Diagnosis and Treatment of Pediatric Acute Myeloid Leukemia

소아 급성골수성백혈병의 진단 및 치료

이재욱ㆍ조 빈

가톨릭대학교 의과대학 소아과학교실

Diagnosis and Treatment of Pediatric Acute Myeloid Leukemia

Jae Wook Lee, M.D., Ph.D. and Bin Cho, M.D., Ph.D.

Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea

Acute myeloid leukemia (AML) is a heterogeneous malignancy that comprises 25-30%

of pediatric leukemias in Korea. Several inherited diseases, such as Down syndrome and Fanconi anemia, predispose towards AML leukemogenesis. Subgrouping of AML is a key diagnostic step, previously done with the French-American-British (FAB) classi- fication and recently complemented by that of the World Health Organization (WHO).

An important feature of AML is the possibility of chloroma at diagnosis, which, if de- tected, requires follow-up evaluation to determine treatment response. Numerous genetic abnormalities with prognostic relevance have recently been found, the most important of which include those of the core-binding factor (CBF) leukemias, and FLT3-ITD mutation. These genetic abnormalities, combined with patient response to initial treat- ment, allow for a scheme of risk stratification, and the current consensus is to treat low risk patients with chemotherapy only, whereas high risk patients may receive allogeneic transplant in first remission, although the benefits of transplant remain inconclusive.

Overall, the outcome of children and adolescents with AML has improved significantly so that many clinical trials now report event-free survival of around 60%. However, much of this improvement stems from better supportive care and transplant methods, and the genetics-based diagnostic advances in AML have yet to result in enhanced treatment.

New therapeutics, including possibly targeted therapy, are necessary to further improve the outcome of pediatric AML.

pISSN 2233-5250 / eISSN 2233-4580 http://dx.doi.org/10.15264/cpho.2015.22.1.8

Clin Pediatr Hematol Oncol 2015;22:8∼14

Received on April 7, 2015 Revised on April 13, 2015 Accepted on April 16, 2015

Corresponding Author: Bin Cho

Department of Pediatrics, College of Medicine, Seoul Saint Mary's Hospital, The Catholic University of Korea, Seocho-gu, Banpo-daero 222, Seoul 137-701, Korea Tel: +82-2-2258-6187 Fax: +82-2-537-4544

E-mail: chobinkr@catholic.ac.kr

Key Words: Acute myeloid leukemia, Children, Genetic abnormalities, Chemotherapy, Hematopoietic cell transplantation

Introduction

Acute myeloid leukemia (AML) is the second most com- mon form of leukemia after acute lymphoblastic leukemia in children and adolescents, and accounts for approx- imately 25-30% of pediatric leukemias in Korea. In the past,

patients with AML had a uniformly dismal prognosis.

However, improvements in risk stratification based on ge-

netic and cytogenetic abnormalities harbored by the leuke-

mic blast, as well as response to therapy, and advances in

hematopoietic cell transplantation (HCT) methodology and

supportive care have all contributed to better survival for

childhood AML. Several national and multi-national trials

Fig. 1. (A) Morphology of AML with maturation (M2), showing myeloblasts with abundant cytoplasmic granulation, as well as more

now report around 60% event-free survival (EFS) and 70%

overall survival (OS).

Predisposition

Most patients with de novo AML do not have significant risk factors for leukemogenesis. However, many inherited diseases may predispose to subsequent diagnosis of AML.

Down syndrome is perhaps the most widely known amongst the inherited diseases with a predilection for acute leuke- mia, including AML, with one large-scale study reporting that Down syndrome patients comprise around 14% of chil- dren with AML [1]. Other genetic diseases that may evolve into AML include Fanconi anemia, Bloom syndrome, Kostmann disease, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, Li-Fraumeni syndrome, and neurofibromatosis type 1. Previous chemotherapy for a different malignancy or im- munosuppressive therapy is also a major risk factor for sec- ondary AML. These cases are currently classified as “thera- py-related myeloid neoplasms” according to the World Health Organization (WHO) classification, and are characterized by cytogenetic abnormalities such as monosomy 5, monosomy 7 and MLL gene rearrangements [2].

Classification of AML

Historically, AML has been classified according to the French-American-British (FAB) system which categorizes AML according to morphology, from minimally differentiated (M0) to megakaryoblastic leukemia (M7). Each subtype of AML is morphologically distinct. For example, AML with maturation (M2) is noted for the presence of myeloblasts with abundant cytoplasmic granulation and Auer rods, co- existing with promyelocytes and myelocytes (Fig. 1A). In contrast, AML, M7 is characterized by megakaryoblasts which often have cytoplasmic bleb or pseudopod formation, and little granulation (Fig. 1B). Bone marrow fibrosis, resulting in a difficult diagnostic aspiration, is a pathologic hallmark of AML, M7 at diagnosis.

In contrast to the morphology-based FAB classification of AML, the WHO classification is notable for grouping AML according to recurrent genetic abnormalities [2]. Included within this group are the genetic abnormalities that make up the core-binding factor (CBF) leukemias, t(8;21)(q22;q22) (RUNX1-RUNX1T1), and inv(16)(p13.1q22) or t(16;16)(p- 13.1;q22)(CBFB-MYH11), which are frequently observed in children with AML, as well as abnormalities that are rela- tively scarce, such as t(6;9)(p23;q34)(DEK-NUP214).

Both the FAB classification and the WHO classification

Fig. 2. (A) 11 year old male patient

have distinct advantages. The FAB classification is important in that it allows the specific diagnosis of AML subtypes that are morphologically unique, such as acute erythroid leuke- mia (M6) and acute megakaryoblastic leukemia (M7), while the WHO classification perhaps aids in better clarifying overall prognosis, based on the genetic features of the leu- kemic blast. Hence, an attempt at subgrouping AML ac- cording to both classification schemes may have comple- mentary benefits in the final diagnosis of the child with AML.

Extramedullary Involvement

A distinct feature of AML is extramedullary involvement (EMI) of leukemia, manifested as chloromas, or granulocytic sarcomas. Large-scale studies indicate that the incidence of EMI in children with de novo AML is 7-23% [3,4]. EMI may occur anywhere in the body, and may be overt at diagnosis resulting in symptoms such as proptosis or paraplegia due to spinal cord compression (Fig. 2A, B), or may include asymptomatic organ involvement. As EMI may be found re- gardless of patient symptoms, imaging evaluations such as whole body MRI at diagnosis may aid in detecting baseline EMI prior to therapy. Due possibly to its rarity in childhood AML, the prognostic importance of EMI remains unclear, when compared to the clear association between certain ge- netic abnormalities and overall prognosis. A Japanese study of 240 children with AML found that the presence of EMI when combined with an initial white blood cell (WBC)

count of greater than 100×10

/L predicted lower EFS [4].

Certainly for patients with EMI, important post-treatment evaluations, such as after remission induction and prior to and after HCT, should include evaluation of EMI as well as the bone marrow.

Initial Treatment

Improvements in HCT methods and enhanced supportive care, especially the treatment of infectious complications, have led to increased survival for pediatric AML, so that many large scale studies report 50-60% EFS and 60-70% OS [5-10].

The key elements of remission induction therapy have remained constant and usually consist of an anthracycline such idarubicin given for 3 days and cytarabine given for 7 days. Either etoposide or thioguanine may be added to this regimen, and the Medical Research Council (MRC) AML 10 trial has shown that both have equivalent therapeutic ef- ficacy [11]. Central nervous system (CNS) directed intra- thecal treatment (for example, cytarabine) should also be given with induction treatment.

An important consideration for patients who start in-

duction chemotherapy is hyperleukocytosis, that is a WBC

count of greater than 100×10

/L at diagnosis. These pa-

tients comprise almost 20% of children with AML, and are

associated with FAB M1, M4 or M5 morphology, inv(16)

(p13.1q22) and FLT3-ITD genetic abnormalities [12]. Hyper-

leukocytosis is clinically significant because it contributes to

early mortality through pulmonary and intracranial hemor- rhage resulting from leukostasis of the large myeloblasts.

Options in this setting include leukapheresis to rapidly re- duce the WBC count, but data on its efficacy is conflicting and at least one study has shown that such procedures do not result in lower early mortality [12]. Optimal manage- ment of such patients may require a combination of leuko- depletion and aggressive treatment of coagulopathy through transfusions of platelets and fresh frozen plasma, and judi- cious supportive care has shown to result in improved sur- vival [13]. At best, children with AML and initial hyper- leukocytosis still remain an oncologic emergency without an ideal treatment standard, and which requires intensive support to prevent early mortality.

Genetic Abnormalities and Prognosis

Amongst the cytogenetic abnormalities with a distinctly good prognosis are those of the CBF leukemias, that is, t(8;21)(q22;q22), and inv(16)(p13.1q22) or t(16;16)(p13.1;q22).

Studies from the MRC and Berlin-Frankfurt-Münster (BFM) group both report OS rates above 90% for patients with these genetic abnormalities [14,15]. One factor, however, which may influence this good prognosis is concurrent mu- tation of the KIT proto-oncogene. A large Children’s Oncology Group (COG) study found that KIT mutation status did not adversely affect outcome of children with CBF leukemia [16], in contrast to several other studies which found that children with mutated KIT had lower survival than those patients with wild type KIT [17,18].

Gene mutations are also prognostic in childhood AML.

For adult AML patients, mutations of the nucleophosmin gene (NPM1) confer a good prognosis when found with a normal karyotype and wild type FLT3 [19]. Results from the Pediatric Oncology Group (POG)-9421 study indicate that the incidence of childhood AML patients with mutated NPM1 is around 8%, and that patients with these mutations have a relatively favorable EFS of 69% when found in the setting of wild type FLT3 [20]. Biallelic mutations of the CEBPA gene have also been linked to favorable outcome, with 5-year EFS of 70% [21].

In contrast, several genetic abnormalities are associated

with a poor prognosis. Internal tandem duplication of the juxtamembrane domain of FLT3 (FLT3-ITD) has clearly been linked to lower survival by several large scale pediatric studies [22,23]. Monosomy 7 has also been proven to be a poor prognostic factor in childhood AML. An international study of 258 AML children with either monosomy 7 or dele- tion 7q found that patients with monosomy 7 had an OS rate of 30% [24]. In particular, patients with monosomy 7 and inv(3)(q21q26.2) or t(3;3)(q21;q26.2), genetic abnor- malities that are considered recurrent according to the WHO classification, had a dismal 5% survival rate.

AML patients with a complex karyotype, that is 3 or more structural or numerical abnormalities in the absence of a WHO designated recurrent genetic abnormality, may also have lower survival, as shown by studies from the MRC and BFM groups [14,15]. The genetic abnormality t(6;9)(p22;q34) is defined as recurrent according to the WHO classification, but is rarely found in childhood, with an incidence of less than 1%. This abnormality is more of- ten found in older children and in male patients. Patients with this abnormality often also have the FLT3-ITD muta- tion, but recent studies indicate that patients with t(6;9) (p22;q34) have a high relapse rate and low survival, irre- spective of the FLT3 mutation status [25,26].

The cryptic translocation t(5;11)(q35;p15.5)(NUP98-NSD1) is often found in conjunction with the FLT3-ITD mutation [27], and a recent study based in part on pediatric patients from 4 consecutive trials found that patients with both NUP98-NSD1 and FLT3-ITD mutation had significantly lower CR rate and OS compared with patients with FLT3-ITD mutation alone [28].

Genetic abnormalities involving the MLL gene (11q23)

are found in 15-20% of pediatric AML, with the prognosis

dictated by the MLL rearrangement depending on its trans-

location partner. An international study on 756 AML chil-

dren with MLL rearrangements found that patients with

t(1;11)(q21;q23) had an extremely favorable outcome with

92% EFS, while patients with t(6;11)(q27;q23) or t(10;11)

(p11.2;q23) had less than 20% EFS [29]. A recent study has

shown a relatively high incidence of t(10;11) and t(6;11)

amongst pediatric patients with MLL-rearranged AML, indicat-

ing that the MLL rearrangement is more likely to predict a

poor prognosis in the pediatric patient population [30].

Table 1. Genetic abnormalities that influence prognosis in

Proven implications

t(8;21)(q22;q22) Favorable

inv(16)(p13.1q22)/t(16;16)(p13.1;q22) Favorable

t(15;17)(q22;q12)^a) Favorable

FLT3-ITD mutation

Monosomy 7 Unfavorable

Probable implications

NPM1 mutation

CEBPA biallelic mutation

t(6;9)(p23;q34) Unfavorable

Complex karyotype^b) Unfavorable

a)Found in AML M3, ^b)3 or more structural or numerical abnor- malities in the absence of a WHO designated recurrent genetic abnormality.

A summary of genetic abnormalities with proven or probable prognostic implications is shown in Table 1. A morphology-based subtype of AML with potentially poor outcome is acute megakaryoblastic leukemia, or AML, M7, in the absence of Down syndrome, with studies from St.

Jude Children’s Research Hospital and the BFM group in- dicating EFS of 14-41%, although one study from Japan re- ported on 10-year OS of 76% [31-33]. A recent study on non-Down syndrome AML M7 showed that all 5 patients with t(1;22)(p13;q13) survived without event, and although the number of patients is small, this result suggests that the t(1;22) genetic abnormality is a good prognostic feature for children with a subtype of AML previously known to have guarded outcome [34].

Post-remission Treatment

Once complete remission (CR) is achieved, patients may receive additional consolidation chemotherapy including high dose cytarabine for a total of 4 to 5 courses of chemo- therapy including remission induction, or proceed to allo- geneic HCT. Whether the patient completes treatment with chemotherapy only or receives HCT may depend on im- portant prognostic factors specific for the leukemic blast

such as the previously mentioned cytogenetic abnormalities and gene mutations, as well as overall response to 1 to 2 courses of remission induction treatment.

The current consensus is that patients with favorable cy- togenetic features and excellent response to remission in- duction chemotherapy should receive chemotherapy-based treatment only so that they may be spared the long-term toxicities of allogeneic transplant. For the remaining inter- mediate risk patients, that is patients whose genetic features are prognostically neutral, and high risk patients, that is pa- tients with clear poor prognosis genetic abnormalities or with inadequate response to initial chemotherapy, the opti- mum treatment modality remains controversial. Results from the Children’s Cancer Group (CCG)-2891 study in- dicated a significant survival advantage for AML patients who received allogeneic HCT, whereas survival for recipi- ents of chemotherapy or autologous transplant was similar [35]. However, a more recent combined study from 4 group clinical trials, which included 1,373 AML children in first CR, showed that allogeneic HCT improved survival in the intermediate risk group of patients by decreasing relapse, whereas neither chemotherapy nor allogeneic transplant proved superior in the favorable risk and poor risk group patients [36]. Overall, a clear trend exists for undertaking HCT in first CR only for those patients who are likely to benefit from allogeneic transplant. Within this context, one method of treatment allocation would be to treat with che- motherapy only for low risk patients, undertake HCT for intermediate risk patients if they have an HLA well-matched donor, and pursue HCT in first CR for high risk patients regardless of matched donor availability, that is, with a mis- matched or haploidentical donor if necessary.

Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is characterized by

genetic fusions involving the RARA gene (17q21), most

commonly with the PML gene (15q22), resulting in sensi-

tivity to all-trans retinoic acid (ATRA). Treatment of pedia-

tric APL is similar to that of adult APL and mainly consists

of induction and consolidation based on ATRA, anthracy-

clines, and cytarabine, and maintenance treatment that also

includes ATRA. Treatment based on such a strategy resulted in 76% EFS and 89% OS according to one pediatric study [37]. The initial diagnosis of APL is an oncologic emergency due to the risk of intracranial and pulmonary bleeding from the associated coagulopathy. Hence, ATRA should be ad- ministered upon suspicion of APL, and concurrent chemo- therapy given upon genetic confirmation of APL. A single institution Korean study confirmed the efficacy of ATRA combined with chemotherapy, with 78% EFS, and also un- derscored the poor prognosis of patients who present with a WBC count greater than 10×10

/L [38].

Conclusions

Recent discovery of important prognostic markers in AML has confirmed that AML is a heterogeneous disease. Genetic and cytogenetic abnormalities combined with patient re- sponse to initial therapy have helped classify patients ac- cording to overall prognosis, so that low risk patients may benefit from chemotherapy-based treatment only, while high risk patients may undergo transplant from alternative donors, if necessary.

Although the outcome of childhood AML has improved considerably, much of this is a result of better supportive care and advances in HCT methodology. Recent genetic findings of AML have yet to translate into better survival for these patients. Improving the outcome of pediatric AML will require a more precise delineation of risk groups, and the implementation of new therapy and perhaps targeted therapy for those who are unlikely to respond to current treatment methods.

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