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
Contemporary pediatric AML protocols result in 85% to 90% complete remission rates.[6-8] Approximately 3% of patients die during the induction phase, most commonly due to treatment-related complications.[6-8] To achieve a complete remission, inducing profound bone marrow aplasia (with the exception of the M3 APL subtype) is usually necessary with currently used combination chemotherapy regimens. 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.[3,9,10] 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, although the thioguanine-containing regimen was associated with increased toxicity.
The anthracycline that has been most used in induction regimens for children with AML is daunorubicin,[3,9,10] although idarubicin and the anthracenedione mitoxantrone have also been used.[6,12,13] 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-Münster (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.[10,12]
- 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).[6,14] 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.
- The AML-BFM 2004 clinical trial compared liposomal daunorubicin (L-DNR) to idarubicin at a higher-than-equivalent dose (80 mg/m2 vs. 12 mg/m2 per day for 3 days) during induction. Five-year results in both treatment arms were similar for both OS and EFS. Treatment-related mortality was significantly lower with L-DNR than idarubicin (2 of 257 patients vs. 10 of 264 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,[16,17] 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.
In children with high-risk AML, the estimated incidence of severe bacterial infections is 50% to 60%, and the estimated incidence of invasive fungal infections is 7.0% to 12.5%.[20-22] Several approaches have been examined in terms of reducing the morbidity and mortality from infection in children with AML.
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.[7,23] 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.
The use of antibacterial prophylaxis in children undergoing treatment for AML has been supported by several studies. A retrospective study from St. Jude Children's Research Hospital (SJCRH) in patients with AML reported that the use of intravenous cefepime or vancomycin in conjunction with oral ciprofloxacin or a cephalosporin significantly reduced the incidence of bacterial infection and sepsis compared with patients receiving only oral or no antibiotic prophylaxis. A retrospective report from the COG-AAML0531 (NCT00372593) trial demonstrated significant reductions in sterile-site bacterial infection and particularly gram-positive, sterile-site infections were both associated with the use of antibacterial prophylaxis. Of note, this study also reported that prophylactic use of G-CSF reduced bacterial and Clostridium difficile infections. In a study that compared the percentage of bloodstream infections or invasive fungal infections in children with ALL or AML who underwent chemotherapy and received antibacterial and antifungal prophylaxis, a significant reduction in both variables was observed compared with a historical control group that did not receive any prophylaxis. While such studies suggest a benefit to the use of antibiotic prophylaxis, prospective randomized trials are needed in this pediatric group of patients.
Similarly, the role of antifungal prophylaxis has not been studied in children with AML using randomized, prospective studies. Nevertheless, two meta-analysis reports have suggested that antifungal prophylaxis in pediatric patients with AML during treatment-induced neutropenia or during bone marrow transplantation does reduce the frequency of invasive fungal infections and in some instances nonrelapse mortality.[29,30] However, another study that analyzed 1,024 patients with AML treated on the COG-AAML0531 (NCT00372593) clinical trial reported no benefit of antifungal prophylaxis on fungal infections or nonrelapse mortality. Several randomized trials in adults with AML, however, have reported significant benefit in reducing invasive fungal infection with the use of antifungal prophylaxis. Such studies have also balanced cost with adverse side effects; when effectiveness at reducing invasive fungal infection is balanced with these other factors, posaconazole, voriconazole, caspofungin, and micafungin are considered reasonable choices.[28,31-35]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): SJCRH 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 (minimal residual disease) 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 Children's Cancer Group, 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.
In a study of 1,459 children with newly diagnosed AML, patients with orbital granulocytic sarcoma and CNS granulocytic sarcoma had 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
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