Myelogenous Leukemia and Acute Leukemias

Many of the Philadelphia-positive adult ALL cases (50-75%) have a different type of gene rearrangement. The gene fusion BCR/c-abl takes place after the breakpoints in intron 1 of the BCR gene and the common sequence of the C-abl gene (H2). 

The BCR/c-abl fusion is followed by an abnormal fusion mRNA containing 

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Chronic Myelogenous Leukemia and Acute Leukemias Current Diagnostics. 57... 

Cytarabine is used in the chemotherapy of acute myelogenous leukemia, usually in combination with anthracyclines, thioguanine, or both. It is less useful in acute lymphoblastic leukemia and lymphomas and has marginal activity against other tumors. Myelosuppres-sion is a major toxicity, as is severe bone marrow hypoplasia nausea and mucositis may also occur. 

In chronic myelogenous leukemia (CML) as well as in a subset of acute lymphoblastic leukemia (ALL) Bcr-Abl, a fusion protein of c-Abl and the breakpoint cluster region (bcr), is expressed in the cytosol of leukemic cells. This fusion protein forms homo-oligomeric complexes that display elevated kinase activity and is the causative molecular abnormality in CML and certain ALL. The transforming effect of Bcr-Abl is mediated by numerous downstream signaling pathways, including protein kinase C (PKC), Ras-Raf-ERK MAPK, JAK-STAT (see below), and PI3-kinase pathways. 

A detailed study of the 0-linked oligosaccharides present on the surface of normal granulocytes, chronic myelogenous leukemia cells, and acute myelogenous leukemia cells has been completed. Structures were elucidated by f.a.b.-m.s. after permethylation, and methylation analysis before and after specific exo-glycosidase treatments. Some of the components were shown by f.a.b.-m.s. to be poly(N-acetyllactosaminyl) oligosaccharides, for example, 29. 

Acute myelogenous leukemia has been observed in 0.07% of MS patients treated with mitoxantrone.46 This form of acute leukemia appears within 2 to 4 years of initiating mitoxantrone and is generally responsive to standard antileukemic therapy. 

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. 

Topotecan inhibits topoisomerase I to cause single-strand breaks in DNA. The pharmacokinetics of topotecan can be described by a two-compartment model, with a terminal half-life of 80 to 180 minutes, with renal clearance accounting for approximately 70% of the clearance.19 Topotecan has shown clinical activity in the treatment of ovarian and lung cancer, myelodysplastic syndromes, and acute myelogenous leukemia. The intravenous infusion may be daily for 5 days or once weekly. Side effects include myelosuppression, mucositis, and diarrhea. 

Idarubicin inhibits both DNA and RNA polymerase, as well as topoisomerase II. The pharmacokinetics of idarubicin can best be described by a three-compartment model, with an a half-life of 13 minutes, a (3 half-life of 2.4 hours, and a terminal half-life of 16 hours.22 Idarubicin is metabolized to an active metabolite, idarubicinol, which has a half-life of 41 to 69 hours. Idarubicin and idarubicinol are eliminated by the liver and through the bile. Idarubicin has shown clinical activity in the treatment of acute leukemias, chronic myelogenous leukemia, and myelodysplastic syndromes. Idarubicin causes cardiomyopathy at cumulative doses of greater than 150 mg/m2 and produces cumulative cardiotoxic effects with other anthracyclines. Idarubicin is a vesicant and causes red-orange urine, mucositis, mild to moderate nausea and vomiting, and bone marrow suppression. 

The oncologist prescribes the normal doses of idarubicin 12 mg/m2 IV daily for 3 days and cytarabine 100 mg/m2 per day by continuous infusion for 7 days to treat her acute myelogenous leukemia. Her baseline laboratory measurements are significant for an elevated WBC count, a creatinine concentration of 2.5 mg/dL (221 pmol/L), and a bilirubin level of 1.6 mg/dL (27 pmol/L). 

The current induction therapy for acute myelogenous leukemia (AML) usually consists of a combination of cytara-bine and daunorubicin, with the frequent addition of a steroid and/or an antimetabolite such as 6-thioguanine. The risk of infection is so high during this period that patients receive antibiotic and fungal prophylaxis. 

For all newly diagnosed patients with leukemia, an aspirate of the liquid marrow and a bone marrow core biopsy are obtained.5 Morphologic and cytochemical analysis of these samples distinguishes three subtypes of ALL (LI, L2, and L3) and eight subtypes of AML (M0-M7) as classified by the French-American-British (FAB) scheme. See Tables 92-2 and 92-3 for the FAB classification of acute myelogenous leukemia and acute lymphocytic leukemia. 

AS is a 65-year-old woman with relapsed acute myelogenous leukemia. PMH is significant for type II diabetes and renal insufficiency (CrCI 20 mL/minute). She is day +1 from a nonmyeloablative HCT with fludarabine (30 mg/m2 per day IV for 3 days) and total-body irradiation preparative regimen and a graft from a full HLA-matched sibling. 

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.)... 

Vogler, W.R. et al. 1992. A phase HI trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia A Southeastern Cancer Study Group study. J Clin Oncol. 10 1103. 

Acute MI (myocardial infarction), 5 107 antianginal agents for, 5 110t and coronary arterial thrombosis, 5 170 Acute myelogenous leukemia (AML), and benzene exposure, 3 616 Acute oral toxicity... 

Moscinski L, Atadja P, Bhalla K (2004) Superior activity of the combination of histone deacetylase inhibitor LAQ824 and the FLT-3 kinase inhibitor PKC412 against human acute myelogenous leukemia cells with mutant FLT-3. Clin Cancer Res 10 4991 997 Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F, Rocha K, Kumarawsamy S, Boyapalle S, Atadja P, Seto E, Bhalla K (2005) Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90 a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem 280(29) 26729-26734 Bannister AJ, Schneider R, Kouzarides T (2002) Histone methylation Dynamic or static Cell 109 801-806... 

Figure 2. Percentage of CD34+33+117+ cells in acute myelogenous leukemia and myelodysplasia.

Cammenga, J., Niebuhr, B., Horn, S., Bergholz, U., Putz, G., Buchholz, F., Lohler, J. and Stocking, C. (2007) RUNXl DNA-binding mutants, associated with minimally differentiated acute myelogenous leukemia, disrupt myeloid differentiation. Cancer Res 67, 537-545. 

Miyamoto, T., Weissman, I. and Akashi, K. (2000) AMLl/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8 21 chromosomal translocation. Proc. Natl. Acad. Scl. USA 97, 7521-7526. 

Thiede, C., Steudel, C., Mohr, B., Schaich, M., Schakel, U., Platzbecker, U., Wermke, M., Bornhauser, M., Ritter, M., Neubauer, A., et al. (2002) Analysis of FLT3 activating mutations in 979 patients with acute myelogenous leukemia association with FAB subtypes and identification of subgroups with poor prognosis. Blood99, 4326 4335. 

The lARC has concluded that epidemiological studies have established the relationship between benzene exposure and the development of acute myelogenous leukemia and that there is sufficient evidence that benzene is carcinogenic to humans. Although a benzene-leukemia association has been made, the exact shape of the dose-response curve and/or the existence of a threshold for the response is unknown and has been the source of speculation and controversy. Some risk assessments suggest exponential increases in relative risk (of leukemias) with increasing cumulative exposure to benzene. At low levels of exposure, however, a small increase in leukemia mortality cannot be distinguished from a no-risk situation. In addition to cumulative dose other factors such as multiple solvent exposure, familial connection, and individual sus-... 

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