Pediatric Hematology and Oncology, 28:269–278, 2011Copyright C© Informa Healthcare USA, Inc.ISSN: 0888-0018 print / 1521-0669 onlineDOI: 10.3109/08880018.2010.533249

ORIGINAL ARTICLEMalignant Hematology - Acute Myeloid Leukemia

Improved Survival Outcome of Childhood AcuteMyeloid Leukemia with Intensified Chemotherapyin Chinese Children

Xiao Wen Zhai, PhD,1 Frankie Wai Tsoi Cheng, MD,2 Vincent Lee, MRCP,2

Wing Kwan Leung, MRCPCH,2 Margaret Heung Ling Ng, MD,3 Kam SzeTsang, PhD,3 Ming Kong Shing, FRCP,2 and Chi Kong Li, MD2

1Department of Pediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong,Shatin, New Territories, Hong Kong; and Department of Pediatrics, Children’s Hospital ofFudan University, Shanghai, China; 2Department of Pediatrics, Prince of Wales Hospital,Shatin, New Territories, The Chinese University of Hong Kong, Hong Kong; 3Department ofAnatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin,New Territories, Hong Kong

With the use of intensive chemotherapy and hematopoietic stem cell transplantation (HSCT), theprognosis of childhood acute myeloid leukemia (AML) improved over the last 2 decades. Survivaldata of Chinese pediatric patients were seldom reported. The authors adopted modified UK Med-ical Research Council (MRC) AML protocols for treatment of childhood AML since 1994. From 1994to 2008, the outcomes of Chinese AML patients were studied. Sixty-eight patients were studied.The median age at diagnosis was 9.9 years. Twenty-five patients (36.8%) had favorable cytoge-netic karyotypes, including t(15;17), t(8;21) and inv(16). Complete remission (CR) rate was 91.2%.The relapse rate was 29.4%. For non-M3 patients, the 5-year overall survival (pOS) was 64% ±7% and event-free survival (pEFS) was 53% ± 7%. For those non–good-risk patients who achievedCR, there were no significant differences in outcomes between patients who received HSCTin CR1 and those received chemotherapy alone (5-year pOS 80% ± 13% and 69% ± 9%,P = .52), 5-year pEFS 69% ± 15% and 55% ± 10%, P = .40). The pOS of the 20 relapsedpatients was 29% ± 11%. Sixteen patients with t(8;21) and inv(16) had similar outcome withthose without favorable cytogenetics (pOS 66% ± 12% versus 65% ± 7%, P = .39; pEFS60% ± 11% versus 54% ± 8%, P = .45). Patients who achieved CR after 2 or more courses ofchemotherapy and presenting white blood cell count (WBC) ≥ 100 × 109/L had poorer outcome(pOS 40% versus 80%P < .01; 43% versus 70%, P = .02, respectively). Intensified chemotherapyimproved outcome of Chinese AML children. CR after first course of chemotherapy and WBC atdiagnosis were important prognostic factors.

Keywords AML, chemotherapy, children

Acute leukemia is the most common childhood malignancy. Acute myeloidleukemia (AML) accounts for 20% of childhood acute leukemia [1]. With the use of in-tensive chemotherapy and hematopoietic stem cell transplantation (HSCT), the prog-

Received 2 June 2010; accepted 15 October 2010.Address correspondence to Dr. Chi Kong Li, Consultant Pediatrician, Department of Pediatrics,Room G15, G/F, Lady Pao Children’s Cancer Center, Prince of Wales Hospital, Shatin, NewTerritories, Hong Kong. E-mail: ckli@cuhk.edu.hk

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nosis of childhood AML improves significantly. About 90% of patients can achievecomplete remission (CR). The 5-year overall survival rate (pOS) and event-free sur-vival rate (pEFS) are 50% to 60% and 40% to 50%, respectively. Relapse is still the maincause of treatment failure [2–5]. HSCT can improve outcome in selected patients withAML, but carries significant risk of transplant-related morbidity and mortality.

The Medical Research Council (MRC) of United Kingdom (UK) has conducted se-ries of AML trials, including UK MRC AML 8, 10, and 12, for childhood AML. MRCAML 10 consisted of 4 blocks of intensive chemotherapy (ADE [daunorubicin + Ara-C + etopside] 3 + 10 + 5, ADE 3 + 8 + 5, MACE [amasacrine + Ara C + etoposide],and MidAC [mitoxantrone + Ara C]). HSCT was recommended for all children witha matched sibling donor (MSD). Children without MSD were randomized to receiveautologous HSCT in first CR following 4 blocks of intensive chemotherapy, or to re-ceive no further treatment. In the MRC AML 12 trial, allogeneic HSCT was restrictedto standard and poor-risk patients in whom relapse remained the main cause of treat-ment failure. In the absence of benefit in overall survival with substantial morbidityin children receiving autologous HSCT, it was omitted from the MRC AML 12 trial.The survival of children with AML on these trials has improved dramatically over thepast 2 decades. The 5-year pOS and pEFS were 66% and 56%, respectively. Intensivechemotherapy and advanced supportive care have improved the treatment outcome.Risk-group stratification based on karyotype and response to the first induction coursewere identified in UK MRC AML 10 and subsequently adopted as stratification criteriain subsequent trials [2].

Data from our local study showed that 3-year disease-free survival was only 26.6%in the 1980s [6]. Since 1994, our center adopted modified UK MRC AML protocols fortreatment of childhood AML. From 1994 to 1996, we treated patients with a modifiedUK MRC AML 10 protocol. The modified UK MRC AML 12 protocol was adopted after1996. Data on survival of Chinese children treated with intensive chemotherapy proto-cols were scarce. We retrospectively reviewed the treatment outcome of Chinese AMLpatients based on modified UK MRC AML protocols.

METHODS

EligibilityThe inclusion criteria included (1) de novo AML and (2) less than 18 years old. Pa-tients with the following conditions were excluded: (1) previously received cytotoxicchemotherapy; (2) blastic transformation of chronic myeloid leukemia; (3) secondarymalignancy; and (4) Down syndrome. Informed consents were obtained from patientsand/or parents.

DiagnosisThe diagnosis of AML was established by morphological examination of bone mar-row according to the French-American-British (FAB) and World Health Organization(WHO) classifications [7]. Central nervous system (CNS) involvement was diagnosed ifmore than 5 leucocytes per microliter in the cerebrospinal fluid (CSF) and/or presenceof identifiable blasts, with or without presence of neurological signs and symptoms.

Cytogenetic analysis was performed in our cytogenetics laboratory, whose qualitycontrol was monitored by an external quality assurance scheme. Karyotypes were re-viewed and described in accordance with the International System for Human Cyto-genetic Nomenclature. Quality performance was reflected in the 2 proficiency testingschemes separately organized by College of American Pathologists and AustralasianSociety of Cytogeneticists.

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Improved Outcome of AML in Chinese Children

TABLE 1 Treatment Schema of Modified MRC AML Protocol

Course 1 induction ADE 10 + 3 + 5Daunorubicin 50 mg/m2 daily by 6 hours infusion on days 1, 3,and 5Cytarabine 100 mg/m2 q12h i.v. bolus on days 1–10Etoposide 100 mg/m2 daily by 4 hours infusion on days 1–5

Course 2 induction ADE 8 + 3 + 5Daunorubicin 50 mg/m2 daily by 6 hours i.v. on days 1, 3, and 5Cytarabine 100 mg/m2 q12h by i.v. bolus on days 1–8Etoposide 100 mg/m2 daily by 4 hours infusion on days 1–5

Course 3 consolidation MACEAmsacrine 100 mg/m2 daily by 1 hour i.v. (in 5% dextrose) on days1–5Cytarabine 200 mg/m2 daily by continuous i.v. on days 1–5Etoposide 100 mg/m2 daily by 4 hours i.v. on days 1–5

Course 4 consolidation MidACMitoxantrone 10 mg/m2 by 6 hours i.v. on days 1–5Cytarabine 1.0 g/m2 q12h by 2 hours i.v. on days 1–3

Course 5 consolidation CLASPCytarabine 3 g/m2 q12h by 3 hours i.v. on days 1, 2, 8, and 9Asparaginase 6000 units/m2 s.c. on days 2 and 9 (on 3 hours aftercompletion of 4th and 8th doses of cytarabine)

Note. i.v. = intravenous; s.c. = subcutaneous.

Favorable cytogenetics were defined as presence of t(15;17), t(8;21) orinv(16)/t(16;16). Adverse cytogenetics were defined as −5, −7, del(5q), abn(3q),and complex karyotypes. Complex karyotype was defined as presence of more than3 chromosomal aberrations, including at least 1 structural aberration. Standard riskwas defined as presence of neither favorable nor adverse genetic abnormalities.

TreatmentPrior to 1996, 6 patients were treated according to the modified MRC AML 10 protocoland followed the ADE arm. We adopted the modified MRC AML 12 protocol after 1996[2]. The first 3 patients followed the mitoxantrone arm, and afterwards all the otherpatients switched to the daunorubicin arm due to apparently greater toxicity after re-ceived mitoxantrone. Risk-group assignment, induction chemotherapy, consolidationchemotherapy, HSCT, and CNS-directed therapy followed MRC AML approaches [2,8]. The protocol is shown in Table 1.

Definitions and StatisticsComplete remission (CR), nonresponse, and resistant disease (RD) were defined bythe criteria as described in the MRC trial reports [2, 8].

Statistical AnalysisSPSS Analysis System Version 11.5 software was used for the statistical analysis. pOSwas calculated from the date of diagnosis to death of any cause or to last follow-up.pEFS was calculated from the date of diagnosis to last follow-up or first event (fail-ure to achieve remission, relapse, secondary malignancy, or death of any cause). Pa-tients who did not attain CR were considered failures at time 0. The probabilities ofpOS and pEFS were calculated using the Kaplan-Meier method and the different sub-groups were compared using log-rank test and Breslow test.

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TABLE 2 Baseline Characteristics

N %

Number eligible patients 68Gender (male) 38 55.9Age (years)<10 34 50.0≥10 34 50.0

WBC (× 109/L)<100 61 89.7≥100 7 10.3

CNS leukemia 8 11.8FAB subtypes

M0 2 2.9M1 9 13.2M2 17 25.0M3 12 17.7M4 8 11.8M5 9 13.2M6 1 1.5M7 9 13.2Others 1 1.5

Karyotypest(8;21) 10 14.7Inv(16) 6 8.8t(15;17) 9 13.2t(9;11) 3 4.4t(10;11) 2 2.9Normal 18 26.5Others 16 23.6ND 4 5.9

Note. WBC = white blood cell count; CNS = central nervous system; ND = not done.

RESULTS

Patient CharacteristicsFrom August 1994 to December 2008, 68 AML patients with 56 (non-M3) patients wereenrolled. The clinical characteristics are presented in Table 2. The male to female ratiowas 1.3:1. The median age at presentation was 9.9 years. Of 68 patients, 50% were ≥10years old at diagnosis. An 11.8% had CNS involvement at diagnosis. The median whiteblood cell count (WBC) at diagnosis was 27 × 109/L and 10.3% of the children hadWBC ≥ 100 × 109/L. Data of FAB subtypes and karyotypes are also shown in Table 2.

Response to Induction Treatment and Early-Death RateSixty patients received DAE (daunorubicin + Ara-C + etopside) induction course,and 3 patients received MAE (mitoxantrone + Ara-C + etopside). Two patients re-ceived IA (idarubicin + Ara-C) course. Three children died in the first induction coursedue to pneumonia, septicemia, and hyperviscosity syndrome. Of 68 children, CR wasachieved in 62 children and CR rate was 91.2%. The induction death rate was 4.4%. Therelapse rate was 29.4%.

Postremission Therapy and OutcomeAllogeneic HSCT in CR1 was performed in 11 patients (16.2%), including 6 patientswith matched sibling donor (MSD), 4 with 1 antigen-mismatched related donor(MRD), and 1 with matched unrelated donor transplantation (MUD). AutologousHSCT was performed in 2 patients who were analyzed in the chemotherapy group.

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Among 11 patients with allogeneic HSCT, 3 died of post-HSCT relapses, 8 patients werealive without disease. The other 51 patients continued with chemotherapy, 17 patientshad relapses and 13 patients died. There were no significant differences in 5-year pOSand pEFS between patients receiving HSCT in CR1 compared to chemotherapy alone(pOS 82% ± 12% versus 70% ± 7%, P = .55; pEFS 72% ± 14% versus 60% ± 7%, P =.45). The relapse rates between the 2 groups were also similar (27% versus 33%, P =.70). For 52 patients achieved CR1 after first induction chemotherapy, 10 patients withHSCT in CR1 had 5-year pOS 80% ± 13% and pEFS 69% ± 15%, and 42 patients withchemotherapy had pOS 68% ± 8% and pEFS 54% ± 8%. The treatment outcomes didnot differ significantly between the 2 groups (pOS, P = .56; pEFS, P = .40). Regard-ing postremission treatment, in 36 non–good-risk patients who achieved CR1, 10 pa-tients received HSCT and 26 patients received postremission chemotherapy only; bothgroups had good outcomes, with 5-year pOS 80% ± 13% and 69% ± 9% (P = .52) andpEFS 69% ± 15% and 55% ± 10% (P = .40), respectively.

Deaths in RemissionThree deaths occurred in CR1 within 6 months from diagnosis. One patient died ofinfection after HSCT and the other 2 patients in the chemotherapy group died of fungalsepticemia and bacterial septicemia. The cumulative incidence of death in continuousCR was 4.4% and 3.9% for the whole group and the chemotherapy group, respectively.

RelapsesTwenty patients relapsed (29.4%) after achieving remission. Three relapses occurredin the HSCT group (total 11 patients), and 17 relapses occurred in the chemotherapygroup. Eighteen patients had isolated bone marrow (BM) relapse, 1 had BM and CNSrelapses, and 1 had CNS and extramedullary relapses. The 5-year pOS of these relapsedpatients was 29% ± 11%. Thirteen of 20 relapsed patients (65%) achieved CR2. HSCTin CR2 was performed in 11 patients: 2 patients with MSD, 1 with MRD, 2 with MUD,and 6 with unrelated cord blood transplantation (UCBT). Four of 11 were alive andthe others died of second relapse or treatment-related toxicity. HSCT was performedin 2 relapsed patients with active leukemia; both achieved CR2 but subsequently hadfurther relapses and died. Five did not achieve CR2 without HSCT and all died.

Survival OutcomeThe treatment outcomes are shown in Table 3. The 5-year overall survival (pOS) was64% ± 7% and event-free survival (pEFS) was 53% ± 7% in non-M3 AML patients. The

TABLE 3 Results of 68 Patients

N %

Number of patients 68 100Early deatha 6 8.8Nonrespondent and resistant disease 0 0CR achieved 62 91.2

CR after the first induction course 52 76.5Death in CCR (cumulative incidence) 3 4.4Relapse (cumulative incidence) 20 29.4Lost follow-up in CCR 2 2.9Allogeneic SCT in first CR 11 16.2

Note. CR = complete remission; CCR = continuous complete remission.aEarly deaths are defined as death before day 42.

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FIGURE 1 (a) Overall survival (OS) and (b) event-free survival (EFS) in patients with AML (excludeM3).

median follow-up time of all patients was 5.8 years (0–14.4 years), and was 9.6 years(1.1–14.4) for survivors.

Prognostic FactorsResponse to First Course of Induction ChemotherapyFifty-two (80%) patients achieved complete remission after the first induction course.They had better outcome compared to 10 patients who achieved CR after 2 or morecourses (pOS 80% ± 6% versus 40% ± 15%, P < .01; and pEFS 66% ± 7% versus 40% ±15%, P = .04) (Figure 1a and b).

White Blood Cell Count (WBC) at DiagnosisSixty-one patients with WBC < 100 × 109/L at diagnosis had a better pOS (70% ± 6%versus 43% ± 19%, P = .02) and a better pEFS (61% ± 7% versus 14% ± 13%, P <.01)compared to 7 patients with WBC ≥ 100 × 109/L at diagnosis. Among 62 patients whoachieved CR1, patients with WBC < 100 × 109/L at diagnosis also had better outcome(pEFS 66% ± 7% versus 20% ± 18%, P <.01). Patients with WBC ≥ 100 × 109/L at di-agnosis had higher relapse rates (72% versus 28%, P = .02).

Age at DiagnosisOf 68 children, older patients (≥10 years of age, n = 34) had similar prognosis asyounger children (n = 34, pOS 56% ± 10% versus 76% ± 7%, P = .19; pEFS 49% ±9% versus 63% ± 9%, P = .31). The relapse rates did not differ between younger andolder children (P = .28).

GenderThe pOS and pEFS were similar in 38 boys and 30 girls (pOS 65% ± 8% versus 69% ±9%, P = .93; pEFS 59% ± 8% versus 54% ± 10%, P = .89). The relapse rates were similarbetween boys and girls (P = .93).

CNS LeukemiaEight patients (11.8%) had CNS involvement at diagnosis. The pOS and pEFS were notdifferent between patients with or without CNS involvement (pOS 53% ± 20% versus70% ± 6%, P = .90; pEFS 53% ± 20% versus 56% ± 7%, P = .73). Relapse rates weresimilar between the 2 groups (P = .83).

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Survival

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FIGURE 2 (a) Overall survival (pOS) and (b) event-free survival (pEFS) in patients with CR achievedwith 1 or more courses of chemotherapy.

CytogeneticsKaryotypic analysis was performed in 64/68 (94.1%) of subjects. Clonal aberrationswere found in 67.6% patients (Table 2). Sixteen patients had favorable cytogenet-ics (28.6%); they had similar outcome as compared to patients without favorablecytogenetics (pOS 66% ± 12% versus 65% ± 7%, P = .39; pEFS 60% ± 11% versus 54%± 8%, P = .45). Ten patients with t(8;21) had EFS 60% ± 15%and 6 patients with inv(16)had EFS 50% ± 20%. Separate analysis was done for the favorable cytogenetic groupand compared with the non–favorable cytogenetic group, there was no statistical sig-nificant difference. For children with 11q23/MLL rearrangement, 3 children had t(9;11) and 2 children had t(10; 11). These 5 children had outcome similar to children with-out 11q23/MLL rearrangement (pOS 80% ± 18% versus 65% ± 6%, P = .55; pEFS 53%± 25% versus 56% ± 7%, P = .75).

Hematopoietic Stem Cell Transplantation (HSCT)HSCT was performed in 24 patients (35.3%). Eleven children had HSCT in CR1, 11 and2 children were transplanted in CR2 and active leukemic state, respectively. Two chil-dren with HSCT in active leukemia both died of second relapses. Eight of 11 patientswith HSCT in CR1 survived with remission, 2 had relapses. Four of 11 patients withHSCT in CR2 survived in remission, 4 had relapses, and 3 died of treatment-relatedcomplications. Eleven patients with HSCT in CR2 had worse outcome compared tothose with HSCT in CR1 (pOS 30% ± 14% versus 82% ± 12%, P = .05). The details areshown in Figure 2.

DISCUSSION

From 1988 to 2002, 758 children with acute myeloid leukemia (AML) were treated withMedical Research Council (MRC) AML 10 and AML 12 protocols. MRC AML 10 eval-uated the role of HSCT following 4 blocks of intensive chemotherapy. Both allogeneicand autologous HSCT significantly reduced the relapse risk but did not translate intosignificant improvement in overall survival (pOS). This was due to significant risk oftransplant-related mortality. Risk-group stratification based on cytogenetics and re-sponse to the first course of chemotherapy derived from MRC AML 10 was used todeliver risk-directed therapy in the MRC AML 12 trial [2].

Since 1994, we adopted similar approach of UK MRC AML protocols to treatmentchildhood AML. The treatment outcomes of 5-year overall survival (pOS) was 64% ±

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7% and event-free survival (pEFS) was 53% ± 7% in non-M3 AML patients, which arecomparable to those reported by European and American trials [2–5].

The CR rate of 91.2% is also similar to those reported by MRC AML 10 and NOPHO-AML 93 [2, 3, 8]. A 76.5% of patients can achieve CR after 1 course of inductionchemotherapy. Death rate in continuous complete remission (CCR) of 4.4% is alsosimilar to other published data [2–5]. There is no nonresponder in our cohort andthis suggests that DAE may be effective in childhood AML. Complications such asCNS bleeding, hyperviscosity syndrome, and other treatment-related complicationsshould be handled carefully to avoid early death. With intensive treatment approach,we do not observe an increase in treatment-related mortality in Chinese children.

The benefit of HSCT must be balanced with the risk of transplant-related mortalityand presence of long-term complications [9]. Most studies reported HSCT with MSDhad better survival. Nowadays, human leukocyte antigen (HLA)-compatible siblingscan only be found in 25% of patients; unrelated donor HSCT in CR1 remains a contro-versial issue in childhood AML. Most investigators agree that low-risk AML subgroupsuch as AML patients with Down syndrome and patients with favorable cytogeneticsshould not undergo HSCT in CR1, whereas there are differences in the view for otherpatients [10, 11]. According to UK MRC AML protocol, HSCT in CR1 is recommendedin non–good-risk group when HLA-matched sibling donor is available. For postrem-ission treatment, our data show that 52 non-M3 patients achieved CR1, 10 patientsreceived HSCT in CR1 and 42 patients continued postremission chemotherapy. Theyhad similar outcomes, with 5-year pOS 80% ± 13% and 68% ± 8% and pEFS 69% ±15% and 54% ± 8%, respectively. In addition, our data also show that there was no dif-ference in relapse rate between the 2 groups. So we should restrict the indications forHSCT in CR1 to avoid unnecessary transplant-related mortality (TRM) and late com-plications of HSCT.

Relapse is the main cause of treatment failure in AML. Recent data from Europeanand American studies show that a cumulative incidence of relapse varied from 26%to 47%. Bone marrow is the most common site of relapse (about 80% of all relapses),and CNS relapse is less common (10% to 15% of all relapses). Most studies show thatpatients with relapsed AML are seldom cured with chemotherapy alone and the sur-vival rate is usually less than 30% [12–15]. To improve the treatment outcome of thesepatients, allogeneic HSCT is always recommended. The pOS of patients with HSCT inCR2 have been reported to be 33% to 36% [14, 16]. The incidence of TRM for AML pa-tients with HSCT in CR2 ranged from 10% to 50%. Posttransplant relapse occurs in 30%to 60% of patients [13, 17]. In our cohort of HSCT in CR2, 36.4% had relapse and died,and the TRM was 27.2%. Thus 5-year pOS was 30% ± 14%, which is similar to otherpublished reports [13, 14]. For those relapsed AML patients who cannot achieve CR2,HSCT may not be a good option. Two patients with refractory leukemia underwentHSCT and both died of early second relapse.

Cytogenetics is one of the best predictors of outcome in AML. t(8;21), inv(16), andt(15;17) are associated with favorable outcome, whereas −5, del(5q), and −7 usuallypredict poor outcome [18]. In the CCG2891 study, patients with favorable cytogeneticsachieved pEFS at 5 years of 45% compared with pEFS of 30% for patients with normaland other cytogenetics [12]. Our study showed that 25 patients with favorable cytoge-netics had similar pOS, pEFS, and relapse rate to non–good-risk patients. This unex-pected finding might be due to relatively small sample size of our study. We observeda higher relapse rate and HSCT did not achieve salvage successfully. For 10 t(8;21) pa-tients achieved CR, 4 patients (40%) relapsed and underwent HSCT. But 3 of these pa-tients died of relapse or septicemia, and only 1 patient survived. Thus the 5-year pEFSwas only 60% ± 15%. Of 6 patients with inv(16), CR rate was also 100%, but 3 patients(50%) relapsed. After relapse, 1 patient survived with chemotherapy alone, 1 patient

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was alive with HSCT, and 1 patient died of septicemia after MUD HSCT in CR2. Ofthese 6 patients with inv(16), the pEFS was only 50% ± 20%.

Other important cytogenetic abnormalities include rearrangements of the mixed-lineage leukemia (MLL) gene, which occurs in about 15% to 20% of AML patients. InAML, the most common 11q23 rearrangements are t(9;11) (in approximately 50% ofcases), t(11;19), t(6;11), and t(10;11) [19]. Balgobind et al evaluated the data of 756children with 11q23- or MLL-rearranged AML from 11 collaborative groups [21]. The5-year pEFS of all patients was 44% ± 5%, and they identified large differences in out-come between subgroups. Patients with t(1;11) had an excellent outcome, with pEFSof 92% ± 5%, whereas patients with t(10;11) and t(6;11) had a poor prognosis, withpEFS 17% ± 11% and 11% ± 5%, respectively; the pEFS of t(9;11) was 50% ± 3% [20].

Racial difference may be an important outcome predictor of AML [21]. Li et al eval-uated the outcomes of childhood AML treated with the AML-XH-99 protocol. The CRrate was 84.1%, with 5-year pEFS 46.1% ± 9.1% and disease-free survival (pDFS) was54.3% ± 10.3% [22]. However, our result did not support any difference in treatmentoutcome in Chinese children as compared to Caucasians.

Our data showed that important prognostic factors were (i) response to inductionchemotherapy: patients achieved CR1 after first induction course had better outcomethan those who achieved CR after 2 or more induction courses; and (ii) patients withWBC ≥ 100 × 109/L at diagnosis had inferior pEFS due to higher relapse rate.

CONCLUSION

Chinese children with AML achieved an improved outcome by using intensifiedchemotherapy protocols. Despite the intensified treatment, treatment-related mortal-ity remained low. WBC at diagnosis and CR after the first induction course were shownto be important prognostic factors. HSCT in CR1 should be limited to high-risk pa-tients to avoid unnecessary treatment-related toxicity and long-term complications.

Declaration of InterestThe authors report no conflicts of interest. The authors alone are responsible for thecontent and writing of the paper.

REFERENCES

[1] Pui CH. Childhood leukemia. N Engl J Med. 1995;332:1618–1627.[2] Gibson BE, Wheatley K, Hann IM, et al. Treatment strategy and long-term results in paediatric pa-

tients treated in consecutive UK AML trials. Leukemia. 2005;19:2130–2138.[3] Lie SO, Abrahamsson J, Clausen N, et al. Long-term results in children with AML: NOPHO-AML

Study Group—report of three consecutive trials. Leukemia. 2005;19:2090–2100.[4] Creutzig U, Zimmermann M, Ritter J, et al. Treatment strategies and long-term results in paediatric

patients treated in four consecutive AML-BFM trials. Leukemia. 2005;19:2030–2042.[5] Ravindranath Y, Chang M, Steuber CP, et al. Pediatric Oncology Group (POG) studies of acute

myeloid leukemia (AML): a review of four consecutive childhood AML trials conducted between1981 and 2000. Leukemia. 2005;19:2101–2116.

[6] Li CK, Leung NK, Wong HW, et al. Acute non-lymphoblastic leukemia-local experience. Hong KongJ Pediatrics. 1991;8:31–37.

[7] Hasle H, Niemeyer CM, Chessells JM, et al. A pediatric approach to the WHO classification ofmyelodysplastic and myeloproliferative diseases. Leukemia. 2003;17:277–282.

[8] Stevens RF, Hann IM, Wheatley K, et al. Marked improvements in outcome with chemotherapyalone in pediatric acute myeloid leukemia: results of the United Kingdom Medical Research Coun-cil’s 10th AML trial. Br J Haemotol. 1998;101:130–140.

[9] Rubnitz JE. Childhood acute myeloid leukemia. Curr Opin Oncol. 2008;9:95–105.[10] Creutzig U, Reinhardt D. Current controversies: which patients with acute myeloid leukaemia

should receive a bone marrow transplantation? A European view. Br J Haematol. 2002;118:365–377.

Copyright C© Informa Healthcare USA, Inc.

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X. W. Zhai et al.

[11] Chen AR, Alonzo TA, Woods WG, et al. Current controversies: which patients with acute myeloidleukaemia should receive a bone marrow transplantation?—an American view. Br J Haematol.2002;118:378–384.

[12] Smith FO, Alonzo TA, Gerbing RB, et al. Long-term results of children with acute myeloid leukemia:a report of three consecutive Phase III trials by the Children’s Cancer Group: CCG 251, CCG 213 andCCG 2891. Leukemia. 2005;19:2054–2062.

[13] Aladjidi N, Auvrignon A, Leblanc T, et al. Outcome in children with relapsed acute myeloidleukemia after initial treatment with the French Leucemie Aique Myeloide Enfant (LAME)89/91 protocol of the French Society of Pediatric Hematology and Immunology. J Clin Oncol.2003;21:4377–4385.

[14] Wells RJ, Adams MT, Alonzo TA, et al. Mitoxantrone and cytarabine induction, high-dose cytara-bine, and etoposide intensification for pediatric patients with relapsed or refractory acute myeloidleukemia: Children’s Cancer Group Study 2951. J Clin Oncol. 2003;21:2940–2947.

[15] Rubnitz JE, Razzouk BI, Lensing S, et al. Prognostic factors and outcome of recurrence in childhoodacute myeloid leukemia. Cancer. 2007;109:157–163.

[16] Nemecek ER, Gooley TA, Woolfrey AE, et al. Outcome of allogeneic bone marrow transplantationfor children with advanced acute myeloid leukemia. Bone Marrow Transplant. 2004;34:799–806.

[17] Aladjidi N, Auvrignon A, Leblanc T, et al. Outcome in children with relapsed acute myeloidleukemia after initial treatment with the French Leucemie Aique Myeloide Enfant (LAME)89/91 protocol of the French Society of Pediatric Hematology and Immunology. J Clin Oncol.2003;21:4377–4385.

[18] Woolfrey AE, Gooley TA, Sievers EL, et al. Bone marrow transplantation for children less than 2 yearsof age with acute myelogenous leukemia or myelodysplastic syndrome. Blood. 1998;92:3546–3556.

[19] Grimwade D, Walker H, Oliver F, et al. The importance of diagnostic cytogenetics on outcome inAML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research CouncilAdult and Children’s Leukaemia Working Parties. Blood. 1998;92:2322–2333.

[20] Raimondi SC, Chang MN, Ravindranath Y, et al. Chromosomal abnormalities in 478 children withacute myeloid leukemia: clinical characteristics and treatment outcome in a cooperative pediatriconcology group study—POG 8821. Blood. 1999;94:3707–3716.

[21] Balgobind BV, Raimondi SC, Harbott J, et al. Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood.2009;114:2489–2496.

[22] Rubnitz JE, Lensing S, Razzouk BI, et al. Effect of race on outcome of white and black children withacute myeloid leukemia: the St. Jude experience. Pediatr Blood Cancer. 2007;48:10–15.

[23] Li J, Gu LJ, Xue HL, et al. Response rate of AML-XH-99 protocol in the treatment of 82 childhoodacute myeloid leukemia. Zhonghau Xue Ye Xue Za Zhi. 2004;25:351–354.

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