Treatment Overview for Acute Myeloid Leukemia (AML)
The mainstay of the therapeutic approach is systemically administered combination chemotherapy. Future approaches involving risk-group stratification and biologically targeted therapies are being tested to improve antileukemic treatment while sparing normal tissues. Optimal treatment of acute myeloid leukemia (AML) requires control of bone marrow and systemic disease. Treatment of the central nervous system (CNS), usually with intrathecal medication, is a component of most pediatric AML protocols but has not yet been shown to contribute directly to an improvement in survival. CNS irradiation is not necessary in patients either as prophylaxis or for those presenting with cerebrospinal fluid leukemia that clears with intrathecal and systemic chemotherapy.
Treatment is ordinarily divided into two phases: (1) induction (to attain remission), and (2) postremission consolidation/intensification. Postremission therapy may consist of varying numbers of courses of intensive chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HSCT). For example, ongoing trials of the Children’s Oncology Group (COG) and the United Kingdom Medical Research Council (MRC) utilize similar chemotherapy regimens consisting of two courses of induction chemotherapy followed by two additional courses of intensification chemotherapy.[3,4]
Maintenance therapy is not part of most pediatric AML protocols as two randomized clinical trials failed to show a benefit for maintenance chemotherapy.[5,6] The exception to this generalization is acute promyelocytic leukemia (APL), for which maintenance therapy has been shown to improve event-free survival and overall survival (OS).
Treatment approaches currently used for AML are usually associated with severe and protracted myelosuppression along with other associated complications. Treatment with hematopoietic growth factors (granulocyte-macrophage colony-stimulating factor [GM-CSF] and granulocyte colony-stimulating factor [G-CSF]) has been used in an attempt to reduce the toxic effects associated with severe myelosuppression but does not influence ultimate outcome. Virtually all randomized trials of hematopoietic growth factors (GM-CSF and G-CSF) in adults with AML have demonstrated significant reduction in the time to neutrophil recovery,[9-12] but varying degrees of reduction in morbidity and little, if any, effect on mortality. The BFM 98 study confirmed a lack of benefit for the use of G-CSF in a randomized pediatric AML trial.
Because of the intensity of therapy utilized to treat AML, children with this disease should have their care coordinated by specialists in pediatric oncology and 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). Approximately one-half of the remission induction failures are due to resistant disease and the other half are due to toxic deaths. For example, in the MRC 10 and 12 AML trials, there was a 4% resistant disease rate in addition to a 4% induction death rate. With increasing rates of survival for children treated for AML comes an increased awareness of long-term sequelae of various treatments. For children who receive intensive chemotherapy, including anthracyclines, continued monitoring of cardiac function is critical. Periodic renal and auditory examinations are also suggested. In addition, total-body irradiation before HSCT increases the risk of growth failure, gonadal and thyroid dysfunction, and cataract formation.
Prognostic Factors in Childhood AML
Prognostic factors in childhood AML have been identified and can be categorized as follows:
Age: Several reports published since 2000 have identified older age as being an adverse prognostic factor.[4,15-19] The age effect is not large, but there is consistency in the observation that adolescents have a somewhat poorer outcome than younger children.
While outcome for infants with ALL remains inferior to that of older children, outcome for infants with AML is similar to that of older children when they are treated with standard AML regimens.[15,20-22] Infants have been reported to have a 5-year survival of 60% to 70%, although with increased treatment-associated toxicity.[15,20-22]
- Race/Ethnicity: In both the Children's Cancer Group (CCG) CCG-2891 and COG-2961 (CCG-2961) studies, Caucasian children had higher OS rates than African American and Hispanic children.[17,23] A trend for lower survival rates for African American children compared with Caucasian children was also observed in children treated on St. Jude Children’s Research Hospital AML clinical trials.
Down syndrome: For children with Down syndrome who develop AML, outcome is generally favorable. The prognosis is particularly good (event-free survival exceeding 80%) in children aged 4 years or younger at diagnosis, the age group that accounts for the vast majority of Down syndrome patients with AML.[26,27]
A large study of children with AML and Down syndrome confirmed the prognostic significance of younger age, and it identified the absence of cytogenetic abnormalities (other than trisomy 21), representing approximately 30% of cases, as an independent predictor of inferior OS and EFS.
- Body mass index: In the COG-2961 (CCG-2961) study, obesity (body mass index more than 95th percentile for age) was predictive of inferior survival.[17,29] Inferior survival was attributable to early treatment-related mortality that was primarily due to infectious complications. Obesity has been associated with inferior survival in children with AML, primarily caused by a higher rate of fatal infections during the early phases of treatment.
- White blood cell (WBC) count: WBC count at diagnosis has been consistently noted to be inversely related to survival.[4,31-33] Patients with high presenting leukocyte counts have a higher risk of developing pulmonary and CNS complications and have a higher risk of induction death.
- FAB subtype: Associations between FAB subtype and prognosis have been more variable. The M3 (APL) subtype has a favorable outcome in studies utilizing all-trans retinoic acid in combination with chemotherapy.[35-37] Some studies have indicated a relatively poor outcome for M7 (megakaryocytic leukemia) in patients without Down syndrome,[25,38] though reports suggest an intermediate prognosis for this group of patients when contemporary treatment approaches are used.[3,39] The M0, or minimally differentiated subtype, has been associated with a poor outcome.
CNS disease: CNS involvement at diagnosis is categorized based on the presence or absence of blasts in cerebrospinal fluid (CSF), as follows:
- CNS1: CSF negative for blasts on cytospin, regardless of CSF WBC count.
- CNS2: CSF with fewer than five WBC/μL and cytospin positive for blasts.
- CNS3: CSF with five or more WBC/μL and cytospin positive for blasts.
CNS2 disease has been observed in approximately 13% of children with AML and CNS3 disease in 11% to 17% of children with AML.[41,42] In another study, patients with CNS3 were younger and had a higher incidence of t(9;11), t(8;21) or inv(16).
The presence of CNS disease (CNS2 and/or CNS3) at diagnosis has not been shown to affect OS; however, it may be associated with an increased risk of isolated CNS relapse.
Cytogenetic and molecular characteristics: Cytogenetic and molecular characteristics are also associated with prognosis. (Refer to the Cytogenetic evaluation and molecular abnormalities section in the Classification of Pediatric Myeloid Malignancies subsection of this summary for detailed information.) Cytogenetic and molecular characteristics that are currently used in clinical trials for treatment assignment include the following:
- Favorable: inv(16)/t(16;16) and t(8;21), t(15;17), biallelic CEBPA mutations, and NPM1 mutations.
- Unfavorable: monosomy 7, monosomy 5/del(5q), 3q abnormalities, and FLT3-ITD with high-allelic ratio.
Response to therapy/minimal residual disease (MRD): Early response to therapy, generally measured after the first course of induction therapy, is predictive of outcome and can be assessed by standard morphologic examination of bone marrow,[31,45] by cytogenetic analysis, by fluorescence in situ hybridization, or by more sophisticated techniques to identify MRD.[47-49] Multiple groups have shown that the level of MRD after one course of induction therapy is an independent predictor of prognosis.[47,49,50]
Molecular approaches to assessing MRD in AML (e.g., using quantitative reverse transcriptase–polymerase chain reaction [RT–PCR]) have been challenging to apply because of the genomic heterogeneity of pediatric AML and the instability of some genomic alterations. Quantitative RT–PCR detection of AML1-ETO fusion transcripts can effectively predict higher risk of relapse for patients in clinical remission.[51-54] Other molecular alterations such as NPM1 mutations  and CBFB-MYH11 fusion transcripts  have also been successfully employed as leukemia-specific molecular markers in MRD assays, and for these alterations the level of MRD has shown prognostic significance. The presence of FLT3-ITD has been shown to be discordant between diagnosis and relapse, although when its presence persists (usually associated with a high allelic ratio at diagnosis), it can be useful in detecting residual leukemia.
For APL, MRD detection at the end of induction therapy lacks prognostic significance, likely relating to the delayed clearance of differentiating leukemic cells destined to eventually die.[58,59] However, the kinetics of molecular remission following completion of induction therapy is prognostic, with the persistence of minimal disease after three courses of therapy portending increased risk of relapse.[59-61]
Flow cytometric methods have been used for MRD detection and can detect leukemic blasts based on the expression of aberrant surface antigens that differ from the pattern observed in normal progenitors. A CCG study of 252 pediatric patients with AML in morphologic remission demonstrated that MRD as assessed by flow cytometry was the strongest prognostic factor predicting outcome in a multivariate analysis. Other reports have confirmed both the utility of flow cytometric methods for MRD detection in the pediatric AML setting and the prognostic significance of MRD at various time points after treatment initiation.[49,50,62]
Risk classification systems under clinical evaluation
Risk classification for treatment assignment on the COG-AAML1031 study is based on cytogenetics, molecular markers, and MRD at bone marrow recovery postinduction I, with patients being divided into a low-risk or high-risk group as follows:
The low-risk group represents about 73% of patients, has a predicted OS of approximately 75%, and is defined by the following:
- Inv(16), t(8;21), nucleophosmin (NPM) mutations, or CEBPA mutations with any MRD status.
- Standard-risk cytogenetics (defined by the absence of either low-risk or high-risk cytogenetic characteristics) with negative MRD at end of Induction I.
The high-risk group represents the remaining 27% of patients, has a predicted OS less than 35%, and is defined by the following:
- High allelic ratio FLT3-ITD-positive with any MRD status.
- Monosomy 7 with any MRD status.
- del(5q) with any MRD status.
- Standard-risk cytogenetics with positive MRD at end of Induction I.
The high-risk group of patients will be offered transplantation in first remission with the most appropriate available donor. Patients in the low-risk group will only be offered transplantation in second complete remission.[62,63]
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