Leukemia acute lymphoblastic, treatment

Riehm H, Gadner H, Henze G. Acute lymphoblastic leukemia treatment results in three BFM studies (1970-1981). In Leukemia research advances in cell biology and treatment. (Murphy SB, Gilbert JR, eds.), Amsterdam Elsevier Science Publishing, 1983 251-163. 

Role of the Folate-Pathway and the Thymidylate Synthase Genes in Pediatric Acute Lymphoblastic Leukemia Treatment Response... 

Although the compounds were isolated in quantities of only a few milligrams per kilogram of cmde plant leaves, extensive work on a variety of animal tumor systems led to eventual clinical use of these bases, first alone and later in conjunction with other materials, in the treatment of Hodgkin s disease and acute lymphoblastic leukemia. Their main effect appears to be binding tightly to tubuHn, the basic component of microtubules found in eukaryotic cells, thus interfering with its polymerization and hence the formation of microtubules required for tumor proliferation (82). 

MTX is part of curative therapeutic schedules for acute lymphoblastic leukemias (ALL), Burkitt s lymphoma, and choriocarcinoma. It was also used in adjuvant therapy of breast cancer. High dose MTX with leucovorin rescue can induce about 30% remissions in patients with metastatic osteogenic sarcoma. MTX is one of the few antineoplastic drugs that can be safely administered intrathecally for the treatment of meningeal metastases and leukemic infiltrations (routine prophylaxis in ALL). In addition, MTX can be used as an immunosuppressive agent for the treatment of severe rheumatoid arthritis and psoriasis. 

Prophylaxis and treatment of hyperuricemia associated with tumor lysis syndrome. ALL, acute lymphoblastic leukemia AML, acute myelogenous leukemia IV, intravenous. (Data from refs. 32 and 33.)... 

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine dmgs, such as 6-mercaptopurine (6-MP), 6-thioguanine and azathioprine, to inactive metabolites [29-32]. Thiopurines form part of the routine treatment for patients with acute lymphoblastic leukemia, rheumatoid arthritis, and autoimmune diseases such as SLE and Crohn s disease, and are used as an immunosuppressant following organ transplantation. 

Deficiency of thiopurine S-methyl transferase (TPMT) is another phenotype that exhibits inter-ethnic differences in frequency. TPMT is an enzyme that catalyzes methylation of therapeutic agents used in the treatment of acute lymphoblastic leukemia, rheumatoid arthritis, and autoimmune/inflammatory diseases, as well as in organ transplantation. Patients who have TPMT deficiency experience less efficient methylation and are at greater risk of fatal toxicity when treated with standard doses of fhiopurines. TPMT phenotype is defined by erythrocyte 6-mercapto-purine methylation. African American populations exhibit a 20% lower erythrocyte TPMT than Caucasian Americans, and persons of Chinese descent tend to exhibit greater activity than either of these other American subpopulations. 

Consider, for example, the drug 6-mercaptopurine, one of the mainstays of treatment for acute lymphoblastic leukemia, a common type of childhood cancer (Rioux, 2000). Researchers have discovered that the reason some... 

Stanulla, M., Schaeffeler, E., Hohr, T., et al. (2005) Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia JAMA. 293, 1485-1489. 

Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia after ima-tinib treatment and for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 and 6 hours (Tmax) following oral administration. Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. CYP3A4 was the primary enzyme responsible for the formation of the active metabolite. The overall mean terminal half-life of dasatinib is 3-5 hours. Adverse events included mild to moderate diarrhea, peripheral edema, and headache. Neutropenia and myelosuppression were common toxic effects. 

The treatment of adult acute lymphoblastic leukemia (ALL) is typically divided into 4 broad categories induction therapy, intensification or consolidation therapy, maintenance therapy and central nervous system (CNS) prophylaxis. 

Methotrexate is one of the few anticancer drugs that can be safely administered intrathecally for the treatment of meningeal metastases. Its routine use as prophylactic intrathecal chemotherapy in acute lymphoblastic leukemia has greatly reduced the incidence of recurrences in the CNS and has contributed to the cure rate in this disease. Daily oral doses of methotrexate are used for severe cases of the nonneoplastic skin disease psoriasis (see Chapter 41), and methotrexate has been used as an immunosuppressive agent in severe rheumatoid arthritis. 

Cytarabine is used in the chemotherapy of acute myelogenous leukemia, usually in combination with an anthracycline agent, thioguanine, or both. It is less useful in acute lymphoblastic leukemia and the lymphomas and has no known activity against other tumors. It has been used intrathecally in the treatment of meningeal leukemias and lymphomas as an alternative to methotrexate. 

The major indication for L-asparaginase is in the treatment of acute lymphoblastic leukemia complete remission rates of 50 to 60% are possible. Lack of crossresistance and bone marrow toxicity make the enzyme particularly useful in combination chemotherapy, l-Asparaginase also can be used in the treatment of certain types of lymphoma. It has no role in the treatment of nonlymphocytic leukemias or other types of cancer. 

S.R. Blattner, R. Tantravahi, P. Leavitt, and S.E. Sallan, Four-agent induction and intensive asparaginase therapy for treatment of childhood acute lymphoblastic leukemia. N Engl J Med, 1986. 315(11) 657-63. 

Indications Treatment of patients with acute lymphoblastic leukemia (ALL) who are hypersensitive to native forms of L-... 

Thiopurines in the Treatment of Childhood Acute Lymphoblastic Leukemia and Genetic Variants of the Thiopurine S-Methyltransferase Gene... 

The thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are essential components of treatment protocols for childhood acute lymphoblastic leukemia... 

THIOPURINES IN THE TREATMENT OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA... 

Pui CH, Evans WE. Treatment of ehildhood acute lymphoblastic leukemia. N Engl J Med 2006 354 166-178. 

Silverman LB, Sallan SE. Newly diagnosed childhood acute lymphoblastic leukemia update on prognostic factors and treatment. Curr Opin Hematol. 2003 10 290-296. 

Kamps WA, Bokkerink JP, Hahlen K et al. Intensive treatment of children with acute lymphoblastic leukemia according to ALL-BFM-86 without cranial radiotherapy results of the Dutch Childhood Leukemia Study Group protocol ALL-7 (1988-91). Blood 1999 94 1226-1236. 

Sackmann-Muriel F, Felice MS, Zubizarreta PA et al. Treatment results in childhood acute lymphoblastic leukemia with a modified ALL-BFM 90 protocol lack of improvement in high-risk group. Leak Res 1999 23 331-340. 

Uckun FM, Sensei MG, Sun L et al. Biology and treatment of childhood T-lineage acute lymphoblastic leukemia. Blood 1998 91 735-746. 

Mastrangelo R, Poplack D, Bleyer A et al. Report and recommendations of the Rome workshop concerning poor-prognosis acute lymphoblastic leukemia in children biologic bases for staging, stratification, and treatment. MedPediatr Oncol 1986 14 191-194. 

Smith M, Arthur D, Camitta B et al. Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. JC/m Oncol 1996 14 18-24. 

Bokkering J, DamenF, Huylscher Met al. Biochemical evidence for synergistic combination treatment with methotrexate and 6-mercaptopurine in childhood acute lymphoblastic leukemia. Haematol Blood Transfus 1990 33 110-117. 

Dervieux T, Hancock ML, Pui CH et al. Antagonism by methotrexate on mercaptopurine disposition in lymphoblasts during up-front treatment of acute lymphoblastic leukemia. Clin Pharmacol Ther 2003 73 506-516. 

Stanulla M, Schaeffeler E, Moricke A et al. Thiopurine methyltransferase genotype is not a risk factor for secondary malignant neoplasias after treatment for childhood acute lymphoblastic leukemia on Berlin FrankfurtMunster protocols. Blood 2006 108 48a. 

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer with a erne rate of approximately 80%. However, despite the generally favorable outeome of ALL treatment, some children relapse or experience severe treatment side effeets. Reeent research eiforts have focused on understanding the patient genetie eharaeteris-ties that underlie treatment response. To date, several studies have demonstrated that... 

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