mercaptopurine and Central-Nervous-System-Neoplasms

The regimen of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) has demonstrated significant activity in adult lymphocytic leukemia (ALL) and in other hematologic malignancies, including Burkitt's disease, lymphoblastic lymphoma, mantle cell lymphoma, and multiple myeloma. This article presents the rationale for the development of this regimen, describes the program, summarizes the results of the large clinical trials developed at the University of Texas M. D. Anderson Cancer Center, and discusses strategies to improve the results.

Topics: Adolescent; Adult; Aged; Anti-Infective Agents; Antibiotic Prophylaxis; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Central Nervous System Neoplasms; Child; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Doxorubicin; Drug Administration Schedule; Granulocyte Colony-Stimulating Factor; Humans; Immunization, Passive; Immunophenotyping; Infusions, Intravenous; Injections, Spinal; Karyotyping; Mercaptopurine; Methotrexate; Middle Aged; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Risk; Rituximab; Survival Analysis; Texas; Treatment Outcome; Vincristine

Prophylactic cranial irradiation has been a standard treatment in children with acute lymphoblastic leukemia (ALL) who are at high risk for central nervous system (CNS) relapse.. We conducted a clinical trial to test whether prophylactic cranial irradiation could be omitted from treatment in all children with newly diagnosed ALL. A total of 498 patients who could be evaluated were enrolled. Treatment intensity was based on presenting features and the level of minimal residual disease after remission-induction treatment. The duration of continuous complete remission in the 71 patients who previously would have received prophylactic cranial irradiation was compared with that of 56 historical controls who received it.. The 5-year event-free and overall survival probabilities for all 498 patients were 85.6% (95% confidence interval [CI], 79.9 to 91.3) and 93.5% (95% CI, 89.8 to 97.2), respectively. The 5-year cumulative risk of isolated CNS relapse was 2.7% (95% CI, 1.1 to 4.3), and that of any CNS relapse (including isolated relapse and combined relapse) was 3.9% (95% CI, 1.9 to 5.9). The 71 patients had significantly longer continuous complete remission than the 56 historical controls (P=0.04). All 11 patients with isolated CNS relapse remained in second remission for 0.4 to 5.5 years. CNS leukemia (CNS-3 status) or a traumatic lumbar puncture with blast cells at diagnosis and a high level of minimal residual disease (> or = 1%) after 6 weeks of remission induction were significantly associated with poorer event-free survival. Risk factors for CNS relapse included the genetic abnormality t(1;19)(TCF3-PBX1), any CNS involvement at diagnosis, and T-cell immunophenotype. Common adverse effects included allergic reactions to asparaginase, osteonecrosis, thrombosis, and disseminated fungal infection.. With effective risk-adjusted chemotherapy, prophylactic cranial irradiation can be safely omitted from the treatment of childhood ALL. (ClinicalTrials.gov number, NCT00137111.)

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Central Nervous System Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Daunorubicin; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Infant; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Risk Factors; Secondary Prevention; Survival Analysis; Treatment Outcome; Vincristine

Pediatric Oncology Group (POG) protocol 9201 enrolled children with lesser-risk B-lineage acute lymphoblastic leukemia (ALL) defined by age (1-9), white blood cell count (WBC) less than 50 x 10(9)/L (50,000/microL), DNA findings of trisomies 4 and 10 (or DNA index > 1.16), and lack of overt central nervous system (CNS) leukemia. After vincristine, prednisone, and asparaginase induction, 650 of 653 eligible patients attained remission (3 induction deaths) and received 6 courses of intravenous methotrexate (1 g/m(2)) with daily mercaptopurine. Weekly intramuscular methotrexate was added during maintenance; pulses of vincristine and prednisone were administered with periodic intrathecal chemotherapy. Treatment duration was 2.5 years. No alkylators, epipodophylotoxins, anthracyclines, or radiation were given. The 6-year event-free survival (EFS) was 86.6% with overall survival (OS) of 97.2%. Patients with less than 5% marrow blasts on induction day 15 had superior EFS. A difference not reaching conventional statistical significance (P = .068) was noted for superior outcomes in patients with trisomies of chromosomes 4 and 10 versus those lacking double trisomies. Sex, ethnicity, CNS status, and WBC were not predictive. This indicates the great majority of children with lesser-risk B-lineage ALL are curable without agents with substantial late effects.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; B-Lymphocytes; Cell Lineage; Central Nervous System Neoplasms; Child; Child, Preschool; Disease-Free Survival; Female; Humans; Infant; Infusions, Intravenous; Injections, Intramuscular; Injections, Spinal; Male; Mercaptopurine; Methotrexate; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Treatment Outcome; Vincristine

Between January 1989 and July 1995, a prospective study of the therapeutic efficacy of the LALA 87 protocol in adult acute lymphoblastic leukaemia (ALL) has been conducted.. A total of hundred and twelve patients with ALL have been analysed. The median age of the patients was 40 years (range: 15-65), the gender ratio (M/F) was 66/46, and the morphologic FAB (French-American-British) profile was L1 in 30 (26.9%) patients, L2 in 71 (63.3%) and L3 morphology in 11 (9.8%) of the patients. The LALA 87 protocol includes five phases: induction, consolidation, reinforcement, maintenance and central nervous system (CNS) prophylaxis with intrathecal methotrexate and irradiation. The induction phase comprised daunorubicin 50 mg/m(2) (days 1-3), cyclophosphamide 600 mg/m(2) (days 1 and 8), vincristine 1.5 mg/m(2) (on days 1, 8, 15 and 22) and daily oral prednisone on days 1-21. Maintenance therapy was given for 2 years and consisted of different drugs as reinforcement, daily 6-mercaptopurine and weekly methotrexate.. Complete remission (CR) was achieved in 81 (72.3%) of the patients. The causes of induction failure were partial response in 10 (8.9%), and hypoplastic death in 12 patients (10.7%), and 9 were non-responders (8.0%). Of the 81 patients who achieved CR, 62 relapsed (76%). Among the relapsed patients, 9 developed CNS disease in spite of CNS prophylaxis during induction chemotherapy. Median follow-up for the living patients was 110 months. Median disease-free survival (DFS) was 16 months; 19 patients are still in remission with an estimated 10-year DFS (24%). Adverse prognostic factors were >50 years of age, immunologic subtype and cytogenetic profile.. The results support the strategy of applying more effort and other treatment modalities in the therapy of ALL.

Topics: Administration, Oral; Adolescent; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Cyclophosphamide; Daunorubicin; Disease-Free Survival; Female; Humans; Infusions, Intravenous; Male; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Treatment Outcome; Vincristine

This trial evaluated the toxicity and preliminary efficacy of a repeated oral low dose (LD) methotrexate schedule with intravenous mercaptopurine infusions as intensification therapy for children with lower risk B-lineage acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS. From December 1986 to January 1991, 96 children with newly diagnosed, lower risk ALL were enrolled. Vincristine, L-asparaginase, and prednisone were used for remission induction. Age-based methotrexate was administered intrathecally (IT) for central nervous system (CNS) prophylaxis. An outpatient-based intensification treatment included LD methotrexate 30 mg/M2 every 6 hours for 5 doses, followed by intravenous mercaptopurine 1000 mg/M2 for 6 hours every 2 weeks for 12 courses. Leucovorin rescue was administered 48 hours after methotrexate treatment was begun. Maintenance therapy included standard daily oral mercaptopurine, weekly intramuscular methotrexate, and IT methotrexate every 12 weeks, for 2 years.. All patients had disease remission. Thirty-two patients relapsed; there were 17 isolated bone marrow relapses, 10 isolated CNS relapses, 2 isolated testicular relapses, 1 marrow plus CNS relapse, 1 marrow plus testicular relapse, and 1 CNS plus testicular relapse. Event free survival (EFS) at 4 years was 66% (standard error, 7%) by Kaplan-Meier analysis. Complications associated with LD methotrexate/mercaptopurine courses were few and resulted in hospital readmissions in 2.4% of courses. Two patients were unable to comply with the oral LD methotrexate schedule and received intravenous methotrexate. Three patients were unable to complete scheduled maintenance because of hepatic or hematopoietic dysfunction.. Low dose methotrexate/mercaptopurine can be administered safely on an outpatient basis to children with lower risk B-lineage ALL. However, there was a higher than expected incidence of bone marrow and CNS relapse. The reasons for this outcome were not completely clear but raise the possibility that LD methotrexate therapy may be less effective in preventing relapse than are higher dose, parenteral methotrexate regimens.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; B-Lymphocytes; Central Nervous System Neoplasms; Child; Disease-Free Survival; Female; Humans; Infusions, Intravenous; Injections, Intramuscular; Injections, Spinal; Male; Mercaptopurine; Methotrexate; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Treatment Outcome; Vincristine

Seventy-three patients with Stage III abdominal non-Hodgkin's lymphoma were prospectively treated following two sequential protocols (P): L278 P (group A, 33 patients) (1978-1983) and L384 P (group B, 40 patients), (1984-1991). No patient received radiotherapy. The L278 P included 7 drugs: cyclophosphamide, vincristine (VCR), adriamycin (ADR), prednisone, methotrexate (MTX), dexamethasone, and 6-mercaptopurine, given for remission induction, maintenance, and CNS prophylaxis. In the L384 P we introduced a consolidation phase consisting of intravenous MTX and citrovorum factor rescue, and IV cytosine arabinoside. VCR was also added to the monthly doses and the maintenance phase was reduced from 18 to 15 months. From January 1988 we changed ADR for epirubicin in the same doses. Prophylactic treatment of the CNS, in the L384 P, was intensified by increasing the number of doses of MTX IT in the remission, induction, and consolidation phases, and with the use of ara-C IT. Laparotomy in 50 patients allowed partial resection in 16, and second-look laparotomy was performed in 27 patients. Viable tumor was found in four patients. Three patients (G-A) died from metabolic complications and another 4 (2 G-A and 2 G-B) failed to attain CR and died. A total of 28 (85%) of 33 children of G-A and 38 (95%) of 40 children in G-B achieved CR. Five children died in remission (2 G-A, 3 G-B). Three patients (G-A) relapsed in the CNS and one (G-B) relapsed in the abdomen and died. Disease-free survival at 120 months was 70% in G-A and 84% in G-B.

Topics: Abdominal Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Child; Child, Preschool; Costa Rica; Cyclophosphamide; Cytarabine; Dexamethasone; Doxorubicin; Female; Humans; Infusions, Intravenous; Leucovorin; Life Tables; Lymphatic Metastasis; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Prednisone; Prospective Studies; Remission Induction; Survival Rate; Vincristine

Central nervous system (CNS) involvement is rarely observed in acute promyelocytic leukemia (APML). Most cases of CNS involvement occur at relapse rather than at presentation. Because of the extremely low incidence of CNS disease, diagnostic lumbar puncture is not routinely required and prophylactic intrathecal chemotherapy is not routinely administered. Here, we describe a teenage patient with newly diagnosed APML, chloromas, and symptomatic CNS involvement confirmed by MRI and cerebrospinal fluid (CSF) findings.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Combined Modality Therapy; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Promyelocytic, Acute; Leukemic Infiltration; Mercaptopurine; Methotrexate; Oncogene Proteins, Fusion; Radiotherapy; Sarcoma, Myeloid; Tretinoin

Since 01.07.1993 to 30.09.2002, 640 children (48.2% girls and 51.8% boys) with ALL-SR were diagnosed and treated according to the modified ALL-BFM 90 protocol. In 29 children the treatment was intensified because of poor corticosteroid response. Subject to statistical analysis (Kaplan-Meier method) were thus 611 children with ALL-SR. Among them, 89 patients failed to respond to therapy: 10 (1.6%) early deaths, 15 (2.5%) deaths during I complete remission, 64 (10.5%) relapses. Relapses occurred: 45 (7.4%) in bone marrow, 11 (1.8%) in central nervous system, 4 (0.7%) in testicular and in 4 (0.7%) children combined relapses were observed. Probability rates for 9-year event free survival (EFS) and relapse free survival (RFS) for all patients were 0.77 (0.02) and 0.79 (0.02), respectively. Application of high dose of methotrexate is effective in prevention of relapses, especially meningeal and testicular involvement.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow; Bone Neoplasms; Central Nervous System Neoplasms; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Infant; Infant, Newborn; Male; Mercaptopurine; Methotrexate; Poland; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Remission Induction; Retrospective Studies; Risk Factors; Secondary Prevention; Survival Analysis; Testicular Neoplasms; Time Factors; Treatment Outcome; Vincristine

Topics: Alleles; Antimetabolites; Central Nervous System Neoplasms; Child; Germany; Humans; Incidence; Mercaptopurine; Methyltransferases; Neoplasms, Radiation-Induced; Neoplasms, Second Primary; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma

We conducted a retrospective study of 32 patients with histologically confirmed primary central nervous system lymphoma treated in our institute between 1971 and 1995 with an emphasis on the role of chemotherapy. Thirty of the 32 patients underwent tumor resection, whereas 2 patients had biopsies only. Twenty-eight patients received adjuvant therapy, 9 of whom received radiation therapy alone, 2 received chemotherapy alone, and 17 received both radiation therapy and chemotherapy. Chemotherapies performed were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone). VEMP or VENP (vincristine, cyclophosphamide, mercaptopurine [or Natulan], and prednisolone), intravenous ACNU (nimustine), and intravenous or intra-arterial MCNU (ranimustine) and CBDCA (carboplatin). Survival data were available for 30 of the 32 patients. The median survival time of this study was 12.5 months. Twenty-seven patients died from one month through 79 months after the initiation of therapy, and 3 patients were alive for 13 to 69 months. Two patients who received the combination of radiation therapy and chemotherapy survived longer than 5 years. Although radiation therapy and chemotherapy were individually both effective and prolonged the survival time, their combination was more effective. The median survival time was significantly shorter (7.0 vs 16.5 months, p < 0.05) for the patients who received radiation therapy alone than for the patients who received the combination of radiation therapy and chemotherapy. We conclude from our results and review of previous studies that it is important for the chemotherapy of primary central nervous system lymphoma 1) to apply a combination of a variety of effective drugs, similar to that for systemic malignant lymphoma, and 2) to make a sufficient amount of anti-cancer drugs penetrate the whole central nervous system, thereby satisfying the adequate dose intensity for each drug.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Lymphoma; Male; Mercaptopurine; Middle Aged; Nimustine; Prednisolone; Prednisone; Procarbazine; Survival Rate; Vincristine

A 61-year-old man with multiple subcutaneous, ileocecal and neurologic manifestations was reported. Histological examination of subcutaneous and ileocecal mass showed non-Hodgkin's lymphoma (diffuse medium cell type [LSG classification]), B-cell type. Headache, somnolence and incontinence of urine were considered owing to the CNS involvement by lymphoma cells. The cranial CT findings showed diffuse spread involving the lateral and third ventricle and hypothalamus with adjacent edema. Then he was treated by VEMP regimen and repeated intrathecal MTX injections. The neurologic remission with improvement of cranial CT findings was obtained and he has been free of the disease for 15 years.

Topics: Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Cyclophosphamide; Humans; Lymphoma, B-Cell; Male; Mercaptopurine; Methotrexate; Middle Aged; Neoplasm Invasiveness; Prednisolone; Survivors; Vincristine

Although central nervous system (CNS) leukemic relapse is frequent in adult acute lymphocytic leukemia (ALL), the need for prophylaxis in different risk groups for CNS relapse, the value of high-dose systemic and intrathecal (IT) chemotherapy, and the timing of prophylaxis are not well defined. This analysis was conducted to investigate these questions and to assess the value of a risk-oriented CNS prophylaxis approach. We analyzed the incidence of CNS leukemia after initiation of therapy in patients treated on 4 consecutive trials for adult ALL including different CNS prophylactic modalities. The treatment groups included (1) the program preceeding the vincristine-Adriamycin-dexamethasone (VAD) regimen, with no CNS prophylaxis; (2) the VAD regimen with prophylaxis using high-dose systemic chemotherapy; (3) the modified VAD program with high-dose systemic chemotherapy to all patients and IT chemotherapy for high-risk patients after achieving complete remission; and (4) the hyperCVAD program with early high-dose systemic and IT chemotherapy starting during induction to all patients, with more IT injections (16IT) administered to the high-risk group for CNS relapse compared with the low-risk group (4IT). A total of 391 patients were included, 73 of whom were treated with preVAD, 112 with VAD, 114 with modified VAD, and 92 with hyperCVAD. The overall CNS relapse rates were 31%, 18%, 17%, and 3%, respectively for the 4 groups (P < .001). For the high-risk group for CNS relapse, they were 42%, 26%, 20%, and 2%, respectively (P < .001). The differences in CNS relapse rates in the low-risk group were not statistically significant. At 3 years, the overall CNS leukemia event-free rates were 48%, 76%, and 98%, respectively (P < .001). In the high-risk group, the CNS event-free rates were 38%, 66%, 75%, and 98%, respectively (P < .001); however, there was no difference in the low-risk group. We conclude that (1) high-dose systemic chemotherapy is a useful prophylactic measure; (2) early IT chemotherapy is necessary to reduce the incidence of CNS leukemia overall and in the high-risk group; and (3) a risk-oriented approach is appropriate to tailor the intensity of CNS prophylaxis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Cytarabine; Dexamethasone; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Humans; Infusions, Intravenous; Injections, Spinal; Life Tables; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Retrospective Studies; Risk Factors; Survival Rate; Vincristine

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Central Nervous System Neoplasms; Diagnosis, Differential; Humans; Male; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Time Factors; Vincristine