소아급성골수성백혈병의진단및치료. Diagnosis and Treatment of Pediatric Acute Myeloid Leukemia 이재욱ㆍ조빈. Introduction

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1 Clinical Pediatric Hematology-Oncology Volume 22 ㆍ Number 1 ㆍ April 2015 REVIEW ARTICLE 소아급성골수성백혈병의진단및치료 이재욱ㆍ조빈 가톨릭대학교의과대학소아과학교실 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) classification 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 detected, 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 treatment, 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. Key Words: Acute myeloid leukemia, Children, Genetic abnormalities, Chemotherapy, Hematopoietic cell transplantation pissn / eissn 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 , Korea Tel: Fax: chobinkr@catholic.ac.kr Introduction Acute myeloid leukemia (AML) is the second most common form of leukemia after acute lymphoblastic leukemia in children and adolescents, and accounts for approximately 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 genetic and cytogenetic abnormalities harbored by the leukemic 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 8

2 Pediatric Acute Myeloid Leukemia now report around 60% event-free survival (EFS) and 70% overall survival (OS). Predisposition Classification of AML Historically, AML has been classified according to the French-American-British (FAB) system which categorizes Most patients with de novo AML do not have significant AML according to morphology, from minimally differentiated risk factors for leukemogenesis. However, many inherited (M0) to megakaryoblastic leukemia (M7). Each subtype of diseases may predispose to subsequent diagnosis of AML. AML is morphologically distinct. For example, AML with Down syndrome is perhaps the most widely known amongst maturation (M2) is noted for the presence of myeloblasts the inherited diseases with a predilection for acute leuke- with abundant cytoplasmic granulation and Auer rods, co- mia, including AML, with one large-scale study reporting existing with promyelocytes and myelocytes (Fig. 1A). In that Down syndrome patients comprise around 14% of chil- contrast, AML, M7 is characterized by megakaryoblasts which dren with AML [1]. Other genetic diseases that may evolve often have cytoplasmic bleb or pseudopod formation, and into AML include Fanconi anemia, Bloom syndrome, Kostmann little granulation (Fig. 1B). Bone marrow fibrosis, resulting disease, Shwachman-Diamond syndrome, Diamond-Blackfan in a difficult diagnostic aspiration, is a pathologic hallmark anemia, Li-Fraumeni syndrome, and neurofibromatosis type of AML, M7 at diagnosis. 1. Previous chemotherapy for a different malignancy or im- In contrast to the morphology-based FAB classification of munosuppressive therapy is also a major risk factor for sec- AML, the WHO classification is notable for grouping AML ondary AML. These cases are currently classified as thera- according to recurrent genetic abnormalities [2]. Included py-related myeloid neoplasms according to the World Health within this group are the genetic abnormalities that make Organization (WHO) classification, and are characterized by up the core-binding factor (CBF) leukemias, t(8;21)(q22;q22) cytogenetic abnormalities such as monosomy 5, monosomy (RUNX1-RUNX1T1), and inv(16)(p13.1q22) or t(16;16)(p- 7 and MLL gene rearrangements [2]. 13.1;q22)(CBFB-MYH11), which are frequently observed in children with AML, as well as abnormalities that are relatively scarce, such as t(6;9)(p23;q34)(dek-nup214). Both the FAB classification and the WHO classification Fig. 1. (A) Morphology of AML with maturation (M2), showing myeloblasts with abundant cytoplasmic granulation, as well as more mature myeloid precursors (Wright Giemsa, 1,000). (B) Morphology of AML, M7 characterized by megakaryoblasts with cytoplasmic bleb formation and sparse cytoplasmic granulation (Wright Giemsa, 1,000). Clin Pediatr Hematol Oncol 9

3 Jae Wook Lee and Bin Cho 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 leukemia (M6) and acute megakaryoblastic leukemia (M7), while the WHO classification perhaps aids in better clarifying overall prognosis, based on the genetic features of the leukemic blast. Hence, an attempt at subgrouping AML according to both classification schemes may have complementary 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 regardless 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 genetic 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 /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 efficacy [11]. Central nervous system (CNS) directed intrathecal treatment (for example, cytarabine) should also be given with induction treatment. An important consideration for patients who start induction chemotherapy is hyperleukocytosis, that is a WBC count of greater than /L at diagnosis. These patients 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]. Hyperleukocytosis is clinically significant because it contributes to Fig. 2. (A) 11 year old male patient with AML1-ETO (+) AML with periorbital EMI (arrow) resulting in proptosis at diagnosis. (B) 13 year old female patient with AML1-ETO (+) AML with sacral EMI (arrow). 10 Vol. 22, No. 1, April 2015

4 Pediatric Acute Myeloid Leukemia early mortality through pulmonary and intracranial hemorrhage resulting from leukostasis of the large myeloblasts. Options in this setting include leukapheresis to rapidly reduce 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 management of such patients may require a combination of leukodepletion and aggressive treatment of coagulopathy through transfusions of platelets and fresh frozen plasma, and judicious supportive care has shown to result in improved survival [13]. At best, children with AML and initial hyperleukocytosis 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 mutation 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 deletion 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 abnormalities 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 often found in older children and in male patients. Patients with this abnormality often also have the FLT3-ITD mutation, but recent studies indicate that patients with t(6;9) (p22;q34) have a high relapse rate and low survival, irrespective 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 translocation partner. An international study on 756 AML children 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, indicating that the MLL rearrangement is more likely to predict a poor prognosis in the pediatric patient population [30]. Clin Pediatr Hematol Oncol 11

5 Jae Wook Lee and Bin Cho 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 indicating EFS of 14-41%, although one study from Japan reported 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]. Table 1. Genetic abnormalities that influence prognosis in childhood AML Proven implications t(8;21)(q22;q22) inv(16)(p13.1q22)/t(16;16)(p13.1;q22) t(15;17)(q22;q12) a) FLT3-ITD mutation Monosomy 7 Probable implications 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 chemotherapy including remission induction, or proceed to allogeneic HCT. Whether the patient completes treatment with chemotherapy only or receives HCT may depend on important prognostic factors specific for the leukemic blast NPM1 mutation CEBPA biallelic mutation Rearranged MLL - t(1;11)(q21;q23) Rearranged MLL - t(6;11)(q27;q23) Rearranged MLL - t(10;11)(p11.2;q23) t(6;9)(p23;q34) Complex karyotype b) a) Found in AML M3, b) 3 or more structural or numerical abnormalities in the absence of a WHO designated recurrent genetic abnormality. 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 cytogenetic features and excellent response to remission induction chemotherapy should receive chemotherapy-based treatment only so that they may be spared the long-term toxicities of allogeneic transplant. For the remaining intermediate risk patients, that is patients whose genetic features are prognostically neutral, and high risk patients, that is patients with clear poor prognosis genetic abnormalities or with inadequate response to initial chemotherapy, the optimum treatment modality remains controversial. Results from the Children s Cancer Group (CCG)-2891 study indicated a significant survival advantage for AML patients who received allogeneic HCT, whereas survival for recipients 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 chemotherapy 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 mismatched 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 sensitivity to all-trans retinoic acid (ATRA). Treatment of pediatric APL is similar to that of adult APL and mainly consists of induction and consolidation based on ATRA, anthracyclines, and cytarabine, and maintenance treatment that also 12 Vol. 22, No. 1, April 2015

6 Pediatric Acute Myeloid Leukemia 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 administered upon suspicion of APL, and concurrent chemotherapy given upon genetic confirmation of APL. A single institution Korean study confirmed the efficacy of ATRA combined with chemotherapy, with 78% EFS, and also underscored the poor prognosis of patients who present with a WBC count greater than /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 response to initial therapy have helped classify patients according 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. References 1. Zeller B, Gustafsson G, Forestier E, et al. Acute leukaemia in children with Down syndrome: a population-based Nordic study. Br J Haematol 2005;128: Swerdlow SH, Campo E, Harris NL, et al, editors, WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: IARC Press, Johnston DL, Alonzo TA, Gerbing RB, Lange BJ, Woods WG. Superior outcome of pediatric acute myeloid leukemia patients with orbital and CNS myeloid sarcoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 2012;58: Kobayashi R, Tawa A, Hanada R, et al. Extramedullary infiltration at diagnosis and prognosis in children with acute myelogenous leukemia. Pediatr Blood Cancer 2007;48: Rubnitz JE, Inaba H, Dahl G, et al. Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial. Lancet Oncol 2010;11: Creutzig U, Zimmermann M, Lehrnbecher T, et al. Less toxicity by optimizing chemotherapy, but not by addition of granulocyte colony-stimulating factor in children and adolescents with acute myeloid leukemia: results of AML-BFM 98. J Clin Oncol 2006;24: Gibson BE, Webb DK, Howman AJ, et al. Results of a randomized trial in children with acute myeloid leukaemia: medical research council AML12 trial. Br J Haematol 2011; 155: Abrahamsson J, Forestier E, Heldrup J, et al. Response-guided induction therapy in pediatric acute myeloid leukemia with excellent remission rate. J Clin Oncol 2011;29: Tsukimoto I, Tawa A, Horibe K, et al. Risk-stratified therapy and the intensive use of cytarabine improves the outcome in childhood acute myeloid leukemia: the AML99 trial from the Japanese Childhood AML Cooperative Study Group. J Clin Oncol 2009;27: Cooper TM, Franklin J, Gerbing RB, et al. AAML03P1, a pilot study of the safety of gemtuzumab ozogamicin in combination with chemotherapy for newly diagnosed childhood acute myeloid leukemia: a report from the Children's Oncology Group. Cancer 2012;118: Stevens RF, Hann IM, Wheatley K, Gray RG. Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukemia: results of the United Kingdom Medical Research Council's 10th AML trial. MRC Childhood Leukaemia Working Party. Br J Haematol 1998;101: Sung L, Aplenc R, Alonzo TA, Gerbing RB, Gamis AS; AAML0531/PHIS Group. Predictors and short-term outcomes of hyperleukocytosis in children with acute myeloid leukemia: a report from the Children's Oncology Group. Haematologica 2012;97: Inaba H, Fan Y, Pounds S, et al. Clinical and biologic features and treatment outcome of children with newly diagnosed acute myeloid leukemia and hyperleukocytosis. Cancer 2008; 113: Harrison CJ, Hills RK, Moorman AV, et al. Cytogenetics of childhood acute myeloid leukemia: United Kingdom Medical Research Council Treatment trials AML 10 and 12. J Clin Oncol 2010;28: von Neuhoff C, Reinhardt D, Sander A, et al. Prognostic impact of specific chromosomal aberrations in a large group of pediatric patients with acute myeloid leukemia treated uni- Clin Pediatr Hematol Oncol 13

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