Chapter 104. Acute and Chronic Myeloid Leukemia (Part 7) Acute Myeloid Leukemia: Treatment Treatment of the newly diagnosed patient with AML is usually divided into two phases, induction and postremission management (Fig. 104-2). The initial goal is to quickly induce CR. Once CR is obtained, further therapy must be used to prolong survival and achieve cure. The initial induction treatment and subsequent postremission therapy are often chosen based on the patient's age. The influence of intensifying therapy with traditional chemotherapy agents such as cytarabine and anthracyclines in younger patients (<60 years) appears to increase the cure rate of AML. In older patients the benefit of intensive therapy is controversial; novel therapies are being pursued. Figure 104-2 Flow chart for the therapy of newly diagnosed acute myeloid leukemia. For all forms of AML except acute promyelocytic leukemia (APL), standard therapy includes a 7-day continuous infusion of cytarabine (100–200 mg/m 2 per day) and a 3-day course of daunorubicin (45–60 mg/m 2 per day) or idarubicin (12–13 mg/m 2 per day) with or without 3 days of etoposide. Patients who achieve complete remission undergo p ostremission consolidation therapy, including sequential courses of high- dose cytarabine, autologous stem cell transplant (SCT), high- dose combination chemotherapy with allogeneic SCT, or novel therapies, based on their predicted risk of relapse (i.e., risk- stratified therapy). Patients with APL usually receive tretinoin together with anthracycline chemotherapy for remission induction and then consolidation chemotherapy (daunorubicin) followed by maintenance tretinoin, with or without chemotherapy. The role of cytarabine in APL induction and consolidation is controversial. Induction Chemotherapy The most commonly used CR induction regimens (for patients other than those with APL) consist of combination chemotherapy with cytarabine and an anthracycline. Cytarabine is a cell cycle S-phase–specific antimetabolite that becomes phosphorylated intracellularly to an active triphosphate form that interferes with DNA synthesis. Anthracyclines are DNA intercalaters. Their primary mode of action is thought to be inhibition of topoisomerase II, leading to DNA breaks. Cytarabine is usually administered as a continuous intravenous infusion for 7 days. Anthracycline therapy generally consists of daunorubicin intravenously on days 1, 2, and 3 (the 7 and 3 regimen). Treatment with idarubicin for 3 days in conjunction with cytarabine by 7-day continuous infusion is at least as effective and may be superior to daunorubicin in younger patients. The addition of etoposide may improve the CR duration. After induction chemotherapy, the bone marrow is examined to determine if the leukemia has been eliminated. If ≥5% blasts exist with ≥20% cellularity, the patient is usually re-treated with cytarabine and an anthracycline in doses similar to those given initially, but for 5 and 2 days, respectively. Our recommendation, however, is to change therapy in this setting. Patients who fail to attain CR after two induction courses should immediately proceed to an allogeneic stem cell transplant (SCT) if an appropriate donor exists. This approach is only applied to patients under the age of 70 with acceptable end-organ function. With the 7 and 3 cytarabine/daunorubicin regimen outlined above, 65–75% of adults with de novo AML under the age of 60 years achieve CR. Two-thirds achieve CR after a single course of therapy, and one-third require two courses. About 50% of patients who do not achieve CR have a drug-resistant leukemia, and 50% do not achieve CR because of fatal complications of bone marrow aplasia or impaired recovery of normal stem cells. Higher induction treatment–related mortality and frequency of resistant disease have been observed with increasing age and in patients with prior hematologic disorders (MDS or myeloproliferative syndromes) or chemotherapy treatment for another malignancy. High-dose cytarabine-based regimens have very high CR rates after a single cycle of therapy. When given in high doses, more cytarabine may enter the cells, saturate the cytarabine-inactivating enzymes, and increase the intracellular levels of 1-β-D-arabinofuranylcytosine-triphosphate, the active metabolite incorporated into DNA. Thus, higher doses of cytarabine may increase the inhibition of DNA synthesis and thereby overcome resistance to standard-dose cytarabine. In two randomized studies, high-dose cytarabine with an anthracycline produced CR rates similar to those achieved with standard 7 and 3 regimens. However, the CR duration was longer after high-dose cytarabine than after standard-dose cytarabine. . Chapter 104. Acute and Chronic Myeloid Leukemia (Part 7) Acute Myeloid Leukemia: Treatment Treatment of the newly diagnosed patient. being pursued. Figure 104- 2 Flow chart for the therapy of newly diagnosed acute myeloid leukemia. For all forms of AML except acute promyelocytic leukemia (APL), standard therapy includes. synthesis and thereby overcome resistance to standard-dose cytarabine. In two randomized studies, high-dose cytarabine with an anthracycline produced CR rates similar to those achieved with standard