thioguanine-anhydrous and Leukemia-Lymphoma--Adult-T-Cell

Children with acute lymphoblastic leukemia with multiple poor prognostic factors and who have a lymphomatous mass at diagnosis, whether of T- or non-T-immunophenotype, are at increased risk of short term remission and extramedullary recurrence, and are in need of better therapies.. Six hundred and ninety-four eligible patients ranging in age from 1-20 years were entered on the study. Sixty-five percent of the patients had T-cell immunophenotype. Of these, 678 were randomized to one of four regimens: Regimen A: Berlin-Frankfurt-Munster (BFM) 76/79; Regimen B: LSA2-L2 with cranial irradiation; Regimen C: LSA2-L2 without cranial irradiation; and Regimen D: the New York (NY) regimen.. Complete remission was induced in 97% of patients. The overall event free survival (EFS) +/- the standard deviation was 60 +/- 4% 6 years after diagnosis, in contrast to 36 +/- 6% in a comparable historic group. The EFS of the 371 T-cell patients was 62 +/- 7%. EFS was best on the NY (67 +/- 7%) and the BFM (67 +/- 6%) arms. These were significantly better than the EFS on the 2 LSA-L2 regimens, with an EFS of 53 +/- 8% (Regimen B) and 42 +/- 11% (Regimen C) (P = 0.03 and 0.0003 for NY vs. Regimen B and NY vs. Regimen C; P = 0.01 and 0.0001 for BFM vs. Regimen B and BFM vs. Regimen C). Regimen C had a 3-fold greater central nervous system (CNS) recurrence rate than the identical chemotherapy Regimen B (16 +/- 5% vs. 6 +/- 4%; P = 0.02), although the difference in overall EFS did not reach the required level for significance. Testicular recurrence varied from 2-8% in comparison with 20% in the historic group. EFS was not influenced by age, gender, CNS disease at diagnosis, morphology, or immunophenotype. In addition to treatment regimen and early response rate, initial leukocyte count, hemoglobin level, liver, spleen, and lymph node enlargement, and the presence of a mediastinal mass had univariate prognostic influence on EFS. In multivariate analysis, only the kinetics of response, leukocyte count (unfavorably, P < 0.0001), and mediastinal mass status (favorably, P = 0.01) were prognostic.. The adverse prognostic implications of lymphomatous ALL can be minimized by the NY and BFM regimens. Cranial irradiation resulted in better CNS disease control when added to the LSA2-L2 regimen, but did not improve the overall disease free survival. With improved systemic chemotherapy, there was no excess of lymph node, testicular, or other local recurrence without prophylactic irradiation to sites of initial bulk disease or to the testes.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; Humans; Infant; Leukemia-Lymphoma, Adult T-Cell; Methotrexate; Prednisone; Prognosis; Recurrence; Remission Induction; Thioguanine; Vincristine

One hundred and ninety-three children with T-cell acute lymphocytic leukemia (T-ALL) whose leukemia cells were E-rosette positive were treated on a Pediatric Oncology Group study (1979-1986) designed specifically for patients with T-ALL. The results of modified LSA2L2 therapy with or without intensified intrathecal chemotherapy and cranial irradiation (radiotherapy) were compared with those obtained using a simpler multi-agent protocol which included radiotherapy (T-cell 2). The complete remission (approximately 90%) and 3-year event-free survival rates (approximately 40%) were similar in the three treatment groups. However, the pattern of extramedullary relapse varied according to specific treatment regimen. Patients who received LSA2L2 therapy with less intensive intrathecal chemotherapy and no radiotherapy had a central nervous system (CNS) relapse rate (i.e. isolated CNS +/- other site) of over 20%, compared to only 10% for patients receiving the same systemic chemotherapy with intensified intrathecal therapy and radiotherapy, and less than 5% for those receiving T-cell 2 therapy. In contrast, males receiving T-cell 2 therapy had a testicular relapse rate of greater than 20% compared to less than 10% for patients receiving either regimen (i.e. +/- intensified intrathecal chemotherapy and radiotherapy) of modified LSA2L2 therapy. We conclude that, in the context of these therapies, central nervous system irradiation plus intensive triple (hydrocortisone, methotrexate, cytarabine) intrathecal chemotherapy is more effective than CNS preventative therapy comprised of intrathecal low-dose methotrexate only, and that the more complex multi-agent chemotherapy used in the modified LSA2L2 regimens appeared to be more effective in prevention of testicular leukemia, indicating that the effectiveness of sanctuary site treatment was therapy-specific.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Central Nervous System Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Erythrocytes; Female; Humans; Hydrocortisone; Infant; Injections, Spinal; Leukemia-Lymphoma, Adult T-Cell; Male; Methotrexate; Prednisone; Recurrence; Remission Induction; Rosette Formation; Thioguanine; Treatment Outcome; Vincristine

In order to better understand the mechanisms of resistance to thiopurines, we studied two sublines of the MOLT4 T-lymphoblastic leukemia cell line, resistant to 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). We found that the underlying mechanism of resistance in both resistant cell lines was a markedly reduction in initial transport of 6-MP (3- and 5-fold, respectively, in 6-MP- and 6-TG-resistant cells). No significant alteration of activities of hypoxanthine-guanine phosphoribosyl transferase, thiopurine methyltransferase or inosine monophosphate dehydrogenase, the key enzymes involved in the metabolism of thiopurines was detected. We conclude that defected initial transport of thiopurines by cells may very well explain their resistance to these drugs.

Topics: Antimetabolites, Antineoplastic; Biological Transport; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Hypoxanthine Phosphoribosyltransferase; IMP Dehydrogenase; Leukemia-Lymphoma, Adult T-Cell; Mercaptopurine; Methyltransferases; Thioguanine; Time Factors

Thioguanine and mercaptopurine are prodrugs requiring conversion into thiopurine nucleotides to exert cytotoxicity. Thiopurine S-methyltransferase (TPMT), an enzyme subject to genetic polymorphism, catabolizes thiopurines into inactive methylated bases, but also produces methylthioguanine nucleotides and methylmercaptopurine nucleotides from thioguanine and mercaptopurine nucleotides, respectively. To study the effect of TPMT on activation versus inactivation of mercaptopurine and thioguanine, we used a retroviral gene transfer technique to develop human CCRF-CEM cell lines that did (TPMT+) and did not (MOCK) overexpress TPMT. After transduction, TPMT activities were 14-fold higher in the TPMT+ versus the MOCK cell lines (P < 0.001). TPMT+ cells were less sensitive to thioguanine than MOCK cells (IC(50) = 1.10+/- 0.12 microM versus 0.55 +/- 0.19 microM; P = 0.02); in contrast, TPMT+ cells were more sensitive to mercaptopurine than MOCK cells (IC(50) = 0.52 +/- 0.20 microM versus 1.50 +/- 0.23 microM; P < 0.01). The lower sensitivity of TPMT+ versus MOCK cells to thioguanine was associated with lower thioguanine nucleotide concentrations (917 +/- 282 versus 1515 +/- 183 pmol/5 x 10(6) cells; P = 0.01), higher methylthioguanine nucleotide concentrations (252 +/- 34 versus 27 +/- 10 pmol/5 x 10(6) cells; P = 0.01), less inhibition of de novo purine synthesis (13 versus 95%; P < 0.01), and lower deoxythioguanosine incorporation into DNA (2.0 +/- 0.6% versus 7.2 +/- 2.0%; P < 0.001). The higher sensitivity of TPMT+ cells to mercaptopurine was associated with higher concentrations of methylmercaptopurine nucleotide (2601 +/- 1055 versus 174 +/- 77 pmol/5 x 10(6) cells; P = 0.01) and greater inhibition of de novo purine synthesis (>99% versus 74%; P < 0.01) compared with MOCK cells. We conclude that methylation of mercaptopurine contributes to the antiproliferative properties of the drug, probably through inhibition of de novo purine synthesis by methylmercaptopurine nucleotides, whereas thioguanine is inactivated primarily by TPMT.

Topics: 3T3 Cells; Animals; Antimetabolites, Antineoplastic; Biotransformation; Cytosol; Deoxyguanosine; DNA, Neoplasm; Gene Transfer Techniques; HeLa Cells; Humans; Leukemia-Lymphoma, Adult T-Cell; Mercaptopurine; Methyltransferases; Mice; Purine Nucleotides; Purines; Retroviridae; Thioguanine; Thionucleosides; Thionucleotides; Tumor Cells, Cultured

During T cell selection in the thymic cortex more than 90% of the thymocytes are eliminated by apoptosis. Based on this biology, we propose to define blasts of T cell acute lymphoblastic leukemia (ALL) with the phenotype of cortical thymocytes (CD1+ and/or CD4+ 8+) as selection-related (SR) and all other T-ALL immunophenotypes as non-selection-related (NSR). The COALL cooperative treatment studies for childhood ALL offer a tool to study the outcome in T-ALL subgroups as children with T-ALL are allocated uniformly to the high risk arm of the protocol. In the COALL-85, -89 and -92 protocols, 39/83 cases presented as SR and 44/83 cases as NSR. Five-year event-free survival of SR phenotype is significantly better compared to the NSR group (0.87 +/- 0.06 vs 0.66 +/- 0.07, log rank test, P = 0.01). T-ALL with SR phenotype is a distinct subgroup of leukemia with excellent prognosis under a high risk treatment protocol.

Topics: Adolescent; Antigens, CD; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Central Nervous System; Child; Child, Preschool; Clonal Deletion; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Doxorubicin; Female; Follow-Up Studies; Germany; Humans; Immunophenotyping; Infant; Leukemia-Lymphoma, Adult T-Cell; Leukemic Infiltration; Male; Mercaptopurine; Methotrexate; Multicenter Studies as Topic; Neoplastic Stem Cells; Prednisolone; Remission Induction; Risk; T-Lymphocyte Subsets; Teniposide; Thioguanine; Treatment Outcome; Vincristine

Topics: Antimetabolites, Antineoplastic; Cell Division; Cell Line; Cell Survival; Drug Screening Assays, Antitumor; Humans; Isoxazoles; Leukemia-Lymphoma, Adult T-Cell; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine

An 8-year-old white boy with a T-cell acute lymphoblastic leukemia (T-ALL) developed chromosomal abnormalities t(1;18)(p36;q22) and del (6)(q21) at the first bone marrow relapse. Rearrangements of the chromosome region 1p36 have been reported previously in adults with T-ALL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Chromosome Aberrations; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 18; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Humans; Leukemia-Lymphoma, Adult T-Cell; Male; Prednisone; Thioguanine; Vincristine

Co-incubation of human leukemia cell lines with naturally occurring nucleobases (hypoxanthine or adenine) significantly prevented the cytotoxic activity of 6-thiopurines. Extracellular hypoxanthine decreased the transport of 6-mercaptopurine into cells, but adenine had no significant effect. However, intracellular thioinosine monophosphate accumulation in the presence of 10 microM, 6-mercaptopurine was reduced to below 1% or 10% of that of the controls when 50 microM hypoxanthine or adenine was added, respectively. Finally, in adenine phosphoribosyl transferase deficient mutants, adenine provided no protective effect against 6-thiopurines, whereas hypoxanthine retained its modulating activity. These data suggest that the nucleobases compete with 6-thiopurines for the ribose-phosphate donor, 5'-phosphoribosyl-1-pyrophosphate, thus preventing the formation of active metabolites of 6-thiopurines.

Topics: 2-Aminopurine; Adenine; Adenine Phosphoribosyltransferase; Antineoplastic Agents; Biological Transport; Humans; Hypoxanthine; Hypoxanthine Phosphoribosyltransferase; Hypoxanthines; Inosine Monophosphate; Leukemia-Lymphoma, Adult T-Cell; Leukemia, Promyelocytic, Acute; Mercaptopurine; Thioguanine; Thionucleotides; Tumor Cells, Cultured