mercaptopurine and Meningeal-Neoplasms

Topics: Adolescent; Adult; Asparaginase; B-Lymphocytes; Bacterial Infections; Child; Child, Preschool; Chromosome Aberrations; Chromosome Disorders; Diagnosis, Differential; Drug Therapy, Combination; Female; Humans; Infant; Leukemia; Leukemia, Lymphoid; Leukocyte Count; Male; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Prednisolone; T-Lymphocytes; Testicular Neoplasms; Vincristine

A multicenter prospective study was conducted in 114 children with acute lymphoblastic leukemia receiving 4 intravenous methotrexate (MTX) courses (5 g/m2 as a 24 hour-infusion) to determine the diffusion of MTX in cerebrospinal fluid (CSF) and to correlate the drug levels to central nervous system (CNS) relapse occurrence. Serum and CSF levels were measured at the end of 446 MTX courses. A significant correlation was found between CSF and serum MTX concentration. CSF MTX level was greater than 1 mumol/l in 66% of the courses. Twelve patients (11%) failed to achieve this potentially cytotoxic drug level at the end of the 4 consecutive MTX courses: only one CNS relapse was observed and the mean age of these children was lower than that of the others. To date 9 (7.8%) children had CNS relapse and no difference was observed in terms of CSF MTX levels when compared to data of children free of CNS relapse. With a median follow up of 32 months, pharmacokinetic data during high-dose MTX therapy do not seem to be an exclusive predictive factor of CNS relapse.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Blood-Brain Barrier; Child; Child, Preschool; Cytarabine; Female; Follow-Up Studies; Humans; Infant; Infusions, Intravenous; Leucovorin; Male; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Risk Factors

Using the CCLSG-S811 protocol for children with standard-risk acute lymphoblastic leukemia (ALL), late intensification therapy (LIT) with high-dose methotrexate (HD-MTX) was conducted without randomization. Of 118 eligible patients, 114 attained complete remission and 82 maintained continuous complete remission (CCR) for at least 3 years, completing the entire S811 regimen. Among the latter, 74 patients received LIT with HD-MTX between 2-3 years after CCR onset. MTX (2,000 mg/m2 per dose per week) was administered by 24 h infusion and three doses were given every 12 weeks. Leucovorin rescue (15 mg/m2 i.v.) every 6 h was initiated 12 h after the end of MTX infusion for seven doses. As regular maintenance chemotherapy, intermittent (Regimen A) or continuous (Regimen B) MTX plus 6-mercaptopurine (6MP) combined with pulses of prednisolone and vincristine was administered (Koizumi S, Fujimoto T, Takeda T, et al. Cancer 1988; 61: 1292-1300). Retrospective analysis revealed that patients on Regimen A who started LIT earlier (within 2 years of CCR onset (n = 23)) showed a higher rate of event-free survival (EFS) at 8 years (95.5% +/- 4.4%, mean +/- S.E.) than patients who started LIT later (2.5 years after CCR onset (n = 18, 66.2% +/- 11.3%, p less than 0.01)). In addition, the superiority of four or five courses of the LIT (n = 39) as compared to 2 or 3 courses (n = 35) was noted for both regimens. The data suggest that early and aggressive LIT with HD-MTX may improve the long-term survival of childhood ALL patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cranial Irradiation; Humans; Infant; Leucovorin; Life Tables; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Retrospective Studies; Survival Rate; Vincristine

For over 30 years, oral 6-mercaptopurine (6-MP) has been a mainstay of systemic maintenance therapy for acute lymphoblastic leukemia. Despite its efficacy as an antileukemic agent, 6-MP has not been previously administered by the intrathecal (IT) route. In anticipation of a clinical trial of IT 6-MP, preclinical cytotoxicity and pharmacology studies were performed to define a safe, effective dose. The optimal concentration (greater than 1 microM) and duration of exposure (greater than 12 h) to 6-MP required for cytotoxicity were determined in vitro using human leukemia cell lines. The dose required to achieve the desired cerebrospinal fluid concentrations in humans was derived from pharmacokinetic parameters determined in rhesus monkeys. A phase I/II study was then performed in pediatric patients with refractory meningeal leukemia. Nine patients (aged 3.5 to 16 years) with chronic meningeal leukemia (2 to 6 central nervous system relapses) were entered onto the study. All had previously failed, at a minimum, IT methotrexate, IT cytarabine, and cranial (+/- spinal) radiation. A 10-mg IT dose of 6-MP (calculated to produce cytotoxic cerebrospinal fluid levels for 12 h) was administered twice weekly for 4 weeks. There were four complete responses and three partial responses. The duration of complete responses ranged from 7 to 22 weeks. Observed toxicities were not dose limiting and included mild headache (three patients) and minimal nausea (two patients). Pharmacokinetic studies performed in patients confirmed that cerebrospinal fluid concentrations of 6-MP were greater than 1 microM for 12 h. These results indicate that the IT administration of 6-MP is feasible, is not associated with significant toxicity, and has definite activity in patients with refractory meningeal leukemia.

Topics: Adolescent; Animals; Child; Child, Preschool; Drug Evaluation; Female; Humans; Injections, Spinal; Leukemia; Lymphoma, Non-Hodgkin; Macaca mulatta; Male; Meningeal Neoplasms; Mercaptopurine; Tumor Cells, Cultured

229 children with acute lymphoblastic leukaemia (ALL) and with clinical and laboratory features associated with a high risk of treatment failure entered a randomised study of three treatment regimens. Before 1981, such patients had a 3-year event-free survival (EFS) of 47%. Two intensive therapies, the Berlin-Frankfurt-Munster (BFM) 76/79 regimen and the New York (NY) regimen were compared with a control regimen that had achieved the best outcome in previous Trials. Data on 214 cases (93.4%) were analysed. The 3-year EFS was 78% for the BFM and NY regimens and 49% for the control regimen, a significant difference. The differences persisted after stratification by age at onset, sex, white blood cell count at diagnosis, and marrow blast morphology. Control patients were 2.7 times more likely to fail induction, to die, or to relapse than were patients on the intensive regimens.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Drug Combinations; Female; Humans; Infant; Male; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Radiotherapy Dosage; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Between 1972-1977, 92 patients with acute lymphoblastic leukemia, between 0 and 14 years of age, were treated with C2-72 and D-74 protocols. Induction treatment consisted of prednisolone (PRED)-vincristine (VCR) with the addition of daunorubicin (prot. C2-72) or asparaginase (prot. D-74). In both protocols, preventive therapy on the CNS consisted of cranial irradiation (24 Gy) and 5 doses of methotrexate i.t. (MTX). For the maintenance phase in protocol C2-72, three combinations: mercaptopurine (MP)-MTX, MP-Ara.C and MTX-cyclophosphamide, were sequentially administered for 3 years, with reinductions of PRED-VCR every three months. In protocol D-74, only MP-MTX was used for 3 years; the random half of the patients also received "reinductions". In protocol C2-72, BCG was administered by scarifications for 2 years to patients in remission after 36 months; in D-74, the random-half patients received BCG and irradiated allogeneic blasts for one year. The other half of the patients received no other treatment. The overall disease-free survival rate is 45.6% with a duration of between 84 and 156 months. Only one death occurred after 7 years. In protocol C2-72, 9 of 26 initial patients (34.6%) and in protocol D-74, 33 of 66 initial patients (50%) are still alive, off treatment and with no sign of disease. Ten patients (10.8%) died in continuous remission of infection (8) or toxic encephalopathy (2); five deaths were caused by "Pn. carinii". The incidence of meningeal relapse was 11% and isolated testicular relapse in males 15.7%; moreover, in 6 of the 22 boys in remission, programmed testicular biopsy showed interstitial leukemic infiltrates. Analysis of initial risk factors permitted the establishment of a risk index (r.i.): in cases with a r.i. below 3 (76% of cases) the survival rate was 53%; in the group with a higher r.i. (24%), it was 22%. Further conclusions of this study were: the lack of effectivity of "reinductions" and immunotherapy and proof of a higher rate of relapses in males mainly owing to isolated testicular relapse.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; BCG Vaccine; Child; Child, Preschool; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Immunotherapy; Infant; Infant, Newborn; Leukemia, Lymphoid; Male; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Prednisolone; Random Allocation; Testicular Neoplasms; Vincristine

The meninges are a unique site of recurrence for certain malignancies because of the limited penetration of systemically administered cytotoxic drugs across the blood-brain barrier. While this phenomenon was first recognized in children with acute lymphoblastic leukemia, a similar pattern is also occurring in breast cancer, ovarian cancer, and small cell lung cancer. Recognition of the limitations of standard systemic antileukemic therapy for the treatment of meningeal disease led to the development of new therapeutic strategies targeted directly at the CNS. These include intralumbar therapy using methotrexate or cytarabine, intraventricular chemotherapy, and high-dose systemic drug administration. New agents showing promise are intrathecal diaziquone, 6-mercaptopurine, and mafosfamide.

Topics: Adolescent; Adult; Antineoplastic Agents; Aziridines; Benzoquinones; Blood-Brain Barrier; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Humans; Infant; Infant, Newborn; Leukemia; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Thiotepa

In three children receiving oral remission maintenance therapy for acute lymphoblastic leukemia, the concentrations of 6-mercaptopurine (6-MP) in cerebrospinal fluid (CSF), plasma and red blood cells were compared. CSF samples were obtained from an Ommaya reservoir previously inserted for treatment of CNS relapse. At the time of the study, the children were all in remission and had been on oral 6-MP (42-63 mg m-2) once daily for at least 24 weeks. Immediately before dose intake on the day of study (about 24 h after last dose), the concentrations of 6-MP in CSF, plasma and red blood cells were rather similar and below 20 ng ml-1 in all patients. After dose intake, the concentrations in plasma and in red blood cells increased to 40-200 ng nl-1 within 0.5-4 h. In contrast, the concentration of 6-MP in the CSF remained fairly constant around 4-10 ng ml-1 throughout the time period studied (up to 4 h). It is concluded that 6-MP can be detected in CSF during oral maintenance therapy and that the drug has different pharmacokinetic profile in CSF to that in plasma and red blood cells. Further studies are necessary to evaluate the significance of the 6-MP concentrations obtained in CSF for the prevention of CNS relapse.

Topics: Administration, Oral; Child; Erythrocytes; Female; Humans; Leukemia, Lymphoid; Male; Meningeal Neoplasms; Mercaptopurine; Remission Induction

20 consecutive adult patients with acute lymphoblastic leukemia were treated with an intense induction regimen including vincristine, doxorubicin, prednisolone, L-asparaginase and cyclophosphamide. 16 patients (80%) achieved complete remission and were then given CNS prophylaxis and 3 years of maintenance therapy. With minimum follow-up of 24 months, the median duration of first remission is 37+ months. Out of 10 patients who have completed maintenance therapy, 2 have relapsed after 14 and 22 months, respectively, and 7 are in continuous complete remission 1+-55+ months off therapy.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Blood Transfusion; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Evaluation; Humans; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Middle Aged; Nervous System Diseases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Combined Modality Therapy; Cranial Irradiation; Cytarabine; Daunorubicin; Doxorubicin; Humans; Hydrocortisone; Leukemia, Monocytic, Acute; Male; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Prednisone; Remission Induction; Testicular Neoplasms; Thioguanine

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

The widespread use of neurosurgical devices for intraventricular drug delivery has led to an escalation in the number of CSF pharmacokinetic studies. When experimental data for ventricular CSF concentration vs. time are normalized for dose and plotted for drugs with a wide range of physical properties, there is a remarkably narrow range. Simulations from a distributed model for the central nervous system suggest that the narrow range of observed CSF half-times following bolus administration is a consequence of physiologic limits upon rate of drug removal from CSF. Whereas bulk flow of CSF establishes minimum rate of drug washout, diffusion through brain tissue and subsequent removal by capillaries establishes a maximum rate of drug egress which is only seven times the minimum rate. Predictions of CSF concentration vs. time can be made based upon the capillary exchange rate for a particular drug, which could be estimated or calculated from CSF concentration measurements following systemic administration. Simulations are also presented of steady-state CSF concentrations during continuous ventricular infusions.

Topics: Animals; Antineoplastic Agents; Blood-Brain Barrier; Cisplatin; Haplorhini; Humans; Injections, Intraventricular; Kinetics; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Models, Biological

One hundred four children with acute lymphoblastic leukaemia were diagnosed at the University Hospital, Kuala Lumpur, Malaysia, between 1976 and 1982; 87 were evaluable with respect to treatment. They were divided into good prognosis (GP) and bad prognosis (BP) groups based on their initial total white cell count, their treatment differing only during the maintenance phase. Remission was achieved in 82 patients (94%) of whom ten (12%) subsequently died in remission from infection. Twenty-eight (34%) relapsed while on treatment and three while off therapy. Eleven patients ceased treatment after 3 yr of continuous complete remission (CCR). Three of these later relapsed, two within the first year. Survival in CCR was significantly better in the GP group up to 30 months, after which the difference diminished. There was no difference in survival between boys and girls. The overall disease-free survival at 3 yr and 5 yr was 40% and 25%, respectively, with a median follow-up period of 20 months (range 4-69 months). The reasons for the relatively low survival rates as compared with those in developed countries are discussed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Doxorubicin; Female; Humans; Leukemia, Lymphoid; Male; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Prednisolone; Prognosis; Vincristine

Sixty-two adult patients with acute lymphoblastic leukemia (ALL) were treated with an induction regimen including vincristine, daunorubicin and prednisone (VDP) followed by CNS prophylaxis. Forty-five patients (72.5%) achieved complete remission (CR). The CR were maintained with daily 6-MP and weekly MTX. Monthly reinduction cycles with vincristine and prednisone (plus daunorubicin every three courses) were also given. Median duration of CR was 10.4 months. Overall survival was 17.4 months. The remission rate and length of CR were studied in relation to the clinical and hematological features present at diagnosis. CR rate was adversely influenced by age only over 40 and by tumoral presentation. The length of remission was negatively influenced by tumoral presentation, CNS involvement, high circulating blast count, L2 and L3 cytology, and T or B immunological phenotype. Multiple regression analysis confirmed the weight of FAB morphology in determining the length of remission. Among L2 adult patients, tumoral presentation appears to be the major unfavourable prognostic factor.

Topics: Adolescent; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Lymphoid; Male; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Middle Aged; Prednisone; Vincristine

Children with acute lymphoid leukemia (ALL) were treated according to two protocols. A group of 65 patients in which prognostic factors were no taken into account were treated with a combination of vincristine, asparaginase and prednisone to induce remission, followed by neuromeningeal prophylaxis with intraraquideal methotrexate and cranial irradiation with 2400 rads, two years maintenance therapy with 6-mercaptopurine and methotrexate, and then reinforcing chemotherapy, BCG scarification and injection of irradiated leukemic cell. No relapses were observed in the first 4.5 years. After 7.5 year, general survival was of 60 per 100, with 44 per 100 disease-free. A group of ALL children having a good prognosis were treated as indicated but adding adriamycin during the induction of remission and vindesine during the maintenance period. During the first three years no relapses were seen, and the general survival was 82 per 100, including a high proportion of disease-free children.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; BCG Vaccine; Child; Combined Modality Therapy; Doxorubicin; Humans; Leukemia, Lymphoid; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Prednisone; Prognosis; Vincristine; Vindesine

This is a review of the progress achieved in the treatment of acute lymphoblastic leukaemia, based on a series of 1580 children treated in Prof. Jean Bernard's unit, Paris, from 1956 to 1976. The children are retrospectively divided into three prognostic classes and five therapeutic categories. The benefits obtained from successive additions to the therapeutic armentarium during that period are conspicuous in all classes and categories and particularly striking in children with poor initial prognosis. The role of each component of the therapeutic measures applied is discussed.

Topics: Adolescent; Child; Child, Preschool; Cyclophosphamide; Daunorubicin; Humans; Infant; Leukemia, Lymphoid; Male; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Prednisone; Testicular Neoplasms; Vincristine

55 children suffering from acute lymphoblastic leukemia were treated wih prednisone, vincristin-sulfate, daunorubicine and L-asparaginase (1st month), 6-mercapto-purine, cytosine-arabinoside. cyclophospamide, methotrexate-i.th. and cranial irradiation (2nd month). Maintenance-therapy comprised 6-mercapto-purine, cyclophosphamide and methotrexate-i.v. Serial EEG-examination were done in most of them during the course of treatment. 4 children presented with meningeal leukemia at the time of diagnosis. Their EEGs showed moderate slowing before treatment and at the end of the first month. One of them suffered a focal convulsion two days after the last VCR/daunorubine-injection. All EEG-changes were completely reversible later on. 3 patients showed severe focal EEG-disturbances and convulsions during serious neurological complications (intracranial bleeding, rubella-encephalitis). The remaining patients were free of complications at the time of the EEG-examination. Before therapy 24% of them presented normal findings, 57% slightly and 19% moderately abnormal EEGs. At the end of the first month there was an increase of moderate and severe EEG-slowing to 37% and 23%, only 11% of findings were normal. Improvement during the second month of therapy led to 37% normal and 57% slightly abnormal EEG-findings at its end. After maintenance-therapy of 1/2--1 year duration there were 65% normal EEGs and no moderate and severe disturbances any longer. Quantitative spectral analysis of the EEG in 6 additional children revealed similar changes.

Topics: Adolescent; Asparaginase; Berlin; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Electroencephalography; Germany, West; Humans; Infant; Leukemia, Lymphoid; Male; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Prednisone; Registries; Vincristine

Acute lymphoblastic leukaemias which are, at the present time, curable are those which go 01.cfhçinto remission following treatment with the combination prednisone-vincristine, in which lymphoblastic meningitis does not occur after preventive treatment of the central nervous system and which show no recurrence during maintenance chemotherapy. In order that the largest possible number of these potentially curable patients may be transformed into truly cured cases, we propose here a simple outline of treatment: induction of remission by one month of treatment with prednisone 40 mg/m2/day and vincristine 1.5 mg/m2/week, immediately followed by treatment of the central nervous system: 2 400 rads to the brain down to C2 in two weeks and an half and 6 injection (2 per week) of intrathecal methotrexate 5 mg/m2/injection and maintenance chemotherapy for two years with 6 MP, 25 to 50 mg/m2/day and parenteral methotrexate, 10 to 15 mg/m2/week, then immunotherapy with BCG, for a minimum of three years and a maximum of five.

Topics: BCG Vaccine; Daunorubicin; Drug Administration Schedule; Drug Therapy, Combination; Humans; Immunotherapy; Injections, Spinal; Leukemia, Lymphoid; Long-Term Care; Lymphocytes; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Mycobacterium bovis; Prednisone; Remission, Spontaneous; Vincristine