Pediatric acute myeloid leukemia (AML) is a heterogeneous group of diseases classified according to morphology, lineage, and genetics . The overall survival (OS) rates of children with AML have improved over the past three decades, with the current 5-year survival rate ranging from 65% to 75% [2-5]. Overall remission-induction rates are approximately 85% to 95% and event free survival (EFS) rates from the time of diagnosis range from 50% to 65% [2-5]. These improvements were driven by chemotherapy intensification, allogeneic hematopoietic stem cell transplantation (HSCT), and improved supportive care. During this period, most international cooperative study groups have coalesced to derive a treatment strategy that includes four to five courses of intensive myelosuppressive chemotherapy, including two courses of induction, predominantly based on cytarabine and anthracyclines with or without HSCT at the first complete remission (CR).
However, a wide range of outcomes exists for the different biological subtypes of AML. Specific biological factors can shift the predicted outcome for an individual patient to either a much better or a much worse outcome than the overall result of the general population of children with AML. Genomic investigations of AML have led to new genomic classifications and predictive biomarkers, resulting in better risk stratification and survival outcomes [6, 7].
Despite advancements in chemotherapy and supportive care, primary refractory or relapsed pediatric AML has resulted in significant morbidity and mortality, and long-term survival in patients with these disorders remains poor . As a result, efforts to identify new target therapy and cell therapy to improve OS in these individuals remain under continuous investigation.
AML prognosis is dependent on a range of cytogenetic and molecular characteristics. The risk factors used for stratification vary according to the pediatric and adult cooperative clinical trial groups, and the prognostic impact of a given risk factor can vary in significance according to the administered therapy. Most protocols warrant treatments based on cytogenetics at diagnosis and the responses after induction (Table 1). According to risk group stratification, survival from CR at 5 years significantly varied and the survival percentages for favorable, standard, and poor risks were 84, 76, and 47% (
Cytarabine and anthracycline are the two most important drugs administered to induce remission. Cytarabine is usually administered for 10 days, followed by daunorubicin for 3 days. Commonly used regimens for the induction phase in pediatric AML patients are cytarabine and anthracycline in combination with etoposide or thioguanine . The MRC AML 10 trial conducted a randomized comparison of the DAT (daunorubicin, cytarabine, thioguanine) and ADE (cytarabine, daunorubicin, etoposide) regimens but found no significant differences in CR rate or induction death. Moreover, the 10-year survival, OS, disease free survival (DFS), and EFS were recognized to be similar between the two regimens [3, 11]. However, the percentages of patients achieving remission after treatment and failing to achieve CR due to disease resistance were slightly better with the ADE regimen. Additionally, a relatively higher CR death rate was found during consolidation chemotherapy with ADE (9%) than with DAT (6%;
Among anthracyclines, daunorubicin is the most commonly administered drug in induction regimens. Cytarabine and etoposide in combination with either daunorubicin or idarubicin (ADE or AIE) were compared in the Berlin-Frankfurt-Münster (BFM) study, and similar EFS and OS were observed for both regimens [13, 14]. Likewise, a previous MRC trial showed no significant overall survival benefit from cytarabine, mitoxantrone, and etoposide (MAE) relative to ADE . Although idarubicin and mitoxantrone outcomes were not superior to those of daunorubicin, liposomal daunorubicin significantly reduced treatment-related mortality compared to idarubicin .
First-line treatments were intensified by the introduction of courses of high-dose cytarabine, new anthracyclines, or anthracycline formulations. High-dose cytarabine with mitoxantrone (HAM) or etoposide (HAE) was administered in the BFM-AML studies. The recent MRC 17 study used high-dose cytarabine containing FLAG-IDA in the poor risk group, and two courses of high-dose cytarabine in the other risk groups.
In the past, five chemotherapy courses served as the standard for frontline treatment. However, comparisons between the COG AAML0531 and AAML1031 studies showed that MRD level at the end of induction I, and not the removal of a fifth cytarabine-containing course, was the most significant predictor of relapse . Likewise, a fifth course showed no survival benefit in MRC AML15 .
CNS treatment, usually with intrathecal medication, is a standard component of most pediatric AML protocols; however, research has yet to directly associate this treatment with improvements in survival. Although CNS involvement (CNS2 or CNS3) at diagnosis was not correlated with OS in most studies, two consecutive COG trials found that CNS involvement, particularly CNS3 status, was associated with worse outcomes, including CR rate, EFS, disease-free survival, and an increased risk of relapse involving the CNS . In contrast to acute lymphoblastic leukemia, traumatic tapping did not increase CNS relapse incidence.
GO (Mylotarg) is a humanized anti-CD33-calicheamicin conjugate developed for the targeted treatment of AML. GO was approved for use by the United States FDA in 2000 ; however, in 2010, it was withdrawn from the market due to concerns of increased liver toxicity and myelosuppression. Nonetheless, GO has been incorporated into prospective trials for adults and children with AML. As a result, the manufacturer reapplied for FDA approval in 2017, with support from additional clinical results.
The COG AAML03P1 pilot study administered two doses of GO to 350 children with AML in courses 1 and 4 . Patients achieved a CR rate of 83% after one course and 87% after two courses. Although a mortality rate of 2.6% was obtained after two induction courses, the 3-year EFS and OS percentages were 53% and 66%. Based on these findings, a subsequent COG AAML0531 study randomly administered the standard five-course chemotherapy with or without two doses of GO (3 mg/m2/dose) to 1,022 patients ages 0 to 29 years with newly diagnosed AML . Based on their results, GO significantly reduced relapse risk (3 yr: 32.8% vs. 41.3%;
The use of allogeneic HSCT as a consolidation therapy for pediatric patients with AML in the first CR has been continuously evaluated in prospective clinical trials. In an analysis of 1,373 pediatric patients with AML, HLA-matched relative bone marrow transplantation only conferred survival benefits to intermediate cytogenetic risk groups. In prospective trials of allogeneic HSCT compared to chemotherapy and/or autologous HSCT, a superior DFS was observed for patients assigned to received allogeneic HSCT [21, 22]. However, results comparing allogeneic HSCT to chemotherapy remain inconclusive. Allogeneic HSCT has been limited to intermediate or poor risk groups in the first CR because of improved outcomes in patients with favorable cytogenetics or mutations receiving contemporary myelosuppressive combination chemotherapy. Conflicting reports on the efficacy of HSCT in intermediate risk groups [23, 24] have led many childhood AML studies to employ upfront allogeneic HSCT for poor risk groups alone; these include patients with unfavorable cytogenetics, genetic mutations, or elevated end-of-induction MRD levels . As the definitions of high-, intermediate-, and low-risk AML are evolving due to ongoing discoveries of the molecular characteristics of AML and more sophisticated assessments of MRD, a further analysis of the subpopulations of patients treated with allogeneic HSCT will be an ongoing need in current and future clinical trials.
The optimal preparative regimen and the source of donor cells have yet to be determined. For approximately 20 years, myeloablative doses of busulfan and high doses of cyclophosphamide were used in many studies. However, ongoing efforts to reduce toxicity- and treatment-related mortalities have led to the replacement of cyclophosphamide with fludarabine to introduce reduced intensity conditioning. There is no prospective randomized study comparing different conditioning regimens; however, previously, two large retrospective studies performed by the Center for International Blood and Marrow Transplant Research (CIBMTR) showed no significant survival difference between myeloablative and reduced-intensity conditioning regimens or busulfan/cyclophosphamide and busulfan/fludarabine regimens [26, 27].
Early responses to therapy, which are generally measured after the first course of induction therapy, is predictive of outcomes [28, 29]. Molecular approaches using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) to assess MRD in AML has proven challenging owing to the genomic heterogeneity of pediatric AML and the instability of some genomic alterations. Nonetheless, flow cytometric methods have been successfully used for MRD detection and can detect leukemic blasts according to the expression of aberrant surface antigens that differ from patterns observed in normal progenitors.
Quantitative RT-PCR detection of
Multiple groups have shown that the level of MRD after one course of induction therapy is an independent predictor of prognosis. The COG AAML03P1 study prospectively investigated MRD at the end of inductions I and II by flow cytometry and correlated these values with clinical outcomes in 350 patients . In a multivariate analysis that included cytogenetic and molecular risk factors, residual disease was an independent predictor of relapse. According to the St. Jude hospital AML02 study where high-dose or low-dose cytarabine was randomly administered with daunorubicin and etoposide (ADE; induction I) to 232 patients with de novo pediatric AML, an MRD ≥1% after induction I was the only significant independent adverse prognostic factor of survival .
Next-generation sequencing (NGS) is emerging as an important tool for the molecular analysis of AML at the time of initial diagnosis, especially in cytogenetically normal AML patients . Although more standardization of the methods of testing and interpretation is required, NGS has been used to assess MRD in AML patients.
Acute promyelocytic leukemia (APL) represents -6% to 11% of children with AML . This distinct patient group has t(15;17) in their blasts and is administered different treatments relative to other AML patient groups. Although the WHO 2016 revision does not include the t(15;17) cytogenetic designation, it references the
Maintenance therapy for APL consisting of ATRA and chemotherapy has been shown to improve EFS and OS . More recently, APL clinical trials have evaluated treatment with arsenic trioxide (ATO) . In a pediatric study (AAML0631), all patients received two cycles of ATO therapy during consolidation 1, an additional two (standard risk) or three (high risk) consolidation courses that included high-dose cytarabine and anthracycline, and maintenance therapy comprising of ATRA, oral methotrexate, and mercaptopurine . As a result, the ATO consolidation cycles were well tolerated and allowed a significant reduction in cumulative anthracycline doses while maintaining excellent survival and a low relapse risk for both risk groups. ATO is currently being used in clinical trials for newly diagnosed and relapsed APL.
Approximately 10% of neonates with Down syndrome develop transient abnormal myelopoiesis (TAM). The subsequent myeloid leukemia associated with Down syndrome also occurs in 10% to 30% of children with a spontaneous resolution of TAM when reported at a mean age of 16 months (range, 1–30 mo) [41, 42]. Survival outcomes of patients with Down syndrome and AML are superior to those of children with AML but without Down syndrome. Current treatment for children with Down syndrome and AML is less intensive than the standard chemotherapy for those with AML, and HSCT is not indicated at the first remission . In this group of patients, reduced doses of anthracyclines and treatment duration are recommended because of toxicity. According to a recent COG trial (AAML0431), substituting anthracycline with high-dose cytarabine-based regimens reduced the cumulative anthracycline dose. Moreover, the reduced doses of intrathecal chemotherapy did not negatively affect the final survival outcomes and relapse rates of patients compared to previous studies . Instead, intensification included two cycles of cytarabine and etoposide. Currently, the first prospective trial based on risk stratification in this patient group is being conducted through an assessment of MRD levels at the end of induction I .
The presence of the
Survival in children with relapsed or refractory AML remains unsatisfactory. Despite the induction of second remission in 60% to 70% of children with AML treated with similar drugs at their initial induction, their prognosis for recurrent or progressive AML is generally poor [51, 52]. For relapsed patients, the most significant prognostic factors associated with a favorable outcome include the achievement of a second CR, early response after salvage, late relapse, no previous allogeneic HSCT, and initial favorable cytogenetics [53, 54]. Consolidation chemotherapy followed by HSCT is generally recommended for these individuals, despite the lack of controlled prospective data.
Regimens for salvage chemotherapy in relapsed or refractory patients include new agents with conventional chemotherapeutics, such as cytarabine or daunorubicin (Table 2) [55-66]. Liposomal daunorubicin yields a favorable pharmacokinetic profile that causes a ten-fold increase in concentration compared to that achieved with conventional preparations . In a study by the BFM group, FLAG was compared to FLAG plus liposomal daunorubicin . Based on their findings, no significant survival differences were found; however, the addition of liposomal daunorubicin increased response rates by 10% and led to significant improvements in OS in patients with CBF mutations (82% vs. 58%;
Clofarabine is a purine nucleoside antimetabolite that is used to treat relapsed or refractory AML either as a single agent or in combination therapy [56-58,61,62,65,68,69]. The COG AAML0532 trial evaluated the combination of clofarabine and high dose cytarabine in relapsed pediatric patients with AML. Based on their findings, response rate was 48% and OS was 46% .
CPX-351 is a fixed liposomal formulation of daunorubicin and cytarabine approved by the FDA as Vyxeos (Jazz Pharmaceuticals) for the treatment of adults with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes. In adult AML patients, Vyxeos improved OS (estimated median OS, 9.6 mo) compared to the “7+3” control arm (5.9 mo) [60, 70]. Furthermore, Vyxeos was administered to relapsed pediatric patients with AML as a Phase I trial; this study comprised of 37 children and adolescents with relapsed or refractory AML . One treatment cycle consisted of three doses of Vyxeos on days 1, 3, and 5, and after up to two cycles of therapy (Cycle 1, CPX-351; Cycle 2, FLAG), response rates were assessed. The overall response rates (CR+CRp+Cri) were relatively high (81%; 20 CR, 5 CRp, and 5 CRi), with 70% of these responses being achieved after cycle 1. In this study, 23/29 responders (79%) received HSCT at follow-up. These promising results in relapsed or refractory pediatric patients with AML led to the adoption of a randomized study arm and GO compared to DA+GO in de novo pediatric patients with AML (AAML1831).
Epigenetics is defined as alterations in the transcriptional potential of genes owing to modifications of histones and chromatins rather than DNA itself. DNA methylation signatures have been used to identify biologically distinct subtypes of AML. By sequencing the DNA in AML cells, recurrent mutations in genes that encode proteins that alter DNA methylation patterns, such as
In AML, current developments of CAR-T cells aim to express CD33 or CD123 on the surface of AML blasts . Furthermore, researchers are targeting cell surface proteins that are often overexpressed or mutated in AML blasts, such as FLT3 . However, these strategies are confounded by the lack of specific markers for AML blasts and the significant adverse events caused by off-tumor effects.
Because of the heterogeneity of AML, an intervention or experimental agent that is beneficial to a subgroup of patients might not be suitable for the overall population. As a result, current and future trials of pediatric patients with AML are aiming or will aim to examine new agents that are designed for specific subgroups of patients. However, there may also be developments of new immunotherapeutic approaches that may be applicable to a wider range of AML subtypes . By gaining new insights into the genetics of AML and the biology and microenvironment of leukemia stem cells, new avenues could be established to aid in the future treatment of childhood AML.
No potential conflicts of interest relevant to this article were reported.