Treatment Overview for Acute Myeloid Leukemia (AML)
Because of the intensity of therapy utilized to treat AML, children with this disease must have their care coordinated by specialists in pediatric oncology, and they must 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.[4,15,16,17,18] The age effect is not large, but there is consistency in the observation that adolescents have a somewhat poorer outcome than younger children.
Infants have been reported to have a 5-year survival of about 50%, although with increased treatment-associated toxicity when treated with standard AML regimens.
- 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.[17,20] 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.[23,24]
- 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.[17,25] Inferior survival was attributable to early treatment-related mortality that was primarily due to infectious complications.
- White blood cell (WBC) count: WBC count at diagnosis has been consistently noted to be inversely related to survival.[4,26,27]
- 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.[28,29,30] Some studies have indicated a relatively poor outcome for M7 (megakaryocytic leukemia) in patients without Down syndrome,[22,31] though reports suggest an intermediate prognosis for this group of patients when contemporary treatment approaches are used.[3,32] 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.[34,35]
The presence of CNS disease (CNS2 and/or CNS3) at diagnosis has not been shown to affect overall survival; 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 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 either by standard morphologic examination of bone marrow,[26,38] by cytogenetic analysis, or by more sophisticated techniques to identify MRD.[40,41,42] Multiple groups have shown that the level of MRD after one course of induction therapy is an independent predictor of prognosis.[40,42,43]
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. However, there has been success with these approaches as evidenced by the demonstration that the persistence of the PML-RARA fusion product in APL is significantly associated with a high risk of relapse, and that early therapeutic intervention prior to morphologic relapse may improve outcome.[44,45] Similarly, quantitative RT–PCR detection of AML1-ETO fusion transcripts can effectively predict higher risk of relapse for patients in clinical remission.[46,47,48] 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, it can be useful in detecting residual leukemia.
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.[42,43,52]