evaluate the feasibility, the toxicity and the efficiency of a BFM-like treatment protocol for acute nonlymphoblastic leukemia (ANLL) of children in which mitoxantrone was substituted for conventional anthracycline. The chemotherapy called for induction (mitoxantrone, cytosine arabinoside, etoposide), consolidation (mitoxantrone, cytosine arabinoside, 6 thioguanine), followed by two intensification courses with cytosine arabinoside plus, respectively, mitoxantrone during the first and etoposide during the second courses. Maintenance therapy consisted of daily 6 thioguanine, four-weekly courses of cytosine arabinoside (s.c. daily during 4 days) and eight-weekly courses of mitoxantrone. The latter drug was pursued up to a total cumulative dose of 150 mg/sqm. Maintenance therapy was stopped at 2 years of diagnosis. Out of 108 patients, 84 (77%) achieved a complete remission, 10 died during induction of hemorrhage, sepsis or pulmonary infiltration by leukemic cells. A total of 32 relapses occurred. The median follow-up was 3.5 years. Actuarial event-free survival, disease-free survival and overall survival at 3 years as 41%, 52%, 56%, respectively. These results compare favorably with most reported data, and cytogenetic findings appear to be the most important prognostic factor.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Disease-Free Survival; Etoposide; Feasibility Studies; Female; Heart; Heart Function Tests; Humans; Infant; Leukemia, Myeloid; Male; Mitoxantrone; Prognosis; Thioguanine; Vincristine

The value of autologous bone marrow transplantation in the treatment of children with acute myeloid leukemia (AML) is unknown. We compared autologous bone marrow transplantation with intensive consolidation chemotherapy as treatments for children with AML in first remission.. We induced remission with one course of daunorubicin, cytarabine, and thioguanine, followed by one course of high-dose cytarabine (3 g per square meter of body-surface area for six doses). Patients in remission after the second course of induction therapy were eligible for randomization. Between June 1988 and March 1993, 552 of 649 enrolled patients who could be evaluated (85 percent) entered remission. A total of 209 patients were not eligible for randomization; of the remaining 343 patients, 232 were randomly assigned to receive six courses of intensive chemotherapy (117 patients) or autologous transplantation (115 patients). Of the original 649 patients, 189, including 21 with Down's syndrome, were nonrandomly assigned to receive intensive chemotherapy.. The rates of event-free survival and overall survival for the entire group at three years were 34 +/- 2.5 percent and 42 +/- 2.6 percent, respectively. For patients who were randomly assigned to one of the two treatment groups, the mean (+/- SE) rates of event-free survival three years after randomization were not significantly different in the two groups when examined by intention-to-treat analysis: 36 +/- 5.8 percent for the intensive-chemotherapy group as compared with 38 +/- 6.4 percent for the autologous-transplantation group; and the relative risk of treatment failure for the chemotherapy group as compared with the autologous-transplantation group was 0.81 (P = 0.20 by the log rank test; 95 percent confidence interval, 0.58 to 1.12). Overall survival at three years followed a similar pattern. There was a lower relapse rate (31 percent vs. 58 percent, P < 0.001) but a higher rate of treatment-related mortality (15 percent vs. 2.7 percent, P = 0.005) in the group treated with autologous transplantation than in the intensive-chemotherapy group. The event-free survival at three years for the nonrandomized intensive-chemotherapy group was 39 +/- 5.1 percent, and for a contemporaneous group of patients each of whom received a histocompatible bone marrow transplant from a sibling, it was 52 +/- 8.0 percent.. Treatment of children with AML in first remission with either autologous bone marrow transplantation or intensive chemotherapy prolongs event-free survival equally.

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Cytarabine; Daunorubicin; Disease-Free Survival; Humans; Infant; Infant, Newborn; Leukemia, Myeloid; Survival Analysis; Thioguanine; Transplantation, Autologous

Timed sequencing of cycles of induction chemotherapy in acute myeloid leukemia (AML) has been proposed as a way to achieve maximal leukemic cell kill through recruitment and synchronization of residual neoplastic cells. Furthermore, whether intensive induction therapy should be continued in the presence of profound myelosuppression is an important question. The Children's Cancer Group (CCG) conducted a prospective randomized trial in which 589 patients with AML were randomized at diagnosis to one of two induction approaches involving a 4-day cycle of five active chemotherapeutic agents, with the second cycle administered either 10 days after the first cycle, despite low or dropping blood counts (intensive timing), or 14 days or later from the beginning of the first cycle, depending on bone marrow status (standard timing). All patients achieving remission received a total of four cycles of induction therapy. They were then allocated to allogeneic bone marrow transplantation (BMT) if a compatible family donor was present or randomized to aggressive nonmyeloablative therapy or to myeloablative therapy with purged autologous BMT rescue. The three postremission arms remain coded. Induction success and median days to complete induction were similar for the 295 patients randomized to the intensive timing arm (75%, 99 days) compared with the 294 patients randomized to the standard timing arm (70%, 105 days; P = .18 for remission). However, a marked improvement in outcome was demonstrated in patients randomized to the intensive timing arm, with an actuarial event-free survival at 3 years of 42% +/- 7% (95% confidence interval [CI]) versus 27% +/- 6% for patients on the standard timing arm (P = .0005). Disease-free survival results at 3 years from the end of induction were superior for patients receiving intensively timed induction therapy (N = 211), 55% +/- 9% versus 37% +/- 9% for standard timing patients (N = 195, P = .0002), with a median follow-up from achieving remission of 28 months. Superior results were documented for patients receiving intensive timing irrespective of the postremission therapy to which they were allocated. Intensively timed induction therapy for patients with AML markedly improves event-free survival, even for patients undergoing myeloablative therapy with BMT rescue. Without controlling for the type of induction therapy received, results of various BMT studies in AML comparing different preparative regimens will be difficult to interpret

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bone Marrow Transplantation; Child; Child, Preschool; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Drug Administration Schedule; Etoposide; Female; Humans; Infant; Infant, Newborn; Leukemia, Myeloid; Life Tables; Male; Prospective Studies; Remission Induction; Survival Analysis; Survival Rate; Thioguanine; Treatment Outcome

Myelodysplastic syndrome (MDS) in children is often considered as a variant of acute myeloid leukemia (AML) and frequently treated as such. However, there are very few reported data on the outcome following AML treatment. We analyzed 20 consecutive cases of de novo MDS treated in Denmark according to the NOPHO AML protocols. The results were compared with those obtained in 31 children with de novo AML treated with the same protocols, and with the outcome in 10 children with MDS who received allogeneic bone marrow transplantation (BMT) without prior AML therapy. Distinction between MDS and AML was made morphologically according to the FAB criteria. All children were followed for at least 37 months. The proportion of complete remission in MDS and AML was 35 percent vs 74 percent. (P = 0.005), resistant disease 25 percent vs 10 percent (P = 0.14), death in cytopenia 40 percent vs 16 percent (P= 0.06), and 3-year survival 15 percent vs 35 percent. (P = 0.11), respectively. Duration of treatment-related cytopenia was similar in MDS and AML, except for a longer period of leukopenia in MDS following the second course of induction. Seven of 10 MDS children receiving BMT without prior chemotherapy are long-term survivors. Our data suggest that conventional AML regimens are associated with a low rate of complete remission, a high risk of death in cytopenia, and a limited curative potential in childhood MDS. Allogeneic BMT was in contrast associated with a high survival rate. BMT may, at least in some patients, be performed successfully without prior induction chemotherapy. The different response to therapy in MDS and AML may reflect fundamental biological differences between the two conditions.

Topics: Acute Disease; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Cytarabine; Doxorubicin; Etoposide; Female; Humans; Infant; Leukemia, Myeloid; Leukocyte Count; Male; Myelodysplastic Syndromes; Platelet Count; Remission Induction; Thioguanine; Treatment Outcome

Between 1984 and 1990, 972 patients aged 1-79 years with acute myeloid leukaemia (AML), from 85 British hospitals, were entered into the MRC's 9th AML trial. Patients were randomized between DAT 1 + 5 (daunorubicin for 1 d, with cytarabine and 6-thioguanine for 5 d) and DAT 3 + 10 (same dose drugs for 3 and 10 d respectively) as induction therapy. The 63% who achieved complete remission (CR) were randomized to receive two courses of DAT 2 + 7 alternating with two courses of either MAZE (m-AMSA, 5-azacytidine, etoposide) or COAP (cyclophosphamide, vincristine, cytarabine, prednisone). Finally, those still in CR were randomized to receive either 1 year of maintenance treatment with eight courses of cytarabine and thioguanine followed by four courses of COAP, or no further cytotoxic therapy. Resistance to induction therapy was less common with the DAT 3 + 10 regimen than with DAT 1 + 5 (13% v 23%; P = 0.0001) and hence, despite a 5% increase in the risk of induction death, the CR rate was higher (66% v 61%; P = 0.15). Moreover, CR was achieved more rapidly with DAT 3 + 10 (median 34 v 46 d; P < 0.0001) and thus patients required less time in hospital (mean 20 v 29 d) and less blood product support. 5-year relapse-free survival (28% v 23%; P = 0.05) and survival (23% v 18%; P < 0.05) were also better with DAT 3 + 10. Post-remission intensification of therapy with MAZE resulted in fewer relapses (66% v 74% at 5 years; P = 0.03) but patients allocated MAZE required considerably more supportive care and 14 (4.5%) died following 312 MAZE courses, whereas no deaths occurred following COAP. 5-year survival was not significantly higher with MAZE (37% v 31%). Finally, although 1 year of outpatient maintenance treatment appeared to delay, but not prevent, recurrence it did not improve 5-year survival which was non-significantly worse for those allocated maintenance treatment (41% v 44%). We conclude that the more intensive induction regimen, DAT 3 + 10, is not only more effective than DAT 1 + 5, even for older patients, but is also less expensive; intensive post-remission therapy with MAZE achieves better leukaemic control but at the cost of substantial toxicity; whereas low-level maintenance therapy confers no apparent advantage in survival as well as being inconvenient and costly.

Topics: Adolescent; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cost-Benefit Analysis; Cytarabine; Daunorubicin; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Humans; Infant; Length of Stay; Leukemia, Myeloid; Middle Aged; Recurrence; Remission Induction; Risk Factors; Survival Analysis; Thioguanine

Peripheral blood stem cell (PBSC) transplantation gives rapid recovery of neutrophils and platelets and sustained haemopoiesis. However in patients with acute myeloid leukaemia (AML) platelet recovery has a distinctive rapid rise and then secondary fall between 3 to 8 weeks post-transplant. This study compares platelet and neutrophil recovery after PBSC transplantation in 15 patients with AML and 29 patients with other diseases consecutively transplanted in a single unit. PBSC were collected during recovery from consolidation chemotherapy in AML patients and after cyclophosphamide or cytokine administration in the other patient groups. Mononuclear cell numbers collected were similar but CFU-GM numbers were greater from the AML patients. A significant secondary fall occurred only in the platelet count and only in AML patients. Long-term recovery of the platelet count was the same in AML as in the other patients. In AML patients, the fall was the same in the long term remitters as in those who eventually relapsed. Previous studies have not, demonstrated a difference in type of precursors mobilized by differing methods, but have not included AML patients. Megakaryocyte precursors were assayed in this study and showed no consistent differences in number between patient groups however pre-progenitor assays are not yet established especially in the megakaryocytic lineage. The possible explanation for this secondary fall in AML patients is discussed.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Blood Platelets; Bone Marrow; Cell Differentiation; Cell Lineage; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid; Lymphoma, Non-Hodgkin; Male; Megakaryocytes; Multiple Myeloma; Ovarian Neoplasms; Platelet Count; Thioguanine; Time Factors

6-Thioguanine (6-TG) was administered as a continuous i.v. infusion for 7 days to 24 patients with relapsed or refractory acute leukemia or in the blast phase of chronic granulocytic leukemia. The daily dose of 6-TG was escalated from 37.5 mg/m2 to 160 mg/m2. Stomatitis was dose-related and dose-limiting with a maximum tolerated dose of 120 mg/m2 daily. Cutaneous reactions were dose-related but not dose-limiting. The recommended dose for phase II trials in acute leukemia is 120 mg/m2 per day as a continuous infusion for 7 days. There were two complete and four partial remissions among all patients. At the suggested phase II dose of 120 mg/m2 there were two complete remissions and one partial remission in five evaluable patients.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Blast Crisis; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine

Survival of older patients with acute nonlymphocytic leukemia treated with chemotherapy was compared with those given only supportive care. The treated group was younger and had better survival. The benefits which measure in months must be balanced against socioeconomic cost, toxicity of therapy, patient wishes, and evolving information about the standards of management in the older leukemia patient.

Topics: Acute Disease; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Doxorubicin; Female; Humans; Idarubicin; Leukemia, Myeloid; Male; Middle Aged; Remission Induction; Sex Factors; Survival Rate; Thioguanine

In order to study the efficacy of an oral induction and consolidation regimen in the treatment of acute myeloid leukemia (AML) in elderly patients assessed not to tolerate full-scale intensive chemotherapy, 51 patients over 65 years of age with newly diagnosed AML were randomized to receive two cycles of either totally oral ETI (25 patients) or conventional 5-day TAD (26 patients). The median age of the patients was 73 years, range 65-87 years. Thirty-eight patients had de novo AML and the remaining patients AML subsequent to myelodysplastic syndrome ((n = 11) or treatment related AML (n = 2)). ETI consisted of etoposide 80 mg/m2 and thioguanine 100 mg/m2 twice a day on days 1-5, and idarubicin 15 mg/m2 on days 1-3, all given orally. TAD consisted of oral thioguanine and i.v. cytarabine, both in the dose of 100 mg/m2 twice a day on days 1-5, and daunorubicin 60 mg/m2 on day 5. The maintenance treatment was daily oral mercaptopurine 70 mg/m2 and weekly oral methotrexate 12 mg/m2. In the ETI group complete remission (CR) was achieved in six patients after the first cycle and in nine more patients after the second cycle. The CR rate was 15/25 = 60%. The corresponding figures for the TAD group were four and two remissions, CR rate 6/26 = 23% (p = 0.007). The survival was significantly longer in the ETI arm (p = 0.042). The median survival was 9.9 months in the ETI group and 3.7 months in the TAD group. There were no significant differences in the side effects between the two arms. In conclusion, the totally oral ETI regimen resulted in a significantly higher remission rate and longer survival than the 5-day TAD regimen in elderly patients with AML, with no more toxicity.

Topics: Acute Disease; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Administration Schedule; Etoposide; Female; Humans; Idarubicin; Injections, Intravenous; Leukemia, Myeloid; Male; Remission Induction; Thioguanine

The Eastern Cooperative Oncology Group (ECOG) conducted a randomized trial in patients less than or equal to 65 years old (median, 44 years) to determine whether increasing the intensity of postremission therapy in acute myeloid leukemia (AML) would improve the outcome. After uniform induction therapy, patients in complete remission (CR) who were less than 41 years old and who had a histocompatible sibling underwent allogeneic bone marrow transplantation (alloBMT) (54 patients). The remainder of patients in CR were randomized to receive either 2 years of continuous outpatient maintenance therapy with cytarabine and 6-thioguanine (83 patients) or a single course of inpatient consolidation therapy consisting of 6 days of high-dose cytarabine plus 3 days of amsacrine (87 patients). The median duration of follow-up is now 4 years, and patients are included in the analyses of outcome regardless of whether they relapsed before starting the intended treatment. Four-year event-free survival (EFS) was 27% +/- 10% for consolidation therapy versus 16% +/- 8% for maintenance therapy (P = .068) and 28% +/- 11% versus 15% +/- 9% (P = .047) in patients less than 60 years old. The outcome for patients receiving alloBMT was compared with the subset of patients less than 41 years old who received consolidation therapy (N = 29) or maintenance therapy (N = 21). Four-year EFS was 42% +/- 13% for alloBMT, 30% +/- 17% for consolidation therapy, and 14% +/- 15% for maintenance therapy. AlloBMT had a significantly better EFS (P = .013) than maintenance therapy, but was not different from consolidation therapy. In patients less than 41 years old, 4-year survival after alloBMT (42% +/- 14%) did not differ from consolidation therapy (43% +/- 18%), but both were significantly better than maintenance therapy (19% +/- 17%), P = .047 and .043, respectively. The mortality rate for maintenance therapy was 0%, consolidation therapy, 21%; and alloBMT, 36%. Consolidation therapy caused an especially high mortality rate in the patients greater than or equal to 60 years old (8 of 14 or 57%). The toxicity of combined high-dose cytarabine and amsacrine is unacceptable, especially in older patients, and alternative approaches to consolidation therapy such as high-dose cytarabine alone need to be tested. In AML, a single course of consolidation therapy or alloBMT after initial CR produces better results than lengthy maintenance therapy. Although EFS and survival of alloBMT and consolidation therap

Topics: Acute Disease; Adolescent; Adult; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Cytarabine; Daunorubicin; Follow-Up Studies; Heparin; Humans; Leukemia, Myeloid; Middle Aged; Remission Induction; Thioguanine

These ECOG trials have demonstrated that progressive increments in the intensity of post-remission therapy result in improving long-term, disease-free survival in adults with AML. The median duration of disease-free survival and long-term outcome from different post-remission therapies are summarized in Table 4. [table: see text] Despite the suggestive evidence of the ordered increment in value of intensive consolidation therapy, allogeneic and autologous bone marrow transplantation, it remains to be proved that the differences observed in our preceding studies are statistically significant and clinically meaningful. These remaining questions led to the current ECOG study, EST 3489, a randomized intergroup study conducted with members of the Southwest Oncology Group. The study includes all patients with de novo AML up to age 55; the schema is shown in Figure 3. Induction therapy consists of idarubicin plus cytarabine instead of DAT. A modified short course of this induction therapy is repeated after CR. Patients who have a histocompatible sibling are offered allogeneic bone marrow transplantation. The remaining patients are randomized to receive either autologous bone marrow transplantation or a single course of high-dose cytarabine. Autologous bone marrow transplantation utilizes the previously described high-dose busulfan and cyclophosphamide regimen plus 4-HC purging of the bone marrow. The dosage of cytarabine in the intensive consolidation arm is 3 gm/M2/day IV on days 1-6. The results of this study should determine the relative merits of these different approaches to post-remission therapy. [table: see text] As mentioned earlier, demonstration of improved CR rates is limited by the morbidity and mortality from the myelosuppression that results from induction therapy. This is especially marked for older patients with AML. In patients, ages 55-70 years old, the ECOG is conducting a randomized trial (EST 1490) of conventional induction therapy +/- GM-CSF to determine if accelerated neutrophil recovery can reduce the mortality of induction therapy and thereby increase the remission rate. It may be that the application of GM-CSF and other colony-stimulating factors can increase the CR rate for all patients, increasing the number of patients potentially eligible for cure by post-remission therapy.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Clinical Protocols; Combined Modality Therapy; Cytarabine; Doxorubicin; Drug Administration Schedule; Humans; Leukemia, Myeloid; Middle Aged; Pilot Projects; Remission Induction; Survival Analysis; Thioguanine; Transplantation, Autologous

Topics: Acute Disease; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Daunorubicin; Drug Administration Schedule; Humans; Infant; Leukemia, Myeloid; Prognosis; Remission Induction; Survival Rate; Thioguanine

The Medical Research Council's AML 10 Children Trial commenced in 1988. It is a multicentre collaborative study based on 4 courses of intensive chemotherapy with additional allogeneic bone marrow transplantation for children with a matched sibling donor. The remaining children are randomised either to an autologous transplant using unpurged marrow or stopping therapy. To date 156 eligible patients have been entered with a CR rate of 91%. 56% of children are still alive 2 years after trial entry and 57% are in CR 3 years after achieving CR. The treatment regimen is intensive but mortality and morbidity are acceptable. The study will need to accrue patients for a further 2 to 3 years in the hope of defining the role of allogeneic and autologous marrow transplantation.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Daunorubicin; Etoposide; Humans; Infant; Leukemia, Myeloid; Recurrence; Remission Induction; Thioguanine; United Kingdom

In order to further improve the cure rate in AML we investigated the effect of more chemotherapy--in terms of its intensity and its duration--in 2 studies. In our 1981 study patients received TAD 1-2 courses for induction, 1 course for consolidation and randomly no further treatment or monthly myelosuppressive maintenance for 3 years. Evaluating 213 responders remission duration was clearly longer in the maintenance group with 24% CCR after 5 and 10 years. In our 1985 study the same successful strategy was further intensified by a second induction course given regardless of response to the first course to all patients up to 60 years of age while older patients received standard induction as before. This age-adapted concept resulted in a further increase of 5 years CCR in the 461 responders to as much as 34% not achieved for unselected patients in other multicenter trials. 20 patients receiving auto-BMT in first CR show the same relapse free survival as their counterparts receiving chemotherapy according to the 1985 protocol in a matched-pair analysis. We conclude that both very early intensification and prolonged maintenance contribute to a higher cure rate that is not further improved even by a maximum intensity short-term treatment. The limits of chemotherapy in AML may be overcome by modulating its myelotoxicity and antileukemic potency using GM-CSF as shown in 2 studies of our group.

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Administration Schedule; Humans; Leukemia, Myeloid; Middle Aged; Recurrence; Remission Induction; Thioguanine

Topics: Actuarial Analysis; Acute Disease; Adolescent; Adult; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Daunorubicin; Drug Administration Schedule; Follow-Up Studies; Humans; Italy; Leukemia, Myeloid; Middle Aged; Remission Induction; Thioguanine

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid; Remission Induction; Thioguanine

70% of patients with newly diagnosed and 50% of patients with relapsed acute myeloid leukemia (AML) can achieve a complete remission with intensive chemotherapy. However, the treatment-associated mortality can be as high as 30% increasing with age, previous chemotherapy and intensity of chemotherapy. GM-CSF was first applied in 36 patients with high risk AML after chemotherapy to reduce the time of critical neutropenia. The early death rate was significantly lower in the GM-CSF group compared to 56 patients of a historic control group with similar risk factors and identical chemotherapy (p less than 0.009). The rate of complete remissions was also significantly higher in the GM-CSF group (p less than 0.09). More recently, GM-CSF was used as a priming agent 24 h prior to start of chemotherapy. 25 patients have entered the study up to now. The cell biological effects of GM-CSF in vivo include an immediate increase of leukemic blasts and of normal myeloid cells in the peripheral blood with a median of 2.0, an increase of cells in the S-phase of the cell cycle in bone marrow biopsies, an increase in DNA polymerase activity, an increase in Ara-C cytotoxicity and immunophenotypic changes compatible with differentiation of leukemic blasts along the pathway of normal myeloid progenitors. GM-CSF has a dual effect on normal and leukemic myeloid cells. It can be safely applied in patients with AML. Prospective randomized trials have to be performed to establish its role in reducing treatment toxicity and in improving the overall treatment results.

Topics: Acute Disease; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cell Division; Cytarabine; Daunorubicin; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Infusions, Intravenous; Leukemia, Myeloid; Mitoxantrone; Recombinant Proteins; Thioguanine; Tumor Stem Cell Assay

Between 1982 and 1986, 326 evaluable patients with acute myeloid leukemia (AML) were randomized to receive cytarabine (Ara-C) at 200 mg/m2 (A200) or 100 mg/m2 (A100) for induction and maintenance therapy. Cycle 1 of induction therapy consisted of 7 days of continuous intravenous (IV) Ara-C and 3 days of i.v. daunorubicin (DNR); cycle 2, if needed, consisted of 5 days of Ara-C and 2 days of DNR. Complete responders (CR) then received monthly subcutaneous (SC) Ara-C at the respective doses (A100 or A200) with 6-thioquanine (6TG) at months 1 and 5, with vincristine (VCR) and prednisone at months 2, 4, 6, and 8, and with DNR at months 3 and 7. Complete response rates were 58% (A100) and 64% (A200) (P = .29). Median survival was 46 weeks (A100) and 38 weeks (A200) (P = .64); 5-year survival was 10% (A200) and 8% (A100). Median time to remission was 6.7 weeks (A200) and 8.1 weeks (A100) (P = .18). Median disease-free survival was 41 weeks (A200) and 44 weeks (A100) (P = .86). Deaths were attributed to therapy-related toxicities in 21% (A200) and 13% (A100) (P = .05). The 5-year survival was 15% for patients with performance status (PS) 0, 8% for PS 1 to 2, and 2% for PS 3 to 4, 18% for patients less than 40 years, 8% for ages 40 to 59, and 3% for age 60 or greater. Stratification of data by age and PS suggested that A200 may improve survival in patients less than 60 years with a good PS 0 (P = .05). This trial does not support the superiority of A200 over A100 in the treatment of AML.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Leukemia, Myeloid; Male; Middle Aged; Prednisone; Remission Induction; Thioguanine; Time Factors; Vincristine

108 consecutive patients with de novo acute myeloid leukaemia at ages 15 to 59 years were treated in a prospective controlled multicentre trial. Induction with combination TAD resulted in a complete remission in 85 cases (79%). After a cyclic consolidation programme for 6 months, 73% of the remissions continued. The maintenance therapy was at random either nothing, or alpha interferon, or monthly 5 day courses with thioguanine and cytarabine. The median duration of all remissions was 13 months; that of those in the control and interferon arms 15 months each, and in the chemotherapy arm 18 months. The median survival of all the 108 patients was 16 months; that of those in the control arm 20 months, in the interferon arm 33 months and in the chemotherapy arm 26 months. At 5 yr, 31%, 22% and 31%, respectively, were alive. The survival curves did not differ from each other significantly. Maintenance treatment after an intensive induction and a moderately intensive consolidation was of no benefit in this study. Interferon did not improve the prognosis.

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Cytarabine; Daunorubicin; Female; Follow-Up Studies; Humans; Interferon-alpha; Leukemia, Myeloid; Male; Prospective Studies; Remission Induction; Thioguanine

The role of early splenectomy in the management of chronic myeloid leukemia (CML) was investigated in a multicentric study with 21 contributing Hospitals. One hundred eighty-nine patients younger than 66 years of age and previously untreated, were first seen between November 1974 and May 1977, were randomized to splenectomy or to nonsplenectomy , were given the same chemotherapy (busulfan, and courses of arabinosyl cytosine, 6-thioguanine, and daunomycin), and were followed up for more than 5 years. Median survival was 45 months. No relationship of splenectomy to survival length could be shown either in the whole series, or in several subgroups that were selected according to presentation features and stage classification. Thromboembolic and vascular accidents were more frequent in the splenectomy group, and this was associated with more difficult control of platelet count. Early splenectomy is not recommended for treatment of CML.

Topics: Actuarial Analysis; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Combined Modality Therapy; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid; Male; Middle Aged; Random Allocation; Splenectomy; Thioguanine; Time Factors

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

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

This report provides information on the progress of two trials by the Italian Cooperative Study on Chronic Myeloid Leukemia (CML). Both trials were designed in order to test the effect of early splenectomy and of cyclic administration of either arabinosyl cytosine and vincristine plus prednisone, or arabinosyl cytosine plus thioguanine plus daunomycin, on the course of CML and on the survival. A preliminary analysis, performed on September, 1977, suggests that neither splenectomy nor the chemotherapy scheduled have resulted in a significant decrease of the rate of blastic transformation of CML, during the first 2 to 3 years from diagnosis.

Topics: Adult; Aged; Antineoplastic Agents; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid; Male; Middle Aged; Prednisone; Splenectomy; Thioguanine; Vincristine

Topics: Animals; BCG Vaccine; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Immunotherapy; Leukemia L1210; Leukemia, Myeloid; Mercaptopurine; Mice; Mycobacterium bovis; Neuraminidase; Thioguanine

Thirty-two patients in the blastic phase of Philadelphia chromosome-positive chronic granulocytic leukemia (CGL) were studied in a prospective randomized trial in which vincristine--prednisone (19 patients) was compared with cytosine arabinoside--6-thioguanine (13 patients). Seven remissions (37%), including two complete remissions, were achieved in the vincristine--prednisone group. Three of the five with predominant hypodiploid blast cell lines treated with vincristine--prednisone had complete or partial remissions. Both complete remitters presented with hypodiploidy consisting of 44 chromosomes. Four patients (30%) who were treated with cytosine arabinoside--6-thioguanine responded with one complete remission. The median survival of the responders was 8 mo, as compared to 1--2 mo for the nonresponders. Crossover to the opposite regimen as secondary therapy following refractoriness or resistance resulted in only 3 partial responses out of 21 treated. All three had previously responded to vincristine--prednisone. Of the 32 cases, 14 had an elective splenectomy during the chronic phase of the disease. Prior splenectomy did not influence the response to chemotherapy, as all three complete remitters occurred in the nonsplenectomized group. Similarly, survival in the blastic phase was not affected by prior splenectomy.

Topics: Adolescent; Adult; Cell Transformation, Neoplastic; Child; Chromosomes, Human, 21-22 and Y; Cytarabine; Diploidy; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid; Male; Middle Aged; Prednisone; Remission, Spontaneous; Thioguanine; Vincristine

Topics: Adult; Antineoplastic Agents; Busulfan; Chromosome Aberrations; Chromosomes, Human, 21-22 and Y; Clinical Trials as Topic; Cytarabine; Daunorubicin; Drug Evaluation; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Humans; Hydroxyurea; Leukemia, Myeloid; Male; Middle Aged; Splenectomy; Thioguanine

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

The introduction of the United Kingdom Medical Research Council's 10th AML trial (MRC AML 10) protocol incorporating high-dose anthracycline therapy has improved outcome of children with acute myeloid leukemia (AML). In this study, we review the results of childhood AML therapy in a Singapore university hospital over the last 17 years emphasizing toxicity and outcome.. Retrospective analysis revealed 34 children with AML between 1988 and 2003. Prior to September 1996, therapy consisted of: POG-8498 (n = 10), others (n = 9). From September 1996, all but one of 15 children received MRC AML 10 treatment.. At the time of analysis, 17 had died from disease, and 17 patients were alive among whom 2 had relapsed. MRC AML 10-treated patients (n = 14) had significantly better 3-year overall, event-free, and disease-free survival (74% vs. 35%, 77% vs. 20%, 83% vs. 31%; P = 0.019, P = 0.002, and P = 0.010, respectively) and were likelier to achieve complete remission (CR) than non-MRC AML 10 patients (P = 0.102). Among patients who achieved CR, MRC AML 10-treated patients were significantly more likely to achieve CR after only one cycle of chemotherapy (P = 0.016). Hematologic toxicity was similar among the different regimens (P = 0.9).. These findings suggest that MRC AML 10 treatment results in significantly superior survival, without excess toxicity. Future studies should attempt to elucidate the relative importance of individual MRC AML 10 components and reduce the high cumulative anthracycline dose without compromising outcome.

Topics: Acute Disease; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cytarabine; Daunorubicin; Developing Countries; Disease-Free Survival; Drug Evaluation; Etoposide; Female; Gastrointestinal Diseases; Heart Diseases; Hematologic Diseases; Humans; Infant; Infections; Kaplan-Meier Estimate; Leukemia, Myeloid; Male; Mercaptopurine; Methotrexate; Mitoxantrone; Prednisone; Remission Induction; Retrospective Studies; Singapore; Survival Analysis; Thioguanine; Treatment Outcome; Vincristine

Infections still remain a major cause of therapy-associated morbidity and mortality in children with acute myeloid leukemia (AML). To improve supportive care measurements, detailed information on frequency and characteristic features of infectious complications is needed. We retrospectively analyzed the medical charts of 304 children, treated in 30 hospitals according to the multi-institutional clinical trial AML-BFM 93. Overall, 855 infectious complications occurred in 304 patients (fever without identifiable source (n=523; 61.2%), clinically (n=57; 6.7%) and microbiologically documented infections (n=275; 32.1%)). Neutropenia was present in 74.1% of the infectious episodes. In all, 20 patients died of infection-associated complications (15/276 (5.4%) patients without and 5/28 (17.9%) with Down syndrome), most of them during early induction therapy (n=11). Blood stream infections occurred in 228 episodes (Gram-positive (n=202) and Gram-negative (n=42) pathogens). Invasive fungal infection was probable or proven in 15 patients. In 113 out of the 855 infectious episodes (13.3%), pneumonia was radiologically diagnosed. Better strategies of supportive care might help to improve overall survival in children undergoing chemotherapy for AML. Therefore, children with AML should be treated in specialized pediatric centers, and there should be a very low threshold to readmit patients, in particular patients with pulmonary symptoms.

Topics: Acute Disease; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bacteremia; Bacteria; Child; Child, Preschool; Clinical Trials as Topic; Cytarabine; Down Syndrome; Etoposide; Female; Fever; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Infant; Infant, Newborn; Leukemia, Myeloid; Male; Mitoxantrone; Neutropenia; Prospective Studies; Retrospective Studies; Thioguanine

To evaluate whether children with acute myeloblastic leukemia (AML) presenting with extramedullary infiltration (EMI) have different clinical, morphologic features and prognosis from children without EMI, a 127 consecutive previously untreated children with AML were entered in this study. Fifty-one children (40%) had EMI at diagnosis and 27% of these showed multiple site involvement. Twenty-seven of 127 children (21%) presented myeloid tumors. No age related differences in the incidence of EMI was noted. However, analysis of clinical and biological features at diagnosis showed that WBC count > or =50 x 10(9) l(-1), hepatosplenomegaly >5 cm, FAB AML-M4 and AML-M5 subtypes and CD13, CD14 expression of bone marrow (BM) leukemic cells (>20%) were more frequent in children with EMI. Two consecutive treatment protocols were used. In both protocols remission was achieved with combined high-dose methylprednisolone (HDMP) as a differentiating and apoptosis inducing agent with mild cytotoxic chemotherapy (low-dose cytosine arabinoside (LD Ara-C), weekly mitoxantrone and Ara-C or 6-thioguanine). Administration of short-course (4-7 days) HDMP (20-30 mg/kg per day) alone resulted in a remarkable decrease in peripheral blood, BM blasts and in the size of EMI in responding patients. In both protocols, remission rate in patients with EMI was 71 and 80%, which was lower than that of the patients without EMI (87 and 89%). This may be attributed to the higher frequency of unfavorable features in children with EMI. However, in patients who presented with myeloblastoma and treated with a more intensive post-remission therapy (AML-94), the 4-year disease-free survival (DFS) and event-free survival (EFS) rates were not found to be significantly different from children who had no EMI (P>0.05). Whereas, the outcome of children who presented with gingival infiltration did not improve. In further studies, the prognostic significance of different localisation of EMI and the effect of addition of HDMP to cytotoxic chemotherapy should be explored in larger series.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Bone Marrow Cells; CD13 Antigens; Child; Child, Preschool; Cytarabine; Female; Humans; Leukemia, Myeloid; Leukemic Infiltration; Lipopolysaccharide Receptors; Male; Methylprednisolone; Mitoxantrone; Prognosis; Remission Induction; Survival Rate; Thioguanine; Treatment Outcome

Early response after induction therapy is an independent prognostic factor in acute myeloid leukemia (AML). We improved the identification of this parameter by implementing multiparameter flow cytometry to quantify bone marrow cells carrying leukemia-associated immunophenotypes (LAIP).. In 106 uniformly treated patients flow cytometric analyses were performed at diagnosis and one week after induction therapy (day 16). The log-difference between LAIP-positive cells on day 1and day 16 (LD16) was determined for each patient.. The LD16 (median, 2.11; range, -0.37 to 4.20) was significantly correlated to CR rate, event-free survival (EFS), overall survival (OS), and relapse-free survival (RFS). Separation of patients by the median LD16 resulted in significant differences in CR rate (81% vs. 51%, p=0.002), EFS (53% at 2 years vs. median 2.8 months, p<0.0001), 2-year OS (58% vs. 43%, p=0.0133), and 2-year RFS (65% vs. 30%, p=0.0037). Multivariate analysis revealed that LD16 was an independent prognostic parameter for CR rate, EFS, and RFS.. Flow cytometric evaluation of early response may serve as a new response parameter in AML. It may be used for development of risk-adapted therapies. High-risk patients can be identified early after the first induction therapy and assigned alternative and salvage treatment strategies.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Cells; Cytarabine; Daunorubicin; Female; Flow Cytometry; Humans; Immunophenotyping; Leukemia, Myeloid; Male; Middle Aged; Mitoxantrone; Neoplasm, Residual; Prognosis; Remission Induction; Stem Cell Transplantation; Survival Analysis; Thioguanine

13-cis retinoic acid + (OH)2 vitamin D3 + low-dose 6-thioguanine and cytarabine were tested in 26 patients with acute myeloid leukemia (AML) and in 4 patients with myelodysplastic syndrome (MDS) (median age 72.5), ineligible for standard chemotherapy. The response rate was 50%, with 27% complete remission. The median survival of the whole group and responders was 7.5 (1-47+) and 16.5 months (3.5-47+), respectively.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Calcitriol; Cytarabine; Disease Progression; Female; Humans; Isotretinoin; Leukemia, Myeloid; Male; Middle Aged; Myelodysplastic Syndromes; Thioguanine

Approximately 40% of children with acute myeloid leukemia (AML) who respond to initial therapy subsequently relapse. Multidimensional flow cytometry employing a standardized panel of monoclonal antibodies enables the detection of small numbers of occult leukemic cells that persist during therapy using technology adaptable by most clinical laboratories. We performed a prospective, blinded evaluation of bone marrow specimens obtained from 252 pediatric patients with de novo AML to determine whether detection of occult leukemia defined as more than or equal to 0.5% blasts with aberrant surface antigen expression as determined by flow cytometry was predictive of subsequent relapse. Occult leukemia was detected in 41 (16%) of the 252 patients who responded to initial induction therapy. In time-dependent multivariate analyses that controlled for allogeneic marrow transplantation, variable intervals between sample submission, age, sex, white blood cell count at diagnosis, presence of splenomegaly or hepatomegaly, and presence of more than 15% blasts in the marrow after the first course of induction, patients harboring occult leukemia were 4.8 times more likely to relapse (95% confidence interval [CI] = 2.8 to 8.4, P <.0001) and 3.1 times more likely to die (95% CI; 1.9 to 5.1, P <.0001) than those lacking leukemia detectable by flow cytometry. In this analysis, flow cytometric evidence of leukemia after the initiation of therapy emerged as the most powerful independent prognostic factor associated with poor outcome. Among patients in whom a marrow sample was available for analysis at the end of consolidation therapy, overall survival at 3 years was 41% versus 69% for patients with and without occult leukemia, respectively (P =.0058).

Topics: Acute Disease; Adolescent; Adult; Antigens, CD; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Examination; California; Child; Child, Preschool; Cytarabine; Daunorubicin; Dexamethasone; Etoposide; Female; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Humans; Idarubicin; Immunophenotyping; Infant; Leukemia, Myeloid; Male; Multicenter Studies as Topic; Myelodysplastic Syndromes; Neoplasm, Residual; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Recurrence; Remission Induction; Risk Factors; Single-Blind Method; Survival Analysis; Thioguanine; Treatment Outcome

The role of autologous peripheral blood stem cell transplantation (APBSCT) in acute myeloid leukaemia (AML) remains controversial. The current study evaluated the application of APBSCT in a large consecutive series of patients with untreated AML, and compared outcome with a predictive model based on MRC AML10 data. Of 148 evaluable patients, 118 patients entered complete remission (CR) after induction therapy comprising three cycles of daunorubicin, cytosine arabinoside and oral 6-thioguanine. Of these patients, 68 (57%) proceeded to consolidation therapy with two courses of intermediate dose cytosine arabinoside, and stem cell mobilisation, and 40 of these patients (34%) underwent the APBSCT procedure after high dose busulphan conditioning. Harvest quality was the main factor precluding APBSCT. Five-year event-free survival (EFS) in patients who achieved CR was 38% and in APBSCT patients was 57%. There were no transplant-related deaths. No significant differences were demonstrated between observed and expected outcomes at 1 and 2 years, based on the predictive model derived from the MRC AML10 study. These data therefore indicate that only a third of eligible adult patients will undergo APBSCT. However, the results demonstrate favourable survival in such patients, with no transplant-related mortality.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Clinical Trials as Topic; Cohort Studies; Combined Modality Therapy; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Leukemia, Myeloid; Life Tables; Male; Middle Aged; Models, Biological; Peripheral Blood Stem Cell Transplantation; Remission Induction; Risk; Survival Analysis; Thioguanine; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Interactions between hemopoietic cells and the stromal microenvironment or immunoreactive cells are mediated by specific cell surface receptors. The expression of those molecules may alter the adhesive qualities (mobility and homing) as well as immune response behavior of leukemic blasts. L-Selectin (CD62L) is suggested to play a role in the redistribution and homing of hemopoietic progenitor cells to the bone marrow (BM). Down-regulation of L-selectin is responsible for mobilization of blasts from the BM into the circulation and ligation of L-selectin stimulates proliferation of progenitor cells. This could have an influence on the process of leukemia.. We have studied the expression of L-selectin on mononuclear BM cells of 36 acute myeloid leukemia (AML) patients at first diagnosis by FACS analysis using a directly fluorescein isothiocyanate conjugated antibody (clone DRE G56).. On average the patients presented with 88% blasts in the BM. The expression tended to be higher in primary (p) AML compared with secondary (s) AML. L-Selectin was very heterogenously expressed in all FAB groups. Highest expression was found in cases with AML-M4 with four of nine cases presenting with an inv(16) karyotype. Separating our patient cohort in cytogenetic risk groups we could detect a significantly higher expression of L-selectin in cases with a 'good risk' karyotype and a very low expression in cases with a 'bad risk' karyotype (P = 0.037). Comparing patients who achieved remission after double induction therapy (responders) with patients who showed persisting disease (non-responders) we found a higher percentage of L-selectin+ cases or cells in the responder group than in the non-responder group, although the differences were not significant because of only five cases in the 'non-responder' group. Evaluating cut-off points greatest differences in relapse-free survival probabilities were found in patients who presented with > or = 30% L-selectin+ BM cells compared with cases with < 30%: 86% of cases with > or = 30% L-selectin+ cells were still in remission after a mean follow up time of only 8 months compared with only 46% in the group with < 30% L-selectin+ cells.. We can conclude that (i) expression of L-selectin on AML blasts is variable. This reveals the great diversitiy of immunophenotypes in AML and might contribute to identify individual blast phenotypes in order to detect minimal residual disease in remission. (ii) Low L-selectin expression correlates with a bad cytogenetic risk, with a lower probability to achieve remission and with a shorter relapse-free survival time. This might reflect a decreased homing of the blasts to the BM as well as an impaired cytotoxic T-cell reaction against leukemic cells. The expression of L-selectin on leukemic blasts might be influenced by different cytokine therapies (e.g. with interferon alpha) and this might result in an altered hematologic reconstitution after cytotoxic therapies as well as in an altered immunologic recognition of blasts.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Cells; Chromosome Aberrations; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Humans; L-Selectin; Leukemia, Myeloid; Male; Middle Aged; Mitoxantrone; Neoplasm Proteins; Neoplastic Stem Cells; Remission Induction; Risk; Thioguanine; Treatment Outcome; Tretinoin

This short report presents the results of a comparison of complete remission rates and reasons for failure, between two series of patients aged 60 years or over with acute myeloid leukaemia (AML), and discusses their interpretation.

Topics: Acute Disease; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Disease-Free Survival; Humans; Leukemia, Myeloid; Remission Induction; Thioguanine

The antimetabolite 6-thioguanine (6-TG) is utilized in the management of acute myelogenous leukemia (AML). Angiogenesis is a possible therapeutic target in hematologic tumors. Thus, we addressed the possibility that 6-TG may also act as an anti-angiogenic molecule. 6-TG inhibited endothelial cell proliferation triggered by fibroblast growth factor-2 (FGF2) and vascular endothelial growth factor (VEGF) and delayed the repair of a mechanically wounded endothelial cell monolayer. Also, 6-TG inhibited sprouting within fibrin gel, morphogenesis on Matrigel, and collagen gel invasion by endothelial cells. 2-Aminopurine was ineffective. In vivo, 6-TG inhibited basal, VEGF-induced, and FGF2-induced vascularization in the chick embryo chorioallantoic membrane and prevented neovascularization triggered by leukemia LIK cells or their conditioned medium. Finally, bone marrow vascularization in AML patients was decreased to control values in the early remission phase and persisted unvaried after 8-12 months of maintenance therapy with 6-TG. Thus, 6-TG inhibits different steps of the angiogenesis process in vitro and exerts a potent anti-angiogenic activity in vivo. Its anti-angiogenic activity, together with its antimetabolite activity towards tumor cells, may contribute to its action during maintenance therapy in AML. These results suggest a new rationale for the use of purine analogs in the management of AML.

Topics: 2-Aminopurine; Acute Disease; Aged; Allantois; Anemia; Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cattle; Cell Line, Transformed; Chick Embryo; Chorion; Cytarabine; Daunorubicin; Drug Evaluation; Endothelial Growth Factors; Endothelium, Vascular; Etoposide; Female; Fibroblast Growth Factor 2; Follow-Up Studies; Humans; Leukemia, Myeloid; Lymphokines; Male; Mice; Mice, Inbred BALB C; Middle Aged; Neovascularization, Pathologic; Neovascularization, Physiologic; Remission Induction; Stress, Mechanical; Thioguanine; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

In 85 adult patients diagnosed with acute myeloid leukaemia (AML) and treated at the same institution during a 5-yr period, the clinical significance of in vitro cellular drug resistance to the anthracyclines aclarubicin (Acla) and daunorubicin (Dau) as well as the nucleoside analogue cytarabine (Ara-C) was investigated using a 4-d MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. In 59 patients of whom 40 were treated by the combination of Acla and Ara-C we found that leukaemia cell drug resistance towards Acla was higher (by a factor 2.80) in patients who failed to enter complete remission (CR) after the first cycle of induction chemotherapy as compared to patients who entered complete remission. The relationship was significant in univariate as well as multivariate analysis (p=0.02 and 0.03, respectively). By contrast, no in vitro single drug resistance values were consistently correlated to other parameters of clinical outcome (overall CR rate, overall survival (OS), or continuous complete remission (CCR)), whereas the combined Acla and Ara-C drug resistance profile (Acla/Ara-C DRP) was of prognostic significance to overall survival of all 85 patients (p=0.004) as well as to the CCR of 39 complete responders (p=0.04). These findings remained statistically significant in multivariate analyses correcting for other variables influencing clinical outcome including patient age, leukocyte count, karyotype, FAB-subtype, and presence/absence of secondary AML. We conclude that the in vitro drug resistance of leukaemia cells at time of disease presentation appears to be independent of prognostic significance to short- and long-term clinical outcome in AML.

Topics: Aclarubicin; Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Etoposide; Female; Humans; Idarubicin; Leukemia, Myeloid; Male; Middle Aged; Mitoxantrone; Neoplastic Stem Cells; Prognosis; Remission Induction; Survival Analysis; Thioguanine; Treatment Outcome; Tumor Cells, Cultured

Sequence-specific combinations of purine analogs, such as fludarabine or 6-mercaptopurine (6-MP), administered prior to cytosine arabinoside (ara-C) have been shown to abrogate ara-C resistance in human leukemia cells in vitro and in patients with relapsed acute myeloid or lymphoblastic leukemias. The two-drug combination of 6-MP plus ara-C results in greater cytotoxicity than that achieved with either ara-C or 6-MP alone. Further preclinical investigations have shown that the addition of PEG-asparaginase (PEG-ASNase) to the combination of 6-MP plus ara-C (6-MP + ara-C + PEG-ASNase) results in 15.6-fold synergism over that achieved with the two-drug regimen. This is due to increased DNA damage leading to apoptotic cell death.. Since the intravenous preparation of 6-MP is no longer available and since oral 6-thioguanine (6-TG) provides higher levels of intracellular thioguanine nucleotides than an isotoxic dose of oral 6-MP, we investigated the potential drug synergism of 6-TG plus ara-C plus PEG-ASNase (TGAP) in myeloid (HL60/S, HL60/SN3, U937) and lymphoblastic (CEM/0, CEM/ ara-C/B, CEM/ara-C/I, MOLT-4) leukemia cell lines. The CEM clones, MOLT-4 and HL60/SN3 cell lines expressed functional or measurable p53 protein, while the other cell lines did not.. The MTT and trypan blue dye exclusion assays were used to determine drug cytotoxicity. In addition, cellular apoptosis and cellular p53, p21/waf-1 and bcl-2 protein concentrations were determined by FACS analysis and ELISA assays.. Sequential exposure to 6-TG (24 h) plus ara-C (24 h) plus PEG-ASNase (24 h) produced 1.3- to 18.3-fold drug synergism over the two-drug combination of 6-TG plus ara-C. The molecular mechanism of synergism was due to the fact that the three-drug combination was capable of downregulating bcl-2 oncoprotein levels in these cell lines even when p53 was absent.. These studies strongly demonstrate that the TGAP regimen is highly synergistic in p53-null and p53-expressing leukemia cell lines. We conclude that this combination regimen is collaterally sensitive with ara-C and further evaluation in an investigational phase I trial in relapsed leukemia patients is warranted.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Asparaginase; Cytarabine; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; HL-60 Cells; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, T-Cell; Polyethylene Glycols; Proto-Oncogene Proteins c-bcl-2; Thioguanine; Tumor Cells, Cultured; Tumor Suppressor Protein p53; U937 Cells

Intensive induction therapy in acute myeloid leukemia (AML) as in some other systemic malignancies is a strategy fundamentally different from post-remission strategies. Approaches such as consolidation treatment, prolonged maintenance, and autologous or allogeneic transplantation in first remission are directed against the minimal residual disease in which a malignant cell population has survived induction treatment and shows resistance due to special genetic or kinetic features. In contrast, induction therapy deals with naive tumor cells possibly different from their counterparts in remission in terms of their kinetic status and sensitivity. Therefore, in AML the introduction of intensification strategies into the induction phase of treatment has been suggested as a new step in addition to intensification in the postremission phase. As expected from the dose effects observed in post-remission treatment with high-dose cytarabine (AraC) or longer treatment, similar dose effects have been found in induction treatment both from the incorporation of high-dose AraC and from the double-induction strategy used in patients up to 60 years of age. As a particular effect, patients with poor-risk AML according to an unfavorable karyotype, high LDH in serum, or a delayed response show longer survival following double induction containing high-dose AraC as compared to standard-dose AraC. A corresponding dose effect in the induction treatment of patients aged 60 years and older has been found with daunorubicin 60 vs 30 mg/m2 as part of the thioguanine/ AraC/daunorubicin (TAD) regimen with the higher dosage significantly increasing the response rate and survival in these older patients who represent a poor-risk group as a whole. Thus we have been able to demonstrate both in younger and older patients that a poor prognosis can be improved by a more intensive induction therapy. High-dose AraC in induction, however, exhibits cumulative toxicity in that repeated courses containing high-dose AraC in the post-remission period lead to long-lasting aplasias of about 6 weeks. Thus after intensive induction treatment, high-dose chemotherapy in remission may be practicable using stem-cell rescue and may contribute to a further improvement in the outcome in poor-risk as well as average-risk patients with AML. These approaches are currently under investigation by the German AML Cooperative Group (AMLCG). "The more intensive the better" is certainly not the way to go in the management

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cytarabine; Daunorubicin; Dose-Response Relationship, Drug; Humans; Leukemia, Myeloid; Middle Aged; Remission Induction; Thioguanine

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

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

The purpose of the paper was to define clinical or biological features associated with the risk for treatment failure for children with acute myeloid leukemia. Data from 560 children and adolescents with newly diagnosed acute myeloid leukemia who entered the Pediatric Oncology Group Study 8821 from June 1988 to March 1993 were analyzed by univariate and recursive partitioning methods. Children with Down syndrome or acute promyelocytic leukemia were excluded from the study. Factors examined included age, number of leukocytes, sex, FAB morphologic subtype, cytogenetic findings, and extramedullary disease at the time of diagnosis. The overall event-free survival (EFS) rate at 4 years was 32.7% (s.e. = 2.2%). Age > or =2 years, fewer than 50 x 10(9)/I leukocytes, and t(8;21) or inv(16), and normal chromosomes were associated with higher rates of EFS (P value = 0.003, 0.049, 0.0003, 0.031, respectively), whereas the M5 subtype of AML (P value = 0.0003) and chromosome abnormalities other than t(8;21) and inv(16) were associated with lower rates of EFS (P value = 0.0001). Recursive partitioning analysis defined three groups of patients with widely varied prognoses: female patients with t(8;21), inv(16), or a normal karyotype (n = 89) had the best prognosis (4-year EFS = 55.1%, s.e. = 5.7%); male patients with t(8;21), inv(16) or normal chromosomes (n = 106) had an intermediate prognosis (4-year EFS = 38.1%, s.e. = 5.3%); patients with chromosome abnormalities other than t(8;21) and inv(16) (n = 233) had the worst prognosis (4-year EFS = 27.0%, s.e. = 3.2%). One hundred and thirty-two patients (24%) could not be grouped because of missing cytogenetic data, mainly due to inadequate marrow samples. The results suggest that pediatric patients with acute myeloid leukemia can be categorized into three potential risk groups for prognosis and that differences in sex and chromosomal abnormalities are associated with differences in estimates of EFS. These results are tentative and must be confirmed by a large prospective clinical trial.

Topics: Adolescent; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bone Marrow Transplantation; Child; Chromosome Aberrations; Chromosome Inversion; Chromosomes, Human; Cohort Studies; Combined Modality Therapy; Cytarabine; Disease-Free Survival; Doxorubicin; Etoposide; Female; Follow-Up Studies; Humans; Leukemia, Myeloid; Life Tables; Male; Multicenter Studies as Topic; Prognosis; Proportional Hazards Models; Randomized Controlled Trials as Topic; Remission Induction; Risk Assessment; Risk Factors; Survival Analysis; Thioguanine; Translocation, Genetic; Treatment Failure; Treatment Outcome; United States

The HPRT mutations in T lymphocytes are widely utilized as biomarkers of environmental exposure and effect. The HPRT gene detects a wide variety of mutation types, many of which are similar at the molecular level to those found in oncogenes in cancers. However, it remains to be determined whether the assay for mutations in T lymphocytes is reflective of mutagenic events in tissues or cells which have high frequencies of malignancy in humans. We now demonstrate that the HPRT gene can be utilized to detect mutations in myeloid stem cells, which are frequent progenitor cells of leukemias. This myeloid stem cell assay shows an age related increase in mutation at HPRT and also detects increases in mutant frequency (M-MF) in patients who have undergone chemotherapy. The myeloid mutants are confirmed to have mutations in the HPRT gene by DNA sequence analysis. Increases in M-MF are seen as expected in the clonally unstable myeloid stem cells of patients with myelodysplastic syndromes; however, unexpectedly these patients also have elevated T-lymphocyte mutant frequencies (T-MF). A good correlation is shown between M-MFs and T-MFs in the same patients. Thus, it appears that the T-lymphocyte assay, which is technically much less demanding than the myeloid assay, appears to faithfully represent the frequency of mutagenic events in the myeloid lineage.

Topics: Adult; Aged; Antigens, CD34; Antineoplastic Agents; Bone Marrow; DNA Mutational Analysis; Fetal Blood; Hematopoietic Stem Cells; Humans; Hypoxanthine Phosphoribosyltransferase; Infant, Newborn; Leukemia, Myeloid; Lymphocytes; Middle Aged; Mutation; Myelodysplastic Syndromes; Predictive Value of Tests; Risk Factors; Thioguanine

The treatment of elderly patients with acute myeloid leukaemia (AML) remains controversial. We present the results of the treatment of a group of patients aged above 70 years with AML diagnosed in our Hospital since 1990.. We have studied retrospectively the cases of AML in patients older than 70 years diagnosed in our Service since January 1990 to June 1996. Induction treatment was performed, in all cases but one, with two cycles of Ara-C 10 mg/m2/12 h s.c. for 21 days and after haematological recuperation, if complete remission had been achieved, monthly maintenance treatment with Ara-C (25 mg/m2/12 h oral x 5 days), prednisone (40 mg/m2/day x 5 days) y vincristine (1 mg/m2 i.v. x 1 day) was begun.. During the period of study 48 patients with AML have been diagnosed in our Service, among them 22 (45.8%) were older than 70 years. One of them could not be considered for the study as not all data from him could be compiled. Among the other 21 patients 5 presented previous haematological processes (4 myelodysplastic syndrome and 1 Waldenström's macroglobulinemia). Initial diagnosis according to FAB classification for AML was as follows: 7 M1, 6 M2, 4 M4, 2 M5 and 2 M6. From these 21 patients 2 received no treatment due to rapid progression and death, among the other 19, one was directly treated with a modification of the maintenance treatment with vincristine and prednisone without response (survival 2 months). The other 18 patients were treated with low-dose Ara-C (described above), among them 3 (16.7%) were not evaluable as they did not finish the first cycle of induction treatment; 8 (44.4%) showed no response; 2 (11.1%) achieved partial remission and 5 (27.8%) complete remission. One patient did not show any response after two cycles of low-dose Ara-C but she obtained complete remission when treated with Ara-C and idaurubicin. Overall mean survival was 5.7 months (median 2; 95% confidence interval 1.6-9.8 months). In the group of patients treated with low-dose Ara-C mean survival was 6.6 months (median 3.5; 95% confidence interval 1.9-11.2 months).. We consider that the treatment with low-dose Ara-C is a valid option in the treatment of elderly patients (aged 70 or above) with AML because 28% complete remissions can be achieved, specially in those ones in which other more aggressive treatments are not possible.

Topics: Acute Disease; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Drug Evaluation; Female; Humans; Leukemia, Myeloid; Life Tables; Male; Myelodysplastic Syndromes; Prednisone; Remission Induction; Retrospective Studies; Survival Analysis; Survival Rate; Thioguanine; Treatment Outcome; Vincristine; Waldenstrom Macroglobulinemia

Older patients with RAEB-T or AML are extremely difficult to treat. They are at high risk of infection and/or bleeding complications and have a low probability of cure and short overall survival with conventional treatments. We treated 12 patients with an outpatient low-dose chemotherapy regimen consisting of Ara-C 100 mg subcutaneously on day 1, and 6-thioguanine 80 mg orally on days 2-5, repeated every week. Nine patients had MDS, six RAEB-T, and three RAEB (median age 57 years) and three had de novo AML (median age 73 years). All patients were transfusion dependent. The mean peripheral blast count at the beginning of treatment was 29% (4-51%). The median follow-up is 13 months (2-34 months) for all the patients and 14 months (2-34 months) for those with RAEB-T. Nine of the 12 patients are alive, including seven RAEB-T patients with a median of 18 months (range 6-34+ months). During treatment, the peripheral blast count was markedly reduced to a mean of 5% (0-23%). The mean pre-therapy platelet count, with transfusion support, was 24.0 x 10(9)/l, while the mean post-therapy platelet count without transfusion support is 95.0 x 10(9)/l. All patients except two became transfusion independent at some time. Treatment for 6-10 weeks was required to show reduction of blast number and increase in hemoglobin, platelet, and WBC counts. Initial cytopenias were the only side effects of this regimen. One patient had granulocytopenic fever. In conclusion, this low-dose regimen is effective and well tolerated for outpatient palliation in high-risk or elderly patients with RAEB-T or AML.

Topics: Acute Disease; Administration, Oral; Adult; Aged; Aged, 80 and over; Cytarabine; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Injections, Subcutaneous; Leukemia, Myeloid; Male; Middle Aged; Myelodysplastic Syndromes; Palliative Care; Platelet Transfusion; Thioguanine; Thrombocytopenia

The present study was undertaken to assess the predictive value of pretherapeutic determinants of ara-C metabolism and proliferative activity of leukemic blasts for early response to antileukemic therapy in the setting of granulocyte-macrophage colony-stimulating factor (GM-CSF)-based priming before and during TAD-9 induction in 36 consecutive patients with de novo acute myeloid leukemia (AML). Ara-C metabolism was assessed by the activities of deoxycytidine kinase (DCK), deoxycytidine deaminase (DCD), DNA polymerase alpha (Poly alpha), and overall polymerase (overall Poly). The fraction of cells in S phase (%S phase) and thymidine kinase (TK) activity were determined as a measure of proliferative activity. Early response to therapy was defined by the percentage of leukemic blasts in the bone marrow 5 to 7 days after completion of TAD-9 with less than 5% signaling an adequate response and greater than 5% indicating an inadequate early reduction, respectively. While neither %S phase, DCK, nor overall Poly activity were predictive for early response, TK and Poly alpha activities were significantly higher for cases with adequate blast cell clearance. The respective median values were for TK 3.8 versus 1.85 pmol/min/mg protein (P = .012), and for Poly alpha 1.9 versus 0.69 pmol/min/mg protein (P = .014). An inverse relation was detected for DCD activity which was significantly lower in responding patients with a median of 0.33 nmol/min/mg protein (range, 0.0 to 29.5) as compared to a median of 5.1 nmol/min/mg protein (range, 0.11 to 8.45) in early nonresponders, (P = .009). Taking the respective median values as arbitrary cut-points for high or low enzyme activities, responders and nonresponders could be discriminated prospectively. Hence, 14 of 16 cases (88%) with DCD activities below the median of 1.56 nmol/min/mg protein responded as compared to only 3 of 14 (22%) patients with higher DCD activities (P = .0004). From the 15 patients with TK activity above the overall median of 3.2 pmol/min/mg protein, 11 cases (73%) achieved an adequate blast cell clearance while only 6 of 17 cases (35%) with lower values responded (P = .035). Similarly, 12 of 15 patients (80%) with high Poly alpha levels (>1.22 pmol/min/mg protein) responded to induction therapy as compared to only 5 of 14 patients (36%) with lower enzyme activities (P = .02). By logistic regression analysis of enzyme activities, DCD activity was found to be the most sensitive parameter to predict an adeq

Topics: Acute Disease; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Cytidine Deaminase; Daunorubicin; DNA Polymerase II; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukemia, Myeloid; Lymphocytes; Male; Middle Aged; Nucleoside Deaminases; Thioguanine; Thymidine Kinase

Leukemic hyperleukocytosis may cause organ- or life-threatening complications. Patients at highest risk appear to be those with acute myeloid leukemia (AML). Blast cell aggregation and thrombus formation in the microvasculature most commonly involves the central nervous system and the pulmonary circulation. We describe a child with AML and renal venous thrombosis (RVT), a previously unreported complication of hyperleukocytosis.. A 17-month-old boy had a white blood cell count of 103 X 10(9) cells/L and RVT (hematuria, arterial systolic hypertension, unilateral nephromegaly, poor renal venous blood flow) at diagnosis of acute myelomonocytic leukemia (AML, FAB M4).. This case emphasizes the danger of hyperleukocytosis in AML and demonstrates that there may be other organ system dysfunction in addition to the well-described central nervous system and pulmonary complications. Renal venous thrombosis should be considered in the patient with leukemic hyperleukocytosis, hematuria, arterial hypertension, and appropriate radiographic findings. Aggressive cytoreductive measures should be pursued in such cases.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Atrophy; Cytarabine; Daunorubicin; Humans; Infant; Kidney; Leukapheresis; Leukemia, Myeloid; Leukocyte Count; Leukocytosis; Male; Renal Veins; Thioguanine; Thrombosis; Tomography, X-Ray Computed; Ultrasonography, Doppler

Flow cytometric immunofluorescent analysis was used to assess Fas antigen (CD95) expression in blasts obtained from the bone marrow of 30 patients with acute myeloid leukaemia. The percentage of positive cells in each sample was highly variable. Fas antigen expression did not correlate with age, FAB subtype, white blood cell counts, or CD34 expression. Low expression of Fas was associated with a low complete remission rate after induction chemotherapy (62.5% in cases with < 20% positive cells v 92.9% in cases with > or = 20% positive cells, P < 0.01). The main cause for not achieving remission was resistant disease. Our results suggest that the quantitation of Fas expression can be predictive of treatment outcome in acute myeloid leukaemia.

Topics: Acute Disease; Adult; Antineoplastic Agents; Bone Marrow; Cytarabine; Daunorubicin; Drug Resistance, Neoplasm; fas Receptor; Female; Humans; Leukemia, Myeloid; Male; Middle Aged; Mitoxantrone; Thioguanine; Treatment Outcome

The use of peripheral blood stem cells (PBSC) with or without bone marrow (BM) in patients with acute myelogenous leukemia (AML) undergoing autologous transplantation in untreated first relapse (Rel1) or in second remission (CR2) was evaluated in a phase II study. Twenty-three patients with AML in untreated Rel1 (n = 8) and CR2 (n = 15) underwent autologous transplant using PBSC with (n = 19) or without (n = 4) BM. Six patients received busulfan (BU) and cyclophosphamide (CY) and 17 received BU, CY and total body irradiation prior to transplant. The median number of CD34+ cells infused was 4.81 x 10(6)/kg (range 0.04-15). Fifteen of 23 patients received post-transplant interleukin-2 (IL-2) at a median of 43 days (range 11-93) in an attempt to decrease relapses. The median day of recovery of granulocytes to 0.5 x 10(9)/I was 12 (range 8-27) and platelets to 20 x 10(9)/I was 15 (range 8-103). Patients received a median of 4 units (range 0-20) of red blood cells and 29 units (range 4-252) of platelets. The probability of 100 day non-relapse mortality was 0.14. The probabilities of survival and relapse at 2 years were 0.24 and 0.65, respectively. The probabilities of relapse in patients receiving (n = 15) and not receiving (n = 8) interleukin-2 (IL-2) were 0.59 and 0.74, respectively (P = 0.1). Overall, seven of 23 (30%) patients are alive and continuously disease-free at a median of 483 days (range 113-835) post-transplant. These data demonstrate that the infusion of PBSC collected after rhG-CSF corrected engraftment problems previously observed with autologous BM transplants in patients with AML but was associated with a high relapse rate.

Topics: Acute Disease; Adolescent; Adult; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Blood Cells; Bone Marrow; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Etoposide; Graft Survival; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid; Life Tables; Middle Aged; Mitoxantrone; Recombinant Proteins; Remission Induction; Retrospective Studies; Salvage Therapy; Survival Analysis; Thioguanine; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation

Despite consolidation and/or maintenance chemotherapy most patients with newly diagnosed acute myelogenous leukemia relapse such that only 20-30% survive free of recurrence at five years. To evaluate the long-term effects of dose-intensive consolidation, we analysed 123 consecutive patients, age 16 to 84 (median 48 years), who received high-dose cytarabine-based consolidation chemotherapy. After a median follow-up of 88 months (range 26 to 126 months), 38 patients remain alive, with 26 in continued remission from 45 to 126+ months. Median remission duration for all eligible patients is 14 months (range 1.3 to 126 months) and actuarial leukemia-free survival at five years is 24 +/- 8%. Median survival from remission is 24 months (range 1.3 to 126 months) and actuarial survival from remission is 31 +/- 9%. Eighty-two patients (67%) have relapsed with an actuarial risk of relapse of 71 +/- 9% at five years. Adverse prognostic factors were age over 45 and male gender. When compared to historical controls (P = 0.02), dose-intensive consolidation produced improved leukemia-free survival for patients age < 45, but compliance and enhanced toxicity in the older age groups may limit further dose intensification.

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; California; Cytarabine; Daunorubicin; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Leukemia, Myeloid; Life Tables; Male; Middle Aged; Mitoxantrone; Preleukemia; Remission Induction; Survival Analysis; Thioguanine; Treatment Outcome

Of 30 women surviving a minimum of 18 months following treatment for AML with a high-dose chemotherapy regimen with autologous bone marrow transplantation (ABMT), 24 were premenopausal at the time of transplantation. All were given a detailed questionnaire concerning menstruation, menopausal symptoms and pregnancy; 22 responded. Of these 22, 10 had received a single transplant procedure and 12 a double transplant procedure. In the 10 recipients of a single transplant, 4 women (age range 32-50 years) developed ovarian failure and 6 (age range 21-32 years) resumed spontaneous cyclical menstruation. Five of the 6 menstruating women became pregnant between 4 and 40 months following ABMT. Three pregnancies went to term and each resulted in the delivery of a full-term apparently normal infant. Of the 12 women who received a double ABMT (age range 32-47 years), 11 developed clinical and/or biochemical evidence of ovarian failure. The median age in the latter group was 35 years, however, compared with 28 years in the single ABMT group. These data show that it is possible to give a single very high-dose course of chemotherapy in younger patients without compromising fertility.

Topics: Abortion, Induced; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Infertility, Female; Leukemia, Myeloid; Menstruation; Middle Aged; Pregnancy; Pregnancy Outcome; Primary Ovarian Insufficiency; Remission Induction; Reoperation; Survivors; Thioguanine; Transplantation, Autologous

The treatment of acute myeloid leukemia (AML) in children with Down's syndrome (DS) has engendered considerable controversy. Because of the concerns for toxicity and increased rate of infections, treatment approaches varied considerably in the past with mixed results. However, experience on the recently completed Pediatric Oncology Group (POG) 8498 AML study suggests that DS children with AML constitute a distinct subgroup that responds well to therapy. Twelve of 285 children on POG 8498 (protocol for newly diagnosed AML) had DS. Children with DS and AML were predominantly male (9 of 12) and were quite younger at diagnosis (< 24 months in 10). The white blood cell count was less than 50 x 10(3)/microL in all 12 and French-American-British types M6 and M7 were frequent (5 of 12). An abnormal cytogenetic marker, in addition to constitutional trisomy 21, was present in 9 of 12 and involved chromosome 8 in 4 of 9. All cases studied (n = 5) were positive for myeloid cell surface markers (CD33, CD13, or CD11b) and, interestingly, were also positive for the CD7 antigen. Chemotherapy included daunorubicin, cytarabine (Ara-C), and 6-thioguanine for remission induction and featured high-dose Ara-C (3 g/m2 per dose) with or without L-asparaginase early in remission. Compared with children without DS, children with DS had a superior event-free survival (EFS at 4 years 100% v 28% +/- 6.2%; P = .003). The EFS remained superior even when compared with non-DS children less than 2 years of age with a white blood cell count less than 10 x 100,000/microL (100% v 48% +/- 17.3%; P = .01).

Topics: Acute Disease; Adolescent; Adult; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Azacitidine; Child; Chromosome Aberrations; Chromosome Disorders; Cytarabine; Daunorubicin; Down Syndrome; Etoposide; Female; Follow-Up Studies; Humans; Leukemia, Myeloid; Male; Mercaptopurine; Methotrexate; Prednisone; Remission Induction; Thioguanine; Vincristine

The increasing insights into the pharmacokinetics and the metabolism of cytosine arabinoside (AraC) have improved the rationale for its application in leukemia therapy and have led to a pharmacologically directed design of antileukemic treatment. The current study aims at adding to this approach by detecting differences in the intracellular metabolism of AraC 5'-triphosphate (AraCTP) between leukemic and normal mononuclear blood cells. Measurements of intracellular AraCTP levels were complemented by determinations of plasma AraC and AraU concentrations and were performed in 32 patients with acute myeloid leukemia undergoing combination therapy including either conventional (100 mg/m2 daily) or high-dose (1.0 or 3.0 g/m2 twice daily) AraC. Plasma AraC concentration showed a linear relationship to the applied AraC dose but did not correlate with intracellular AraCTP levels. During conventional-dose AraC therapy little interpatient variation was observed in AraCTP retention times in leukemic blasts from 5 patients with t1/2 values ranging from 1.70 to 2.50 h (median 2.14 h). In all cases AraCTP levels declined rapidly after the end of the AraC infusion. Substantial differences in AraCTP retention times were revealed, however, during 3 h infusions of either 1.0 or 3.0 g/m2 AraC in leukemic blasts from 10 patients with t1/2 values between 1.60 to 7.63 h (median 2.42 h). In addition, AraCTP levels declined in only one patient by > 10% within the first hour after the end of therapy and remained constant or even increased up to 1.5-fold in a post-treatment period of 1 to 2.5 h in the other nine cases. In contrast, AraCTP retention times were relatively uniform in normal mononuclear blood cells from 11 patients with t1/2 values of 3.34 to 5.29 h (median 3.85 h). More importantly, AraCTP levels dropped by > 10% within the first hour after the end of the high-dose AraC infusion in eight of 11 cases. A post-therapeutic increase > 10% was not observed in any patient. Similar findings emerged after in vitro exposure of normal bone marrow cells from six healthy volunteers to 20 mumol/l AraC for 3 h revealing a > 10% decrease of intracellular AraCTP within the first post-treatment hour in all cases with AraCTP retention times of 2.29 to 8.63 h (median 3.20 h). These differences in AraCTP pharmacokinetics between leukemic and normal blood cells may provide the basis for a modified timing of AraC administration with the aim of selectively maintaining cytotoxic AraCTP level

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Arabinofuranosylcytosine Triphosphate; Arabinofuranosyluracil; Cytarabine; Daunorubicin; Drug Administration Schedule; Humans; Leukemia, Myeloid; Leukocytes, Mononuclear; Lymphoma, Non-Hodgkin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine

An 80 year-old woman presented subleukaemic acute monoblastic leukaemia (AML-M5a). Her bone marrow showed invasion by highly dysplastic histio-monocytic cells of great size and wide cytoplasm, with intense phagocytic activity (erythrophagocytosis was frequently seen), and with abnormal karyotype (50XX, +8, +8, +16, +21). The different malignant and reactive features of the mononuclear phagocytic system are commented, along with the haemophagocytic activity of the histio-monocytic cells in different states. The cytogenetic anomalies more frequently found in AML-M5 are also dealt with as compared to this patient's. The case reported here seems to correspond to subleukaemic acute "monophagocytic" leukaemia, with a biologic phenotype close to that of malignant histiocytosis.

Topics: Aged; Aged, 80 and over; Aneuploidy; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cytarabine; Doxorubicin; Etoposide; Female; Giant Cells; Histiocytic Sarcoma; Humans; Leukemia; Leukemia, Myeloid; Phagocytosis; Thioguanine

To reduce critical neutropenia after chemotherapy (CT) for acute myeloid leukemia (AML) we administered recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) to patients over the age of 65 years with newly diagnosed AML and to patients with early or second relapse. CT was 9-day 6-thioguanine, ara-C, and daunorubicin (TAD9) in newly diagnosed AML and sequential high-dose ara-C and mitoxantrone (S-HAM) for relapse. In patients whose bone marrow was free from blasts a continuous intravenous infusion of GM-CSF 250 micrograms/m2/d started on day 4 after CT. Thirty-six patients entered the study and 30 of them did receive GM-CSF. For comparison, a historical control group of 56 patients was used. Complete remission rate was 50% (18 of 36) versus 32% in controls (P = .09), and early death rate was 14% versus 39% (P = .009). Treatment with GM-CSF was not associated with major adverse events. Two patients showed a marked leukemic regrowth that was completely reversible in one patient and appeared to be GM-CSF independent in the other patient. Remission duration does not seem to be reduced after GM-CSF. Under GM-CSF the blood neutrophils recovered 6 and 9 days earlier in the TAD9 (P = .009) and S-HAM (P = .043) groups associated with a rapid clearance of infections in most patients. We conclude that GM-CSF was of therapeutic benefit to our patients and this provides a basis for larger controlled trials.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukemia, Myeloid; Middle Aged; Mitoxantrone; Neutropenia; Recombinant Proteins; Remission Induction; Thioguanine

One hundred and sixteen adult patients aged 14-73 with previously untreated acute myeloid leukaemia received induction and consolidation chemotherapy with daunorubicin, cytosine arabinoside and thioguanine. Two novel approaches to post consolidation therapy have been investigated. Patients aged 50 years or less who had no suitable matched allogeneic donor were considered for autologous bone marrow transplantation (BMT) using bone marrow which had been cultured in vitro for 14 d. Patients over the age of 50 years with normal bone marrow cellularity and peripheral blood count were treated with a single oral dose of busulphan 100 mg/m2 (without BMT rescue) 3 months following the completion of consolidation therapy. Eighty-seven patients (75%) achieved a complete remission. Of 70 patients who completed consolidation therapy, 40 were aged less than or equal to 50 years and 30 were greater than 50 years. Forty-three patients went on to receive post consolidation therapy in first CR (autologous BMT 12, allogeneic BMT 7, busulphan therapy 24). The event-free survival at 4 years was 47% for autologous BMT, 34% for allogeneic BMT and 45% for busulphan-treated patients. The survival for the older cohort of patients who received post consolidation therapy with single dose busulphan therapy was encouraging, and this agent should be considered for future post consolidation strategies.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Combined Modality Therapy; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid; Male; Middle Aged; Remission Induction; Thioguanine; Time Factors

Nine children with juvenile chronic myelogenous leukemia (JCML) were diagnosed in an 8-year period from 1977 to 1984. The clinical courses and outcomes of five patients who received minimal or no chemotherapy were compared with that of four patients who were treated with intensive acute nonlymphoblastic leukemia (ANLL) combination chemotherapy. None of the five patients in the former group achieved clinical remission and their survivals were 1, 4, 4, 7, and 29 months, respectively. All four patients in the latter group achieved clinical remissions that lasted 11, 21, 21, and 27 + months, respectively. The durations of their survival (21, 26, 30, and 32 + months) were significantly better than the five patients who received minimal or no chemotherapy (P less than .05). Despite hospitalizations for chemotherapy and for treatment of chemotherapy-associated complications, the clinical status and quality of life of the children who achieved clinical remission were superior to those who remained in relapse. Although intensive chemotherapy induced lengthy remissions, three of the four patients have relapsed. Cytogenetic and cell culture data indicated that the monocytic-macrophage cells characteristic of JCML appeared to be suppressed during remission rather than totally eliminated. We recommend that ANLL-type combination chemotherapy be used as the initial treatment of JCML because of its promptness in effecting clinical remissions. Improved maintenance and consolidation protocols have to be developed to produce durable remissions and cures. Alternatively, bone marrow transplantation may be a useful option soon after remission is achieved with chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Child, Preschool; Cytarabine; Daunorubicin; Etoposide; Female; Humans; Infant; Leukemia, Myeloid; Male; Mercaptopurine; Mitoxantrone; Thioguanine

5 patients receiving continuous busulphan and 6-thioguanine for chronic myeloid leukaemia (CML) were found to have oesophageal varices associated with abnormal liver function tests. 3 of these cases presented with gastrointestinal haemorrhage and 1 patient died. The 2 other cases had varices discovered at endoscopy. Nodular regenerative hyperplasia (NRH) of the liver was identified as the cause of portal hypertension in the 4 patients on whom liver biopsies were done. The administration of busulphan and thioguanine in combination is likely to be associated with the development of NRH, with portal hypertension and oesophageal varices occurring in a substantial proportion of cases.

Topics: Adult; Aged; Aged, 80 and over; Busulfan; Drug Therapy, Combination; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Humans; Hyperplasia; Leukemia, Myeloid; Liver; Male; Middle Aged; Thioguanine

Topics: Antineoplastic Combined Chemotherapy Protocols; Busulfan; Clone Cells; Combined Modality Therapy; Cytarabine; Humans; Leukemia, Myeloid; Philadelphia Chromosome; Prednisone; Splenectomy; Thioguanine; Vincristine

Between June 1979 and October 1983, 14 autografts were performed in 13 patients with CML (ten blast crisis, four accelerated phase). Results were disappointing: four patients died during aplasia; seven returned to chronic phase, but three died of hemorrhage, four relapsed, and three did not reverse. The main problem was the very low rate of successful engraftment. Both the collection of bone marrow after treatment with busulfan and a particular sensitivity of CFU-GM to cryoinjury were responsible for the infusion of very low doses of CFU-GM. However, we observed some promising results: In one patient in acute blast crisis, the Ph 1 chromosome disappeared, as well as the cytogenetic marker of transformation; in another patient with acute pure cytogenetic acceleration, the abnormal clone disappeared for 27 months; a third patient was maintained in a second chronic phase for 20 months. Thus we suggest that the results of autografting in chronic myeloid leukemia would be improved by infusing the largest possible dose of stem cells collected before or long after treatment by busulfan, and freezing them following a careful program.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Female; Humans; Karyotyping; Leukemia, Myeloid; Lomustine; Male; Middle Aged; Platelet Transfusion; Thioguanine; Transplantation, Autologous

Our pilot study addresses the problem of early relapse from complete remission in young adults with acute myelogenous leukemia (AML). Twelve patients with AML, 16-58 years of age, were entered in a study of four intense courses of cytotoxic chemotherapy using the following drugs: cytarabine, daunorubicin, 5-azacitidine, and 6-thioguanine. They received no maintenance therapy. Nine of 12 patients achieved complete response. With a minimum follow-up of 35 months, the observed disease-free survival at 2 years was 67% (14 +/- SE) and the actuarial disease-free survival at 4 years was 38% (17 +/- SE). It appears that brief intensive chemotherapy early in the management of AML can produce prolonged remission without the need for maintenance therapy.

Topics: Actuarial Analysis; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bone Marrow; Cytarabine; Daunorubicin; Female; Follow-Up Studies; Humans; Leukemia, Myeloid; Male; Middle Aged; Pilot Projects; Thioguanine

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

Treatment of chronic phase chronic myelogenous leukemia with hydroxyurea or busulfan rarely induces cytogenetic (true) remissions. Intensive chemotherapy induces brief true remissions in approximately 50% of patients. We added 13-cis-retinoic acid to daunorubicin, cytosine arabinoside, and thioguanine to determine if it could increase the incidence and duration of remission induced by cytotoxic chemotherapy. Of the 17 evaluable patients, one patient (6%) achieved complete remission, and seven patients (41%) achieved partial remissions. The median duration of remission was 1.6 months. We conclude that 13-cis-retinoic acid does not increase the incidence and duration of remission in chronic phase chronic myelogenous leukemia.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Chromosomes, Human, 21-22 and Y; Cytarabine; Daunorubicin; Humans; Isotretinoin; Leukemia, Myeloid; Leukopenia; Liver; Middle Aged; Stomatitis; Thioguanine; Thrombocytopenia; Time Factors; Tretinoin

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

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cytarabine; Dacarbazine; Daunorubicin; Doxorubicin; Hodgkin Disease; Humans; Leukemia, Myeloid; Leukemia, Radiation-Induced; Male; Mechlorethamine; Prednisone; Procarbazine; Radiotherapy; Thioguanine; Vinblastine; Vincristine

Even patients with chronic myelogenous leukemia (CML) in blast crisis were treated with chemotherapy, followed by infusion of autologous bone marrow that had been collected during the chronic phase of the disease and cryopreserved at -198 degrees C. The mean age of the nine females and two males in this study was 34 years with an average duration of the chronic phase of the disease of 5.5 years. Seven out of the 11 patients had a splenectomy prior to intensive chemotherapy. The median survival of the first four patients who received 6-thioguanine, cytosine arabinoside, daunorubicin (TAD) chemotherapy was 2.6 weeks and no patient reachieved the chronic phase of CML. The second group of seven patients received more intensive chemotherapy (MAdHAT), which included melphalan 30 mg/m2 days 1, 2, and 3; Adriamycin 50 mg/m2 intravenously (iv) day 1, hydroxyurea 1500 mg/m2 by mouth for 5-7 days, cytosine arabinoside 100 mg/m2 continuous infusion for 5-7 days, and VM-26 100 mg/m2 iv on day 3. Six out of these seven patients reachieved chronic phase CML after bone marrow reinfusion. The median survival was 29.9 weeks for all patients and 33 weeks for the six patients who reachieved chronic phase CML. All patients subsequently died of recurrent blast crisis. There was no correlation between the time of bone marrow storage and the duration of subsequent chronic phase CML. These studies have shown that autologous bone marrow transplantation after high-dose chemotherapy can result in bone marrow engraftment with reestablishment of chronic phase CML, and prolongation of survival.

Topics: Adult; Bone Marrow Transplantation; Cytarabine; Daunorubicin; Doxorubicin; Female; Freezing; Humans; Hydroxyurea; Leukemia, Myeloid; Male; Melphalan; Middle Aged; Teniposide; Thioguanine; Tissue Preservation; Transplantation, Autologous

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

A 9-day high-dose 3-drug induction regimen including ARA-C, DNR, and TG at special time sequencing was given to 93 patients with AML, 15-74 (median 52) years old. After 1-2 courses for remission induction and, if possible, 2 identical courses of consolidation, no further therapy was applied during remission. Complete remission (CR) was achieved in 71% of all patients and in 74% of responders by 1 course only. Median remission duration is at 1 year with 13 patients in continuous CR for 13-38 (median 24) months. Patients completing consolidation reached a median remission duration of 22 months and those with rapid response to 1 induction course and with complete consolidation 38+ months. Patients monitoring included bone marrow DNA-histograms by flow cytometry, blood counts, percentage, and absolute number of blasts in bone marrow and LDH in serum. Among pretherapeutic parameters only LDH (inversely) correlated with CR duration. In contrast during early therapy rapid blast reduction, decrease of S-phase-index and of LDH as well as short recovery time of platelets and neutrophils predicted for low risk (when high risk included non-response and early relapse). Thus, monitoring of early cellular response parameters reflecting cellularity and proliferation seems to provide important individual determinants of therapeutic outcome.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Blood Platelets; Cytarabine; Daunorubicin; Germany, West; Humans; L-Lactate Dehydrogenase; Leukemia, Myeloid; Middle Aged; Thioguanine; Time Factors

Using a recently developed technique for the determination of the pure bone marrow cell count per mm3 bone marrow, two different induction regimens for AML were compared for their efficacy, i.e. the therapy induced cytoreduction. In both protocols cytosine arabinoside, daunorubicin and 6-thioguanine were applied at comparable doses but different schedules. In both regimens a blast cell reduction of more than 2.0 log10 within the first 5 to 6 days of therapy strongly correlated (p less than 0.001) with the achievement of an adequate blast clearance in the marrow and complete remission (n = 18), while an inadequate blast cell reduction was revealed in all patients with a cell kill of less than 2.0 log10 (n = 9). Total cytoreduction on day 5 or 6 of therapy was comparable for both protocols. However, on one protocol a continuous logarithmic blast cell reduction was found while the cell kill followed a biphasic function on the other regimen.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cell Count; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid; Thioguanine

Fourteen untreated patients with Ph1-positive myeloid leukaemia received combination chemotherapy consisting of blocks of doxorubicin, vincristine, cytosine arabinoside and 6-thioguanine. Significant karyotypic conversion occurred in six patients, the percentage of Ph1-positive cells in the bone marrow falling by at least 50%. Maintenance therapy comprised vincristine, busulphan, hydroxyurea, 6-mercaptopurine and dibromannitol in rotation. Reinduction therapy was administered when Ph1 positivity reverted to 100%. Karyotypic reconversion was achieved in three of four patients. After induction, chromosome analysis of the bone marrow was performed every 3-6 months to detect the appearance of aneuploid clones, the intention being to intensify therapy at that stage.

Topics: Acute Disease; Adult; Bone Marrow; Cytarabine; Doxorubicin; Drug Administration Schedule; Follow-Up Studies; Humans; Karyotyping; Leukemia, Myeloid; Leukocyte Count; Middle Aged; Platelet Count; 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: Anemia, Aplastic; Antineoplastic Agents; Bone Marrow; Bone Marrow Cells; Cells, Cultured; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia, Myeloid; Methylprednisolone; Thioguanine

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

Peripheral blood from 4 patients with chronic granulocytic leukemia during blast crisis has been investigated. One case has been studied before and after treatment with Arabinosyl-Cytosine and 6-Thioguanine. The nucleated blood cells have been separated by a discontinuous density gradient. Cells were obtained from six different gradient fractions (F1-F6: density ranging from 1.052 to 1.078). 0.5 X 10(5) cells from each density fraction have been cultured in agar culture system to evaluate the granulocyte-monocyte committed stem cells (Colony Forming Units-granulocyte monocyte: CFU-GM). Cells recovered from the same density fractions have been studied by electron microscopy to evaluate the number of less differentiated cells. A quantitative correlation between plating efficiency and blast cells number was carried out. The results indicate that the highest recovery of both CFU-GM and blast cells is present in light density fractions (specific density below 1.063). However a discrepancy between blast cell frequency and granulocyte-monocyte colony formation in the same density fractions appears to be evident. In the patient studied before and after treatment it appears that only one out of two light density fractions (F1) responds to the antiblastic treatment.

Topics: Blood Cells; Cells, Cultured; Centrifugation, Density Gradient; Colony-Forming Units Assay; Cytarabine; Granulocytes; Humans; Leukemia, Myeloid; Monocytes; Thioguanine

The possibilities were studied of achieving remission more quickly, of preventing conceivably alkylator-induced blastic transformation, and of prolonging survival in chronic myelocytic leukemia (CML) by replacing busulfan induction of remission by antimetabolite induction. The promise of the project was not considered to merit a prospective, controlled, randomized multicenter study, and therefore a retrospective, non-controlled, non-randomized pilot study was elected. One antimetabolite-treated group (cytosine arabinoside and thioguanine) and two busulfan-treated patient groups were studied. One of the latter two groups received splenic irradiation in addition to busulfan. No statistically significant differences between the busulfan groups were found in the time to achieve remission, the length of the first, unmaintained remission, the frequency of blastic metamorphosis or the cost of treatment. The actuarial survival curves of all three groups were similar. The antimetabolite induction was well tolerated and led to a statistically significantly more rapid remission than busulfan. However, the remission was significantly shorter, and no significant difference in the frequency of blastic metamorphosis was found between the groups. The median cost (from diagnosis to death) of hospitalization, visits, treatment, and part of the loss of production was approximately 106 000 Sw. cr. in the busulfan + radiotherapy group, 116 000 in the busulfan group, and 178 000 in the antimetabolite group. It is suggested that a prospective, randomized, controlled study could confirm that the present antimetabolite induction may lead to a more rapid remission induction in CML without more side-effects. However, to prevent early relapse, antimetabolite induction should be combined with busulfan maintenance treatment.

Topics: Busulfan; Costs and Cost Analysis; Cytarabine; Drug Therapy, Combination; Humans; Leukemia, Myeloid; Radiography; Spleen; Thioguanine

After intensive chemotherapy, marrow cells of some patients with Philadelphia chromosome (Ph1) positive chronic myelogenous leukemia (CML) become partially or completely Ph1-negative. However, without a second marker for the neoplastic clone, it could not be determined if these Ph1-negative cells arose from normal progenitors or were still members of an abnormal clone. In the present study, a patient with Ph1-positive CML, also heterozygous for glucose-6-phosphate dehydrogenase (G6PD), was studied before and after intensive chemotherapy. Prior to treatment only G6PD type B was detected in the patient's red cells, platelets, and granulocytes, and all unstimulated marrow metaphases had Ph1. After four cycles of chemotherapy, 76% of marrow cells were Ph1-negative, and approximately 80% of the granulocytes were nonclonal by G6PD analysis. Thus, the frequency of nonclonal cells by G6PD analysis correlated closely with that of the Ph1-negative cells. The data indicate that intensive chemotherapy can restore nonclonal and presumably non-neoplastic hematopoiesis in CML.

Topics: Adult; Chromosome Aberrations; Chromosomes, Human, 21-22 and Y; Clone Cells; Cytarabine; Daunorubicin; Female; Glucosephosphate Dehydrogenase; Heterozygote; Humans; Karyotyping; Leukemia, Myeloid; Thioguanine

Thirty-seven patients with Philadelphia-chromosone-positive (Ph'+) chronic myelogenous leukemia who were untreated or minimally pretreated were entered on the L-5 protocol. This protocol consisted of sequential treatment with splenic irradiation, splenectomy, arabinosylcytosine and 6-thioguanine, and L-asparaginase. Maintenance therapy was hydroxyurea or a multiple-drug regimen. The median survival of the 37 patients is 50 mo. Twelve patients showed a temporary reduction in the percentage of Ph'+ marrow metaphases to less than one-third of the initial values and in 7 of these patients none were found. The duration of the Ph'+ chromosome reduction ranged from 1 to 43 mo. The median survival of the responders has not yet been reached. It is concluded that whereas overall survival is not appreciably extended, patients who have a reduction in Ph'+ cells in the marrow may survive longer than the average; also, the reduction occurs most frequently in patients who have relatively small spleens at diagnosis. The reduction is difficult to maintain, and it may be reinduced in some patients with intensive chemotherapy.

Topics: Adolescent; Adult; Asparaginase; Cell Transformation, Neoplastic; Chromosomes, Human, 21-22 and Y; Cytarabine; Female; Humans; Hydroxyurea; Leukemia, Myeloid; Male; Middle Aged; Radiography; Spleen; Splenectomy; 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

Topics: Cells, Cultured; Cytarabine; Cytidine Deaminase; Drug Synergism; Humans; Leukemia, Myeloid; Thioguanine

Topics: Adult; Blood Cells; Cell Count; Female; Humans; Hydroxyurea; Leukemia, Myeloid; Male; Methotrexate; Middle Aged; Splenectomy; Thioguanine

Sixteen patients with Ph1-positive chronic granulocytic leukemic (CGL) were entered on a pulsing chemotherapy program consisting of cytosine arabinoside 100 mg/sq m/day X 5 and thioguanine 100 mq/sq m/day X 5 every 21 days in an attempt to convert the Ph1-positive marrow to a Ph1-negative state and thereby achieve a complete remission. Twelve patients had an adequate trail of drug treatment, and ten of these had adequate chromosome examinations. There were two "conversions," one of which was maintained for 5+ mo, while the other was transient. The program was unacceptable, however, to most patients due to intolerable nausea and vomiting. Thus a prospective chemotherapeutic attempt to convert a Ph1-positive marrow without splenectomy has induced a conversion in two of ten patients. Other regimens which might induce less nausea and vomiting and a higher rate of conversions should be sought in future attempts to alter the invariably fatal outcome of CGL.

Topics: Blood Cell Count; Blood Platelets; Bone Marrow; Bone Marrow Cells; Chromosomes, Human, 21-22 and Y; Cytarabine; Granulocytes; Humans; Leukemia, Myeloid; Leukocyte Count; Thioguanine; Time Factors

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

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: Acute Disease; Adult; Antineoplastic Agents; Azacitidine; Blood Transfusion; Cytarabine; Daunorubicin; Dexamethasone; Etoposide; Granulocytes; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Patient Isolation; Platelet Transfusion; Pneumonia; Prednisone; Pyrimethamine; Remission, Spontaneous; Thioguanine; Vincristine; Zinostatin

24 patients with Philadelphia chromosome positive chronic myeloid leukaemia (CML) in blast crisis were treated with intensive chemotherapy. 16 patients showed either partial or complete response to this treatment, but median survival remained short (13 weeks), and much of this time was spent in hospital. These results were not significantly better than those obtained by others using vincristine and prednisolone alone, and this combination of drugs can often be given on an outpatient basis. It is concluded that until more effective intensive therapy becomes available patients in CML blast crisis should be managed in such a way that the quality of life is not impaired; and that at present vincristine and prednisolone appears to be the most impaired; and that at present vincristine and prednisolone appears to be the most appropriate initial treatment, though even this is far from satisfactory.

Topics: Adolescent; Adult; Aged; Allopurinol; Antineoplastic Agents; Asparaginase; Chromosome Aberrations; Chromosomes, Human, 21-22 and Y; Cytarabine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid; Male; Middle Aged; Prednisolone; Thioguanine; Vincristine

Survival and response to chemotherapy were evaluated in 84 adults with granulocytic leukemia (AGL) and 22 with acute lymphocytic leukemia (ALL). Twenty-two of the 84 patients with AGL reveived no chemotherapy (untreated group). The median survival for patients with AGL who achieved complete remission (CR) was 17.1 months, compared to 6.5 months for those who achieved partial remission (PR (p less than 0.05), 2.8 months for those who failed chemotherapy (p less than 0.01), and 2.1 months for the untreated group (p less than 0.01). The median survival for patients with ALL who achieved a CR was 18.2 months, compared to 7.3 months for those who achieved a PR and 7.0 months for those who failed chemotherapy. Of patients with AGL who reveived an adequate trial of chemotherapy, 43% achieved a CR and 16% a PR; 75% of patients with ALL achieved a CR and 13% a PR. Improved survival depends on the induction of a complete or partial remission with the use of aggressive chemotherapy.

Topics: Acute Disease; Adolescent; Adult; Aged; Child; Cyclophosphamide; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia, Lymphoid; Leukemia, Myeloid; Mercaptopurine; Methotrexate; Middle Aged; Prednisone; Thioguanine; Thioinosine; Vincristine

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

We have utilized an in vitro clonogenic assay of mouse and human marrow granulocytic progenitor cells to determine the cytotoxic effects on granulopoiesis of the chemotherapeutic agents 1-beta-D-arabinofuranosylcytosine (ara-C) and 6-thioguanine. Concentration- and time-dependent decrements to plateau levels of granulocytic colony-forming capacity occurred. The sequence of drug administration was important and synergistic cytotoxicity was noted when certain schedules of ara-C and 6-thioguanine combinations were used. Endotoxin-stimulated colony-forming cells had increased sensitivity to the in vitro ara-C exposure. High or intermittent doses of ara-C demonstrated enhanced cytotoxicity when short exposure times (1 to 8 hr) were utilized, whereas low doses were markedly cytotoxic with prolonged exposure (10 days). Normal and leukemic human colony-forming cells had similar susceptibility to the cytotoxic effects of ara-C. Exposure of granulocytic precursors to these drugs in vitro produced effects similar to those previously reported with in vivo drug administration. These techniques appear applicable for providing improved screening models to evaluate chemotherapeutic regimens for clinical use.

Topics: Animals; Cell Division; Cells, Cultured; Cytarabine; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Synergism; Endotoxins; Granulocytes; Hematopoietic Stem Cells; Humans; In Vitro Techniques; Leukemia, Myeloid; Leukocytes; Male; Mice; Mice, Inbred C57BL; Thioguanine

Topics: Blood Cell Count; Blood Cells; Blood Platelets; Bone Marrow; Bone Marrow Cells; Cell Division; Cell Separation; Cytarabine; DNA; Doxorubicin; Erythrocytes; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Thioguanine

Possible predictive criteria of the refractoriness to therapy of the blastic phase of Ph-1-positive chronic granulocytic leukemia (CGL) have been sought. Eight cases in the blastic phase were studied. The blasts were noted to be of two types: some displayed a high nuclear:cytoplasmic ratio with deep blue cytoplasm, while others had a comparatively low nuclear:cytoplasmic ratio and bluish gray cytoplasm containing a few small granules. Electron microscopic studies showed a variety of features, including defective organelles and giant mitochondria. Cytochemical staining revealed the majority of blast cells to be peroxidase- and Sudan black-negative; granular PAS positivity was the rule. Serial cytogenetic studies demonstrated increasing aneuploidy. Bone marrow biopsy showed myelofibrotic changes in two cases. Two patients entered complete remission with prednisone and vincristine and with Ara-C and thioguanine, respectively. It is concluded that the blastic phase of CGL may manifest heterogeneity.

Topics: Acute Disease; Adult; Alkaline Phosphatase; Aneuploidy; Biopsy; Bone Marrow; Bone Marrow Cells; Cell Nucleus; Child; Chromosome Aberrations; Cytarabine; Cytoplasm; Female; Histocytochemistry; Humans; Leukemia, Myeloid; Male; Microscopy, Electron; Middle Aged; Mitochondria; Organoids; Peroxidases; Prednisone; Remission, Spontaneous; Staining and Labeling; Thioguanine; Vincristine

In an attempt to convert the bone-marrow population from Philadelphia-chromosome (Ph-1) positivt to partially or wholly Ph-1 negative, thioguanine was used as primary therapy in seven patients with chronic granulocytic leukaemia (C.G.L.). Although eight episodes of neutropenia were induced, prolonged remission or conversion to Ph-1-negativity was not achieved in any patient. However, thioguanine was at least as effective as busulphan for initial therapy in C.G.L., and had the advantage of rapid reversibility of haemopoietic depression when discontinued. Thioguanine merits further evaluation as an agent for the management of C.G.L. in its chronic phase.

Topics: Adult; Alkaline Phosphatase; Allopurinol; Chromosomes, Human, 21-22 and Y; Drug Evaluation; Drug Therapy, Combination; Female; Hematopoietic Stem Cells; Hemoglobins; Humans; Leukemia, Myeloid; Leukocyte Count; Male; Middle Aged; Neutropenia; Neutrophils; Thioguanine

Staining with naphthol AS phosphate and Fast Blue BB salt has been used for the estimation of neutrophil alkaline phosphatase (NAP) scores in patients with chronic granulocytic leukaemia (CGL). The very low scores found at diagnosis rise when the disease is treated, and there is some inverse correlation between the NAP score and the absolute neutrophil count. Patients treated intensively developed high NAP scores. Elective splenectomy performed during the chronic phase of CGL is followed by a pronounced but transient neutrophilia and a concurrent striking rise in the NAP score. Similar changes were observed in patients without CGL who underwent splenectomy. These observations can be explained by assuming that newly formed neutrophils in CGL have a normal content of NAP but are rapidly sequestered in non-circulating extramedullary pools, whereas the circulating neutrophil with a typically low NAP content is a relatively aged cell which has lost enzyme activity. In subjects with or without CGL, removal of the spleen, a major site of such pooling, temporarily permits the circulation of newly formed neutrophils but eventually other organs assume the sequestering functions of the spleen. Thus the aberrations of NAP score seen in CGL might be attributable not to an intrinsic cellular defect but to an exaggeration of the granulocyte storage phenomena which also occur in subjects without CGL.

Topics: Alkaline Phosphatase; Bone Marrow Cells; Busulfan; Chronic Disease; Clinical Enzyme Tests; Histocytochemistry; Leukemia, Myeloid; Leukemoid Reaction; Neutrophils; Polycythemia; Primary Myelofibrosis; Splenectomy; Thioguanine; Time Factors

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

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: 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: Adult; Busulfan; Cytarabine; Diagnosis, Differential; Female; Humans; Leukemia, Myeloid; Lymph Nodes; Lymphoma; Male; Mediastinal Neoplasms; Thioguanine

The response to 60 trials of therapy in 50 patients with chronic granulocytic leukaemia (C.G.L.) in acute transformation is reported. None of the 13 patients who received single-agent chemotherapy had a satisfactory response. The use of two drugs in combination produced only one satisfactory response in 30 patients. Various types of multiple-drug treatments in eight patients achieved one good response which lasted four months. In contrast when nine patients with rapidly progressive acute transformation of C.G.L. received a regimen-TRAMPCO(L)-incorporating seven or eight drugs (thioguanine, daunorubicin, cytarabine, methotrexate, prednisolone, cyclophosphamide, and vincristine, with or without L-asparaginase colaspase) five improved significantly. Four patients had a good clinical and haematological response with survival for over three, eight, over 12, and 14 and a half months; and one patient had a partial response. Toxicity was not extreme and maintenance therapy with the same regimen was given on an outpatient basis. TRAMPCO(L) seems superior to previously reported regimens and should be considered for rapidly progressive transformation of C.G.L. especially when simpler treatments have failed.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Asparaginase; Chromosome Aberrations; Chromosomes, Human, 21-22 and Y; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid; Male; Methotrexate; Middle Aged; Prednisolone; Thioguanine; Vincristine

We have used the technique of human haemopoietic cell culture in agar to study the peripheral blood and bone marrow colony forming capacity of 23 patients with Ph(1) + ve chronic granulocytic leukaemia (CGL) before and after treatment. In comparison with normal controls the number of colony forming cells (CFC) is moderately increased (about three-fold) in the bone marrow and enormously increased in the peripheral blood of untreated patients. In the peripheral blood their number in general is related to the total leucocyte count. In patients whose blood counts have been restored to normal by the use of cytotoxic drugs the number of CFC in the peripheral blood is very greatly reduced. In the marrow of treated patients CFC are present in approximately normal numbers. When used as feeder layer sto support the culture of normal bone marrow cells, the peripheral blood leucocytes of untreated patients are a uniformly poor source of colony stimulating factor (CSF) and fractionation experiments suggest that this is not due merely to a relative scarcity of monocytes. After treatment the peripheral blood has normal CSF activity and this is associated with the monocytic cell component. The last data may be explained in either of two ways: it is possible that restoration of the blood of patients with CGL to normal values removes a homeostatic factor suppressing the formation of CSF by functionally normal monocytes, or alternatively treatment with cytotoxic drugs leads to the replacement of defective monocytes by a population of relatively normal CSF producing cells.

Topics: Adolescent; Adult; Aged; Bone Marrow; Bone Marrow Cells; Busulfan; Cell Division; Cells, Cultured; Child; Clone Cells; Female; Humans; Leukemia, Myeloid; Leukocyte Count; Leukocytes; Male; Middle Aged; Monocytes; Neutrophils; Radiation Dosage; Radiation Effects; Thioguanine

Topics: Acute Disease; BCG Vaccine; Cytarabine; Drug Therapy, Combination; Female; Humans; Immunity, Cellular; Immunosuppression Therapy; Leukemia, Myeloid; Lymphocytes; Middle Aged; Remission, Spontaneous; Thioguanine

Topics: Busulfan; Female; Humans; Leukemia, Myeloid; Leukocytosis; Mannitol; Mercaptopurine; Pregnancy; Pregnancy Complications, Hematologic; Splenectomy; Thioguanine

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: Acute Disease; Adult; Afibrinogenemia; Blood Cell Count; Blood Coagulation Disorders; Blood Transfusion; Bone Marrow Examination; Cytarabine; Ecchymosis; Estrogens, Conjugated (USP); Factor V Deficiency; Female; Humans; Leukemia, Myeloid; Leukocyte Count; Pregnancy; Pregnancy Complications, Hematologic; Prothrombin Time; Remission, Spontaneous; Thioguanine; Uterine Hemorrhage

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: Adult; Aged; Antineoplastic Agents; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid; Male; Middle Aged; Prednisone; Remission, Spontaneous; Thioguanine

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

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: Acute Disease; Adult; Cytarabine; Fluorine; Hematologic Diseases; Hematopoiesis; Humans; Isoflurophate; Leukemia, Myeloid; Leukocyte Count; Leukocytes; Myeloproliferative Disorders; Radioisotopes; Remission, Spontaneous; Thioguanine; Time Factors

Twenty-three patients with acute myelocytic leukemia (aml) were treated with daunomycin and the results contrasted to those obtained in a subsequent group of 18 patients treated with cytosine arabinoside (ara-c) and 6-thioguanine (tg). The complete remission (cr) rate with daunomycin was 17 percent (mean duration 10.6 months) and the partial remission (pr) rate 26 percent (mean duration 44 days). Corresponding figures in the ara-c and tg group were: cr rate 44 percent (mean duration 5.8 months) and pr rate 17 percent (mean duration 48 days). There were 12 deaths resulting from daunomycin-induced pancytopenia and in ten of the patients who died persistent leukemia infiltrate was found in antemortem marrow specimens or at autopsy. This contrasts with death of six patients from ara-c and tg-induced pancytopenia, in four of whom residual leukemic infiltrate was not evident. Daunomycin alone is deemed not suitable for induction of remission in aml. The results obtained with ara-c and tg are encouraging and may be improved if the number of infectious deaths associated with drug-induced pancytopenia can be reduced.

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

Topics: Aged; Alkaline Phosphatase; Anemia; Blood Transfusion; Bone Marrow; Busulfan; Cytarabine; Female; Histocytochemistry; Humans; Leukemia, Myeloid; Leukocytes; Male; Middle Aged; Pneumonia; Purpura; Radiography; Sepsis; Splenomegaly; Staphylococcal Infections; Tetracycline; Thioguanine

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: Antineoplastic Agents; Humans; Leukemia, Myeloid; Pipobroman; Polycythemia Vera; Thioguanine

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Alkylating Agents; Anemia; Anemia, Hemolytic, Autoimmune; Busulfan; Chlorambucil; Cyclophosphamide; Folic Acid Antagonists; Hemorrhage; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Mercaptopurine; Neoplasms; Nitrogen Mustard Compounds; Phosphorus Isotopes; Splenectomy; Thioguanine; Triethylenemelamine