Treatment of Newly Diagnosed AML
The general principles of therapy for children and adolescents with acute myeloid leukemia (AML) are discussed below, followed by a more specific discussion of the treatment of children with acute promyelocytic leukemia (APL) and Down syndrome.
Overall survival (OS) rates have improved over the past three decades for children with AML, with 5-year survival rates now in the 55% to 65% range.[1-5] Overall remission-induction rates are approximately 85% to 90%, and event-free survival (EFS) rates from the time of diagnosis are in the 45% to 55% range.[2-5] There is, however, a wide range in outcome for different biological subtypes of AML (refer to the Cytogenetic Evaluation and Molecular Abnormalities section of this summary for more information); after taking specific biological factors of their leukemia into account, the predicted outcome for any individual patient may be much better or much worse than the overall outcome for the general population of children with AML.Induction Chemotherapy
Because of the intensity of therapy used to treat children with AML, patients should have their care coordinated by specialists in pediatric oncology, and should be treated in cancer centers or hospitals with the necessary supportive care facilities (e.g., to administer specialized blood products; to manage infectious complications; to provide pediatric intensive care; and to provide emotional and developmental support).
Contemporary pediatric AML protocols result in 85% to 90% complete remission rates. Of those patients who do not go into remission, about one-half have resistant leukemia and one-half die from the complications of the disease or its treatment. To achieve a complete remission (CR), inducing profound bone marrow aplasia (with the exception of the M3 APL subtype) is usually necessary. Because induction chemotherapy produces severe myelosuppression, morbidity and mortality from infection or hemorrhage during the induction period may be significant.
The two most effective drugs used to induce remission in children with AML are cytarabine and an anthracycline. Commonly used pediatric induction therapy regimens use cytarabine and an anthracycline in combination with other agents such as etoposide and/or thioguanine.[3,6,7] The United Kingdom Medical Research Council (MRC) 10 Trial compared induction with cytarabine, daunorubicin, and etoposide (ADE) versus cytarabine and daunorubicin administered with thioguanine (DAT); the results showed no difference between the thioguanine and etoposide arms in remission rate or disease-free survival.
The anthracycline that has been most used in induction regimens for children with AML is daunorubicin,[3,6,7] though idarubicin and the anthracenedione mitoxantrone have also been used.[9,10] Randomized trials have attempted to determine whether any other anthracycline or anthracenedione is superior to daunorubicin as a component of induction therapy for children with AML. The German Berlin-Frankfurt-Munster (BFM) Group AML-BFM 93 study evaluated cytarabine plus etoposide with either daunorubicin or idarubicin (ADE or AIE) and observed similar EFS and OS for both induction treatments.[7,9] The MRC-LEUK-AML12 clinical trial studied induction with cytarabine, mitoxantrone, and etoposide (MAE) in children and adults with AML compared with a similar regimen using daunorubicin (ADE).[10,11] For all patients, MAE showed a reduction in relapse risk, but the increased rate of treatment-related mortality observed for patients receiving MAE led to no significant difference in disease-free survival or OS in comparison to ADE. Similar results were noted when analyses were restricted to pediatric patients. In the absence of convincing data that another anthracycline or mitoxantrone produces superior outcome to daunorubicin when given at an equitoxic dose, daunorubicin remains the anthracycline most commonly used during induction therapy for children with AML in the United States.
The intensity of induction therapy influences the overall outcome of therapy. The CCG-2891 study demonstrated that intensively timed induction therapy (4-day treatment courses separated by only 6 days) produced better EFS than standard-timing induction therapy (4-day treatment courses separated by 2 weeks or longer). The MRC has intensified induction therapy by prolonging the duration of cytarabine treatment to 10 days. Another way of intensifying induction therapy is by the use of high-dose cytarabine. While studies in nonelderly adults suggest an advantage for intensifying induction therapy with high-dose cytarabine (2–3 g/m2/dose) compared with standard-dose cytarabine,[12,13] a benefit for the use of high-dose cytarabine compared with standard-dose cytarabine in children was not observed using a cytarabine dose of 1 g/m2 given twice daily for 7 days with daunorubicin and thioguanine. A second pediatric study also failed to detect a benefit for high-dose cytarabine over standard-dose cytarabine when used during induction therapy.
Hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) during AML induction therapy have been evaluated in multiple placebo-controlled studies in adults with AML in attempts to reduce the toxicity associated with prolonged myelosuppression.[16,17] These studies have generally shown a reduction of several days in the duration of neutropenia with the use of either G-CSF or GM-CSF  but have not shown significant effects on treatment-related mortality or OS. A randomized study in children with AML that evaluated G-CSF administered after induction chemotherapy showed a reduction in duration of neutropenia but no difference in infectious complications or mortality. A higher relapse rate has been reported for children with AML expressing the differentiation defective G-CSF receptor isoform IV. Thus, routine prophylactic use of hematopoietic growth factors is not recommended for children with AML.Treatment options under clinical evaluation
The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- AML08 (Clofarabine Plus Cytarabine Versus Conventional Induction Therapy and a Study of Natural Killer Cell Transplantation in Newly Diagnosed AML): St. Jude Children’s Research Hospital is conducting a randomized trial for children with newly diagnosed AML. This trial compares two induction regimens: cytarabine/daunorubicin/etoposide (ADE) versus clofarabine/cytarabine. Responses are assessed via morphology and flow cytometry (MRD) at the end of the induction phase.
- COG-AAML1031 (Bortezomib and Sorafenib Tosylate in Patients With Newly Diagnosed AML With or Without Mutations): COG-AAML1031 uses an ADE induction therapy backbone. For patients without FLT3-ITD–positive AML, the study is using a randomized design to evaluate whether the addition of bortezomib throughout the course of therapy improves EFS and OS. For patients with high allelic ratio FLT3-ITD–positive AML, the primary objective is to evaluate the feasibility of combining sorafenib (a small molecule FLT3 inhibitor) with standard chemotherapy. A secondary objective for this patient population is to determine the antileukemic activity of sorafenib for FLT3-ITD–positive AML.
Although the presence of CNS leukemia at diagnosis (i.e., clinical neurologic features and/or leukemic cells in cerebral spinal fluid on cytocentrifuge preparation) is more common in childhood AML than in childhood acute lymphoblastic leukemia (ALL), survival is not adversely affected. This finding is perhaps related to both the higher doses of chemotherapy used in AML (with potential crossover to the CNS) and the fact that marrow disease has not yet been as effectively brought under long-term control in AML as in ALL. Children with M4 and M5 AML have the highest incidence of CNS leukemia (especially those with inv(16) or 11q23 chromosomal abnormalities). The use of some form of intrathecal chemotherapy as CNS-directed treatment is now incorporated into most protocols for the treatment of childhood AML and is considered a standard part of the treatment for AML. Cranial radiation is no longer routinely employed in the treatment of children with AML.Granulocytic Sarcoma/Chloroma
Granulocytic sarcoma (chloroma) describes extramedullary collections of leukemia cells. These collections can occur, albeit rarely, as the sole evidence of leukemia. In a review of three AML studies conducted by the former CCG, fewer than 1% of patients had isolated granulocytic sarcoma, and 11% had granulocytic sarcoma along with marrow disease at the time of diagnosis. Importantly, the patient who presents with an isolated tumor, without evidence of marrow involvement, must be treated as if there is systemic disease. Patients with isolated granulocytic sarcoma have a good prognosis if treated with current AML therapy.
Patients with marrow disease and extramedullary disease limited to the skin do worse than those without granulocytic sarcoma. In one study, AML patients with orbital granulocytic sarcoma and CNS granulocytic sarcoma appeared to have a better survival than patients with marrow disease and granulocytic sarcoma at other sites and AML patients without any extramedullary disease. The majority of patients with orbital granulocytic sarcoma have a t(8;21) abnormality, which has been associated with a favorable prognosis. The use of radiation therapy does not improve survival in patients with granulocytic sarcoma who have a complete response to chemotherapy, but may be necessary if the site(s) of granulocytic sarcoma do not show complete response to chemotherapy or for disease that recurs locally.Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with untreated childhood acute myeloid leukemia and other myeloid malignancies. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
- Ries LAG, Melbert D, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2005. Bethesda, Md: National Cancer Institute, 2007. Also available online. Last accessed October 18, 2013.
- Gibson BE, Wheatley K, Hann IM, et al.: Treatment strategy and long-term results in paediatric patients treated in consecutive UK AML trials. Leukemia 19 (12): 2130-8, 2005. [PUBMED Abstract]
- Lange BJ, Smith FO, Feusner J, et al.: Outcomes in CCG-2961, a children's oncology group phase 3 trial for untreated pediatric acute myeloid leukemia: a report from the children's oncology group. Blood 111 (3): 1044-53, 2008. [PUBMED Abstract]
- Creutzig U, Büchner T, Sauerland MC, et al.: Significance of age in acute myeloid leukemia patients younger than 30 years: a common analysis of the pediatric trials AML-BFM 93/98 and the adult trials AMLCG 92/99 and AMLSG HD93/98A. Cancer 112 (3): 562-71, 2008. [PUBMED Abstract]
- Kaspers GJ, Creutzig U: Pediatric acute myeloid leukemia: international progress and future directions. Leukemia 19 (12): 2025-9, 2005. [PUBMED Abstract]
- Stevens RF, Hann IM, Wheatley K, et al.: Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukemia: results of the United Kingdom Medical Research Council's 10th AML trial. MRC Childhood Leukaemia Working Party. Br J Haematol 101 (1): 130-40, 1998. [PUBMED Abstract]
- Creutzig U, Ritter J, Zimmermann M, et al.: Improved treatment results in high-risk pediatric acute myeloid leukemia patients after intensification with high-dose cytarabine and mitoxantrone: results of Study Acute Myeloid Leukemia-Berlin-Frankfurt-Münster 93. J Clin Oncol 19 (10): 2705-13, 2001. [PUBMED Abstract]
- Hann IM, Stevens RF, Goldstone AH, et al.: Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia. Results of the Medical Research Council's 10th AML trial (MRC AML10). Adult and Childhood Leukaemia Working Parties of the Medical Research Council. Blood 89 (7): 2311-8, 1997. [PUBMED Abstract]
- Creutzig U, Ritter J, Zimmermann M, et al.: Idarubicin improves blast cell clearance during induction therapy in children with AML: results of study AML-BFM 93. AML-BFM Study Group. Leukemia 15 (3): 348-54, 2001. [PUBMED Abstract]
- Gibson BE, Webb DK, Howman AJ, et al.: Results of a randomized trial in children with Acute Myeloid Leukaemia: medical research council AML12 trial. Br J Haematol 155 (3): 366-76, 2011. [PUBMED Abstract]
- Burnett AK, Hills RK, Milligan DW, et al.: Attempts to optimize induction and consolidation treatment in acute myeloid leukemia: results of the MRC AML12 trial. J Clin Oncol 28 (4): 586-95, 2010. [PUBMED Abstract]
- Weick JK, Kopecky KJ, Appelbaum FR, et al.: A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood 88 (8): 2841-51, 1996. [PUBMED Abstract]
- Bishop JF, Matthews JP, Young GA, et al.: A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 87 (5): 1710-7, 1996. [PUBMED Abstract]
- Becton D, Dahl GV, Ravindranath Y, et al.: Randomized use of cyclosporin A (CsA) to modulate P-glycoprotein in children with AML in remission: Pediatric Oncology Group Study 9421. Blood 107 (4): 1315-24, 2006. [PUBMED Abstract]
- Rubnitz JE, Inaba H, Dahl G, et al.: Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial. Lancet Oncol 11 (6): 543-52, 2010. [PUBMED Abstract]
- Ozer H, Armitage JO, Bennett CL, et al.: 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 18 (20): 3558-85, 2000. [PUBMED Abstract]
- Creutzig U, Zimmermann M, Lehrnbecher T, et al.: Less toxicity by optimizing chemotherapy, but not by addition of granulocyte colony-stimulating factor in children and adolescents with acute myeloid leukemia: results of AML-BFM 98. J Clin Oncol 24 (27): 4499-506, 2006. [PUBMED Abstract]
- Lehrnbecher T, Zimmermann M, Reinhardt D, et al.: Prophylactic human granulocyte colony-stimulating factor after induction therapy in pediatric acute myeloid leukemia. Blood 109 (3): 936-43, 2007. [PUBMED Abstract]
- Ehlers S, Herbst C, Zimmermann M, et al.: Granulocyte colony-stimulating factor (G-CSF) treatment of childhood acute myeloid leukemias that overexpress the differentiation-defective G-CSF receptor isoform IV is associated with a higher incidence of relapse. J Clin Oncol 28 (15): 2591-7, 2010. [PUBMED Abstract]
- Johnston DL, Alonzo TA, Gerbing RB, et al.: The presence of central nervous system disease at diagnosis in pediatric acute myeloid leukemia does not affect survival: a Children's Oncology Group study. Pediatr Blood Cancer 55 (3): 414-20, 2010. [PUBMED Abstract]
- Pui CH, Dahl GV, Kalwinsky DK, et al.: Central nervous system leukemia in children with acute nonlymphoblastic leukemia. Blood 66 (5): 1062-7, 1985. [PUBMED Abstract]
- Creutzig U, Zimmermann M, Bourquin JP, et al.: CNS irradiation in pediatric acute myleoid leukemia: equal results by 12 or 18 Gy in studies AML-BFM98 and 2004. Pediatr Blood Cancer 57 (6): 986-92, 2011. [PUBMED Abstract]
- Dusenbery KE, Howells WB, Arthur DC, et al.: Extramedullary leukemia in children with newly diagnosed acute myeloid leukemia: a report from the Children's Cancer Group. J Pediatr Hematol Oncol 25 (10): 760-8, 2003. [PUBMED Abstract]
- Johnston DL, Alonzo TA, Gerbing RB, et al.: Superior outcome of pediatric acute myeloid leukemia patients with orbital and CNS myeloid sarcoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 58 (4): 519-24, 2012. [PUBMED Abstract]