thioguanine-anhydrous and Acute-Disease

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

The results of treatment of 629 previously untreated adults with acute leukemia at Memorial Hospital are reviewed. During the past 14 years, 135 adults (greater than 15 years) with acute lymphoblastic leukemia (ALL) have been treated with one of three successive multidrug-intensive treatment protocols (L2, L10/10M, and L17/17M), each calling for 2.5 to 3 years of systemic chemotherapy and prophylactic intrathecal methotrexate without cranial irradiation. The complete remission (CR) rates were L2 (n = 22) = 77%; L10/10M (n = 69) = 86%; L17/17M (n = 44) = 77%. The median durations of survival and remission were, respectively, L2 = 33 and 30 months; L10/10M = 62 months and not reached; and L17/17M = not reached. Almost all relapses occurred within the first 3 years while still continuing treatment, and there were only rate late relapses after stopping treatment. It appears that approximately half of the patients may have been cured with the latest two protocols. During the last 17 years, 494 adults aged 15 to greater than 70 with acute nonlymphoblastic leukemia (ANLL) were treated with one of five successive multiple drug treatment protocols of varying intensity (arabinosylcytosine + 6-thioguanine [n = 36]; L6 [n = 101]; L12 [n = 104]; L14/14M [n = 121]; and L16/16M [n = 132]). Patients with myelodysplastic syndromes generally were not treated until they developed acute leukemia, but were then entered and included in the results. Secondary leukemias following treatment of other neoplastic diseases were not included. The complete remission rates were fairly constant between 47 and 64% and the median durations of remissions were between 9 and 21 months. The intensive treatment L14 and L16 protocols were associated with more early deaths and did not result in a significantly improved remission incidence or duration or survival. With all protocols, the majority of relapses occurred within the first 2 years, but relapses continued to occur at a decreasing rate for 4 years and occasionally even later. Whereas a small fraction (approximately 10 to 15%) of adults with ANLL are now apparently being cured with combination chemotherapy, despite intensive efforts there has been little improvement during the last decade and more selective and effective forms of treatment are urgently needed.

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Examination; Cytarabine; Female; Humans; Leukemia; Leukemia, Lymphoid; Male; Middle Aged; Prognosis; Recurrence; Thioguanine; Time Factors

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

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

Chemotherapy of adults with acute nonlymphocytic leukemia has improved in recent years, yielding complete remissions in 65 per cent and cure in 10 to 15 per cent of all treated patients. Allogeneic bone marrow transplantation cures approximately one half of eligible young patients who gain an initial remission with chemotherapy. Autologous bone marrow transplantation may ultimately prove to be of value for the large numbers of patients who are over 40 years of age or who lack histocompatible siblings. Current investigative approaches in all these areas, based on insights into the pathophysiology of disease discussed in this article, should enhance the outcome for affected patients in the next decade.

Topics: Acute Disease; Adult; Aged; Antigens, Neoplasm; Antigens, Surface; Antineoplastic Combined Chemotherapy Protocols; Chromosome Aberrations; Cytarabine; Daunorubicin; Humans; Leukemia; Meningeal Neoplasms; Methotrexate; Middle Aged; Thioguanine

The antineoplastic agents marcellomycin (and related anthracycline antibiotics) and 6-thioguanine are effective inducers of the differentiation of cultured leukemia cells. Studies designed to investigate the relationship between structure and activity conducted with the anthracyclines in HL-60 human acute promyelocytic leukemia cells indicated a dissociation between cytotoxicity and maturation-inducing properties of these agents. In an analogous manner, 6-thioguanine induced effective erythroid and granulocytic differentiation of Friend and HL-60 leukemias, respectively, only in hypoxanthine-guanine phosphoribosyltransferase deficient cells. These findings suggest that 6-thioguanine need not be metabolized to a nucleotide to be active as an inducer of differentiation, and that the concentration of the 6-thiopurine required to initiate the commitment to maturation is greater than that producing cytotoxicity. Erythrodifferentiation of HGPRT negative Friend murine leukemia cells by 6-thioguanine was antagonized by tetracaine, d, 1-propranolol and 12-O-tetradecanoylphorbol-13-acetate, providing evidence for a cell membrane mediated component in the action of the purine antimetabolite. This suggests that the biochemical events that produce differentiation after exposure to 6-thioguanine may differ from those responsible for the toxic actions of the drug. Studies such as these, designed to gain an understanding of the target sites of inducers of differentiation, may lead to the development of new agents of potential therapeutic benefit in the treatment of certain forms of cancer based on the conversion of malignant cells to their non-proliferating mature counterparts.

Topics: Acute Disease; Anthracyclines; Antibiotics, Antineoplastic; Cell Differentiation; Cell Line; Humans; Leukemia, Experimental; Naphthacenes; Structure-Activity Relationship; Thioguanine

Chemotherapy remains the major treatment modality in childhood acute nonlymphocytic leukemia (ANLL). Current remission induction rates range from 60% to 80%; but even with the improved rate of response to therapy, the median duration of remission has seldom exceeded 1 year. On the other hand, an increasing number of children with ANLL who were treated with intensive induction and maintenance chemotherapy regimens for a prescribed period followed by discontinuation of therapy are remaining in remission. The evolution of present-day chemotherapy approaches to childhood ANLL are reviewed in this article.

Topics: Acute Disease; Adolescent; Adult; Asparaginase; Azauridine; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia; Prednisone; Thioguanine; Thioinosine; Vincristine

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

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

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 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

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 value of maintenance therapy after the achievement of complete remission in adult acute nonlymphocytic leukemia (ANLL) has never been clearly established. A randomized Eastern Cooperative Oncology Group (ECOG) study of postremission therapy compared outcomes in patients who received no further therapy to those administered long-term maintenance chemotherapy. Adverse results in the group administered no further therapy led to early termination of this trial after only 51 patients were randomized. Patients receiving no postremission therapy experienced significantly inferior remission durations (P = .002) compared with patients receiving maintenance therapy. All 26 patients in the group administered no postremission therapy have relapsed, with a median duration of remission of 4.1 months. In contrast, four of 25 patients (16%) who received maintenance therapy remain disease free, with a median duration of remission of 8.1 months.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cytarabine; Daunorubicin; Drug Administration Schedule; Follow-Up Studies; Humans; Leukemia; Thioguanine

Although a large majority of adult patients with acute nonlymphocytic leukemia (ANLL) achieve complete remission with present day therapy, eventual relapse and death is the rule rather than the exception. In an effort to improve survival, an intensive maintenance therapy approach was evaluated in 86 patients with ANLL in remission (median age 47 years) entered on study from 1978 to 1982. One-third of patients in remission were randomized to chemotherapy alone, one-third to splenectomy in addition to chemotherapy, and one-third to immunotherapy in addition to chemotherapy. The chemotherapy, which was identical in the three arms of the study, consisted of cytosine arabinoside plus 6-thioguanine, each given at a dose of 100 mg/m2 every 12 hr for a variable number of days, to render the patient's marrow aplastic, and was repeated every three months for three or more years. Median remission duration for patients in all three study groups is 21 months, with 58% of patients remaining in remission at one year. Twenty-five per cent of complete remitters are in continuous complete remission five to nine years after beginning intensive maintenance therapy. The median duration of survival of remitters is 25 months. Neither splenectomy nor immunotherapy had additional impact on remission duration or survival. In comparison with the results of earlier studies at the same institution in patients with similar characteristics, using identical remission induction therapy but less intensive maintenance therapy (46 patients), there has been a significant improvement in remission duration (p less than 0.001) and a significant impact on survival (p = 0.03) attributable to the use of intensive maintenance therapy. Intensive maintenance therapy may cure some adult patients with ANLL.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Central Nervous System Diseases; Cytarabine; Evaluation Studies as Topic; Female; Follow-Up Studies; Humans; Immunotherapy; Leukemia; Male; Middle Aged; Neuraminidase; Remission Induction; Splenectomy; Thioguanine

A total of 232 previously untreated adults with acute nonlymphoblastic leukaemia were consecutively entered into four successive studies. In the first, complete remission rates and survival were inferior to a group treated on the same regimen in London, suggesting population differences, possibly on the basis of late referral and poor nutritional status. In the second study the addition of the epipodophyllotoxin VP16-213 to conventional doses of doxorubicin and cytosine arabinoside improved complete remission rate and median duration of survival. In the third study this induction programme was unchanged and short duration of intensification was compared with an extended period, but no statistically significant difference was demonstrated. In the fourth study, which is currently active, the role of the epipodophyllotoxin VP16-213 (Cape Town Regimen/CTR III) was compared with the same two agents in combination with thioguanine (DAT), but to date no difference in remission rate or survival is evident. Four conclusions are supported by data from these studies. First, the addition of VP16-213 to doxorubicin and cytosine arabinoside improves complete remission rate, prolongs median duration of complete remission and survival, with shortening of the time taken to achieve this status in our population. Second, evidence to date shows no advantage for the DAT programme containing thioguanine over CTR III in which this latter agent is replaced by the epipodophyllotoxin VP16-213. Third, there is no statistically significant difference in survival once patients have achieved complete remission following randomisation to receive 6 months in comparison with 15 months of intensification therapy. Finally, of the previously described prognostic factors, only response to initial chemotherapy has proved significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cytarabine; Doxorubicin; Etoposide; Humans; Leukemia; Podophyllotoxin; Thioguanine

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Child; Cyclophosphamide; Cytarabine; Humans; Leukemia; Thioguanine; Vincristine

Between July 1, 1981 and November 1, 1982, 45 patients with acute nonlymphocytic leukemia (age, greater than or equal to 70 years) were randomly assigned to receive induction chemotherapy using either daunorubicin, cytosine arabinoside, and 6-thioguanine in full dosage (F DAT) or an attenuated schedule of the same drugs (At DAT) as part of an Eastern Cooperative Oncology Group controlled trial. Forty patients were deemed evaluable, 20 on each arm. The overall complete remission (CR) rate for all patients in both arms was 28% (11/40). There was no significant difference in CR rates between the two arms. There were 12 early deaths (less than 60 days) in the F DAT arm compared with only five early deaths on the At DAT arm (P = .05). Due primarily to this early death rate, the median survival for the F DAT group was 29 days v 159 days for the At DAT groups (P = .02). The range of survival of the patients in CR for the At DAT group given either one or two cycles of induction therapy was 121 to 414 days, while the survival range for the F DAT CR patients was 121-186 + days. The median survival for those not achieving CR was 14 days for the F DAT group v 80 days for the At DAT (P less than .02). Fifty-nine percent of the At DAT patients spent greater than 100 days out of the hospital v 12% for the F DAT group. Attenuated chemotherapy with lower doses of DAT is the preferred induction regimen for elderly patients with acute nonlymphocytic leukemia since it causes fewer early deaths, allows a better quality of life, and yields survival times as durable as intensive therapy.

Topics: Acute Disease; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cytarabine; Daunorubicin; Drug Administration Schedule; Heart; Hemorrhage; Humans; Leukemia; Quality of Life; Random Allocation; Respiratory Distress Syndrome; Thioguanine

Twenty-four patients who had a relapse after successful treatment of acute nonlymphocytic leukemia were re-treated with a chemotherapeutic program similar to that which produced the initial remission. Eight of the nine patients who achieved a second remission had received a three-drug reinduction regimen consisting of cytosine arabinoside, an anthracycline, and 6-thioguanine. An increased duration of initial remission before relapse (more than 26 weeks) predicted a greater likelihood of achieving a second remission.

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cytarabine; Daunorubicin; Doxorubicin; Female; Humans; Leukemia; Male; Middle Aged; Retrospective Studies; Thioguanine

The Eastern Cooperative Oncology Group conducted a randomized study to determine the efficacy of consolidation therapy in prolonging the duration of complete remission (CR) in adults with acute nonlymphocytic leukemia (ANLL). Induction chemotherapy with daunorubicin, cytosine arabinoside, and 6-thioguanine (DAT) yielded CR in 65% of 283 patients with ANLL, aged 16-69. For patients aged 60-69, the CR rate was 58%. Of 184 patients in CR, 146 patients were then randomized to receive either maintenance therapy with weekly cytosine arabinoside and 6-thioguanine alone (69 patients) or two courses of reduced doses of DAT 1 mo apart, before commencing the same maintenance program (77 patients). Consolidation therapy resulted in hematologic toxicity, but was not lethal in any of the eligible patients. Patients receiving consolidation plus maintenance therapy experienced a longer CR duration (40 wk) and disease-free survival at 2 yr (28%) than did those patients receiving maintenance therapy alone (34 wk and 14%, respectively). These differences are not statistically significant. These results suggest that approaches to consolidation therapy employing reduced doses of the induction therapy regimen can have, at best, only a small benefit. For consolidation therapy to provide substantial improvement in CR duration, intensive regimens with non-cross-resistant drugs will be required.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Central Nervous System Diseases; Chemical and Drug Induced Liver Injury; Cytarabine; Daunorubicin; Drug Administration Schedule; Drug Evaluation; Female; Humans; Leukemia; Male; Middle Aged; Random Allocation; Thioguanine; United States

Sixty-seven patients with acute nonlymphoblastic leukemia (ANLL) and above the age of 60 years were randomly allocated to treatment with either prednimustine + vincristine or cycles with cytosine arabinoside and thioguanine. Of the 67 patients, 13 (19%) entered a complete remission and four a partial remission. Of 33 patients randomized to prednimustine and vincristine (15 adequately treated), three entered a complete remission and one a partial remission. Four further patients went into complete remission after a switch to other treatment modalities. Of 34 patients randomized to cycles of ARA-C and thioguanine (22 adequately treated), four entered a complete remission and three a partial remission with the correct program. One patient entered a remission with intermittent cytosine arabinoside + thioguanine (wrong program) and one further patient entered a complete remission after a switch to prednimustine and vincristine. Prednimustine + vincristine did not appear to be superior to treatment with cytosine arabinoside thioguanine cycles for elderly patients with ANLL.

Topics: Acute Disease; Aged; Blood Cell Count; Chlorambucil; Cytarabine; Drug Therapy, Combination; Female; Humans; Leukemia; Male; Middle Aged; Prednimustine; Thioguanine; Vincristine

Topics: Acute Disease; Adolescent; Adult; Aged; Child; Child, Preschool; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Infant; Leukemia; Male; Middle Aged; Thioguanine; Time Factors; USSR

One hundred thirty-nine consecutive unselected adults with acute nonlymphoblastic leukemia were treated with a high-dose chemotherapeutic remission-induction regimen consisting of daunomycin (70 mg/m2 IV on days 1, 2, 3), cytosine arabinoside (100 mg/m2 IV every 12 hours), 6-thioguanine (100 mg/m2 orally every 12 hours), prednisone (40 mg/m2 daily), all given on days 1 through 7, and vincristine (1 mg/m2 IV on days 1 and 7). Supportive care consisted of broad spectrum antibiotics for fever in the presence of granulocytopenia and prophylactic platelet transfusions. The complete remission (CR) rate was 60%. The median number of days to CR was 30. Fifty-eight of 77 (75%) patients under age 50 and 26 of 62 (42%) patients over age 50 attained CR. Despite the use of a relatively large dose of daunomycin and monthly maintenance chemotherapy, the median remission duration was only 39 weeks and the medial survival 64 weeks. Most patients who failed to achieve CR died early-77% of deaths occurred within the first six weeks. Infections accounted for the increase mortality in patients over age 50. Thirty-seven percent of patients over age 50 died of infections whereas only 10% under age 50 did so (P less than 0.001). Seven percent of the patients died of fungal infection during attempted remission induction. The incidence of resistance of the leukemia to the remission-induction regimen was low (8%).

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aged; Antineoplastic Agents; Child; Clinical Trials as Topic; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Infections; Leukemia; Middle Aged; Prednisone; Prognosis; Remission, Spontaneous; Thioguanine; Vincristine

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

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

Topics: Acute Disease; Age Factors; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Ifosfamide; Leukemia; Methods; Middle Aged; Thioguanine; Vincristine

One hundred-sixty-three children with acute nonlymphocytic leukemia (ANLL) were treated with a multiple-drug induction program (PATCO) consisting of prednisone (PDN), cytosine arabinoside ((Ara-C), 6-thioguanine (6-TG), cyclophosphamide (CPM), and Oncovin (VCR). Ninety-six, 59%, obtained a remission. Remission was maintained with daily 6-TG and four-day pulses of Ara-C and CPM with a single dose of VCR every 28 days. The median duration of remission was 11.5 months. Certain prognostic factors affected induction rate and remission duration. Initial white blood count (WBC) was a significant factor in achieving a remission, whereas age, sex, and type of ANLL had no effect. Initial WBC, age, and sex had a significant effect on remission duration, but type of ANLL had no effect. Relapsing patients were treated with daunomycin and 5-azacytidine. The reinduction rate was 53% with a median second remission duration of 190 days. Overall survival for the 163 patients is 55.4% at 12 months, 31.5% at 24 months, 21.4% at 36 months, and 19% at 48 months.

Topics: Acute Disease; Adolescent; Antineoplastic Agents; Child; Child, Preschool; Clinical Trials as Topic; Cyclophosphamide; Cytarabine; Drug Therapy, Combination; Female; Humans; Leukemia; Leukocyte Count; Male; Prednisone; Prognosis; Remission, Spontaneous; Thioguanine; Vincristine

One hundred and forty-seven adults with acute nonlymphocytic leukemia were randomized to one of two treatment regimens utilizing cytosine arabinoside and 6-thioguanine. In regimen A the drugs were administered every 12 hours until marrow cellularity was reduced by at least 50%. In regimen B the drugs were administered every 12 hours for 5 days with five to 7 days rest intervals between courses. Decisions to continue or reinstitute therapy were based solely on marrow cellularity and marrow ratings. The overall response in referee-verified cases in both groups was similar (41%); regimen B proved to be the easier protocol to administer but required greater support. Younger patients or those with an initial high hemoglobin count responded best to these drug regimens. Only 36% of our patients experienced severe marrow hypoplasia (i.e., a 75% or greater reduction in marrow cellularity) prior to complete remission, suggesting that cytosine arabinoside and 6-thioguanine in combination may selectively suppress leukemic cells while sparing normal hematopoietic elements.

Topics: Acute Disease; Adolescent; Adult; Aged; Bone Marrow; Clinical Trials as Topic; Cytarabine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leukemia; Male; Middle Aged; Remission, Spontaneous; Thioguanine

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

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

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

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

Drug repositioning is the application of the existing drugs to new uses and has the potential to reduce the time and cost required for the typical drug discovery process. In this study, we repositioned thiopurine drugs used for the treatment of acute leukaemia as new tyrosinase inhibitors. Tyrosinase catalyses two successive oxidations in melanin biosynthesis: the conversions of tyrosine to dihydroxyphenylalanine (DOPA) and DOPA to dopaquinone. Continuous efforts are underway to discover small molecule inhibitors of tyrosinase for therapeutic and cosmetic purposes. Structure-based virtual screening predicted inhibitor candidates from the US Food and Drug Administration (FDA)-approved drugs. Enzyme assays confirmed the thiopurine leukaemia drug, thioguanine, as a tyrosinase inhibitor with the inhibitory constant of 52 μM. Two other thiopurine drugs, mercaptopurine and azathioprine, were also evaluated for their tyrosinase inhibition; mercaptopurine caused stronger inhibition than thioguanine did, whereas azathioprine was a poor inhibitor. The inhibitory constant of mercaptopurine (16 μM) was comparable to that of the well-known inhibitor kojic acid (13 μM). The cell-based assay using B16F10 melanoma cells confirmed that the compounds inhibit mammalian tyrosinase. Particularly, 50 μM thioguanine reduced the melanin content by 57%, without apparent cytotoxicity. Cheminformatics showed that the thiopurine drugs shared little chemical similarity with the known tyrosinase inhibitors.

Topics: Acute Disease; Antimetabolites, Antineoplastic; Azathioprine; Catalytic Domain; Drug Repositioning; Enzyme Assays; Enzyme Inhibitors; Humans; Leukemia; Melanins; Melanoma, Experimental; Mercaptopurine; Molecular Docking Simulation; Monophenol Monooxygenase; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Structure-Activity Relationship; Thioguanine; Tumor Cells, Cultured

Oral thiopurines are effective and widely used in treatment of inflammatory bowel disease (IBD) in humans, although their use is limited due the development of adverse events. Here, we examine the efficacy and toxicity of oral treatment with 6-tioguanine (6-TG) and azathioprine (AZA) in a murine model of IBD.. We induced acute or chronic colitis in BALB/c mice by one or four cycles of 3% dextran sulphate sodium (DSS), respectively. Mice were treated by daily gavages of various dosages of 6-tioguanine, azathioprine, or by phosphate buffered saline (PBS) starting the first day of DSS or after two cycles of DSS, respectively. We monitored the efficacy and toxicity by measuring the weight change and serum alanine aminotransferase (ALT) activity and by disease severity and histology, at the end of the experiment. Moreover, we measured cytokine production after colon fragment cultivation by enzyme-linked immunoabsorbent assay and numbers of apoptotic cells in the spleen by flow cytometry.. 6-TG is effective in the treatment of acute DSS-induced colitis in a dose-dependent manner and 40 μg of 6-TG is significantly more effective in the treatment of acute colitis than both AZA and PBS. This effect is accompanied by decrease of IL-6 and IFN-γ production in colon. We did not observe histological abnormalities in liver samples from control (PBS) or 6-TG treated mice. However, liver samples from most mice treated with AZA showed mild, yet distinct signs of hepatotoxicity. In chronic colitis, all thiopurine derivatives improved colitis, 20 μg of 6-TG per dose was superior. High doses of 6-TG led to significant weight loss at the end of the therapy, but none of the thiopurine derivatives increased levels of serum ALT. Both thiopurine derivatives reduced the proportion of apoptotic T helper cells, but a high production of both IL-6 and TGF-β was observed only in colon of AZA-treated mice.. Use of 6-TG in the treatment of experimental colitis in mice appears superior to AZA administration and placebo. In contrast to 6-TG, the use of AZA resulted in histological liver abnormalities.

Topics: Acute Disease; Alanine Transaminase; Analysis of Variance; Animals; Apoptosis; Azathioprine; Chronic Disease; Colitis; Colon; Dextran Sulfate; Female; Interferon-gamma; Interleukin-6; Liver; Mice; Mice, Inbred BALB C; Models, Animal; T-Lymphocytes, Helper-Inducer; Thioguanine; Transforming Growth Factor beta; Weight Loss

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

An adolescent boy aged 17 years presented with sudden onset of visual impairment, which was rapidly diagnosed as bilateral anterior uveitis by an ophthalmologist. A systemic review noted episodes of nonbloody diarrhea, weight loss of 3 kg and a diminished appetite during the previous 10 months. The patient's family history revealed an older brother with Crohn's disease.. Visual acuity test, slit-lamp examination, ophthalmologic fundoscopy and endoscopic evaluation of the upper and lower gastrointestinal tract with biopsy.. Multifocal Crohn's disease, involving the terminal ileum and cecum, in addition to the stomach and duodenum.. Treatment with topical corticosteroids, in the form of ophthalmic drops and oral budesonide ileal-release capsules. Once remission was achieved, it was maintained with mercaptopurine.

Topics: Acute Disease; Adolescent; Blindness; Colonoscopy; Crohn Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Follow-Up Studies; Glucocorticoids; Humans; Male; Ophthalmic Solutions; Thioguanine

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

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

6-Thioguanine (6-TG), the active metabolite of 6-mercaptopurine and its prodrug azathioprine, are thought to be responsible for clinical efficacy in the treatment of active Crohn's disease. Its use as a therapeutic agent for inflammatory bowel disease (IBD) has been limited to patients who are resistant to or intolerant of other antimetabolites. Short-term experience with this agent has not demonstrated an increased incidence of hematologic or hepatic toxicity; however long-term safety data are scarce. We herein report a patient who developed acute sinusoidal obstruction syndrome after 14 months of successful thioguanine treatment. This is the first report of such a complication in an adult treated with 6-TG for active Crohn's disease.

Topics: Acute Disease; Adult; Antimetabolites, Antineoplastic; Crohn Disease; Hepatic Veno-Occlusive Disease; Humans; Male; Syndrome; 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

T(8;9) is a relatively new translocation that has been reported in a few patients with chronic myeloid leukemia (CML) but never in acute myeloid leukemia (AML). We report here a patient who presented with AML with t(8; 9). He lacked the Philadelphia chromosome but tested positive for the gene by the polymerase chain reaction method. This confirmed the diagnosis of CML with blast crisis, and appropriate treatment could be instituted

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Bone Marrow Transplantation; Child, Preschool; Chromosomes, Human, Pair 8; Chromosomes, Human, Pair 9; Combined Modality Therapy; Cytarabine; Daunorubicin; Ethmoid Sinus; Etoposide; Fusion Proteins, bcr-abl; Humans; Karyotyping; Leukemia, Myeloid, Accelerated Phase; Male; Meninges; Mitoxantrone; Remission Induction; Sacrococcygeal Region; Sarcoma, Myeloid; Thioguanine; Translocation, Genetic

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

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 efficiency and toxicity of treatment regimens for nonintensive cytoreduction in 57 outpatients with refractory acute leukemia (mean age 56 years, 51 AML, six ALL/AUL) were retrospectively studied. Seventeen patients received one treatment regimen, 19 patients two treatment regimens, and 21 patients three or more treatment regimens. The treatment regimens analyzed were 6-thioguanine p.o. (daily) (T), 6-thioguanine p.o. (4-7 days/week) + cytarabine s.c./i.v. (once a week) (T+C), 6-mercaptopurine p.o. (daily) (MP), 6-mercaptopurine p.o. (daily) + methotrexate p.o./i.v. (once a week) (MP+MTX), etoposide p.o. (daily) (E), and mitoxantrone i.v. (M). The median leukocyte count was higher for M (73 x 10(9)/l) than for the other treatment regimens (T: 27 x 10(9)/l, T+ C: 37 x 10(9)/l, MP: 24 x 10(9)/l, MP + MTX: 30 x 10(9)/l, E: 31 x 10(9)/l). A cytoreduction >50% in the peripheral blood was achieved by T in 11/19, by T+C in 7/11, by MP in 5/8, by MP+MTX in 3/6, by E in 3/4, and by M in 16/22 patients. The period of cytoreduction was regarded as the duration of response - T: median 53 days, range 5-98; T+C: median 61 days, range 14-226; MP: median 37 days, range 4-192; MP + MTX: median 58 days, range 36-59; E: median 121 days, range 26-159; M: median 39 days, range 8-78. T and T + C were well tolerated by all but three patients (stomatitis, diarrhea, WHO grade 2). MP was accompanied by a rise of transaminases (WHO 1-3) in 5/6 patients. E led to stomatitis (WHO 1,2) in 4/5 and M to nausea/vomiting (WHO 1,2) in 5/22 and to stomatitis (WHO 2) in 4/22 cases. The mean survival time after start of palliative cytoreduction was 16 weeks (2-65). In summary, 6-thioguanine +/- cytarabine was best tolerated with effective but in oral monotherapy - often protracted cytoreduction in 60% of patients. Mitoxantrone showed tolerable side effects and potent cytoreduction in 73% of patients even after ineffective palliative pretreatment. Palliative cytoreductive therapy does not reduce the quality of life and can prevent complications of significant leukocytosis in refractory acute leukemia.

Topics: Acute Disease; Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Diarrhea; Female; Humans; Injections, Intravenous; Injections, Subcutaneous; Leukemia; Leukocyte Count; Male; Mercaptopurine; Methotrexate; Middle Aged; Nausea; Palliative Care; Retrospective Studies; Stomatitis; 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

Topics: Aclarubicin; Acute Disease; Adult; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cohort Studies; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Etoposide; Female; Finland; Humans; Immunocompromised Host; Incidence; Leukemia; Male; Mercaptopurine; Methotrexate; Middle Aged; Mitoxantrone; Pneumonia, Pneumocystis; Prednisone; Premedication; Retrospective Studies; Thioguanine; Trimethoprim, Sulfamethoxazole Drug Combination; Vincristine

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

Coexpression of myeloid, B-, and T-lineage associated markers was found in a patient with morphologically and cytochemically undifferentiated acute leukemia. Surface marker analysis using two-color immunofluorescence staining characterized blast cells to express CD34, CD38, CD117, and class II antigens, coexpressing TdT, CD4, CD7, CD13, CD19, and CD33. Cytoplasmic expression of myeloperoxidase, CD3, and CD22 could not be demonstrated. Monosomy for chromosome 7 was found by cytogenetic analysis. The absence of clonal rearrangements of immunoglobulin or T-cell receptor genes was shown by Southern blot analysis. Using a 3H-thymidine incorporation assay, DNA synthesis of leukemic blasts could be stimulated by IL-3, IL-6 and G-CSF in vitro. The present case did not offer specific criteria of lineage commitment. Corresponding to an equivalent counterpart in normal hematopoiesis, the involved cell population may reflect an early, most immature developmental stage within a multipotent progenitor cell compartment.

Topics: Acute Disease; Antigens, CD; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Marrow; Cytarabine; Daunorubicin; Fatal Outcome; Female; Hematopoietic Cell Growth Factors; Humans; Immunophenotyping; Leukemia; Middle Aged; Mitoxantrone; Neoplastic Stem Cells; Remission Induction; Thioguanine; Tumor Stem Cell Assay

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

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

A total of 40 patients presenting with chronic myeloid leukaemia in blastic transformation were treated with a non-aggressive chemotherapy regimen consisting of vincristine, cytosine arabinoside and thioguanine. Remissions were achieved by 3/10 (30%) patients displaying lymphoid transformation (remission duration, 2, 3, and 5 months, respectively) and by 5/30 (17%) subjects exhibiting myeloid changes (duration 2+, 4, 4, 5 and 7 months, respectively). Myelosuppression was the major toxicity and non-haematological toxicities were mild and acceptable. The median survival of patients exhibiting lymphoid and myeloid blastic transformation as measured from the time of transformation was 6 and 3 months, respectively, but the difference was not statistically significant. Three subjects displaying lymphoid transformation and five showing myeloid changes survived for greater than 12 months after the time of transformation.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Child; Cytarabine; Daunorubicin; Doxorubicin; Female; Humans; Hydroxyurea; Leukemia; Leukemia, Myeloid, Chronic-Phase; Male; Methotrexate; Middle Aged; Remission Induction; Thioguanine; Vincristine

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

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cytarabine; Daunorubicin; Humans; Leukemia; Magnetic Resonance Imaging; Middle Aged; Mitoxantrone; Remission Induction; Thioguanine

Acute myelofibrosis is a rare and still ill-defined disease. Based on morphological observation, immunophenotyping and ultrastructural analysis, we support the assumption that acute myelofibrosis is a malignant disorder mainly of the megakaryocytic lineage and is closely related to acute megakaryocytic/blastic leukaemia. Consequently, the 11 patients reported here were treated with aggressive polychemotherapy with combinations including daunorubicin and cytosine arabinoside and 6-thioguanin or VP16-213. 4 complete remissions, 2 partial remissions and 1 minor response were observed. Duration of aplasia was not significantly prolonged. These findings indicate that the use of aggressive polychemotherapy is feasible in acute myelofibrosis and results in a significant number of remissions.

Topics: Acute Disease; Adult; Aged; Bone Marrow; Cytarabine; Daunorubicin; Drug Therapy, Combination; Erythrocyte Count; Female; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Megakaryocytes; Middle Aged; Primary Myelofibrosis; Thioguanine

Topics: Acute Disease; Adult; Bone Marrow Transplantation; Cytarabine; Daunorubicin; Female; Humans; Infant, Newborn; Labor, Induced; Leukemia; Pregnancy; Pregnancy Complications, Neoplastic; Thioguanine

A new VP-16-based drug combination was utilized in the treatment of 3 adult patients with acute nonlymphoblastic leukemia. Marrow aplasia was noted in all patients on day 7. While myeloid regeneration was noted on day 14, there was no evidence of regeneration of the erythroid series before day 21 in any of the 3 patients, and maturation of this cell line was never complete before day 35. Such prolonged suppression of the erythroid series has not been described with standard chemotherapy. Because of this protracted suppressive effect of the above regimen on erythroid cells, we propose to explore its therapeutic potential in a pilot study employing such a regimen in the treatment of erythroleukemia.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cytarabine; Erythropoiesis; Etoposide; Hematopoietic Stem Cells; Humans; Leukemia; Thioguanine; Vincristine

Twenty-nine evaluable patients with acute nonlymphoblastic leukemia (ANLL), either in relapse or resistant to initial induction therapy (ara C, daunorubicin + etoposide), received the ATA regime consisting of 100 mg/m2 per day Ara C by i.v. infusion for 4-5 days, 100 mg/m2 per day thioguanine orally for 4-5 days, and 100 mg/m2 per day amsacrine i.v. for 2-5 days. Each patient received 1-6 courses (median, 2) of the regime. There were 7 (24%) complete responders, and their duration of responses were 2, 2, 2, 5, 9+, 19, and 24+ months. The complete remission (CR) rate of patients who had a previous CR beyond 6 months (6/13, 46%) was significantly better (X2 = 4.25, p less than 0.05) than that of those who had previously relapsed within 6 months or were refractory to primary induction chemotherapy (1/16, 6%). The two groups of patients had similar patterns of treatment failure. Myelosuppression was the major toxic side effect, and nonhematological toxicities were mild and acceptable.

Topics: Acute Disease; Adolescent; Adult; Aged; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Drug Resistance; Female; Humans; Leukemia; Male; Middle Aged; Recurrence; Thioguanine

Thirteen patients (7 male, 9 female) aged 22-71 years (means = 55 years) with acute non-lymphocytic leukemia and contraindications for anthracyclin therapy were treated with combined chemotherapy using m-amsacrine primarily or in relapse. The main reasons for avoiding cardiotoxic substances were overt cardiac insufficiency and former administration of daunorubicin with more than 540 mg/m2 body surface area. Amsacrine was combined with 6-thioguanine, VP 16-213 and cytosine arabinoside in conventional or high dosage. Eight out of 13 patients (62%) achieved complete remission after one or two courses of chemotherapy. One patient showed partial remission and could be brought into complete remission with another chemotherapy using high-dose ara-C and mitoxantrone. Three patients died in aplasia after chemotherapy and 1 other patient had to be regarded as a complete non-responder. Remission duration and survival time for the 8 successfully-treated patients so far is 1-12 months; however, medians have not yet been reached, since only one of the eight patients relapsed after 6 months of complete remission. These data indicate a high efficacy of m-amsacrine in combined chemotherapy for acute non-lymphocytic leukemia in high-risk patients with contraindications for anthracyclins.

Topics: Acute Disease; Adult; Aged; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Etoposide; Follow-Up Studies; Humans; Leukemia; Middle Aged; Thioguanine

Topics: Acute Disease; Adolescent; Adult; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Combined Modality Therapy; Cytarabine; Daunorubicin; Etoposide; Female; Humans; Leukemia; Male; Middle Aged; Mitoxantrone; Pilot Projects; Thioguanine

Topics: Aclarubicin; Acute Disease; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Humans; Leukemia; Male; Middle Aged; Naphthacenes; Thioguanine

Topics: Actuarial Analysis; Acute Disease; Adolescent; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Humans; Leukemia; Male; Middle Aged; Prednisone; Thioguanine; Vincristine

Topics: Acute Disease; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Diterpenes; Dose-Response Relationship, Drug; Doxorubicin; Humans; Leukemia; Retinyl Esters; Thioguanine; Vitamin A

Previous studies have shown that clonal growth patterns of leukemic cells from adult patients with acute nonlymphocytic leukemia (ANLL) have prognostic significance for achieving complete remission (CR). In order to determine if a similar correlation between clonal growth patterns and response to chemotherapy exists in childhood ANLL, bone marrow cells from 189 children with newly diagnosed ANLL were cultured in agar. After 7 days of incubation, colonies (greater than 50 cells), large clusters (20 to 50 cells), and small clusters (4 to 20 cells) were counted. Cultures were analyzed for frequency of clusters and colonies as well as for size of clusters. Two growth patterns significantly associated with poor prognosis for achieving CR were large-cluster growth and high cluster incidence (defined as greater than 400 clusters/10(5) bone marrow cells). The CR rate for the former was 53% (versus 79% for non-Group 1 patients; P = 0.03); the CR rate for the latter was 46% (versus 81% for non-Group 2 patients; P = 0.004). These findings indicate that clonal growth characteristics of leukemic cells from childhood ANLL patients are significantly correlated with response to induction chemotherapy and are useful in identifying a subset of patients with poor prognosis.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Cell Division; Child; Clone Cells; Cytarabine; Daunorubicin; Dexamethasone; Humans; Leukemia; Prognosis; Remission Induction; Thioguanine; Tumor Stem Cell Assay; Vincristine

Fifteen patients with relapsed (10) or primarily refractory (5) acute nonlymphocytic leukemia were treated with a combination of cytosine arabinoside (3 g/m2 i.v. every 12 h, 12 doses, days 1-6), 6-thioguanine (100 mg/m2 orally every 12 h, 12 doses, days 1-6) and daunomycin (60 mg/m2 i.v. on days 5 and 6 only). Complete remission was achieved in 11 patients. Eight of 10 relapsed patients and 3 of 5 primarily refractory patients entered remission. Median remission duration was 7.5 months (2-36+ months). Ten of the 11 remissions resulted from a single induction course. The time to hematologic recovery was comparable to that seen with 'standard'-dose cytosine arabinoside regimens. Nonhematologic toxicity, although considerable, was not greater than that seen with high-dose cytosine arabinoside alone. The most significant problem was gastrointestinal toxicity with diarrhea occurring in the majority of patients. Mild neurologic toxicity (reversible cerebellar dysfunction) occurred in 2 patients.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Cerebellar Diseases; Cytarabine; Daunorubicin; Gastrointestinal Diseases; Humans; Leukemia; Recurrence; Remission Induction; Thioguanine

Etoposide combined with cytarabine, doxorubicin, and 6-thioguanine was used to treat 34 patients with acute nonlymphoblastic leukemia (ANLL) in an age-adjusted protocol, with patients greater than 50 years old receiving fewer days of therapy. Complete remissions (CR) occurred in 85% of all patients (29 of 34 patients). Patients less than or equal to 50 years of age achieved a 94% CR rate (17 of 18 patients) compared to a 75% CR rate (12 of 16 patients) in older patients. Duration of remission was less for those greater than 50 years of age. The remission rate for primary ANLL was 86% (19 of 22 patients) and for secondary or relapsed ANLL was 83% (ten of 12 patients). Thus, this is effective therapy for primary and secondary or relapsed ANLL. When the days of therapy are reduced for older patients' age, the remissions are fewer and less durable.

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Bone Marrow; Cytarabine; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Humans; Leukemia; Male; Middle Aged; Thioguanine

Topics: Aclarubicin; Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Humans; Leukemia; Naphthacenes; Thioguanine

Topics: Acute Disease; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cross Infection; Cytarabine; Daunorubicin; Humans; Leukemia; Middle Aged; Patient Care Planning; Prednisone; Thioguanine; Vincristine

Histopathologic changes in core bone marrow biopsies were reviewed in 33 patients with acute leukaemia during chemotherapy to compare the changes in acute lymphocytic leukaemia (ALL) with acute non-lymphocytic leukaemia (ANLL). Cellular, stromal, and bony changes were evaluated with regard to diagnosis and time of biopsy from initiation of chemotherapy. A significant difference was noted in the plasma cell response. Plasmacytosis was present in 19/19 cases of ANLL, but in only 2/14 cases of ALL. Cellular depletion was also significantly less frequent in ALL. Other stromal changes such as haemorrhage, dilatation of sinusoids and fat regeneration, as well as osteoblastic bone activity occurred with similar frequencies in all cases of treated acute leukaemia. Fibrosis, necrosis, and serous atrophy were uncommon. Differing chemotherapeutic regimens and differing patient ages were both correlated with the plasma cell response, but not with the difference in cellular depletion.

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aged; Asparaginase; Bone Marrow; Bone Marrow Cells; Child; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Humans; Leukemia; Leukemia, Lymphoid; Lymphocyte Depletion; Middle Aged; Plasma Cells; Prednisone; Thioguanine; Vincristine

In 31 cases of acute nonlymphoblastic leukemia, bone marrow cells were serially cultured in semi-solid agar during the remission induction therapy. A normal in vitro cell growth pattern returned in 15 out of 22 patients up to 77 days before a complete remission was established by clinical and hematological criteria. In 6 cases the return of normal colonies coincided with clinical and hematological evidence of a complete remission. Nine patients failed to attain a remission and died from complications of bone marrow aplasia. Only one had a normal number of colonies and a normal cluster/colony ratio in cultures prepared 11 days after the completion of the first course of chemotherapy. At this time, his platelet count increased to normal level, possibly indicating a developing remission. Bone marrow cell culture criteria are useful in monitoring the remission induction therapy in patients with acute nonlymphoblastic leukemia. An early return of normal in vitro cell growth pattern suggests an approaching remission, which may be achieved several weeks later.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cells, Cultured; Colony-Forming Units Assay; Cytarabine; Daunorubicin; Humans; Leukemia; Monitoring, Physiologic; Thioguanine

Anthracyclines given by continuous infusion, as opposed to bolus administration, are associated with a reduced incidence of cardiac and gastrointestinal toxicity. Our study was developed to test the antileukaemic effect of anthracyclines given as a continuous infusion. Nineteen sequential patients admitted for treatment of acute nonlymphocytic leukaemia (ANLL) were managed with a regimen utilizing a 3 d continuous intravenous infusion of daunomycin (DNM), and the complete response rate was similar to this institution's past experience with antileukaemic regimens employing 3 d bolus DNM. In our studies, infusion DNM was at least as myelotoxic and antileukaemic as bolus DNM; thus this method of administration should be explored further in remission-induction regimens for ANLL.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Administration Schedule; Humans; Infusions, Parenteral; Leukemia; Middle Aged; Thioguanine; Time Factors

Only few patients (3,8%) affected by ANLL survive for more than 3 years from the time of diagnosis. In the present study the Authors try to determine which clinical and haematological factors can determine long-terme survival. The Authors describe the case of a male patient (25 years old) affected by ANLL (M2), who became and is still now a long-survivor (80 months from 1th complete remission). He has been treated with DNB, ARA-C and TG (TRA schedule) for two cycles. After CR he refused consolidation and reinduction therapy and was treated only with 6-MP and MTX for 3 years, as maintenance chemotherapy. The Authors suggest that important factors for a favourable prognosis are early diagnosis and young age. A relatively high number of platelets can be correlated with a good prognosis.

Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Follow-Up Studies; Humans; Leukemia; Male; Methotrexate; Thioguanine

Sera from patients with aplastic anemia and amegakaryocytic thrombocytopenia contain an activity that stimulates megakaryocyte colony formation in vitro. We have assayed this megakaryocyte colony-stimulating activity (Meg-CSA) in sera of four patients receiving intensive antileukemic chemotherapy to determine whether the appearance of Meg-CSA is a physiologic response to the suppression of megakaryocytopoiesis. Three of the four patients were receiving consolidation or late intensification therapy for acute myoblastic leukemia (AML) in remission. The fourth was receiving induction therapy for de novo AML. During all or part of four chemotherapeutic cycles, serial Meg-CSA levels were assessed and correlated with the corresponding peripheral platelet counts. All courses of cytotoxic chemotherapy resulted in increases in serum Meg-CSA comparable to activity levels present in sera from patients with aplastic anemia. Two of the three patients studied during the early postchemotherapy interval manifested initial serum Meg-CSA elevations seven days before their thrombocytopenic nadirs when platelet counts were still between 100,000/mm3 and 140,000/mm3. Bone marrow recovery from chemotherapy was characterized by a decrease in serum Meg-CSA to pretherapy levels that occurred concurrently with the rise in platelet count to normal. These observations support the hypothesis that Meg-CSA is a physiologic humoral regulator of megakaryocytopoiesis elaborated in response to the depletion of either bone marrow megakaryocytes or megakaryocyte progenitor cells.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cells, Cultured; Colony-Stimulating Factors; Cytarabine; Daunorubicin; Humans; Leukemia; Megakaryocytes; Platelet Count; Thioguanine

Twenty patients treated with maintenance chemotherapy for acute nonlymphoblastic leukemia after achieving complete remission were compared with 13 patients who underwent bone marrow transplantation from an HLA-identical sibling. The median age was 27 years for both maintenance chemotherapy patients (range 17-42 years) and for patients undergoing bone marrow transplantation (range 16-42 years). The 1-year survival for maintenance chemotherapy was 80% vs. 54% with bone marrow transplantation (p = NS). Complete remission durability was 70% at 1 year for maintenance chemotherapy (34% projected for 5 years) compared with no relapses in the first year with bone marrow transplantation (p = 0.01). Patients on maintenance chemotherapy were hospitalized for an average of 22 days (range 0-171 days) during the first 12 months of treatment. Patients undergoing bone marrow transplantation were hospitalized for an average of 82 days (range 41-113 days) in the same time period. Severe hematologic toxicity was seen in 13/13 bone marrow transplantation patients and 6/20 maintenance chemotherapy patients. Chronic graft-vs.-host disease occurred in 3/7 surviving bone marrow transplantation patients. Maintenance chemotherapy had an average first year cost of +3,076.00 for patients who did not relapse and +48,827.00 for patients that relapsed. The first year costs for bone marrow transplantation averaged +84,102.00. Thus, maintenance chemotherapy was associated with a better early survival, less toxicity, and lower cost than bone marrow transplantation in the first year after initiating therapy. However, fewer relapses with bone marrow transplantation suggest that it will yield a higher long-term survival rate.

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Transplantation; Cytarabine; Female; Graft vs Host Disease; Hematologic Diseases; Humans; Leukemia; Male; Recurrence; Thioguanine

The ability of an in vitro clonogenic drug sensitivity assay to predict the outcome of therapy for acute nonlymphocytic leukaemia was evaluated using marrow cells obtained from previously untreated or first relapsed patients treated with either cytosine arabinoside/anthracycline antibiotic or high dose cytosine arabinoside remission induction therapy. While the per cent of leukaemic cells killed in vitro was correlated with the outcome of therapy, this drug sensitivity assay provided little or no clinically useful information.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cell Survival; Colony-Forming Units Assay; Cytarabine; Daunorubicin; Doxorubicin; Humans; Leukemia; Thioguanine; Tumor Stem Cell Assay

The relationship between the pretherapy cell cycle characteristics of leukaemic marrow cells and the outcome of remission-induction therapy for acute nonlymphocytic leukaemia was studied in newly diagnosed and relapsed patients who were then treated with either combination chemotherapy consisting of cytosine arabinoside/anthracycline antibiotic +/- 6 thioguanine or with single agent high-dose cytosine arabinoside therapy. The outcome of high-dose cytosine arabinoside therapy was highly dependent upon the per cent of pretherapy cells in S phase with no remissions occurring in patients in whom the 3H-TdR labelling index was less than 6%. In contrast, the outcome of cytosine arabinoside/anthracycline antibiotic therapy was independent of the pretherapy cell cycle characteristics of the leukaemic cells.

Topics: Acute Disease; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cytarabine; Female; Humans; Interphase; Leukemia; Male; Middle Aged; Naphthacenes; Thioguanine

The growth pattern in agar culture and the karyotype of bone marrow cells were studied in 79 patients with untreated acute non-lymphocytic leukaemia (ANLL). Results were divided into the following groups: (A) colony and cluster formation; (B) growth of less than 600 small clusters per 10(5) cells; (C) growth of more than 600 small clusters; (D) no growth in agar. Cytogenetically, the patients were divided into 3 categories: NN, normal metaphases only; AN, both abnormal and normal metaphases and AA, abnormal metaphases only. An association was seen between growth pattern and karyotype: the majority of NN patients (33/37) belonged to group (A + B) while in group (C + D) 20/24 patients were AN or AA. 37 patients were prognostically evaluable. The growth pattern in agar but not the cytogenetic pattern had prognostic implications. 25 patients with acute lymphocytic leukaemia (ALL) were also studied at diagnosis. Different growth patterns in agar had no impact on prognosis. No relationship was detected between growth pattern and karyotype in ALL.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Cells; Cells, Cultured; Chromosome Aberrations; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Karyotyping; Leukemia; Leukemia, Lymphoid; Male; Middle Aged; Neoplastic Stem Cells; Prednisolone; Prednisone; Prognosis; Thioguanine; Vincristine

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

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

A variety of chemical agents have been shown to induce differentiation in in vitro cultured neoplastic cell lines. We noted that blast cells in the peripheral blood of acute nonlymphoid leukemia patients treated with the drug Harringtonine appeared to undergo morphological changes that suggested differentiation. In view of the relatively minimal myelotoxicity of Harringtonine, we hypothesized that harringtonine was acting by differentiation-induction, which concomitantly arrested cell division. We tested this hypothesis using two different experimental approaches. First, the promyelocytic leukemic cell line, HL-60, was cultured with Harringtonine and shown to differentiate into a cell, which, by functional cell surface marker and morphological criteria, closely resembled normal monocytes. Furthermore, these changes were accompanied, and indeed slightly preceded by, loss of proliferative capacity. Second, to prove that the leukemic blasts were the cells undergoing the changes observed in vivo, freshly isolated leukemia cell populations were cultured with Harringtonine, and morphological changes paralleling those seen in the patients were observed. Thus, the antileukemic effect of Harringtonine appeared to be due to diversion of the proliferating blast cells into a differentiation pathway, which, as in normal myeloid cells, resulted in the arrest of proliferation.

Topics: Acute Disease; Adult; Alkaloids; Cell Differentiation; Cell Division; Cell Line; Clone Cells; Cytarabine; Female; Harringtonines; Humans; Leukemia; Male; Middle Aged; Monocytes; Thioguanine

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

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

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

This study comprises 187 patients aged over 15 years with acute leukaemia, diagnosed and treated between the years 1969 and 1978. Fourteen (7.5%) survived for more than 5 years after diagnosis. In this group of survivors there were 7 patients with AML and 6 with ALL--corresponding to 8.9 and 21.4% of each collective, respectively--and 1 patient with PML. Four patients (28.6%) died after a survival time exceeding 5 years, 1 patient with AML as a result of a gastric carcinoma and the 3 other patients (1 AML, 2 ALL) of the original disease. Hence, survival times over several years do not necessarily mean real cures. From an analysis of our data, no factor correlating with long-term survival was identifiable. In terms of clinical-diagnostic parameters the group of late relapses was also heterogeneous.

Topics: Acute Disease; Adolescent; Adult; Cyclophosphamide; Female; Humans; Leukemia; Lomustine; Male; Methotrexate; Middle Aged; Recurrence; Thioguanine; Time Factors

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

A new technique is introduced for determining the number of bone marrow cells per cubic millimeter marrow, providing an accurate and objective means for quantitating therapy-induced cytoreduction. The method requires a correction for admixed peripheral blood in bone marrow aspirates to measure the fraction of remaining pure marrow. While cell kinetic differences between blood, aspirates, and biopsies identify the proportion of contaminating blood cells, the ratio of red cell hematocrits in blood and aspirate gives the volume of trapped blood. By combining both procedures, bone marrow cell counts per unit volume pure marrow result (BMC/cu mm BM), which were found highly reproducible. Blast cell counts (BMBC/cu mm BM) were obtained by additional morphological differentiation. BMC and BMBC/cu mm BM were monitored in 16 patients with acute nonlymphoblastic leukemia treated with daunorubicin, cytosine arabinoside, and 6-thioguanine in combination and in 4 patients with end-stage acute leukemias and non-Hodgkin's lymphomas during high-dose thymidine therapy. Total and daily therapy-induced cytoreduction rates were significantly greater (P less than 0.01) in responders than nonresponders to either regimen. Changes in BMC/cu mm BM were also found representative for changes in BMBC/cu mm BM, since the majority of bone marrow cells were blasts. In acute leukemia. BMC/cu mm BM thus provides accurate and objective measurements of treatment efficacy in vivo and after short periods of drug exposure. Differences in cytoreduction rates within the group of responders also suggest possible prognostic implications.

Topics: Acute Disease; Bone Marrow; Cell Count; Cytarabine; Daunorubicin; Humans; Leukemia; Thioguanine; Thymidine

Seventy-nine adult patients with acute nonlymphoblastic leukemia (ANLL) were treated on the L-6 protocol at Memorial Sloan-Kettering Cancer Center between May 1970 and January 1974. Forty-two patients achieved a complete remission (CR) and nine of these are still disease free, with a minimum of seven years of follow-up. An extensive statistical analysis has been carried out on a large number of pretreatment and treatment characteristics to identify factors related to CR and remission duration. Multivariate regression techniques yielded as favorable characteristics associated with CR, in order of importance: young age at diagnosis, the presence of Auer rods at diagnosis, and treatment with Pseudomonas vaccine. A regression model for remission duration identified as favorable prognostic factors for long-term remission: at most two courses of induction therapy, an intermediate age range, and a low platelet count at diagnosis.

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bacterial Vaccines; Carmustine; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hydroxyurea; Leukemia; Male; Methotrexate; Middle Aged; Platelet Count; Prognosis; Pseudomonas; Statistics as Topic; Thioguanine; Vincristine

A novel alkaline phosphatase (AP) isozyme has been observed in the serum of 4 patients suffering from acute non-lymphocytic leukemia (ANLL). It resembled the AP of liver/bone origin in most physico-chemical characteristics, but particular electrophoretic characteristics in agar and starch gel and a distinct molecular weight gave this novel AP isozyme its unique character. Its leukemic origin has been demonstrated by isolation from peripheral blood and bone and bone marrow blasts. The appearance of the novel AP isozyme in the patients' sera appeared to be an ominous sign as, in all four, it shortly preceded death. In patients it may have contributed to the observed resistance towards thioguanine therapy.

Topics: Acute Disease; Adolescent; Alkaline Phosphatase; Bone Marrow; Electrophoresis, Agar Gel; Electrophoresis, Starch Gel; Female; Humans; Isoenzymes; Leukemia; Male; Middle Aged; Thioguanine

Sixty-five patients with acute nonlymphoblastic leukemia, ranging in age from 16 to 73 years (median, 54), were treated with thioguanine, cytarabine, daunorubicin, prednisone, and vincristine to induce complete remission. Remission was maintained with monthly 5-day courses of cytarabine and thioguanine for 4 years. Of the entire group, 57% achieved complete remission and 29% died in the first 30 days of treatment. The median remission duration was 15 months, with 20% of the complete responders predicted to remain in complete remission for 4 years. No primary central nervous system relapses have occurred. Of six variables examined by multivariate analysis, only age was predictive of remission success. Before analysis, the patients were divided into groups by age: group 1--ages 16-42 years (n = 17); group 2--ages 43-59 years (n = 25); and group 3--ages 60-73 years (n = 23). Complete remission rates were 76% in group 1, 64% in group 2, and 35% in group 3 (P = 0.002). Lower remission rates for older patients resulted from more early deaths rather than resistant disease. Age and LDH levels affected remission duration. The median complete remission duration was 48 months in group 1 and 10 months in groups 2 and 3 (P = 0.004). In group 1, 41% of patients achieving complete remission are predicted to remain in complete remission for 4 years. We concluded that this five-drug induction regimen is highly effective for induction therapy in younger adults with acute nonlymphoblastic leukemia. The results in patients greater than or equal to 60 years of age are less satisfactory due to a lower remission rate and greater chance of early death. Furthermore, these results demonstrate that the program as described results in a longer duration of complete remission for patients of younger age.

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aged; Antineoplastic Agents; Cytarabine; Daunorubicin; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Humans; Leukemia; Male; Middle Aged; Prednisone; Thioguanine; Time Factors; Vincristine

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia; Male; Middle Aged; Prednisolone; Thioguanine

Topics: Acute Disease; Adult; BCG Vaccine; Cytarabine; Doxorubicin; Hematopoietic Stem Cells; Humans; Immunotherapy; Leukemia; Thioguanine

Twenty-six of 45 adults (58%) with acute nonlymphocytic leukemia who were treated with intensive induction chemotherapy over 5 yr ago entered complete remission. All patients entering remission were placed on weekly maintenance chemotherapy consisting of cytosine arabinoside and 6-thioguanine. The median duration of complete remission was 17 mo and 7 patients (27%) remained in their initial remission for 62 + to 102 + mo. All but one of the patients in complete remission over 5 yr have had treatment discontinued. Only 1 of 7 patients in remission for more than 5 yr has relapsed. Median survival is 26.5 mo, and 8 patients (31%) currently remain alive without evidence of leukemia 63--105 mo from diagnosis. It is possible to achieve long-term disease-free survival with chemotherapy alone in acute nonlymphocytic leukemia.

Topics: Acute Disease; Adolescent; Adult; Aged; Cytarabine; Daunorubicin; Female; Humans; Leukemia; Long-Term Care; Male; Middle Aged; Prednisone; Recurrence; Thioguanine

Thirty-seven patients with acute leukemia in relapse were treated with a three-drug combination that included a 3- or 4-day course of AMSA with total doses ranging from 600 mg/m2 to 740 mg/m2 I.V., cytosine arabinoside 25 mg/m2 I.V. followed by 200 mg/m2 by continuous infusion daily for 5 days, and thioguanine 100 mg/m2 p.o. q 12h for 5 days. Eight of the 25 patients with acute nonlymphoblastic leukemia achieved a complete remission and 3 a partial remission. None of the five patients with acute lymphoblastic leukemia achieved a response and there was one partial remission in the seven patients with myelodysplastic syndrome or blastic CML. Reversible toxicity included nausea and vomiting (78%), alopecia (100%), pancytopenia (100%), mild stomatitis (63%), and hepatic dysfunction (24%). One patient developed seizures and cardiac arrhythmias. The activity of this combination in heavily treated patients with ANLL is comparable to that of the anthracycline-containing regimens, and its use in previously untreated patients with ANLL should now be explored.

Topics: Acute Disease; Adolescent; Adult; Aged; Aminoacridines; Amsacrine; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Cytarabine; Drug Therapy, Combination; Female; Humans; Leukemia; Male; Middle Aged; Neoplasm Recurrence, Local; Thioguanine

The necessity of intensive maintenance chemotherapy in enhancing the duration of life in patients with acute nonlymphocytic leukemia (ANLL) in remission has been evaluated. Twenty-four patients were managed with maintenance chemotherapy and 24 were not. In patients under 50, there was no evidence that maintenance prolonged survival. In patients over the age of 50, maintenance chemotherapy prolonged survival (p = 0.03). In both groups the duration of first remission appeared to be lengthened in patients on maintenance chemotherapy (p = 0.09). Since patients 50 and older were difficult to reinduce, it appears that the greatest prolongation of life for them is afforded by continuous maintenance chemotherapy which may forestall relapse. On the other hand, patients less than 50 years of age have a high likelihood of achieving a second complete remission; it is in this group that maintenance chemotherapy adds only to morbidity.

Topics: Acute Disease; Adult; Aged; Cytarabine; Drug Therapy, Combination; Female; Humans; Leukemia; Male; Middle Aged; Statistics as Topic; Thioguanine; Time Factors

Twenty-one patients with acute nonlymphocytic leukemia were treated with a regimen including daunorubicin, cytosine arabinoside, and 6-thioguanine and 15 patients (71%) achieved a complete remission. Thirteen of the 15 remissions occurred after a single course of therapy and two after two courses of treatment resulting in a rapid time to complete remission. The time from treatment initiation to complete remission was 21-82 days with a median of 29 days. Nine of the 15 patients who gained a complete remission were then treated with two cycles of consolidation therapy utilizing the three induction drugs in modified dosages to determine the toxicity of a consolidation program. With the doses used in consolidation, pancytopenia regularly occurred but only 5/15 courses were associated with complications of bleeding or infection that required hospitalization. No patient died as a result of consolidation therapy. This study confirms the rapid effectiveness of the induction program which provided equivalent complete remission rates for adults at any age (up to 66 years). The consolidation regimen is now being used in a randomized study to determine whether it contributes to the duration of complete remission.

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

Diffusion chambers (DC) were used to culture bone marrow of ANLL patients firstly at the onset, secondly in complete remission and thirdly in the relapse of the disease. At the onset of the disease an increase in cellular concentration mainly due to the granulocytic differentiation was observed in DC in all ANLL patients, in contrast to no growth in ANLL patients in complete remission and in relapse. The DC technique reveals a marked pathological pattern of proliferation in every phase of ANLL, at the presentation, in complete remission and in relapse.

Topics: Acute Disease; Adolescent; Adult; Aged; Animals; Cell Differentiation; Cells, Cultured; Child; Culture Techniques; Cytarabine; Daunorubicin; Female; Humans; Leukemia; Male; Methylprednisolone; Mice; Middle Aged; Thioguanine

Sixty patients with ANLL were given intensified remission induction therapy consisting of thioguanine, cytosine arabinoside and daunorubicin (TAD). The mean age of patients was 47.6 years (range 18 to 74 years). Basing on leukemic cell kinetic data time sequencing of drugs was different from the original TAD protocol. Complete remission (CR) waa achieved in 43/60 patients (72%) with 10 CR in 15 patients over 60 years of age. Seventy-nine percent of the CR were induced by one cycle vs thirty percent reported from the original TAD regimen. The major cause of induction failure--in ten of the 60 patients--was thrombocytopenia refractory to platelet transfusions. Persisting leukemia after two induction cycles was documented in only two patients. Median remission duration by life table analysis is 10 months with 17 patients in continuous CR for 1+ to 22+ months.

Topics: Acute Disease; Adolescent; Adult; Aged; Cytarabine; Daunorubicin; Humans; Leukemia; Middle Aged; Thioguanine; Thrombocytopenia

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Agents; Bone Marrow; Cell Count; Cytarabine; Doxorubicin; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; Female; Humans; Leukemia; Male; Middle Aged; Prednisone; Prognosis; Thioguanine; Time Factors; Vincristine

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Agents; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia; Middle Aged; Prednisolone; Thioguanine; Thioinosine

Twenty-two newly diagnosed adults with acute non-lymphocytic leukemia (ANLL) and 18 who had relapsed from a prior complete remission (CR) obtained with intensive chemotherapy were treated with a combination of Adriamycin, cytosine arabinoside, 6-thioguanine, prednisone, and vincristine. Eighteen (82%) of the patients undergoing initial induction therapy, including 4 of 6 patients over 60 years of age, achieved CR. Twelve patients (67%) undergoing reinduction therapy also achieved CR. Twenty-three (77%) of the 30 CRs were obtained with only one course of chemotherapy. The median time to CR for those undergoing initial treatment was 32 days, and the median duration of CR is 10+ months. The median survival for all 22 newly diagnosed patients is 15+ months. This intensive five-drug regimen is highly effective for the remission induction of both newly diagnosed and previously treated patients with ANLL producing a high percentage of CRs with only one course of therapy.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Agents; Arrhythmias, Cardiac; Cytarabine; Doxorubicin; Drug Administration Schedule; Drug Therapy, Combination; Female; Heart Failure; Humans; Leukemia; Male; Middle Aged; Prednisone; Prognosis; Remission, Spontaneous; Thioguanine; Vincristine

Topics: Acute Disease; Adult; Cytarabine; Daunorubicin; Female; Fertility; Humans; Leukemia; Male; Pregnancy; Thioguanine

Topics: Acute Disease; Aged; Cytarabine; Drug Therapy, Combination; Female; Humans; Leukemia; Male; Middle Aged; Remission, Spontaneous; Thioguanine

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

Treatment of therapy-resistant acute leukemia with 7 cytostatics (TRAMPCO) 13 adult patients with acute leukemia, primarily and secondarily resistant to other combined therapy, as well as 2 untreated patients were treated with 7 cytostatic drugs according to the so called TRAMPCO-regimen. 5 complete remissions and 5 partial remissions were obtained corresponding to a degree of response of 66%. The duration of remission was relatively short with 1 to 5 months, in one case more than 6 months. The toxicity of the combined therapy could be tolerated, the personal subjective tolerance was good. The Trampco-regiment therefore represents a realistic possibility in the treatment of acute leukemia resistant to other forms of treatment.

Topics: Acute Disease; Adolescent; Adult; Aged; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Resistance; Drug Therapy, Combination; Female; Humans; Leukemia; Male; Methotrexate; Middle Aged; Prednisolone; Thioguanine; Vincristine

Ninety-two patients suffering from various forms of acute non-lymphoblastic leukaemia were seen at the Johannesburg General Hospital between January 1972 and December 1977. Seventy-four completed at least one course of therapy, and were therefore available for evaluation. Three basic regimens were used for inducing remissions. These included daunorubicin and cytosine arabinoside (regimen 1-19 patients); larger doses of daunorubicin together with cytosine arabinoside (regimen 2-29 patients); and a combination of cyclophosphamide, vincristine, cytosine arabinoside and prednisone (regimen 3-22 patients). Regimen 3 was normally used only in older patients. Supportive measures included the use of red cell, granulocyte and platelet transfusions. Complete remission rates with the 3 regimens were 36,8%, 55,1% and 40,9% respectively, with corresponding partial remission rates of 5,2%, 0% and 18,1% respectively. The mean duration of survival in those patients who achieved remission was 10 months, 18 months and 8 months respectively. In addition, a complete remission rate of 28,6% was obtained in 14 patients, 10 of whom had relapsed while being treated with other regimens and who were later treated with an 8-drug combination (TRAMPCOL).

Topics: Acute Disease; Adult; Aged; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia; Middle Aged; Prednisone; Thioguanine; Vincristine

Twenty-seven patients over 60 years of age with acute nonlymphocytic leukemia (ANLL) were prospectively treated with one of three intensive chemotherapeutic regimens. Complete remissions were achieved in eight patients (30%). Remissions were obtained in seven of 14 patients (50%) age 61 to 70 years, but in only one of 13 patients (8%) 71 years and older. The most effective regimen in patients 61 to 70 years consisted of a combination of daunorubicin and cytosine arabinoside. The median duration of remission for all eight responders is 9+ months and their median survival is 14+ months. Intensive therapy is indicated in the elderly patient 61 to 70 years of age with ANLL.

Topics: Acute Disease; Aged; Antineoplastic Agents; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Infections; Length of Stay; Leukemia; Male; Middle Aged; Prednisone; Prospective Studies; Remission, Spontaneous; Thioguanine; Time Factors

Twenty-one children with acute nonlymphoblastic leukemia (ANLL) were treated with a combination regimen consisting of arabinosyl cytosine (Ara-C), 6-thioguanine (TG), and Adriamycin, The incidence of complete remission was 74%. For consolidation, addition courses of Ara-C and TG were given, followed by L-asparaginase. The maintenance program was the same as that for the lymphoblastic type (L-2) including intrathecal methotrexate for prophylaxis of meningeal leukemia. Of the 16 who were evaluable for the duration of complete remission, six developed bone marrow relapse, one meningeal leukemia within 3-14 months after entering complete remission and one was lost to follow-up. Eight remain in complete remission for 9-72 months. In five of eight, chemotherapy has been terminated after 3 years, and all continue in remission for 11-32 months post-treatment. Although the results do not compare well to those of the lymphoblastic morphology, long-term disease-free survival can be achieved with multiple-drug intensive treatment in childhood ANLL.

Topics: Acute Disease; Adolescent; Antineoplastic Agents; Asparaginase; Child; Child, Preschool; Cytarabine; Doxorubicin; Drug Therapy, Combination; Female; Humans; Infant; Leukemia; Male; Meningeal Neoplasms; Remission, Spontaneous; Thioguanine

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

Beta-thioguanine deoxyriboside (betaTGdR) is a purine nucleoside derivative which was studied alone or in combination with arabinosyl cytosine (Ara-C) in patients with solid tumors and acute leukemia. No significant responses were observed in 22 patients with solid tumors. The response rate with betaTGdR alone in acute leukemia was 26% and in combination with Ara-C was 24%. Responses were generally of short duration. Toxicity included myelosuppression, nausea, stomatitis, hyperpigmentation, photosensitivity, and liver function abnormalities.

Topics: Acute Disease; Adolescent; Adult; Aged; Child; Child, Preschool; Cytarabine; Deoxyguanosine; Deoxyribonucleosides; Drug Therapy, Combination; Female; Guanosine; Humans; Leukemia; Leukopenia; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Remission, Spontaneous; Thioguanine; Thionucleosides; Thrombocytopenia; Time Factors

Twenty adults (median age, 58 yrs) with acute nonlymphoblastic leukemia who had achieved complete remission were given maintenance therapy with monthly courses of cytosine arabinoside and 6-thioguanine, each in a dose of 100 mg/m2 every 12 hours for ten doses. The toxicity was minimal with no severe infections, bleeding, or treatment-related deaths. The treatment was often administered on an outpatient basis. The predicted life-table median remission duration is 14 months with 11 patients still in remission from 3+ to 29+ months.

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

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

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

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

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

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

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

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

Topics: Acute Disease; Antineoplastic Agents; Asparaginase; Carmustine; Cyclophosphamide; Cytarabine; Dacarbazine; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia; Mercaptopurine; Thioguanine

A case of megakaryoblastic leukemia is presented. Megakaryoblastosis and erythrocytic hyperplasia of the bone marrow, thrombocythemia, and hepatosplenomegaly were the essential features; 100% of the marrow-derived metaphases were found to be Ph1-positive. Cytologic and chromosomal findings are compatible with the assumption that all three marrow systems were involved in the leukemic process.

Topics: Acute Disease; Autoradiography; Blood Cell Count; Blood Platelets; Bone Marrow; Carmustine; Chromosome Aberrations; Chromosomes, Human, 16-18; Chromosomes, Human, 19-20; Chromosomes, Human, 21-22 and Y; Chromosomes, Human, 6-12 and X; Cytarabine; Female; Humans; Lymph Nodes; Megakaryocytes; Middle Aged; Mitosis; Pneumonia; Thioguanine; Thrombocythemia, Essential; Vincristine

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

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

Topics: ABO Blood-Group System; Acute Disease; Blood Group Incompatibility; Bone Marrow Cells; Bone Marrow Transplantation; Child; Chimera; Cyclophosphamide; Cytarabine; Drug Resistance; Drug Therapy, Combination; Female; Graft vs Host Reaction; Histocompatibility; Humans; Leukemia; Leukemia, Lymphoid; Male; Methotrexate; Nitrosourea Compounds; Thioguanine; Transplantation, Homologous

Topics: Acute Disease; Adult; Allopurinol; Anti-Bacterial Agents; Bacterial Infections; Child; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Hydroxyurea; Leukemia; Leukemia, Lymphoid; Metabolic Diseases; Prednisone; Remission, Spontaneous; Thioguanine; Uric Acid; Vincristine

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

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

Topics: Acute Disease; Adult; Antineoplastic Agents; Asparaginase; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Infection Control; Leukemia; Life Expectancy; Male; Mercaptopurine; Methotrexate; Middle Aged; Patient Isolators; Prednisolone; Thioguanine; Time Factors; 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: 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

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

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

Topics: Acute Disease; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Combinations; Drug Interactions; Drug Synergism; Humans; Leukemia; Mercaptopurine; Prednisone; 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: Acute Disease; Adult; Aged; Autoradiography; Bone Marrow; Bone Marrow Cells; Cell Division; Cell Nucleus; Culture Techniques; Cytarabine; Down Syndrome; Female; Floxuridine; Humans; Karyotyping; Leukemia; Leukocytes; Lymphocytes; Male; Mitosis; Prednisone; Thioguanine; Thymidine; Tritium; Vincristine

Topics: Acute Disease; Humans; Leukemia; Mercaptopurine; Thioguanine