thioguanine-anhydrous and Leukemia--Lymphoid

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

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Drug Evaluation; Drug Resistance; Etoposide; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Melphalan; Neoplasm Recurrence, Local; Neoplasms; Thioguanine; Transplantation, Autologous

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

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

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

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

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cytarabine; Doxorubicin; Europe; Humans; Leukemia, Lymphoid; Methotrexate; Prednisone; Prognosis; Random Allocation; Remission Induction; Thioguanine; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Belgium; Child; Clinical Trials as Topic; Cyclophosphamide; Cytarabine; Doxorubicin; France; Humans; Leukemia, Lymphoid; Methotrexate; Prednisone; Prognosis; Remission Induction; Risk; Thioguanine; Vincristine

Between 1 September 1981 and 31 December 1985, 382 previously untreated children with ALL were entered into study VII/81, a multicentric and randomized study with a modified BFM protocol. Patients were divided into three risk groups according to the initial lymphoblast count and liver and spleen enlargement: standard- (SR), medium- (MR), and high-risk (HR) groups. Of all patients, 94% attained complete remission. The actuarial probability of event-free survival is 0.62 +/- 0.04 (SR group, 0.66 +/- 0.06; HR group, 0.29 +/- 0.12). Sixty-one patients relapsed, 10 had isolated CNS relapses, and 11 CNS relapses were combined with bone marrow relapses. Concerning the duration of maintenance therapy, patients were randomized into two groups of 18 and 24 months respectively. Up to now, there has been a slight advantage for the 18-month group. Two different methods of CNS preventive therapy for SR patients (irradiation plus intrathecal methotrexate and intermediate-dose methotrexate (IDMTX) plus intrathecal methotrexate) were used and revealed a higher rate of CNS relapses but a lower rate of bone marrow relapses in the intermediate-dose MTX group.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Doxorubicin; Germany, East; Humans; Leukemia, Lymphoid; Meningeal Neoplasms; Methotrexate; Prednisone; Random Allocation; Remission Induction; Risk; Thioguanine; Vincristine

From January 1981 through July 1983, 141 children with newly diagnosed acute lymphoblastic leukemia were registered in a cooperative clinical study whose objective was to evaluate the toxicity and the feasibility of the German Berlin-Frankfort-Münster (BFM) protocol. The results were comparable with those reported by the BFM group. For the 133 patients (94%) who achieved complete remission, the actuarial disease-free survival was 67% at 4 years. These results were obtained in spite of a high rate of deaths in complete remission during the initial year of the study. Subsequently, probably as a result of improved expertise in the handling of the protocol, the proportion of toxic deaths declined sharply. Although the current BFM protocol adjusts for aggressiveness of therapy according to the volume of the liver and spleen, splenomegaly (but not hepatomegaly) remained of prognostic significance. Moreover, for patients with bad risk features, an initial high hemoglobin level was found to represent an additional factor of negative significance.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Female; Hemoglobins; Humans; Infant; Leukemia, Lymphoid; Male; Methotrexate; Prednisone; Prognosis; Thioguanine; Vincristine

Fifty-one patients with lymphoblastic lymphoma (LBL) treated with one of five successive intensive chemotherapy protocols for acute lymphoblastic leukemia (ALL) since 1971 were reviewed. The patients were divided into leukemic and nonleukemic groups, and their clinical and laboratory parameters compared. The projected 5-year survival rate for all patients treated with the L10/17 protocols was 45% for both leukemic and nonleukemic LBL. The response to treatment was compared with that of 111 patients with ALL and was nearly identical. Poor prognostic factors were age beyond 30, WBC greater than 50,000/microL, failure to achieve a complete response (CR), and a late CR during induction. Leukemia at presentation, T cell surface markers, and the presence of a mediastinal mass did not adversely affect survival. The use of intensive chemotherapy protocols has proven to be a significant advance in the treatment of LBL.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Clinical Trials as Topic; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Lymphoid; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Neoplasm Staging; Prednisone; Prognosis; Thioguanine; Vincristine

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Drug Evaluation; Drug Resistance; Etoposide; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Melphalan; Neoplasm Recurrence, Local; Neoplasms; Thioguanine; Transplantation, Autologous

An intensive multimodal therapy was developed for the treatment of a subpopulation of children with acute lymphoblastic leukemia (ALL) who had a predicted event-free survival of less than 40% on previously reported therapeutic regimens (at high risk for early relapse). Induction with multiagent chemotherapy and radiotherapy to bulky disease-bearing areas (peripheral lymph nodes and mediastinum) was followed by consolidation, CNS prophylaxis, and cyclical remission maintenance therapy. Ninety-six (96%) of 100 previously untreated patients, 1 to 17 years of age, attained a complete remission. Seven patients received other maintenance therapy or a bone marrow transplant in remission. Sixty-six of the remaining 89 (74%) are in continuous complete remission at 22+ to 72+ months (median, 44+ months). Marrow relapse occurred in 15 (17%), CNS relapse in 5 (6%), and testicular relapse in one. Sixty-six of the 93 evaluable patients (71%) (including the induction failures) are event-free survivors. Two patients died of infection during the induction phase. No patient died during consolidation or maintenance without recurrent disease. The patients spent a median of 19, 0, and 0 days hospitalized during induction, consolidation, and maintenance, respectively. The most common complications were bacteremia and mucositis during induction and mucositis and fever during periods of neutropenia in consolidation. Maintenance was well tolerated. We conclude that the treatment protocol is intensive, but the inherent toxicities are manageable with adequate supportive care. The life table--projected event-free survival of 69% +/- 5% 48 months from diagnosis is encouraging.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow Transplantation; Child; Child, Preschool; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Infant; Leukemia, Lymphoid; Male; Methotrexate; Prednisone; Prognosis; Radiotherapy Dosage; Recurrence; Risk; Thioguanine; Time Factors; Vincristine

In an attempt to improve the poor outlook for children with T-cell leukemia (T-ALL), the Southwest Oncology Group, Pediatric Division, used a modified LSA2-L2 multidrug regimen to treat 53 patients with E-rosette-positive T-ALL. This regimen was chosen because of its demonstrated efficacy in T-cell (mediastinal) non-Hodgkin's lymphoma. Complete remission (CR) rate was 88%. Range of follow-up for those patients remaining in CR is 24-49 mo (median 39 mo). Life table analysis estimates that 40% (SE 8.3%) of all patients who started induction therapy will remain failure-free at 3 yr. For patients achieving CR, 46% (SE 9%) are projected to remain in both marrow and extramedullary CR at 3 yr. Median failure-free duration was 13 mo, but only 1 patient has relapsed beyond 16 mo. Twenty-nine percent of initial relapses were isolated CNS relapses. The following presenting factors did not relate significantly to outcome: hemoglobin, platelet count, uric acid, race, and mediastinal mass. Age greater than 10 yr was a poor prognosis indicator only in the less than 50,000/microliter WBC group. Sex was not a significant factor after adjusting for WBC. WBC was the most important prognostic factor: 19% (SE 8%) of patients with WBC greater than 50,000/microliter are projected to remain failure-free at 3 yr as compared to 67% (SE 11%) of patients with WBC less than 50,000/microliter. Although the overall results are better than those previously reported for pediatric patients with T-ALL, the long-term failure-free rate remains low for patients presenting with greater than 50,000/microliter WBC.

Topics: Adolescent; Allopurinol; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Carmustine; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Injections, Spinal; Leukemia, Lymphoid; Male; Methotrexate; Prednisone; Prognosis; Rosette Formation; T-Lymphocytes; Thioguanine; Vincristine

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

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

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

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

Seventeen adults with previously untreated acute lymphocytic leukemia (ALL) received thioguanine, vincristine, dexamethasone, and pyrimethamine for remission induction. Nine patients (53%) achieved complete and 5 (30%) partial remissions. Once in complete remission patients were given two closely separated consolidation courses followed by monthly maintenance courses of the same regimen with the addition of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) every other month during maintenance therapy. The median duration of complete remission was 176 days (range 38 to 605). The median survival for all patients was 405 days (range 30 to 1,058+). Oral pyrimethamine and CCNU were used for their potential activity as prophylactics against meningeal leukemia. Dexamethasone was used instead of prednisone because of the potential enhancement of granulocyte mobilization by the former. Six patients (35%) developed meningeal leukemia while on initial induction or maintenance therapy, 5 within 6 months of diagnosis. Life-threatening infections occured in 10 patients (59%) during induction. Whereas the regimen effectively induced complete remission in about half of previously untreated adults with ALL, it was not effective in maintenance. The incidence of meningeal leukemia and infection during induction was high. Oral pyrimethamine was inadequate prophylaxis for meningeal leukemia; dexamethasone did not reduce the incidence of serious infection.

Topics: Adolescent; Adult; Clinical Trials as Topic; Dexamethasone; Drug Administration Schedule; Drug Therapy, Combination; Humans; Leukemia, Lymphoid; Lomustine; Middle Aged; Pyrimethamine; Remission, Spontaneous; Thioguanine; Vincristine

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

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

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

Mutations induced in cultured human cells by 254-nm UV light were analyzed within exon 3 of the hypoxanthine guanine phosphoribosyl transferase (HPRT) gene. Five large independent cultures of human lymphoblastoid cells, line TK6, were exposed to 4 J/m2 of 254-nm UV light and mutants at the HPRT locus were selected en masse by 6-thioguanine (6TG) resistance. Exon 3 of the HPRT gene was amplified from the mutant cells by polymerase chain reaction (PCR) using modified T7 DNA polymerase. Denaturing gradient gel electrophoresis (DGGE) was used to separate the mutant sequences from the wild type as mutant/wild-type heteroduplexes. Individual mutant bands were isolated from the gel and the nature of the mutations was determined by direct sequencing. Eight predominant mutations were detected in the 184-bp exon 3 sequence. Of these, 3 transition, including 2 G-C to A-T and 1 A-T to G-C and 2 A-T to C-G transversions, appeared in all 5 UV-treated cultures but not in untreated cultures and were thus considered to be mutational hotspots. These observations are similar in nature to those previously reported in bacterial and rodent cells. A single G deletion, a tandem substitution of CpT for TpA, and a tandem triple substitution of GpGpA for ApApG were also observed but in only 2, 2 and 3 of the 5 UV-treated cultures, respectively. Numerical analysis of the mutant fractions of these 8 mutations indicated that each of them was distributed as a set of non-random and independent events, i.e., a mutational hotspot.

Topics: Alleles; Autoradiography; Base Sequence; Electrophoresis, Polyacrylamide Gel; Exons; Hot Temperature; Humans; Hypoxanthine Phosphoribosyltransferase; Leukemia, Lymphoid; Male; Molecular Sequence Data; Mutation; Polymerase Chain Reaction; Thioguanine; Tumor Cells, Cultured; Ultraviolet Rays

During A-ALL induction treatment, HD-ara-C (2.5 g/m2 IV, day 1), does not produce any beneficial effect, whereas the hematologic toxicity is increased. A 3-month consolidation phase comprising intermittent MTX, ara-C and 6-TG is not significantly affecting either DFI or survival in A-ALL. The association of HD-ara-C and m-AMSA appears to be a promising salvage therapy for the 20% A-ALL refractory to first induction therapy. The quality of autologous bone marrow graft, harvested after HD-ara-C, seems to be impaired as suggested by a delayed recovery of PMN and platelets. HD-ara-C (3 g/m2 X N) given the days before cyclophosphamide and TBI as conditioning treatment for BMT does not seem to induce prohibitory additional toxicity. Whether HD-ara-C was given four to six times or eight to 12 times gave no significant difference in early toxicity.

Topics: Adult; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Cyclophosphamide; Cytarabine; Daunorubicin; Humans; Leukemia, Lymphoid; Methotrexate; Middle Aged; Prednisone; Thioguanine; Vincristine

The genetic stability of normal and neoplastic lymphocytes was compared by using base-line mutation frequency and mutation rate/cell generation. Mutations at the hypoxanthine-guanine phosphoribosyltransferase locus were studied by enumerating thioguanine-resistant cells in a clonogenic assay. The base-line ("spontaneous") mutation frequency was 1.52 X 10(-6), 6.38 X 10(-6), and 1.06 X 10(-6) for normal cells from three individuals and was 1.16 X 10(-3), 6.08 X 10(-5), and 3.06 X 10(-5) for the three malignant cell lines, Jurkat (JM), HRIK, FMC-Hu1B, respectively. The mutation cell/generation rate was 24.6 X 10(-8), 15 X 10(-8), and 5.5 X 10(-8) for lymphocytes from the three normal individuals, and 666.4 X 10(-8), 52.8 X 10(-8), and 131 X 10(-8) for the three malignant cell lines. The results suggest that neoplastic lymphocytes are more genetically unstable than normal lymphocytes.

Topics: Burkitt Lymphoma; Cell Division; Cells, Cultured; Humans; Leukemia, Lymphoid; Lymphocytes; Mutation; Thioguanine

Eighty two children with acute lymphoblastic leukaemia presenting at this hospital received one or two modules of intensive chemotherapy to consolidate remission. Modules were given after four and roughly 19 weeks on treatment. Each included two doses of daunorubicin (45 mg/m2/day), cytosine arabinoside (100 mg/m2 twice daily X 5), etoposide (100 mg/m2/day X 5), and 6-thioguanine (80 mg/m2/day X 5). A total of 132 courses were given. This study included all new patients except girls aged 1-14 years with presenting leucocyte count less than 20 X 10(9)/l. Twenty patients with recurrent disease were also included. The first 32 patients were given cytosine as a 24 hour infusion, but combined with the other agents this was associated with severe intestinal toxicity, which necessitated a change to a less toxic 12 hourly bolus regimen. The complications of the module are reviewed in terms of myelosuppression, enterotoxicity, infection, and other clinical problems encountered. All patients became profoundly neutropenic and thrombocytopenic. The latter was significantly more severe after cytosine infusion. Overall, 64% received platelet transfusions and 85% were re-admitted with fevers requiring intravenous antibiotics for between four and 56 days. Gastrointestinal toxicity with the modified module occurred in 38% of patients and was severe in 13%. This intensification module has been adopted by the Medical Research Council Working Party on Childhood Leukaemia for use in a multicentre study (UKALL X) and the details of the problems encountered in the pilot study may be of value to other centres now using this protocol.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Daunorubicin; Etoposide; Female; Humans; Infant; Infections; Leukemia, Lymphoid; Male; Neutropenia; Pilot Projects; Thioguanine; Thrombocytopenia

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

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

The effect of folic acid supplements on 6-mercaptopurine remission maintenance therapy in lymphoblastic leukaemia (ALL) was investigated in a retrospective longitudinal study of 10 children. Red cell concentrations of 6-thioguanine nucleotide, a cytotoxic metabolite of 6-mercaptopurine, were measured and the peripheral neutrophil count was used as an index of myelosuppression. During the control period of the study there were significant correlations between 6-mercaptopurine dose and 6-thioguanine nucleotide concentration (rs = 0.59, P less than 0.0005) and between 6-thioguanine nucleotide concentration and the peripheral neutrophil count at 14 days (rs = 0.58, P less than 0.0005). These relationships were absent when the same children were subsequently taking folate supplements. Also when taking folate supplements the children tolerated significantly more 6-mercaptopurine (P less than 0.005) for a significantly longer time (P less than 0.005) before neutropenia developed. There was no significant difference in red cell 6-thioguanine nucleotide concentration in the absence and presence of folate supplements. These findings suggest that folate supplements may interfere with remission maintenance therapy in ALL.

Topics: Adolescent; Child; Child, Preschool; Drug Therapy, Combination; Female; Folic Acid; Humans; Leukemia, Lymphoid; Leukocyte Count; Male; Mercaptopurine; Neutropenia; Neutrophils; Thioguanine

6-Mercaptopurine (6MP) pharmacokinetics and red blood cell 6-thioguanine nucleotide (TGN) concentrations were studied in 19 children receiving remission maintenance treatment for lymphoblastic leukemia. There was a high interpatient variation in all the pharmacokinetic parameters measured. The pharmacokinetic parameters measured in two children who subsequently had relapses were within the 95% confidence limits of the 17 other children. There was no difference in 6MP pharmacokinetic parameters with respect to neutropenia either after or before the study. The children who developed neutropenia 10 to 19 days after study had significantly higher TGN concentrations (U = 8; P less than 0.001) and had spent a longer time receiving reduced 6MP dosage in the 12 weeks before the study (U = 19.5; P less than 0.025). TGN concentrations are a better index of a child's ability to form active cytotoxic metabolites than 6MP dose or plasma concentrations.

Topics: Administration, Oral; Child; Child, Preschool; Erythrocytes; Humans; Infant; Kinetics; Leukemia, Lymphoid; Mercaptopurine; Thioguanine

Twenty-four poor-risk patients with acute lymphoblastic leukemia received a modified regimen of carmustine, cytarabine, cyclophosphamide, and 6-thioguanine (BACT) followed by autologous bone marrow transplantation (ABMT). Nineteen patients were in second or subsequent complete remission (CR) when treated with this regimen; 3 died early, 2 died of pneumonia in CR, 11 relapsed within 3 months (median), and 3 remain in CR with no maintenance therapy 14-24 months after ABMT. Of the 5 patients with measurable disease who were treated, 3 had CR and 1 remains in CR without maintenance therapy more than 28 months after ABMT. The toxicity of this regimen was acceptable, but late pulmonary toxic effects remain a major concern. These results are poor in terms of efficacy, and new effective methods of eradicating acute lymphoblastic leukemia in patients with poor prognosis should be investigated.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Female; Humans; Leukemia, Lymphoid; Male; Recurrence; Risk; Thioguanine; Transplantation, Autologous

Predictive capacity and clinical usefulness of the short term predictive assay (STPA) in the inductive treatment of patients with acute nonlymphoblastic leukemia (ANLL) was studied. Inductive treatment consisted of daunorubicin, arabinoside C and 6-thioguanine (TAD regimen). Leukemic cells of 20 previously untreated patients with ANLL were incubated in vitro with two doses of daunorubicin (1 microgram/ml and 10 micrograms/ml), arabinoside C (10 micrograms/ml and 100 micrograms/ml) and 6-thioguanine (10 micrograms/ml and 100 micrograms/ml). The 3H-thymidine as well as 3H-uridine uptake was measured in the treated and untreated cells. The highest predictive presence of the in vivo drug-sensitive disease was adequately reflected by the level of 3H-uridine incorporation suppression 30% of control value in the case of daunorubicin (concentration: 10 micrograms/ml) and 80% in the case of 6-thioguanine (concentration: 100 micrograms/ml). In the case of arabinoside C (concentration: 10 micrograms/ml) the limit of 3H-thymidine uptake depression was 20% of control value. It was rather difficult to define the indicative degree of precursors incorporation inhibition for prediction of the drug-resistant disease, because of low number of patients primary resistant to TAD regimen. No correlation was found between the degree of the pre-treatment DNA synthesis rates and the precursors uptake inhibition by the tested drugs.

Topics: Antineoplastic Agents; Cytarabine; Daunorubicin; Humans; Leukemia, Lymphoid; Thioguanine; Time Factors

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cyclophosphamide; Daunorubicin; Humans; Leukemia; Leukemia, Lymphoid; Mercaptopurine; Methotrexate; Prednisone; Prognosis; Risk; Thioguanine; Vincristine

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cytarabine; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Infant; Leukemia, Lymphoid; Male; Poland; Tennessee; Thioguanine

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

Twelve adults with newly diagnosed acute lymphocytic leukemia (ALL) received a combination of daunorubicin, cytarabine, and 6-thioguanine (DAT) as induction chemotherapy. Eleven patients (91%) gained complete remission (ten patients after a single course of treatment). Because DAT alone seems effective in ALL, the combination of vincristine, prednisone, and DAT could improve the complete remission rate. Moreover, the resulting early leukemic cytoreduction could enhance remission duration in adults with ALL.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Doxorubicin; Humans; Leukemia, Lymphoid; Middle Aged; Mitolactol; Prednisone; Tamoxifen; Thioguanine; Time Factors; Vincristine

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

Human T-cell hybrids with helper activity were obtained after fusion of phytohemagglutinin-activated normal human T cells with a 6-thioguanine-resistant, aminopterin-sensitive human T-cell line. This mutant line, designated CEM-T15, was derived from the human T-cell line CEM after mutagenesis with ethyl methanesulfonate. The polyethylene glycol induced fusion and the selection in hypoxanthine- aminopeterin -thymidine medium were performed by modification of standard somatic cell hybridization techniques. After fusion, the strategy for selecting hybrids consisted in screening growing cultures for the presence of cells expressing the OKT3 cell surface differentiation antigen. OKT3 was chosen because it is present in 85-95% of normal human T cells but absent from CEM-T15 cells. Thus, OKT3+ cells growing 5-7 weeks after fusion most likely represented hybrids between normal T cells (OKT3+) and continuously growing CEM-T15 cells (OKT3-). Several of the hybrids were tested for their capacity to promote pokeweed mitogen-induced antibody production by B cells. These experiments demonstrated that many of the hybrids had helper activity. Periodical testing of these uncloned hybrids for helper activity revealed functional instability, with most of the hybrids losing helper activity after 20 weeks of continuous culture. However, early and repeated cloning of the same hybrids resulted in a series of hybrid clones with helper activity still present more than 8 months after fusion. In more recent fusions, we have demonstrated that human helper hybrids producing helper factor(s) can also be obtained. These and similar hybrids with different functions will be of considerable importance in further studies of the immunobiology of human T lymphocytes.

Topics: Antigens, Surface; Bromodeoxyuridine; Cell Line; Chromosomes, Human; Clone Cells; Culture Techniques; Drug Resistance; Humans; Hybrid Cells; Leukemia, Lymphoid; Lymphocyte Activation; Mutation; T-Lymphocytes; T-Lymphocytes, Helper-Inducer; 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

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

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

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Lymphoid; Male; Prednisone; Thioguanine; Vincristine

An assay for 6-thioguanine (6-TG) nucleotide, a major metabolite of the cytotoxic drugs azathioprine, 6-mercaptopurine and 6-thioguanine in human red blood cells (RBCs) has been developed. The metabolite was not detected in RBCs when azathioprine or 6-mercaptopurine was incubated with whole blood in-vitro. The assay for intracellular 6-TG nucleotide is specific and requires 8 X 10(8) RBCs (100 microliters packed cells) for which the limit of sensitivity is 30 pmole 6-TG nucleotide. Pre-dose blood samples were obtained, 12 h after the last azathioprine dose, from 10 renal transplant recipients with stable functioning cadaver grafts on a total daily dose of 150 mg azathioprine. The mean 6-TG nucleotide concentration was 171 pmole/8 X 10(8) RBCs (s.d. = 84). The assay is also suitable for use in measuring 6-TG nucleotide in the RBCs of leukaemic children undergoing 6-mercaptopurine treatment.

Topics: Azathioprine; Erythrocytes; Guanine Nucleotides; Humans; In Vitro Techniques; Leukemia, Lymphoid; Mercaptopurine; Thioguanine; Thionucleotides

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

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

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

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

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

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

Topics: 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

6-Mercaptopurine is extensively used in the treatment of childhood lymphoblastic leukaemia to prolong the duration of remission achieved with other drugs. The response to remission maintenance therapy varies widely. We investigated the relationship between red blood cell 6-thioguanine nucleotide, a metabolite of 6-mercaptopurine, and myelosuppression in 22 children with acute lymphoblastic leukaemia in remission. The peripheral neutrophil count was used as an index of myelosuppression. 6-Mercaptopurine dose was related to 6-thioguanine nucleotide concentration (r = 0.4; P less than 0.001; n = 90; y = 18.51 + 0.36 x). Large individual variations around the regression line are observed. Neither 6-mercaptopurine dose nor 6-thioguanine nucleotide concentration was related to the neutrophil count at the time of sampling (day 0) or 7 days later. Both 6-mercaptopurine dose and 6-thioguanine nucleotide concentration correlated with the neutrophil count at day 14 (r = -0.33; P less than 0.01; n = 90 and r = -0.3; P less than 0.01; n = 90 respectively). This delay is compatible with a cytotoxic action on bone marrow stem cells. Excluding children with other, uncontrolled, potentially myelosuppressive influences the correlation between 6-thioguanine nucleotide concentration and neutropenia improved (r = -0.6; P less than 0.001; n = 37). A significant degree of neutropenia was observed by day 14 if the 6-thioguanine nucleotide concentration (day 0) was greater than 210 pmol/8 X 10(8) RBCs. The assay of 6-thioguanine nucleotide may highlight those individuals with pharmacokinetic resistance. Two children on continuous high dose 6-mercaptopurine, had low red blood cell 6-thioguanine nucleotide concentrations and neutropenia was not observed.

Topics: Adolescent; Agranulocytosis; Bone Marrow Diseases; Child; Child, Preschool; Erythrocytes; Female; Humans; Leukemia, Lymphoid; Male; Mercaptopurine; Neutropenia; Thioguanine

Topics: Child; Child, Preschool; Cytarabine; Humans; Leukemia, Lymphoid; Long-Term Care; Recurrence; Thioguanine

Twenty-five consecutive adult patients with acute lymphocytic leukaemia (ALL) all achieved complete remission, twenty-two with vincristine-prednisone, while thirteen patients also received daunorubicin (DNR). Three patients obtained remission only after treatment with cytosine arabinoside (Ara-C), 6 thioguanine (6-TG) and adriamycin (ADM). Despite central nervous system (CNS) prophylaxis by intraventricular infections via an Ommaya reservoir, 2/22 patients had a CNS relapse. The median remission duration of the whole group was 19 months. Four patients could stop therapy after 3 years. The median survival duration of all patients was 38 months. The quality of life of the patients during this chemotherapeutic regimen was good.

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

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

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

Between January 1979 and December 1980 64 children with acute lymphoblastic leukemia were treated in 9 pediatric clinics in austria according to the BFM study 76/790-protocol. For remission induction all patients received an 8 week multidrug regimen (West-Berlin ALL-protocol). High risk patients were defined according to a risk score at diagnosis and additionally treated with a 6 week reinforced reinduction protocol during the first half year after diagnosis. Maintenance therapy was stopped after about 22 months. The life table-analysis after 30 months showed a 75.5% disease free survival for the total group of patients. Compared with a control group of 228 patients treated between 1974 and 1980 in 9 different clinics in Austria according to 3 consecutive national treatment regimens (modifications of Memphis protocol VII and VIII), therapeutic results were markedly improved. After a follow-up of 36 to 90 months the overall oumulative remission rate was 37.7%. The results could be improved especially in the group of high risk patients for replase by 35% in contrast to the historical studies. A prognostic difference between low- and high risk-patients was not seen in the BFM study (84.3% vs. 69.9%). Without doubt, the marked improvement of prognosis is due to the intensification of therapy.

Topics: Antineoplastic Agents; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Doxorubicin; Drug Therapy, Combination; Female; Humans; Infant; Injections, Spinal; Leukemia, Lymphoid; Male; Mercaptopurine; Methotrexate; Prednisone; Risk; Thioguanine; Vincristine

Topics: Child; Cytarabine; Drug Therapy, Combination; Humans; Leukemia, Lymphoid; Lymphoma; Thioguanine

Clinically reversible veno-occlusive disease of the liver developed in a 23-year-old man with acute lymphocytic leukemia after 10 months of maintenance therapy with 6-thioguanine. Serial liver biopsies showed the development and resolution of intense sinusoidal engorgement. Although this disease was clinically reversible, some subintimal fibrosis about the terminal hepatic veins persisted. This case presented a unique opportunity to observe the histologic features of clinically reversible hepatic veno-occlusive disease over time, and may be the first case of veno-occlusive related solely to 6-thioguanine.

Topics: Adult; Hepatic Veins; Humans; Leukemia, Lymphoid; Liver; Male; Thioguanine; Vascular Diseases

Seventeen adult patients with previously untreated acute lymphoblastic leukaemia (ALL) were entered into a schedule of chemotherapy in which 3 combinations, each of 4 drugs, were administered in a predetermined cyclical rotation in combination with cranial irradiation and intrathecal injections of methotrexate. Of the 17 patients, 16 completed induction therapy and 15 (94%) entered remission. The only patient with T-ALL died before receiving any therapy. The median survival for all patients (17) was 22 months. Meningeal leukaemia did not occur during the haematological remission phase although 3 patients developed this complication following relapse. The authors conclude that the addition of cyclophosphamide and cytosine arabinoside to vincristine/prednisone provides excellent remission induction but the aggressive maintenance schedule employed has not led to significant long-term survival.

Topics: Adolescent; Adult; Antineoplastic Agents; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Lymphoid; Male; Mercaptopurine; Methotrexate; Middle Aged; Prednisolone; Thioguanine; Vincristine

Topics: Antineoplastic Agents; Asparaginase; Child; Child, Preschool; Cytarabine; Doxorubicin; Drug Therapy, Combination; Female; Humans; Infant; Leukemia, Lymphoid; Male; Methotrexate; Prednisone; Thioguanine; Vincristine

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

We have examined the properties of hybrid cells formed by polyethylene glycol-mediated fusion of the GRC+L-73 line of Chinese hamster ovary (CHO) cells with peripheral blood cells from patients with chronic lymphocytic leukemia (CLL) or with bone marrow cells from patients with malignant lymphoma. The results indicate that hybrid cells can be detected by their ability to form "foci" of characteristic morphology in the presence of a monolayer of parental CHO cells and that clones isolated from such foci express aspects of the differentiation status, as detected by immunologic markers, of the human parental cells.

Topics: Animals; Cell Fusion; Cricetinae; Humans; Hybrid Cells; Karyotyping; Leukemia, Lymphoid; Lymphoma; Ouabain; Receptors, Antigen, B-Cell; Temperature; Thioguanine

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

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

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

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

Two distinct cell populations with lymphoblastic and monocytic characteristics were separated and characterized by multiple cell markers in a patient with terminal transferase-positive acute acute leukemia. The clinical course and sequential cell marker studies were consistent with the interpretation of a defect at the level of a common stem cell giving rise to a terminal transferase--positive lymphoblastic cell population at diagnosis and, following initial therapy, a terminal transferase--negative monocytic population.

Topics: Adult; Cell Separation; Female; Flucytosine; Humans; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Lymphocytes; Monocytes; Nucleotidyltransferases; Prednisone; Thioguanine; Vincristine

31 adult patients (study A) with acute myelocytic leukaemia were treated for remission induction with cytosine arabinoside (ARA-C, 100 mg/m2/day) by a 7 (5) day continuous infusion. 3 (2) doses of daunorubicin (DNR, 45 mg/m2 i.v.) were added at daily intervals. For maintenance 5 day ARA-C was given monthly in sequential combination with DNR, thioguanine (TG), or ifosfamide (IFOS). 16 (52%) patients achieved complete remission (C.R.) after 1.8 (1-3) courses and 6.7 (3-10) weeks from treatment start. The median survival for responders and non-responders was 11.5 months, early death rate within 6 weeks was 3 (10%). Median remission duration was 13.5 months. Among 11 patients surving for 7-22 months 7 patients are in first remission for 5.5-20.5 months. DNR, IFOS and TG were given before the 3rd day of ARA-C infusion. In a previous group of 34 leukaemic patients and in 44 therapy courses DNA histograms of bone marrow cells using pulse cytophotometry showed marked accumulation in S-phase for 75% of courses. Also (G2 + M)-cells in the DNA distribution and thymidine pulse labelling indices were markedly increased in most cases, whereas thymidine uptake by scintillation counter was diminished and mitotic indices had not changed significantly. In now 15 patients (study B) the induction regimen was intensified by adding vincristine (VCR, 2 mg i.v.) and 3 doses of IFOS (600 mg/m2 i.v.). Preliminary results are 50% C.R. after 1,7 (1-2) courses and 6.8 (5-10) weeks from initiation of therapy. 2 patients died in the first 6 weeks.

Topics: Adolescent; Adult; Aged; Cell Movement; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Ifosfamide; Leukemia, Lymphoid; Middle Aged; Remission, Spontaneous; Thioguanine; Vincristine

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

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

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

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

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

Topics: Adolescent; Adult; Bone Marrow Cells; Bone Marrow Transplantation; Child; Cyclophosphamide; Cytarabine; Daunorubicin; Graft vs Host Reaction; Humans; Leukemia, Lymphoid; Middle Aged; Recurrence; Thioguanine; Transplantation, Homologous

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

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

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

Topics: Adolescent; Child; Child, Preschool; Cyclophosphamide; Female; Humans; Infant; Injections, Spinal; Leukemia, Lymphoid; Male; Mercaptopurine; Methotrexate; Prednisone; Thioguanine; Vincristine

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

Topics: 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

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

Twenty-three adult patients (ages greater than 15 years) and 75 children with acute lymphoblastic leukemia were treated with similar intensive, sequential cytotoxic protocols (L-2). The adult patients have lower remission rate (78%) than the children (98%). The duration of remission and the length of survival are also shorter in adults. The incidence of central nervous system (CNS) relapse in adults (27.7%) is higher than in children (7.1%) suggesting that prolonged prophylactic intrathecal methotrexate as given to the children is more effective than the schedule used for adults where intrathecal methotrexate was given only in the first 2 months of therapy. The low incidence of CNS involvement in children on the L-2 protocol compares favorably with other series reported using a combination of cranial irradiation and intrathecal methotrexate. In both adults and children there seemed to be a higher incidence of CNS involvement in patients with initial white blood cell counts greater than 25,000 cells/mm3.

Topics: Adolescent; Adult; Age Factors; Aged; Asparaginase; Brain Neoplasms; Carmustine; Child; Child, Preschool; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Infant; Injections, Spinal; Leukemia, Lymphoid; Male; Methotrexate; Middle Aged; Prednisone; Remission, Spontaneous; Spinal Neoplasms; Thioguanine; Vincristine

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

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

Between 1969-1973, 75 consecutive children under the age of 15 years with acute lymphoblastic leukemia were treated with a multiple-drug regimen (L-2). Prophylaxis for meningeal leukemia was limited to the repeated intrathecal injections of methotrexate. Seventy-four patients achieved remission; the duration of remissions could be evaluated only for 70. Relapse terminated complete remission within 1-54 months in 21 children. Four of these relapses were confined to the central nervous system. Forty-nine patients continue in complete remission from 23 to 63 months. Chemotherapy has been discontinued in 29 children, and 25 of these remain without evidence of recurrence for 2-27 months posttreatment.

Topics: Adolescent; Antineoplastic Agents; Asparaginase; Central Nervous System Diseases; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Hydroxyurea; Infant; Injections, Spinal; Leukemia, Lymphoid; Male; Methotrexate; Nitrosourea Compounds; Prednisone; Remission, Spontaneous; Thioguanine; Vincristine

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

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

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

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

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

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

The results obtained with very intensive treatment in previously untreated patients early in the disease are encouraging, and we hope will change the philosophy of most investigators that even in far advanced disease such as those with marrow metastases or multiple primary sites, one can still obtain complete regression at all tumour sites within 1 to 1 1/2 months from onset of therapy by combined treatment with multiple chemotherapeutic agents and radiation therapy to one or more sites.

Topics: Adolescent; Antineoplastic Agents; Asparaginase; Bone Neoplasms; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Hydroxyurea; Leukemia; Leukemia, Lymphoid; Lymph Nodes; Lymphoma; Male; Mediastinal Neoplasms; Methotrexate; Nasopharyngeal Neoplasms; Ovarian Neoplasms; Skin Neoplasms; Stomach Neoplasms; Thioguanine; Vincristine

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

Forty-two adults and children with previously untreated acute lymphoblastic leukaemia (ALL) were entered into a programme of chemotherapy in which three combinations, each of four drugs were administered in a predetermined cyclical rotation together with cranial irradiation and intrathecal injections of methotrexate. Forty-one patients (98%) entered remission and no patient developed neuroleukaemia. Relapse of ALL occurred in 10 patients, and three patients died during remission, while eight patients stopped treatment after two and a half years and have remained in remission for two to 26 months. Comparison of remission and survival experience in this mixed group of children and adults with the experience of children treated at Memphis and in the Medical Research Council's UKALL-I trial showed no significant differences. On the other hand, analysis by prognostic factors showed that neither age nor blast cell count at presentation had any adverse effect in patients treated in this study. No relapses occurred in nine patients with blast cell counts greater than 20 x 109/1 at presentation. This regimen is effective treatment for ALL and may be of special value in patients with poor prognoses. The regiment has not as yet proved superior for the treatment of children with ALL who do not have adverse prognostic features.

Topics: Adolescent; Adult; Antineoplastic Agents; Asparaginase; Blood Cell Count; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Lymphoid; Male; Methotrexate; Prednisolone; Prognosis; Remission, Spontaneous; Thioguanine; Vincristine

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

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

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

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

Topics: Adolescent; Age Factors; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cytarabine; Drug Therapy, Combination; Female; Humans; Infant; Leukemia, Lymphoid; Leukopenia; Liver; Liver Function Tests; Male; Remission, Spontaneous; Thioguanine; Thrombocytopenia

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

Topics: Administration, Oral; Adolescent; Age Factors; Antineoplastic Agents; Asparaginase; Carmustine; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Follow-Up Studies; Humans; Hydroxyurea; Infant; Infections; Injections, Intravenous; Leukemia, Lymphoid; Male; Meningitis; Methotrexate; Prednisone; Remission, Spontaneous; Thioguanine; Vincristine

Topics: Adenine; Alkaline Phosphatase; Drug Resistance; Guanine; Humans; Hypoxanthines; Leukemia; Leukemia, Lymphoid; Lymphocytes; Mercaptopurine; Pentosyltransferases; Thioguanine

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: Animals; Cell Division; Cell Line; Cell Survival; Inosine; Leukemia, Experimental; Leukemia, Lymphoid; Mercaptopurine; Mice; Purine Nucleotides; Sulfides; Thioguanine; Thymidine

Topics: Animals; Antimetabolites; Cell Line; Cell Survival; Deoxyribonucleosides; Deoxyribonucleotides; DNA, Neoplasm; Drug Synergism; Drug Tolerance; Guanine Nucleotides; Guanosine; Inosine; Leukemia, Experimental; Leukemia, Lymphoid; Mercaptopurine; Mycophenolic Acid; Ribonucleotides; RNA, Neoplasm; Stimulation, Chemical; Sulfides; Sulfur Radioisotopes; Thioguanine

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

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

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

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

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

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

Topics: Adolescent; Blood Cell Count; Bone Marrow Examination; Cytarabine; Eosinophilia; Female; Humans; Karyotyping; Leukemia, Lymphoid; Mercaptopurine; Mycoses; Sulfamethoxazole; Thioguanine; Trimethoprim; Vincristine

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

Topics: Administration, Oral; Adolescent; Adult; Asparaginase; Child; Child, Preschool; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Injections, Intravenous; Injections, Spinal; Leukemia, Lymphoid; Methotrexate; Prednisone; Remission, Spontaneous; Thioguanine; Vincristine

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

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

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

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

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

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

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

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

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

Topics: Animals; Antibiotics, Antineoplastic; Asparaginase; Asparagine; Carmustine; Cell Line; Child, Preschool; Cytarabine; Dactinomycin; Drug Resistance; Drug Synergism; Female; Half-Life; Humans; Leukemia, Experimental; Leukemia, Lymphoid; Mice; Neoplasm Proteins; Podophyllin; Pyridines; Stereoisomerism; Thioguanine; Thiosemicarbazones; Time Factors; Tritium; Valine

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

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

Topics: Adolescent; Antineoplastic Agents; Blood; Child; Complement System Proteins; Cyclophosphamide; Humans; Leukemia; Leukemia, Lymphoid; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Serologic Tests; Spectrophotometry; Thioguanine

Topics: Blood Cell Count; Blood Chemical Analysis; Bone Marrow Examination; Chromium Isotopes; Erythrocytes; Hemoglobinometry; Imidazoles; Insecticides; Iron; Iron Isotopes; Leukemia; Leukemia, Lymphoid; Lymphocytes; Organophosphate Poisoning; Paint; Phosphorus; Poisons; Thioguanine; Toxicology

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