Leukemia acute lymphocytic, treatment

Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine S-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediatric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP. 

Teniposide, a topoisomerase II inhibitor, is administered as an infusion over 30 to 60 minutes to prevent hypotension. The pharmacokinetics are described by a three-compartment model, with an a half-life of 0.75 hours, a (5 half-life of 4 hours, and a terminal half-life of 20 hours. Considerable variability in clearance of teniposide in children has been reported.17 Teniposide has shown activity in the treatment of acute lymphocytic leukemia, neuroblastoma, and non-Hodgkin s lymphoma. Side effects include myelosuppression, nausea, vomiting, mucositis, and venous irritation. Hypersensitivity reactions may be life-threatening. 

Children with acute lymphocytic leukemia (ALL) are classified according to their risk of relapse. Risk assessment is an important factor in the selection of treatment. The goal is to match treatment to risk and minimize over- or undertreatment. 

Susceptibility to excessive myelosuppression from 6-mercaptopurine, 6-thioguanine, azathioprine in treatment of acute lymphocytic leukemia (thiopurine methyltransferase)... 

Thiopurine methyltransferase methylates 6-mercaptopurine, a commonly used treatment for childhood acute lymphocytic leukemia, reducing its conversion to the active form of the drug. Approximately 10% of patients have intermediate enzyme activity, and 0.3% are deficient for TPMT activity. Intermediate activity patients have a greater incidence of thiopurine toxicity, whereas TPMT-deficient patients have severe or fatal hematological toxicity from 6-mercaptopurine therapy. In one study, patients deficient for TPMT tolerated only 7% of a 2.5-yr mercaptopurine treatment regimen. Patients with intermediate TPMT activity tolerated 65% of total weeks of therapy and patients with normal TPMT activity tolerated 84% of total weeks of therapy (3). 

The existence of the blood-brain barrier is an important consideration in the chemotherapy of neoplastic diseases of the brain or meninges. Poor drug penetration into the CNS has been a major cause of treatment failure in acute lymphocytic leukemia in children. Treatment programs for this disease now routinely employ craniospinal irradiation and intrathecally administered methotrexate as prophylactic measures for the prevention of relapses. The testes also are organs in which inadequate antitumor drug distribution can be a cause of relapse of an otherwise responsive tumor. 

After validating the database they used the connectivity map to obtain new information they queried the database with expression signatures from patients and animal models to find small molecules that were already in the database that may mimic or suppress particular diseases. In subsequent studies, they identified geduin, an HSP90 inhibitor, as a new lead compound for the treatment of prostate cancer (59) and ra-pamycin as a potential useful drug for treatment of acute lymphocytic leukemia resistant to dexamethasone (60). 

A 14-year-old African-American girl with acute lymphocytic leukemia was treated with dexamethasone 24 mg/day for 25 days. Four days after starting to taper the dose she had a psychotic reaction with visual hallucinations, disorientation, agitation, and attempts to leave the floor. Her mother refused treatment with haloperidol. Steroids were withdrawn and lorazepam was given as needed. Nine days later the symptoms had not improved. She was given risperidone 1 mg/day within 3 days the psychotic reaction began to improve and by 3 weeks the symptoms had completely resolved. 

D. KillaruJcr, A. Dahlwitz. L. Engstedt, et al. Hypersensitivity reactions and antibody formation during 1-asparaginase treatment of children and adults with acute lymphocytic leukemia. Cancer 37 220 (1976). 

J, van Eys, D, Berry, W, Crist, el al. Treatment intensity and outcome for children with acute lymphocytic leukemia of standard risk. Cancer 63 1466 (1989). si. A. Van dec Does, E, R. van Wering, 5. Sudu. et ai. Effectiveness of rubidomycin in induction therapy with vincristine, prednisone, and 1-asparaginase for standard ride childhood acute lymphocytic leukemia results of a Dutch phase HI study (ALL V). 

S. G. Castnman, F. Rodeghriero. and E. Dim. Thrombotic comphcations during l-Mpuiginise treatment for acute lymphocytic leukemia. Haematologica 75 367 (1990). 

Therapeutic applications Applications for these two agents differ despite their structural similarity and their apparently similar mechanisms of action. Doxorubicin is one of the most important and widely used anticancer drugs. It is used for treatment of sarcomas and a variety of carcinomas, including breast and lung, as well as acute lymphocytic leukemia and lymphomas. Daunorubicin is used in the treatment of acute lymphocytic and myelocytic leukemias. 

Therapeutic applications Prednisone is primarily employed to induce remission in patients with acute lymphocytic leukemia, and in the treatment of both Hodgkin s and non-Hodgkin s lymphomas. 

Combination therapy in treatment of acute lymphocytic leukemia... 

C. X-irradiation of the cranio-spinal axis is an effective adjuvant therapy in the treatment of acute lymphocytic leukemia. 

Vincristine is part of many chemotherapeutic regimens, based on its lack of myelosuppressive toxicity. It is used, for example, in the treatment of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), lymphomas, neuroblastoma, brain tumors, and Wilms tumor. The generally recommended dose in adults is 1.4 mg/m /week intravenously (5). Some clinicians have recommended an absolute upper limit of 2 mg, but this limitation is still a matter of debate (6). The usual pediatric dosage is 1.5-2 mg/m, but for children weighing 10 kg or less or who have a body surface area less than 1 m, the manufacturers recommend that treatment should be begun at 0.05 mg/kg once a week (5). 

Kantarjian HM, O Brien S, Smith TL, et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 2000 18 547-561. 

J. van Eys, D. Berry, W. Crist, et al. Treatment intensity and outcome for children with acute lymphocytic leukemia of standard risk. Cancer 65 1466 (1989). 

Pennybacker J, Russell DS Necrosis of the brain due to radiation therapy clinical and pathological observations. J Neurol Neurosurg Psychiatry 11 183-198, 1948 Peylan-Ramu N, Poplack DG, Pizzo PA, et al Abnormal CT scans of the brain in asymptomatic children with acute lymphocytic leukemia after prophylactic treatment of the central nervous system with radiation and intrathecal chemotherapy. N Engl J Med 298 815-818,1978... 

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