Lay Summary: I review standard approaches to AML
Standard Therapy of of acute myelogenous leukemia (excluding acute promyelocytic leukemia).Induction therapy: Various acceptable induction regimens are available. The most common approach is called ”3 and 7,” which consists of 3 days of a 15- to 30-minute infusion of an anthracycline (idarubicin or daunorubicin) or anthracenedione (mitoxantrone), combined with 100 mg/m2 of arabinosylcytosine (araC) as a 24-hour infusion daily for 7 days. Idarubicin is given at a dose of 12 mg/m2/d for 3 days, daunorubicin at 45-60 mg/m2/d for 3 days, or mitoxantrone at 12 mg/m2/d for 3 days. Using these regimens, approximately 50% of patients achieve remission with one course. Another 10-15% enter remission following a second course of therapy. Alternatively, high-dose araC combined with idarubicin, daunorubicin, or mitoxantrone can be used as induction therapy in younger patients. The use of high-dose araC outside the setting of a clinical trial is considered controversial. However, 2 studies demonstrated improved disease-free survival rates in younger patients who received high-dose araC during induction. Consolidation therapy in younger patients: In patients aged 60 years or younger, treatment options for consolidation therapy include high-dose araC, autologous stem cell transplantation, or allogeneic stem cell transplantation.High-dose araC therapy: Mayer et al conducted a randomized study of 3 different doses of araC in patients with acute myelogenous leukemia (AML) who achieved remission after standard “3 and 7” induction chemotherapy. Patients received 4 courses of araC at one of the following doses: (1) 100 mg/m2/d by continuous infusion for 5 days, (2) 400 mg/m2/d by continuous infusion for 5 days, or (3) 3 g/m2 in a 3-hour infusion every 12 hours on days 1, 3, and 5. The probability of remaining in continuous complete remission (CR) after 4 years in patients aged 60 years or younger was 24% in the 100-mg group, 29% in the 400-mg group, and 44% in the 3-g group (P = .002). The outcome in older patients did not differ. Based on this study, high-dose araC for 4 cycles is a standard option for consolidation therapy in younger patients.Stem cell transplantationIn order to define the best postremission therapy for young patients, several large, randomized studies have compared allogeneic bone marrow transplantation (BMT), autologous BMT, and chemotherapy without BMT. Unfortunately, the results of these studies are conflicting.Some studies suggest an advantage to BMT.In a Dutch study, patients received either allogeneic BMT or autologous BMT based on the availability of a sibling donor matched via human leukocyte antigen (HLA). This study demonstrated a decreased rate of relapse at 3 years for patients receiving allogeneic BMT versus autologous BMT (34% vs 60%, respectively; P = .03) and an increased overall survival rate at 3 years for patients receiving allogeneic BMT versus autologous BMT (66% vs 37%, respectively; P = .05). However, the median age of patients who received allogeneic BMT was 10 years younger that those who received autologous BMT.In the Medical Research Council AML 10 trial, patients without an HLA-matched donor received 4 courses of intensive chemotherapy followed by either no further treatment or autologous BMT. In this study, the number of relapses was lower for patients receiving autologous BMT versus no further treatment (37% vs 58%, respectively; P <.001), and the rate of disease-free survival at 7 years was improved for patients receiving autologous BMT versus no further treatment (53% vs 40%, respectively; P = .04). However, no improvement in the overall survival rate at 7 years was observed for autologous BMT versus no further treatment (57% vs 45%, respectively; P = .2).In a European Organization for Research and Treatment of Cancer/Gruppo Italiano Malattie Ematologiche Maligne dell’Adul study, patients with an HLA-identical sibling underwent allogeneic BMT. Other patients randomly received either autologous BMT or a second course of intensive chemotherapy with high-dose araC and daunorubicin. The disease-free survival rate at 4 years was 55% for patients who received allogeneic BMT, 48% for patients who received autologous BMT, and 30% for patients who received intensive chemotherapy (P = .04). Again, the overall survival rate was similar in all 3 groups because patients who relapsed after chemotherapy had a response to subsequent autologous BMT.Several other studies have failed to show any advantage to BMT.In a study by Groupe Ouest Est Leucemies Aigues Myeloblastiques, patients as old as 40 years with a matched donor received allogeneic BMT. All other patients received a course of consolidation chemotherapy with high-dose araC and an anthracycline and then randomly received either a second course of consolidation chemotherapy or autologous BMT. In this study, the type of postremission therapy had no effect on outcome.In a US Intergroup study, patients in remission with a matched donor received allogeneic BMT. Other patients randomly received either autologous BMT or one additional course of high-dose araC. In this study, the survival rate was better for patients receiving chemotherapy without BMT compared with the other groupsIn view of these conflicting results, the following recommendations can be made:Patients with good-risk AML, ie, t(8;21) and inversion of chromosome 16(inv16), have a good prognosis following consolidation with high-dose araC and should be offered such therapy. This is given as araC at 3 g/m2 twice a day on days 1, 3, and 5 of each cycle, repeated monthly (after recovery from the previous cycle) for 4 consolidation cycles. Transplantation should be reserved for patients who relapse.Patients with high-risk cytogenetics findings are rarely cured with chemotherapy and should be offered transplantation in first remission. However, these patients also are at high risk for relapse following transplantation.The best approach for patients with intermediate-risk cytogenetics findings is controversial. Some refer patients in first remission for transplantation, whereas others give consolidation chemotherapy with high-dose araC for 4 courses and reserve transplantation for patients who relapse.Consolidation therapy in older patients: No standard consolidation therapy exists for patients older than 60 years. Options include a clinical trial, high-dose araC in select patients, or repeat courses of standard-dose anthracycline and araC (2 and 5; ie, 2 d of anthracycline and 5 d of araC). Select patients can be considered for autologous stem cell transplantation or nonmyeloablative allogeneic transplantation.
John Koreth, et al, Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia in First Complete Remission Consolidation Therapy With Autologous Bone Marrow Transplantation in Adults With Acute Myeloid Leukemia: A Meta-analysis 2009;301(22):2349-2361Ades L, Sanz MA, Chevret S et al.: Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood 111,1078-1084 (2008).
Schlenk RF, Dohner K, Krauter J et al.: Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N. Engl. J. Med. 358,1909-1918 (2008).
Richard M. Stone, Consolidation Chemotherapy for Adults With AML in First Remission: Is There a Best Choice?Journal of Clinical Oncology 31, no. 17 (June 2013) 2067-2069.
Hervé Dombretcorresponding author and Claude Gardin,An update of current treatments for adult acute myeloid leukemia.Blood. 2016 Jan 7; 127(1): 53–61.