Chapter 104. Acute and Chronic Myeloid Leukemia (Part 7)

Acute Myeloid Leukemia: TreatmentTreatment 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 patients age.
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Chapter 104. Acute and Chronic Myeloid Leukemia (Part 7) Chapter 104. Acute and Chronic Myeloid Leukemia (Part 7) Acute Myeloid Leukemia: Treatment Treatment of the newly diagnosed patient with AML is usually divided intotwo phases, induction and postremission management (Fig. 104-2). The initialgoal is to quickly induce CR. Once CR is obtained, further therapy must be used toprolong survival and achieve cure. The initial induction treatment and subsequentpostremission therapy are often chosen based on the patients age. The influence ofintensifying therapy with traditional chemotherapy agents such as cytarabine andanthracyclines in younger patients ( Figure 104-2 Flow chart for the therapy of newly diagnosed acute myeloid leukemia.For all forms of AML except acute promyelocytic leukemia (APL), standardtherapy includes a 7-day continuous infusion of cytarabine (100–200 mg/m2 perday) and a 3-day course of daunorubicin (45–60 mg/m2 per day) or idarubicin(12–13 mg/m2 per day) with or without 3 days of etoposide. Patients who achievecomplete remission undergo postremission consolidation therapy, includingsequential 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 withAPL usually receive tretinoin together with anthracycline chemotherapy forremission induction and then consolidation chemotherapy (daunorubicin)followed by maintenance tretinoin, with or without chemotherapy. The role ofcytarabine in APL induction and consolidation is controversial. Induction Chemotherapy The most commonly used CR induction regimens (for patients other thanthose with APL) consist of combination chemotherapy with cytarabine and ananthracycline. Cytarabine is a cell cycle S-phase–specific antimetabolite thatbecomes phosphorylated intracellularly to an active triphosphate form thatinterferes with DNA synthesis. Anthracyclines are DNA intercalaters. Theirprimary mode of action is thought to be inhibition of topoisomerase II, leading toDNA breaks. Cytarabine is usually administered as a continuous intravenousinfusion for 7 days. Anthracycline therapy generally consists of daunorubicinintravenously on days 1, 2, and 3 (the 7 and 3 regimen). Treatment with idarubicinfor 3 days in conjunction with cytarabine by 7-day continuous infusion is at leastas effective and may be superior to daunorubicin in younger patients. The additionof etoposide may improve the CR duration. After induction chemotherapy, the bone marrow is examined to determineif the leukemia has been eliminated. If ≥5% blasts exist with ≥20% cellularity, thepatient is usually re-treated with cytarabine and an anthracycline in doses similarto 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 aftertwo induction courses should immediately proceed to an allogeneic stem celltransplant (SCT) if an appropriate donor exists. This approach is only applied topatients 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-thirdsachieve 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, and50% do not achieve CR because of fatal complications of bone marrow aplasia orimpaired recovery of normal stem cells. Higher induction treatment–relatedmortality and frequency of resistant disease have been observed with increasingage and in patients with prior hematologic disorders (MDS or myeloproliferativesyndromes) or chemotherapy treatment for another malignancy. High-dose cytarabine-based regimens have very high CR rates after a singlecycle of therapy. When given in high doses, more cytarabine may enter the cells,saturate the cytarabine-inactivating enzymes, and increase the intracellular levelsof 1-β-D-arabinofuranylcytosine-triphosphate, the active metabolite incorporatedinto DNA. Thus, higher doses of cytarabine may increase the inhibition of DNAsynthesis and thereby overcome resistance to standard-dose cytarabine. In tworandomized studies, high-dose cytarabine with an anthracycline produced CR ratessimilar to those achieved with standard 7 and 3 regimens. However, the CRduration was longer after high-dose cytarabine than after standard-dose cytarabine.