PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of jcoHomeThis ArticleSearchSubmitASCO JCO Homepage
 
J Clin Oncol. 2015 December 20; 33(36): 4247–4258.
Published online 2015 November 16. doi:  10.1200/JCO.2015.61.1947
PMCID: PMC5321085

Clinical Impact of Additional Cytogenetic Aberrations, cKIT and RAS Mutations, and Treatment Elements in Pediatric t(8;21)-AML: Results From an International Retrospective Study by the International Berlin-Frankfurt-Münster Study Group

Abstract

Purpose

This retrospective cohort study aimed to determine the predictive relevance of clinical characteristics, additional cytogenetic aberrations, and cKIT and RAS mutations, as well as to evaluate whether specific treatment elements were associated with outcomes in pediatric t(8;21)-positive patients with acute myeloid leukemia (AML).

Patients and Methods

Karyotypes of 916 pediatric patients with t(8;21)-AML were reviewed for the presence of additional cytogenetic aberrations, and 228 samples were screened for presence of cKIT and RAS mutations. Multivariable regression models were used to assess the relevance of anthracyclines, cytarabine, and etoposide during induction and overall treatment. End points were the probability of achieving complete remission, cumulative incidence of relapse (CIR), probability of event-free survival, and probability of overall survival.

Results

Of 838 patients included in final analyses, 92% achieved complete remission. The 5-year overall survival, event-free survival, and CIR were 74%, 58%, and 26%, respectively. cKIT mutations and RAS mutations were not significantly associated with outcome. Patients with deletions of chromosome arm 9q [del(9q); n = 104] had a lower probability of complete remission (P = .01). Gain of chromosome 4 (+4; n = 21) was associated with inferior CIR and survival (P < .01). Anthracycline doses greater than 150 mg/m2 and etoposide doses greater than 500 mg/m2 in the first induction course and high-dose cytarabine 3 g/m2 during induction were associated with better outcomes on various end points. Cumulative doses of cytarabine greater than 30 g/m2 and etoposide greater than 1,500 mg/m2 were associated with lower CIR rates and better probability of event-free survival.

Conclusion

Pediatric patients with t(8;21)-AML and additional del(9q) or additional +4 might not be considered at good risk. Patients with t(8;21)-AML likely benefit from protocols that have high doses of anthracyclines, etoposide, and cytarabine during induction, as well as from protocols comprising cumulative high doses of cytarabine and etoposide.

INTRODUCTION

Core binding factor (CBF) acute myeloid leukemia (AML), which includes inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFB-MYH11 and t(8;21)(q22;q22)/RUNX1-RUNX1T1 (t(8;21)-AML), is associated with relatively favorable outcome.1 Although CBF-AML is a well-known cytogenetic subgroup, separate stratification of t(8;21) and inv(16) has been suggested because of their different, clinically distinct entities.2,3

Although overall survival (OS) rates for pediatric patients with t(8;21)-AML specifically may reach up to 90%,4 many patients continue to experience relapse. Event-free survival (EFS) rates seldom exceed 50% to 60%, and it has been suggested that event-free or disease-free survival might not be better than for other subgroups of AML.5,6 For CBF-AML, including t(8;21), high WBC count at diagnosis is often associated with an inferior outcome.7,8 Patients who have higher blast percentages,9 extramedullary or CNS involvement,7,10 or older age reportedly have inferior outcomes also.2,7,8 The prognostic impact of commonly occurring additional cytogenetic aberrations has been variably described.1013

The different outcomes among study groups may be explained by clinical features or by the treatment schedules or doses of important agents (eg, cytarabine, anthracyclines, etoposide). Evidence is lacking to unequivocally interpret single-agent–specific effects in this cytogenetic subgroup of patients, so the collaborative International Berlin-Frankfurt-Münster Study Group aimed to study the predictive relevance of patient- and leukemia-specific characteristics and to study different treatment elements in children with t(8;21)-AML.

PATIENTS AND METHODS

Data from patients with t(8;21)-AML were retrospectively collected from 19 pediatric AML study groups between 1988 and 2010. Data on diagnostics, treatment, response, events, survival, and follow-up were gained with specifically designed forms. The study was approved by institutional review boards of the participating study groups.

Cytogenetic and Molecular Analyses

Cytogenetic reports of each patient were submitted to the coordinating Dutch Childhood Oncology Group. All reports were centrally reviewed and karyotypes were described according to the International System for Human Cytogenetic Nomenclature (2009).14 Data from patients without proof of t(8;21) presence and patients with absent or incomplete karyotypes were excluded from analyses.

Aberrations arbitrarily occurring in 10 or more patients were regarded sufficiently recurrent to define an additional cytogenetic subgroup. Karyotype complexity was determined by counting the number of unrelated chromosomal abnormalities within the karyotypes (≥ 3 or ≥ 5 abnormalities).

Genomic DNA was isolated from cytospin slides, frozen cell pellets, or cells cryopreserved in liquid nitrogen for mutational analysis. Available samples (n = 228) were screened for cKIT, N-RAS, and K-RAS mutations by high-resolution–melting analysis. Samples with aberrant profiles were validated by Sanger sequencing as previously described.15,16 This method implies that mutations are designated positive only when they were confirmed by sequencing, which has a sensitivity of approximately 20%.

Therapy

Induction was defined as the first two courses of chemotherapy. Except for one protocol, the treatment protocols consisted of an anthracycline- and cytarabine-based induction with or without other agents, such as etoposide. The prognostic impact of both induction and cumulative doses of anthracyclines, etoposide, and cytarabine were evaluated. Combinations of these agents were always assimilated in the multivariable models. To overcome the widely ranged doses within the different protocols, commonly used or the most discriminating cutoff values for these agents were determined (Appendix Table A1, online only). Patients who were not treated according to their applicable protocols were excluded from the final analyses. Allogeneic stem-cell transplantation (SCT) was evaluated for protocols that contained first-line SCT in first complete remission (CR1) only.

End Points

Outcomes were evaluated by using the probabilities of complete remission (pCR), cumulative incidence of relapse (CIR), probabilities of EFS (pEFS), and probabilities of OS (pOS; Appendix Table A2, online only).

Statistics

Mutual univariable analyses of characteristics were conducted by using the Wilcoxon test for quantitative variables and Fisher's exact test or the χ2 test for qualitative variables. To identify factors associated with pCR, variables significant at P < .10 in univariable analyses and elements of induction treatment entered a logistic regression model with limited backward elimination (α < .05). Results were presented as odds ratios and 95% CIs.

The Kaplan-Meier method was used to estimate survival probabilities, and associations with covariates were tested by the log-rank test. Cox proportional hazard regression analyses were used to assess effects of covariates on pOS and pEFS. Variables significant at P < .10 in univariable analyses entered an explorative multivariable Cox regression model. After a backward elimination procedure, the remaining important covariates were used in a multivariable model to assess the effects of induction elements (induction model) and overall therapy elements (overall model). To overcome multicollinearity, the most relevant course per agent entered the induction model.

For CIR, subdistributional hazards were calculated to correct for death or secondary malignancies as competing events for relapse. The Fine and Gray multivariable regression model, with similar conditions as the survival models, was used to assess the effects of both induction therapy and overall therapy on CIR. Estimates for (subdistributional) hazard ratios and corresponding 95% CIs were obtained for each significant factor.

Data were analyzed by using the intention-to-treat principle. To check for lead-time bias, the overall models were tested for the whole study population and for patients in CR1 only.

The proportional hazards assumptions were tested by assessing the Schoenfeld residuals. Two-sided P values less than .05 were considered statistically significant. Statistical analyses were performed by using IBM SPSS Statistics for Windows, version 20.0, and Stata 11.0 (StataCorp LP).

RESULTS

The prevalence of t(8;21) among patients with AML from the 19 participating study groups was 6% to 16%. In total, data on 916 patients were collected. Data from 78 patients without proven t(8;21) presence or with incomplete karyotypes were excluded. Data from 12 patients were excluded in final multivariable models; nine patients were excluded because they had not received cytarabine, etoposide, or anthracyclines, and three patients were excluded because it was not known whether they received one of the agents. Figure 1 gives details on study enrollment, and Table 1 provides baseline characteristics for included patients.

Fig 1.
Study enrollment. AIEOP, Associazione Italiana Ematologia Oncologia Pediatricia; AML, acute myeloid leukemia; AML1-ETO, RUNX1-RUNX1T1; BFM-A, Berlin-Frankfurt-Münster Study Group Austria; BFM-G, Berlin-Frankfurt-Münster Study Group Germany; ...
Table 1.
Demographic and Clinical Characteristics of Pediatric Patients With t(8;21) and Full Karyotype

Approximately 68% (n = 573) of patients had one or more additional chromosomal aberration. Appendix Table A3 (online only) gives clinical characteristics by the number of additional cytogenetic aberrations. Loss of a sex chromosome (LOS), deletion of the long arm of chromosome 9 (del(9q)), gain of chromosome 8 (+8), gain of chromosome 4 (+4), and abnormalities of the long arm of chromosome 7 (abn(7q)) occurred in more than 10 patients (Appendix Fig A1, online only, shows distribution of these aberrations). Differences in clinical characteristics and treatment aspects between patients with these aberrations are shown in Appendix Table A4 (online only). Patient characteristics among samples that were or were not evaluated for cKIT and RAS mutations did not significantly differ; however, several treatment aspects were significantly different (Appendix Table A5, online only) because not all study groups provided samples.

cKIT mutations were identified in 24% (n = 53) of the 222 successfully evaluated samples. No significant differences between patients with or without cKIT mutations were found with respect to age, sex, WBC count, or blast percentage. Seventy percent (n = 10) of the patients with +4 had cKIT mutations, compared with 21% (n = 46) of the patients without +4 (P = .002). Patients with cKIT mutations received significantly more cytarabine and more anthracyclines during the first induction course (Appendix Table A6, online only).

RAS mutations were identified in 15% (n = 29) of 188 successfully evaluated samples. These patients had higher WBCs at diagnosis (P = .034), but lower blast percentages (P = .001), than those without RAS mutations. There were no clinical differences between patients with N-RAS (n = 17) or K-RAS (n = 5) mutations (data not shown).

Outcome

Complete remission (CR) was achieved by 92% of the patients (n = 767), and 59% (n = 452) remained in CR1 until the last date of follow-up. The median overall time from diagnosis to achievement of CR was 38 days (interquartile range, 32 to 56 days). The time until CR did not significantly differ between patients with or without events.

Of the 838 patients, 228 patients (27%) died: 11 patients died during induction, 30 died as a result of refractory disease, 121 died after they experienced relapse, and 66 patients died in CR during or after treatment. The most-reported causes of death were progressive disease (n = 89), infection (n = 70), transplantation-related death (n = 21), and other toxicity (n = 9).

The 5-year pEFS was 58% (SE, 1.7%); the 5-year pOS, 74% (SE, 1.5%); and the 5-year CIR, 26% (SE, 1.5%). The pOS and pEFS improved significantly during the study period (Appendix Fig A2, online only).

Clinical Characteristics and Aberrations

In multivariable analysis, patient-specific factors or the number of additional aberrations were not associated with pCR; however, the presence of additional del(9q) was associated with lower pCR (P = .010; Fig 2A). cKIT mutations or RAS mutations were not significantly associated with pCR. Table 2 shows the results of univariable and multivariable analyses for pCR.

Fig 2.
Outcomes for patients with t(8;21) and significantly important additional cytogenetic aberrations. (A) Complete remission (CR) rates for patients with del(9q) [n = 104] or without del(9q) [n = 734]. (B) Cumulative incidence of relapse for patients with ...
Table 2.
Univariable and Multivariable Analyses of Prognostic Factors for Achieving Complete Remission in t(8;21)-Positive Patients With AML and Full Karyotype

WBCs greater than 20 × 109/L were associated with inferior outcomes on all end points (P < .01). CNS involvement was associated with a higher CIR (P = .001) but did not affect pOS or pEFS. Although the number of additional chromosomal aberrations was not associated with survival or CIR, the presence of +4 was associated with a higher CIR (P = .005), inferior pEFS (P = .005), and inferior pOS (P = .001; Fig 2B, B,2C,2C, and and22D).

In explorative analysis, age 12 years or older and complex karyotype did not comply with the proportional hazards of assumption, which resulted in a time-dependent statistical correction for the first 2 years of follow-up.

Appendix Tables A7 and andA8A8 (online only) show the results of univariable and explorative multivariable analyses, respectively. There were no significant survival differences in patients with or without cKIT or RAS mutations (Appendix Fig A3, online only).

Induction Regimen

Use of anthracycline doses greater than 150 mg/m2 during the first induction course was associated with superior pCR (P = .039), pEFS (P = .033), and pOS (P = .031). High-dose (HD) cytarabine 3 g/m2 during induction was associated with better pCR (P = .015) and higher pEFS (P = .034). Etoposide doses greater than 500 mg/m2 during the first induction course were associated with higher pEFS (P = .009) and pOS (P = .022). None of the determined cutoff doses for induction was significantly associated with a lower CIR. Figure 3 shows Kaplan-Meier curves of induction regimens.

Fig 3.
Kaplan-Meier curves of event-free survival with regard to induction therapy. (A) Event-free survival with anthracyclines ≤ 150 mg/m2 (n = 594) or greater than 150 mg/m2 (n = 244) in first induction course. (B) Event-free survival with etoposide ...

Overall Treatment

Use of cumulative cytarabine doses greater than 30 g/m2 was associated with a lower CIR (P = .029) and better pEFS (P = .007). Cumulative etoposide doses greater than 1,500 mg/m2 were associated with a lower CIR (P = .020) and better pEFS (P = .012). Maintenance therapy after the last consolidation course was not significantly associated with better outcome. Allogenic SCT in CR1 was significantly associated with a lower CIR but not with inferior pOS or pEFS. The time-varying effect of SCT was not significant (data not shown).

Tables 3 and and44 show the results of the multivariable models for the induction and overall regimens, respectively. When the cumulative models were applied for patients in CR1 only, results were similar (data not shown). Mortality rates for patients in CR were not significantly higher in any of the HD groups (Appendix Table A9, online only).

Table 3.
Multivariable Model of Induction Therapy for t(8;21)-Positive Patients With AML and Full Karyotype
Table 4.
Multivariable Model of Overall Therapy for t(8;21)-Positive Patients With AML and Full Karyotype

DISCUSSION

Although the previously reported mediocre EFS and high relapse rate were confirmed in this cohort, the 5-year OS of 74% was relatively good, especially given the number of patients who were diagnosed many years ago. Novel potential prognostic factors were identified, and several known ones, like high WBC count8,17 and CNS involvement,18 were confirmed. However, in contrast to a previous report by Rubnitz et al,11 our results suggest superior OS for women compared with men.

Consistent with previous findings, the prevalence of additional cytogenetic aberrations was high (68%), and the most frequently occurring cytogenetic aberrations were LOS and del(9q).1,4,1113,19 Although the number of additional aberrations or complex karyotype (≥ 3) did not affect outcome in our or other cohorts,4 specific additional aberrations did. Del(9q) was significantly associated with refractory disease. Conversely, Rege et al10 suggested, with borderline significance, a favorable outcome for patients with t(8;21) plus del(9q), but that study had low patient numbers and mainly involved adults. Other studies reported inferior outcome in adults20 and children4 with the additional del(9q). To our knowledge, this is the first study to report lower pCR in children. Although we did not identify significant associations with survival probabilities, these patients might represent a subgroup that could benefit from adaptation or intensification of induction regimen.

Although the occurrence of t(8;21) with +4 was low (3%), the significant association with inferior outcome in these patients may be an important novel finding. These results are consistent with previous findings in adults, in whom +4 is reported as a rare sole karyotypic aberration that is associated with relatively low CR rates and a poor prognosis.21 On the basis of differences in morphologic features, phenotypic findings, and clinical features, Nishii et al22 suggested that t(8;21) with +4 constitutes a distinctive subtype of t(8;21)-AML. Therefore, patients with +4 may represent a high-risk subgroup that warrants additional research at the molecular and clinical levels, with consideration for adaptation or intensification of conventional treatment.

Borderline higher pOS (univariately) for patients with LOS was not confirmed in the multivariable analysis. Other study groups have reported prognostic benefits for additional LOS in adults9 and children3,4 with t(8;21)-AML, however, these results were based mainly on univariable analyses and/or small patient numbers. Conversely, inferior outcome for these patients has been reported as well,10 so the prognostic impact remains uncertain.

We did not identify associations between cKIT or N-RAS/K-RAS mutations and outcome. Previous studies on cKIT mutations are conflicting and report both inferior2325 and similar outcomes.3,2628 Although we do not have an explanation for these contradictions, we hypothesize that some form of ethnic/genetic susceptibility or treatment-related influence occurs in specific subgroups. Alternatively, the effect of cKIT mutations may have ceased because of various treatment regimens. In addition, patients with cKIT mutations received significantly more cytarabine in our cohort, so one could speculate that this difference resulted in similar outcomes for patients with the mutations compared with patients without cKIT mutations. However, we could not confirm this after multivariable testing was performed on the subgroup of patients who had available molecular data (data not shown). Both groups were treated as (in)frequent according to high-risk protocols, and both achieved CR equally often.

Interestingly, Beghini et al29 reported that trisomy 4 can lead to duplication of the cKIT mutated allele, consistent with the significant correlation between trisomy 4 and cKIT mutations in our cohort. Shimada et al23 reported a poor outcome for cKIT-mutated pediatric patients with t(8;21)-AML but also reported an association between cKIT mutations and +4, so it would be interesting to evaluate the prognostic relevance of this combination. Because of the low number of patients in our study, we were unable to do so.

Present RAS mutations were not associated with impact on outcome, in line with previous reports about patients with CBF-AML.24,26 However, despite the lack of significant survival differences for patients with cKIT and/or RAS mutations in our study, in vitro sensitivity profiles suggest that patients with these mutations may still benefit from treatment with tyrosine kinase inhibitors.30

Previous studies about adults with AML demonstrated a benefit for intensive induction regimens with anthracyclines, etoposide, and intermediate-dose cytarabine31 and for intensive use of HD cytarabine in both induction and intensification regimens.18,32,33 Pediatric study groups reported superior outcomes for patients with t(8;21)-AML who received higher doses of cytarabine as well, in line with our results.3,34,35 Although the role of HD cytarabine during consolidation was not specifically evaluated in this study, cumulative cytarabine doses greater than 30 g/m2 were met only in protocols that comprised repetitive cycles of intermediate-dose or HD (ie, ≥ 1 g/m2) cytarabine. In our study and previous studies, the timing, doses, and number of courses of HD cytarabine and the cumulative doses cytarabine differed substantially among protocols.

Few studies have reported about the individual role of anthracyclines in pediatric t(8;21)-AML. Creutzig et al3 suggested beneficial effects of anthracyclines during reinduction as part of courses comprising HD cytarabine and mitoxantrone; however it is not clear whether these patients benefited the most from either agent or from their combination. Our results support the use of HD anthracyclines during induction, but the role of its approach during consolidation remains unclarified. Furthermore, the use of HD anthracyclines may be limited by potential (cardio)toxicity, which could have been insufficiently considered in this study. To decrease severe toxicity as a result of high doses of anthracyclines, patients with t(8;21)-AML might benefit from liposomal daunorubicin in future protocols,13 because it can be administered in higher doses with equal or less toxicity than the nonliposomal form.36

To our knowledge, this is the first study to report an association between the cumulative dose of etoposide and improved outcome in children with t(8;21)-AML, although a beneficial effect of etoposide has been described for other AML subgroups.37 Otherwise, the effect in our cohort might be explained by synergistic effects of combination therapy, which we could not confirm after testing for interaction terms (data not shown).

Although SCT in CR1 was associated with lower CIR in this cohort, pEFS or pOS were not affected. Mortality rates in CR1 were nonsignificantly higher in the allogenic SCT group (27%) than in the nontransplantation group (24%). Unfortunately, data on SCT-related toxicity were not available for the majority of patients. An international expert panel no longer recommends SCT in pediatric patients with favorable risk who are in CR1, because morbidity rates are high and there is not a survival advantage.18

The most important limitation of this study is the retrospective design, which leads to missing data and potential unknown confounders (eg, supportive care regimens, other molecular aberrations). Moreover, multivariable analyses were complex because of the heterogeneity of the study population, the divergent treatment protocols (Appendix Table A10, online only), and the wide study period.

The pOS and the pEFS were better for patients diagnosed in 1998 or later than for those diagnosed before 1998. This year was chosen, because several new protocols were initiated then, and 1998 appeared to be the most important year of influence among several tested cutoff points (data not shown). Nevertheless, dichotomization of time, instead of control for time as a continuous factor, may be inaccurate.

Application of intention-to-treat analyses hampers interpretation, because it is unknown whether patients actually received the treatment. However, results for the cumulative models were similar for all of the study population and for only patients in CR1 (data not shown), which demonstrates the low influence of the potential remaining lead-time bias.

Our results support the use of anthracycline doses greater than 150 mg/m2 and etoposide doses greater than 500 mg/m2 in the first induction course, HD cytarabine 3 g/m2 during induction, as well as the use of cumulative cytarabine doses greater than 30g/m2 and of cumulative etoposide doses greater than 1,500 mg/m2 in future pediatric t(8;21)-AML protocols. However, evaluation of single agents without adequate consideration of the potential synergistic effects of combination therapy could not be performed accurately in this retrospective setting. Furthermore, treatment evolves, and these data were obtained almost completely before novel agents, such as gemtuzumab ozogamicin or tyrosine kinase inhibitors, were introduced; therefore, these novel agents were not taken into account.

Multicenter, randomized trials are required to validate our results, establish combination therapy, define doses with acceptable toxicity, and identify the impact of different treatment aspects among cytogenetic subgroups. Nevertheless, this is, to our knowledge, the largest pediatric t(8;21)-AML cohort evaluated for clinical, cytogenetic, and treatment-related prognostic factors. Therefore, it provides valuable information about risk stratification for this AML subgroup.

Acknowledgment

We thank all participants of the various study groups for providing data. We thank Professor Adalet Meral Günes for providing the Turkish data, Marta Fiocco for additional statistical advice, and Vani Shanker from the Department of Scientific Editing at St Jude Children's Research Hospital for revision of the manuscript. We thank the Swedish Childhood Cancer Foundation for supporting the Nordic Society of Paediatric Haematology and Oncology study group and the European Organisation for Research and Treatment of Cancer (EORTC) for permission to use the data from EORTC study 58921 for this research.

Glossary Terms

AML-ETO (t[8;21]-AML):
the t(8;21)(q22;q22) translocation replaces the C terminus of acute myeloid leukemia, including its transactivation domain, with ETO, a nuclear protein of unknown function. The fusion protein acts as a transcriptional repressor.
anthracyclines:
a class of antineoplastic agents derived from Streptomyces bacterium used to treat a variety of hematologic and solid malignancies. Anthracyclines have a well-established dose-related risk of cardiomyopathy and congestive heart failure. Anthracyclines include agents like daunorubicin, doxorubicin, epirubicin, and idarubicin.
c-KIT:
a tyrosine kinase receptor that dimerizes after ligand binding and is autophosphorylated on intracellular tyrosine residues.
cumulative incidence of relapse (CIR):
the use of competing risk analyses indicated in the presence of competing events (such as death and relapse); the Gray's test is a recommended method to estimate cumulative incidence of relapse.
event-free survival:
calculated from the date of diagnosis to the date of the first event, which is resistance, relapse, death, or second malignant neoplasm.
karyotype:
an organized chromosomal profile defining chromosomal arrangement and number. In a karyotype, chromosomes are photographically arranged and displayed in pairs, ordered by size. Chromosomal size, banding pattern, and centromere position are typically used as guides to determine chromosomal abnormalities, but improved resolution may be obtained by combining traditional banding techniques with genome-wide molecular cytogenetics such as multicolor fluorescent in situ hybridization (FISH) and locus-specific FISH.
overall survival:
the duration between random assignment and death.
RAS:
gene family consisting of H-RAS, N-RAS, and K-RAS. The RAS proteins are typically small triphosphate-binding proteins and are the common upstream molecules of several signaling pathways that play a key role in signal transduction, which results in cellular proliferation and transformation.
tyrosine kinase inhibitors:
molecules that inhibit the activity of tyrosine kinase receptors. Tyrosine kinase inhibitors are small molecules developed to inhibit the binding of ATP to the cytoplasmic region of the receptor (eg, gefitinib), thus further blocking the cascade of reactions that is activated by the pathway.

Appendix

Table A1.

Treatment ElementCutoff ValueOther
AnthracyclineConversion factors*: daunorubicin:mitoxantrone ratio, 1:5; daunorubicin:idarubicin ratio, 1:5; and daunorubicin:doxorubicin, ratio 1:1
    First induction course≤/> 150 mg/m2
    First two courses≤/> 300 mg/m2
    Cumulative≤/> 400 mg/m2
Cytarabine
    First induction course≤/> 1,400 mg/m2
    First two courses≤/> 5,000 mg/m2
    HD cytarabine, first two courses3 g/m2The potentially beneficial dose of 3 g/m2 was chosen to define HD cytarabine.18
    Cumulative dose≤/> 30 g/m2
Etoposide
    First induction course≤/> 500 mg/m2
    First two courses≤/> 1,000 mg/m2
    Cumulative dose≤/> 1,500 mg/m2
Allogeneic stem-cell transplantation in first complete remissionYes or no
MaintenanceYes or no

Cutoff Values of Evaluated Chemotherapeutic Agents

Abbreviation: HD, high dose.

*Kaspers GJ, et al: Leukemia 19:2025-2029, 2005.

Table A2.

End PointAbbreviationDefinition
Complete remissionCRMorphologically, < 5% blasts in the bone marrow with signs of regeneration of normal hematopoiesis, in the absence of leukemia elsewhere after 60 days.* Patients with early death during induction were considered CR failures at t = 0.
Cumulative incidence of relapseCIRThe cumulative probability of relapse during the follow-up time, with death in CR and development of a secondary malignancy as competing events
Overall survival (time)OSSurvival, measured from the date of diagnosis to the date of last follow-up or death
Event-free survival (time)EFSSurvival without experiencing an event, measured from the date of diagnosis to the date of last follow-up or an event
Event
    RelapseThe reoccurrence of leukemic blasts in the bone marrow or peripheral blood or leukemic infiltrates elsewhere after patients achieved CR1
    Refractory diseaseMorphologically, ≥ 5% leukemic blasts in the bone marrow, peripheral blood, or extramedullary leukemia after the second induction course
    Induction death/early deathDeath before achieving CR; considered CR failure at t = 0
    Death
    Secondary malignancy

Definitions of End Points

Abbreviations: CR1, first complete remission; t, time point.

*Cheson BD, et al: J Clin Oncol 8:813-819, 1990.

Table A3.

CharacteristicNo. (%) With Aberrations
t(8;21) Only (n = 265)+1 (n = 366)+2 (n = 154)+3 (n = 31)+4 or More (n = 22)
Year of diagnosis
    1988-1997109 (41.1)154 (42.1)68 (44.2)14 (45.2)7 (31.8)
    1998-2010156 (58.9)212 (57.9)86 (55.8)17 (54.8)15 (68.2)
Male sex127 (47.9)243 (66.4)94 (61.0)20 (64.5)11 (50.0)
Median (IQR) age, years9 (6-13)9 (6-9)9 (6-13)7 (4-14)11 [(5-14)
    < 12169 (63.8)244 (66.7)107 (69.5)20 (64.6)12 (54.6)
    ≥ 1296 (36.2)122 (33.3)47 (30.5)11 (35.4)10 (45.4)
Median (IQR) WBC count, × 109/L)14.9 (6.6-32.8)13.8 (7.4-26.2)12.6 (7.0-27.6)11.9 (4.3-29.8)20.1 (10.1-55.9)
    ≤ 20161 (61.0)236 (64.8)97 (63.8)20 (66.7)11 (50.0)
    > 20103 (39.0)128 (35.2)55 (36.2)10 (33.3)11 (50.0)
Median (IQR) BM blasts,* %62 (41-79)55 (39-71)58 (39-75)48 (35-62)56 (32-83)
FAB classification
    M2199 (77.4)298 (84.4)127 (83.6)22 (73.3)14 (63.6)
    M other58 (22.6)55 (15.6)25 (16.4)8 (26.7)8 (36.4)
CNS involvement15 (7.4)23 (7.7)10 (7.9)1 (4.0)3 (16.7)
Additional cytogenetic aberration
    Loss of sex chromosome243 (66.4)109 (70.8)22 (71.0)7 (31.8)
    Deletion chromosome 9q42 (11.5)45 (29.2)13 (41.9)4 (18.2)
    Abnormalities chromosome 7q15 (4.1)17 (11.0)5 (16.1)4 (18.2)
    Gain of chromosome 814 (3.8)25 (16.2)7 (22.6)3 (13.6)
    Gain of chromosome 49 (2.5)7 (4.6)1 (3.2)4 (18.2)

Demographic and Clinical Characteristics by the Number of Additional Cytogenetic Aberrations in Patients With Cytogenetic Confirmation of t(8;21) and Full Karyotype

NOTE. Percentages may not add up to 100% because of rounding.

Abbreviations: BM, bone marrow; FAB, French-American-British classification of acute myeloid leukemia; IQR, interquartile range.

*Overall BM blasts were normally distributed; however, in one of these subgroups it was not; therefore, median (IQR) is presented.

Table A4.

CharacteristicNo. (%) of Patients by Aberration
LOS
Del(9q)
Abn(7q)
+8
+4
Absent (n = 457)Present (n = 381)PAbsent (n = 734)Present (n = 104)PAbsent (n = 797)Present (n = 41)PAbsent (n = 789)Present (n = 49)PAbsent (n = 817)Present (n = 21)P
Year of diagnosisNSNSNSNSNS
    1988-1997199 (44)153 (40)310 (42)42 (40)333 (42)19 (46)332 (42)20 (41)342 (42)10 (48)
    1998-2010258 (56)228 (60)424 (58)62 (60)464 (58)22 (54)457 (58)29 (59)475 (58)11 (52)
Sex< .001NSNSNSNS
    Male228 (50)267 (70)434 (59)61 (59)476 (60)19 (46)467 (59)28 (57)481 (59)14 (67)
    Female229 (50)114 (30)300 (41)43 (41)321 (40)22 (54)322 (41)21 (43)336 (41)7 (33)
Age, yearsNSNSNSNSNS
    < 12292 (64)260 (68)486 (66)66 (63)521 (65)31 (76)517 (66)35 (71)539 (66)13 (62)
    ≥ 12165 (36)121 (32)248 (34)38 (37)276 (35)10 (24)272 (34)14 (29)278 (34)8 (38)
WBC count, × 109/L.010NS.042NS.001
    ≤ 20268 (59)257 (68)458 (63)67 (66)493 (62)32 (78)489 (62)36 (73)519 (64)6 (29)
    > 20185 (41)122 (32)272 (37)35 (34)298 (38)9 (22)294 (38)13 (27)292 (36)15 (71)
BM blasts, %*.019.035NS.015NS
    < 60194 (48)200 (57)336 (51)58 (62)375 (52)19 (49)378 (53)16 (35)388 (53)6 (33)
    ≥ 60209 (52)153 (43)327 (49)35 (38)342 (48)20 (51)332 (47)30 (65)350 (47)12 (67)
FAB classification*.005NSNS< .001NS
    M2338 (86)325 (92)583 (89)80 (86)631 (89)32 (91)631 (90)32 (73)648 (89)15 (94)
    M other56 (14)27 (8)70 (11)13 (14)80 (11)3 (9)71 (10)12 (27)82 (11)1 (6)
CNS involvement*NSNSNSNSNS
    No326 (92)291 (93)540 (92)77 (95)589 (92)28 (93)579 (92)38 (95)603 (92)14 (93)
    Yes29 (8)23 (7)48 (8)4 (5)50 (8)2 (7)50 (8)2 (5)51 (8)1 (7)
Additional cytogenetic aberrations
    LOS presentNA338 (46)43 (41)NS369 (46)12 (29).033355 (45)26 (53)NS377 (46)4 (19).014
    del(9q) present61 (13)43 (11)NSNA98 (12)6 (15)NS99 (13)5 (10)NS102 (13)2 (10)NS
    +8 present23 (5)26 (7)NS44 (6)5 (5)NS49 (6)0 (0)NSNA47 (6)2 (10)NS
    abn(7q) present29 (6)12 (3).03335 (5)6 (6)NSNA41 (5)0 (0)NS39 (5)2 (10)NS
    +4 present17 (4)4 (1).01419 (3)2 (2)NS19 (2)2 (5)NS19 (2)2 (4)NSNA
    Complex karyotype (≥ 3) present69 (15)138 (36)< .001145 (20)62 (60)< .001181 (23)26 (63)< .001172 (22)35 (71)< .001195 (24)12 (57)< .001
    Complex karyotype (≥ 5) present15 (3)7 (2)NS18 (3)4 (4)NS18 (2)4 (10).01919 (2)3 (6)NS18 (2)4 (19).002
Molecular aberrations*
    cKIT mutation
        Present34 (26)19 (20)NS48 (25)5 (17)NS50 (24)3 (25)NS52 (25)1 (6)NS46 (22)7 (70).002
        Absent95 (74)74 (80)NS144 (75)25 (83)NS160 (76)9 (75)NS154 (75)15 (94)NS166 (78)3 (30)NS
    RAS mutation
        Present21 (19)8 (10)NS26 (16)3 (10)NS29 (16)0 (0)NS28 (16)1 (11)NS28 (16)1 (14)NS
        Absent87 (81)72 (90)NS133 (84)26 (90)NS148 (84)11 (100)NS151 (84)8 (89)NS153 (85)6 (86)NS
Induction therapy
    Course 1
        Anthracycline > 150 mg/m2130 (28)114 (30)NS215 (29)29 (28)NS238 (30)5 (15).036231 (29)13 (27)NS239 (29)5 (24)NS
        Cytarabine > 1,400 mg/m2129 (28)114 (30)NS205 (28)38 (37)NS230 (29)13 (32)NS226 (29)17 (35)NS233 (29)10 (48)NS
        Etoposide > 500 mg/m2145 (32)125 (33)NS233 (32)37 (36)NS259 (33)11 (27)NS253 (32)17 (35)NS261 (32)9 (43)NS
    Courses 1 and 2
        Anthracycline > 300 mg/m248 (11)51 (13)NS84 (11)15 (14)NS96 (12)3 (7)NS90 (11)9 (18)NS97 (12)2 (10)NS
        Cytarabine > 5,000 mg/m2150 (54)126 (46)NS246 (34)30 (29)NS260 (33)16 (39)NS259 (33)17 (35)NS271 (33)5 (24)NS
        HD cytarabine > 30 g/m2126 (28)110 (29)NS211 (29)25 (24)NS225 (28)11 (27)NS224 (29)12 (25)NS233 (29)3 (14)NS
        Etoposide > 1,000 mg/m2142 (31)119 (31)NS225 (31)36 (35)NS250 (31)11 (27)NS244 (31)17 (35)NS252 (31)9 (43)NS
Overall treatment
    Anthracycline > 400 mg/m2197 (43)174 (46)NS323 (44)48 (46)NS353 (44)18 (44)NS344 (44)27 (55)NS360 (44)11 (52)NS
    Cytarabine > 30 g/m2177 (39)146 (38)NS288 (39)35 (34)NS307 (39)16 (39)NS302 (38)21 (43)NS316 (39)7 (33)NS
    Etoposide > 1,500 mg/m2212 (46)177 (47)NS336 (46)53 (51)NS369 (46)20 (49)NS369 (47)20 (41)NS377 (46)12 (57)NS
    Allo-SCT in first complete remission47 (10)61 (16).01393 (13)15 (15)NS101 (13)7 (18)NS100 (13)8 (16)NS107 (13)1 (5)NS

Demographic and Clinical Characteristics by Specific Additional Cytogenetic Aberration in Patients With Cytogenetic Confirmation of t(8;21) and Full Karyotype

NOTE. Percentages may not add up to 100% because of rounding.

Abbreviations: +4, gain of chromosome 4; +8, gain of chromosome 8; abn(7q), abnormalities or a deletion in the long arm of chromosome 7; allo-SCT, allogenic stem-cell transplantation; BM, bone marrow; del(9q), deletion in the long arm of chromosome 9; FAB, French-American-British classification of acute myeloid leukemia; HD, high dose; LOS, loss of sex chromosome; NA, not applicable; NS, nonsignificant at P < .05.

*Data on BM blast percentages, FAB classification, CNS involvement, and molecular aberrations were not complete for all patients.
Dichotomous covariates: present (> mg/m2 or g/m2) compared with absent (≤ mg/m2 or g/m2).

Table A5.

CharacteristicNo./Total Not Screened for cKIT/RAS Mutations (n = 610)No. (%) of Patients Screened for cKIT/RAS Mutations (n = 228)P
Year of diagnosis
    1988-1997263/610 (43.1)89/228 (39.0).287
    1998-2010347/610 (56.9)139/228 (61.0)
Sex
    Male367/610 (60.2)128/228 (56.1).292
    Female243/610 (39.8)100/228 (43.9)
Mean ± SD age, years
    < 12412/610 (67.5)140/228 (61.4).095
    ≥ 12198/610 (32.5)88/228 (38.6)
Median (IQR) WBC count at diagnosis, × 109/L13.6 (6.5-27.9)13.9 (7.9-28.9)
    ≤ 20385/605 (63.6)140/227 (61.7).601
    > 20220/605 (36.4)87/228 (38.2)
Mean ± SD hemoglobin, g/dL7.81 ± 2.617.54 ± 2.48.184
Median (IQR) platelets, × 109/L37 (19-69)35 (18-70).457
Mean ± SD BM blasts, %58 ± 2254 ± 23
    < 60278/548 (50.7)116/208 (55.8).215
    ≥ 60270/548 (49.3)92/208 (44.2)
FAB classification
    M2486/550 (88.4)177/196 (90.3).458
    other64/550 (11.6)19/196 (9.7)
CNS involvement37/472 (7.8)15/197 (7.6).921
Additional cytogenetic aberrations
    ≥ 1 additional aberration
    Loss of sex chromosome284/610 (46.6)131/228 (57.5).299
    Deletion chromosome 9q73/610 (12.0)31/228 (1.4).524
    Gain of chromosome 833/610 (5.4)16/228 (7.0).377
    Abnormalities in chromosome 7q28/610 (4.6)13/228 (5.7).507
    Gain of chromosome 411/610 (1.8)10/228 (4.4).033
    Complex karyotype (≥ 3 aberrations)151/610 (24.8)56/228 (24.6).954
    Complex karyotype (≥ 5 aberrations)14/610 (2.3)8/228 (3.5).328
Induction regimen*
    Course 1
        Anthracycline > 150 mg/m2185/610 (30.3)59/228 (25.9).207
        Cytarabine > 1,400 mg/m2135/610 (22.1)108/228 (47.4)< .001
        Etoposide > 500 mg/m2187/610 (30.7)83/228 (36.4).113
    Courses 1 and 2
        Anthracycline > 300 mg/m271/610 (11.6)28/228 (12.3).798
        Cytarabine > 5,000 mg/m2240/610 (39.3)36//228 (15.8)< .001
        HD cytarabine > 3 g/m2210/607 (34.6)26/228 (11.4)< .001
        Etoposide > 1,000 mg/m2178/610 (29.2)83/228 (36.4).044
Overall treatment*
    Anthracycline > 400 mg/m2258/610 (42.2)113/228 (49.6).059
    Cytarabine > 30 g/m2242/610 (39.7)81/228 (35.5).272
    Etoposide > 1,500 mg/m2228/610 (37.4)161/228 (70.6)< .001
    Allo-SCT in first complete remission78/600 (13.0)30/228 (13.2).952
    Maintenance175/610 (28.7)23/228 (10.1)< .001

Demographic and Clinical Characteristics From Pediatric t(8;21)-Patients With Full Karyotype, From Whom Samples Were or Were Not Screened for cKIT and RAS Mutations

NOTE. Percentages may not make 100% because of rounding. Normally distributed data are represented with mean ± SD instead of with median and IQR. The differences between patients of whom samples were or were not screened for presence of cKIT and/or RAS mutations are shown. Differences in treatment regimen are explained by the fact that only a part of the participating study groups provided samples.

Abbreviations: allo-SCT, allogeneic stem-cell transplantation; BM, bone marrow; FAB classification, French-American-British classification of acute myeloid leukemia; HD, high dose (ie, 3 g/m2); IQR, interquartile range; SD, standard deviation.

*Dichotomous covariates: present (> mg/m2 or g/m2) compared with absent (≤ mg/m2 or g/m2).

Table A6.

CharacteristicNo. (%) of Patients by Aberration
cKIT Mutation (n = 222)
RAS Mutation (n = 188)
AbsentPresentPAbsentPresentP
Year of diagnosis
    1988-199761 (27.5)25 (11.3)NS56 (35)15 (52)NS
    1998-2010108 (48.6)28 (12.6)103 (65)14 (48)
Sex
    Male92 (41.4)31 (14.0)NS86 (54)17 (59)NS
    Female77 (34.7)22 (9.9)73 (46)12 (41)
Age, years
    < 12103 (46.4)32 (14.4)NS98 (62)21 (72)NS
    ≥ 1266 (29.7)21 (9.5)61 (38)8 (28)
WBC count, × 109/L
    ≤ 20106 (47.8)30 (13.5)NS107 (68)12 (41).007
    > 2062 (27.9)23 (5.9)51 (32)17 (59)
BM blasts, %*
    < 6091 (41.0)22 (9.9)NS79 (55)20 (83).009
    ≥ 6064 (28.8)25 (11.3)65 (45)4 (17)
FAB classification*
    M2133 (59.9)40 (18.0)NS124 (79)23 (89)NS
    M other14 (6.3)4 (1.8)33 (21)3 (12)
CNS involvement*
    No138 (62.2)40 (18.0)NS126 (91)27 (96)NS
    Yes8 (3.6)6 (2.7)13 (9)1 (4)
Additional cytogenetic aberrations
    LOS present74 (44)19 (36)NS72 (45)8 (28)NS
    Del(9q) present25 (15)5 (9)NS26 (16)3 (10)NS
    +8 present15 (9)1 (2)NS8 (5)1 (3)NS
    Abn(7q) present9 (5)3 (6)NS11 (7)0 (0)NS
    +4 present3 (2)7 (13).0026 (4)1 (3)NS
    Complex karyotype (≥ 3) present43 (25)10 (19)NS41 (26)4 (14)NS
    Complex karyotype (≥ 5) present6 (4)2 (4)NS6 (4)1 (3)NS
Induction therapy
    Course 1
        Anthracycline > 150 mg/m237 (22)20 (38).02147 (30)12 (41)NS
        Cytarabine > 1,400 mg/m278 (46)28 (53)NS69 (43)10 (35)NS
        Etoposide > 500 mg/m261 (36)21 (40)NS55 (35)9 (31)NS
    Courses 1 and 2
        Anthracycline > 300 mg/m220 (12)7 (13)NS24 (15)4 (14)NS
        Cytarabine > 5,000 mg/m221 (12)14 (26).01521 (13)5 (17)NS
        HD cytarabine > 3 g/m213 (8)12 (23).00321 (13)5 (17)NS
        Etoposide > 1,000 mg/m261 (36)21 (40)NS55 (35)9 (31)NS
Overall treatment
    Anthracycline > 400 mg/m280 (47)31 (59)NS75 (47)14 (48)NS
    Cytarabine > 30 g/m252 (31)27 (51).00755 (35)12 (41)NS
    Etoposide > 1,500 mg/m2123 (73)34 (64)NS120 (76)19 (66)NS
    Allo-SCT in first complete remission23 (14)7 (13)NS16 (10)4 (14)NS

Demographic and Clinical Characteristics by Specific Additional Molecular Aberration in Patients With Cytogenetic Confirmation of t(8;21)

NOTE. Percentages may not add up to 100% because of rounding.

Abbreviations: +4, gain of chromosome 4; +8, gain of chromosome 8; abn(7q), abnormalities or a deletion in the long arm of chromosome 7; BM, bone marrow; del(9q), deletion in the long arm of chromosome 9; FAB, French-American-British classification of acute myeloid leukemia; LOS, loss of sex chromosome; NS, nonsignificant at P < .05.

*Data on BM blast percentage, FAB classification, CNS involvement, and molecular aberrations were not complete for all patients.
Dichotomous covariates: present (> mg/m2 or g/m2) compared with absent (≤ mg/m2 or g/m2).

Table A7.

CharacteristicNo. of Patients5-Year pEFS (SE)P (pEFS log-rank)5-Year pOS (SE)P (pOS log-rank)
Year of diagnosis
    1988-19973520.49 (0.03)< .0010.65 (0.03)< .001
    1998-20104860.65 (0.02)0.80 (0.02)
Sex
    Male4950.55 (0.02).0330.71 (0.02).049
    Female3430.63 (0.03)0.77 (.02)
Age, years
    < 125520.60 (0.02).1700.76 (0.02).014
    ≥ 122860.55 (0.03)0.69 (0.03)
WBC count at diagnosis, × 109/L
    ≤ 205250.63 (0.02)< .0010.78 (0.02)< .001
    > 203070.50 (0.03)0.65 (0.03)
    ≤ 507370.58 (0.02).8850.73 (0.02).385
    > 50950.60 (0.05)0.76 (0.04)
    ≤ 1008040.58 (0.02).8020.73 (0.02).177
    > 100280.64 (0.09)0.86 (0.07)
Blasts in BM, %
    < 502910.57 (0.03).7260.72 (0.03).767
    ≥ 504640.58 (0.02)0.73 (0.02)
    < 603940.55 (0.03).0760.70 (0.02).143
    ≥ 603620.61 (0.03)0.75 (0.02)
FAB type*
    M26630.59 (0.02).4870.74 (0.02).410
    M other830.55 (0.06)0.72 (0.05)
CNS involvement
    Yes6170.45 (0.07).0200.75 (0.06).720
    No520.61 (0.02)0.75 (0.02)
Additional cytogenetic aberrations
    t(8;21) alone2650.57 (0.03).3630.72 (0.03).164
    + 1 cytogenetic aberration3660.62 (0.03)0.76 (0.02)
    + 21540.54 (0.04)0.72 (0.04)
    + 3310.61 (0.09)0.80 (0.07)
    + 4 or more220.40 (0.11)0.58 (0.11)
Loss of sex chromosome
    Present3810.61 (0.03).0510.76 (0.02).173
    Absent4570.56 (0.02)0.72 (0.02)
Deletion chromosome 9q
    Present1040.55 (0.05).4330.79 (0.04).293
    Absent7340.59 (0.02)0.73 (0.02)
Abnormalities chromosome 7q
    Present410.54 (0.08).4200.71 (0.07).312
    Absent7970.59 (0.02)0.74 (0.02)
Gain of chromosome 4
    Present210.18 (0.09)< .0010.33 (0.11)< .001
    Absent8170.59 (0.02)0.75 (0.02)
Gain of chromosome 8
    Present490.71 (0.07).0630.85 (0.05).092
    Absent7890.57 (0.02)0.73 (0.02)
Complex karyotype (≥ 3)
    Present2070.54 (0.04).1920.72 (0.03).431
    Absent6310.60 (0.02)0.74 (0.02)
Complex karyotype (≥ 5)
    Present220.59 (0.02).2260.58 (0.11).027
    Absent8160.40 (0.11)0.74 (0.02)
Molecular aberration
    cKIT mutation
        Present530.60 (0.07).8840.70 (0.06).365
        Absent1690.60 (0.04)0.77 (0.03)
    RAS mutation
        Present290.72 (0.08).3270.72 (0.08).250
        Absent1590.56 (0.04)0.76 (0.03)
Induction regimen
    Course 1 anthracycline, mg/m2
        ≤ 1505940.56 (0.02).0110.72 (0.02).039
        > 1502440.65 (0.03)0.79 (0.03)
    Course 1 cytarabine, mg/m2
        ≤ 1,4005950.58 (0.02).5970.74 (0.02).950
        > 1,4002430.60 (0.03)0.73 (0.03)
    Course 1 etoposide, mg/m2
        ≤ 5005680.54 (0.02).0010.71 (0.02).003
        > 5002700.67 (0.03)0.80 (0.03)
    Courses 1-2 anthracycline, mg/m2
        ≤ 3007390.58 (0.02).9740.73 (0.02).459
        > 300990.60 (0.05)0.77 (0.04)
    Courses 1-2 cytarabine, mg/m2
        ≤ 5,0005620.56 (0.02).1340.73 (0.02).739
        > 5,0002760.62 (0.03)0.75 (0.03)
    Courses 1-2 HD cytarabine
        No5990.56 (0.02).0250.73 (0.02).465
        Yes2360.64 (0.03)0.76 (0.03)
    Courses 1-2 etoposide, mg/m2
        ≤ 1,0005770.55 (0.02).0020.71 (0.02).003
        > 1,0002610.66 (0.03)0.80 (0.03)
Overall treatment
    Cumulative anthracycline, mg/m2
        ≤ 4004670.56 (0.02).1520.71 (0.02).012
        > 4003710.61 (0.03)0.78 (0.02)
    Cumulative cytarabine, g/m2
        ≤ 305150.54 (0.02).0050.72 (0.02).082
        > 303230.65 (0.03)0.77 (0.02)
    Cumulative etoposide, mg/m2
        ≤ 1,5004490.57 (0.02).4800.73 (0.02).207
        > 1,5003890.60 (0.03)0.75 (0.02)
    Allo-SCT in CR1
        Yes1040.62 (0.05).2700.75 (0.04).925
        No7340.58 (0.02)0.74 (0.02)
    Maintenance
        Yes1980.65 (0.03).0220.80 (0.03).046
        No6400.56 (0.02)0.72 (0.02)

Five-Year Outcomes and Univariable Analyses for Probabilities of EFS and OS for t(8;21)-Positive Patients With AML and Full Karyotype

Abbreviations: allo-SCT in CR1, allogeneic stem-cell transplantation in first complete remission; BM, bone marrow; EFS, event-free survival; FAB type, French-American-British classification system of acute myeloid leukemia; HD (ie, 3 g/m2); , OR, odds ratio; OS, overall survival; pEFS, probability of EFS; pOS, probability of OS.

*FAB type M2 included three occurrences that were classified as FAB type M1/M2.

Table A8.

CharacteristicMultivariable Analyses
CIR
pEFS
pOS
SHR (95% CI)PHR (95% CI)PHR (95% CI)P
Year of diagnosis
    1988-1997RefRef
    1998-2010*0.76 (0.58 to 1.00).0460.57 (0.43 to 0.76)< .001
Sex
    MaleRefRef
    Female*0.82 (0.63 to 1.07).1400.76 (0.58 to 1.00).048
Age, years
    < 12NANARef
    ≥ 12
        Follow-up in first 2 years1.71 (1.25 to 2.33).001
        Follow-up after 2 years0.56 (0.30 to 1.05).072
WBC count at diagnosis, × 109/L
    ≤ 20RefRefRef
    > 201.66 (1.20 to 2.28).0021.52 (1.18 to 1.97).0011.58 (1.21 to 2.05).001
Blasts in BM, %NANA
    < 60Ref
    ≥ 600.81 (0.63 to 1.04).099
CNS involvement1.96 (1.21 to 3.18).0071.37 (0.91 to 2.06).133NA
Additional cytogenetic aberrations
    Loss of sex chromosome*0.80 (0.62 to 1.03).083NA
    Gain of chromosome 42.82 (1.34 to 5.91).0062.36 (1.30 to 4.28).0052.56 (1.44 to 4.55).001
    Gain of chromosome 8NA0.56 (0.27 to 1.13).106
    Complex karyotype (≥ 3)NANANA
    Complex karyotype (≥ 5)NANA
        Follow-up in first 2 years1.02 (0.41 to 2.53).967
        Follow-up after 2 years4.76 (1.39 to 16.33).013
Molecular aberration
    cKIT mutationNANA
    RAS mutationNANA
Induction regimen
    Course 1 anthracycline, mg/m2NA
        ≤ 150RefRef
        > 1500.74 (0.57 to 0.98).0330.71 (0.52 to 0.97).031
    Course 1 cytarabineNANANA
    Course 1 etoposide, mg/m2
        ≤ 500RefRefRef
        > 5000.70 (0.50 to 1.00).0470.67 (0.50 to 0.90).0090.69 (0.49 to 0.95).022
    Courses 1-2 anthracyclineNANANA
    Courses 1-2 cytarabineNANANA
    Courses 1-2 HD cytarabineNA
        NoRef
        Yes*0.71 (0.51 to 0.97).034
    Courses 1-2 etoposide§NA
Overall therapy
    Cumulative anthracycline, mg/m2NANA
        ≤ 400
        > 400
    Cumulative cytarabine, g/m2NA
        ≤ 30
        > 30
    Cumulative etoposideNANANA
    Allo-SCT in CR10.55 (0.32 to 0.94).030NANA
    MaintenanceNA

Explorative Multivariable Analyses in t(8;21)-Positive Patients With AML and Full Karyotype

NOTE. The results of the explorative analyses, which were performed to determine variables relevant for the assessment of treatment elements in the final induction model and the overall treatment model (Tables 3 and and4),4), are shown. Significant variables with (S)HR > 1 were associated with inferior outcome, whereas significant variables with (S)HR < 1 were associated with superior outcome. Data were analyzed according to the intention-to-treat principle. Statistical correction was made for violation of proportional hazard assumption, because hazard rates were not proportional for the complete follow-up time; an HR for the first 2 years of follow-up and an HR for follow-up after the first 2 years were estimated.

Abbreviations: allo-SCT in CR1, allogeneic stem-cell transplantation in first complete remission; BM, bone marrow; CR, complete remission; CIR, cumulative incidence of relapse, with death during CR and secondary malignancy as competing events; EFS, event-free survival; HD, high dose (ie, 3 g/m2); HR, hazard ratio; NA, not applicable, because these variables were not significant in univariable analyses; OS, overall survival; pEFS, probability of EFS; pOS, probability of overall survival; Ref, reference category; SHR, subdistributional hazard ratio.

*By stepwise backward elimination, variables with P > .2 were omitted from the competing risk model.
By stepwise backward elimination, variables with P > .2 were omitted from the EFS model.
Not included as variables in the Fine and Grey model for CIR because of the large amount of missing molecular data.
§Etoposide > 1,000 mg/m2 correlated highly with etoposide > 500 mg/m2 and therefore was omitted from the models of pEFS and pOS.
By stepwise backward elimination variables with P > .2 were omitted from the OS model.

Table A9.

Treatment GroupNo. of Patients in CR1No. (%) of Patients
P
AliveDead
Cumulative anthracycline, mg/m2
    ≤ 400408307 (73)111 (27).125
    > 400349273 (78)76 (22)
Cumulative cytarabine, g/m2
    ≤ 30464341 (74)123 (27).089
    > 30303239 (79)64 (21)
Cumulative etoposide, mg/m2
    ≤ 1,500417310 (74)107 (26).368
    > 1,500350270 (77)80 (23)
No allo-SCT in CR1656499 (76)157 (24).539
Allo-SCT in CR110476 (73)28 (27)

Distribution of Incidence of Death for Patients With t(8;21) in CR1 Among Different Treatment Groups

Abbreviations: allo-SCT, allogeneic stem-cell transplantation; CR1, first complete remission.

Table A10.

Study GroupProtocolNo. of coursesCourse 1
Courses 1 and 2
SCTCumulative Treatment
CNS CytarabineMaintenanceAdditional SCTAuthor
Cytarabine (mg/m2)HD Cytarabine (3 g/m2)Anthracycline (mg/m2)Etoposide (mg/m2)Cytarabine (mg/m2)HD Cytarabine (g/m2)Anthracycline (mg/m2)Etoposide (mg/m2)Cytarabine (g/m2)Anthracycline (mg/m2)Etoposide (mg/m2)
AIEOPAML2002/0131,400No150 ida5002,800No3001,00020.84001,000NoAllo or auto for all patientsPession et al6
BFM (no HR in patients with t[8;21])AML-BFM19874 + MT1400No1804503,200No300450No (HR only)413001,450YesYes, tg and cytarabine SCHR onlyCreutzig et ala
AML-BFM1993 (R: ADE or AIE and 6-week consolidation)3 + MT1400No1804503,200No300450No (HR only)SR 21.2SR 300950YesYes, tg and cytarabine SCHR onlyCreutzig et ala
AML-BFM19985 + MT1400No18045019,400Yes: 3 g300450No (HR only)39.2 if consolidation; 45.4 if AI+HAM420 if consol; 450 if AI+HAM950YesYes, tg and cytarabine SCHR onlyCreutzig et alb
AML-BFM2004 (R: ADxE or AIE)4 +MT1400No180 if AIE 240 if ADxE450SR 3,400No300 if AIE, 360 if ADxE450SR 27.4SR, 350 if AIE 410 if ADxE950YesYes, tg and cytarabine SCHR onlyCreutzig et al13 (via personal comment at time of analyses)
EORTCEORTC-CLG 58,8724+MT1,400No1504505,000No35045029 if no SCT; 5 if SCT500950YesYesEntz-Werle et alc
EORTC-CLG 58,921 (R: mitox or ida)4+MT1,400No15045025,400 if no SCT; 19,400 if allo-SCTYes: 3 g30045038.2; 19.4 if SCT380; 300 if allo-SCT1,350YesYesHR onlyEntz-Werle et alc
COGCOG28915800No804001,600No160800Allo-SCT if donor, R auto-SCT, or consolidation27.23201,600YesNoYes if donor, otherwise R auto-SCT or consolidation chemotherapySmith et ald
COG2961 R1: DCTEI or DCTER, R2: DCTEI/R or FAMPIf DCTEI/R, 5; if FAMP, 4800No1004001,600No180800SCT or HD cytarabineIf 2*DCTEI/R, 27.2; if FAMP, 33.1360800YesR IL-2 or no maintenanceAllo-SCT or HD cytarabineLange et ale
AAML03P152,000No1505003,600No3001,000SCT after 3rd course or not69.65401,750YesNoRelated donor if availableCooper et alf
CPHAML-BFM protocols (AML-BFM93, -98, -98interim, and -2004)27.4 39.2 45.4Protocols 93 and 98; 420, 350 SR; protocol 98 interim SR, and protocol 2004: 350825Received data per patient were slightly different from BFM protocols
DCOGANLL8741,600No1804501,400No30045038.23001,450YesNoHR onlyKardos et alg
ANLL92/9441,600No18045013,600Yes: 3 g28045032.2400950NoNoAllo if donor, auto-SCT otherwiseHählen et alh (from DCOG archive)
ANLL97= MRC12
GATLANo HAM41,400No1504502,600No27045021.2270950YesNoArmendariz et ali
With HAM51,400No15045019,400Yes: 3 g25045039.2370950YesNoArmendariz et ali
HongKong= MRC10
JPLSG (only few patients had Ida ([nduction B])AML9961400No12575019,400Yes: 3 g1751,25059.4-78.4300-3753150-3,200YesNoAllo-SCT if donor and intermediate risk; allo-SCT for all HRTsukimoto et al34
CCLSG 9805 (pirarubicin)FAB M1 or M281,120No8002,240No160025.4560600YesNoAllo-SCT if no CR after induction 1Taga et alj
Other21.45601,200
FRALLELAME-89 and LAME-913 + MT1,400No30001,800No460400Allo-SCT if donor, otherwise chemotherapy9.8; 13.4 if MT460 + amsacrine, 450400Yes for M4/M5 or WBC > 50 × 109/L at diagnosisR MP and cytarabine SC or noneAllo-SCTPerel et alk
LAME-974800No18001,400No3000Allo-SCT if donor, otherwise chemotherapy9.8;
13.4 if MT (not given from 1996)
460 + 450, amsacrine400Yes, for M4/M5 or WBC > 50 × 109/L at diagnosisNoAllo-SCT if donorPerel et alk
MRCMRC-AML10 (RDAT or ADE)42000No1500 if DAT; 500 if ADE3,600No3000 v 1,000Allo-SCT if donor, otherwise R between auto-SCT or no additional therapy10.6550 + 500, amsacrine500-1,500YesNoAllo-SCT or auto-SCTHann et all
MRC-AML12 (R: ADE or MAE and with/without CLASP)4-52,000no150 (ADE) or 180 (MAE)50036,00No300 (ADE) or 360 (MAE)1,000if GR, SR, or HR and without donor without CLASP
Allo-SCT = no midac
10.6
34.6 if with CLASP
4.6/28.6 if CLASP
550 or 610 if MAE;
500, amsacrine if with CLASP
300 or 360 if MAE
1,500YesNoIf donor available and SR or HRGibson et alm
NOPHONOPHO-AML 19887800No754001,300No22540050.14501,600YesNoNoLie et aln
NOPHO-AML 1993SR 6800No754001,600No15080049.63001,600YesNoNoLie et aln
PR 6 or 71,30022540049.3 or 61.3 if 3 × HA2E3751,200 or 1,600 if 3 × HA2E
NOPHO-AML 20046800No1804001,300No33040049.34801,200YesNo (post-consolidation R: GO)If donor availableHasle et alo
POGPOG8821 R: auto-SCT or chemotherapy9700no135018,700Yes: 3 g135055.7
18.7 if auto-SCT
360
135 if auto-SCT
2250
750 if auto-SCT
YesNoRandom assignment between auto-SCT or chemotherapyRavindranath et alp
POG9421 R: DAT/HDAT5700 v 14,000No/yes: 1 g135010,700 or 24,000Yes: 1 g135020.7-345351,000YesNoIf donor availableBecton et alq
PPLLSGAdapted BFM protocol(s)
Pinda/ChileAML-BFM protocols
RussiaUnknown41,600No1805002,600; 1 patient received HAMNo (1 patient, HAM)300-32050014.6300-3201,500YesYesAllo-SCTPersonal correspondence
St JudeAML8762,000No, 500 mg02,0004,500No, 500 mg1002,000SCT after consolidation92008,000YesNoAll patients: allo-SCT or auto-SCTRibeiro et alr
AML91 2-CDA 2x40No000No90400SCT after consolidation5180800YesNoAll patients: allo-SCT or auto-SCTRibeiro et alr
AML97 Based on AML91; induction 2-CDA plus cytarabine32,500No, 500 mg003,750No, 500 mg90400SCT after consolidation35430800YesNoAll patients: allo-SCT or auto-SCTCrews et als ; Ribeiro et alr
AML02 random assignment: HD-cytarabine for course 1; t(8;21), no HD cytarabine52000 v 18,000No; yes: 3 g if HD cytarabine1504004,000 or 20,000No, Yes: 3 g if HD cytarabine300800SCT after consolidation52 or 68550800YesNoHR/SR with donor allo-SCTRubnitz et alt

Overview of Treatment Protocols

Abbreviations: ADE, cytarabine, daunorubicin, etoposide; ADxE, cytarabine, daunoxome, etoposide; AI, cytarabine, idarubicin; AIE, cytarabine, idarubicin, etoposide; AIEOP, Associazione Italiana Ematologia Oncologia Pediatricia; allo-SCT, allogeneic SCT; AML, acute myeloid leukemia; ANLL, acute nonlymphoblastic leukemia; Ara-C, arabinofuranosyl cytidine (cytarabine); auto-SCT, autologous SCT; BFM, Berlin-Frankfurt-Münster; CCLSG, Children's Cancer and Leukemia Study Group; CDA, chlorodeoxyadenosine; CLASP, cytarabine, l-asparaginase; COG, Children's Oncology Group; CR, complete remission; DAT, Ara-C, daunorubicin, thioguanine; DCOG, Dutch Childhood Oncology Group; DCTEI/R, dexamethasone cytarabine, thioguanine, etoposide, idarubicin/daunorubicin; EORTC-CLG, European Organisation for Research and Treatment of Cancer–Children's Leukemia Group; FAB, French-American-British; FAMP, fludarabine, cytarabine, idarubicin; FRALLE, French Acute (Lymphoblastic) Leukaemia Study Group; GATLA, Grupo Argentino de Tratamiento de la Leucemia Aguda; GO, gemtuzumab ozogamicin; GR, good response; HA2E, HD cytarabine 2 g/m2, etoposide; HAE, HD cytarabine, etoposide; HAT, HD cytarabine, thioguanine; HD, high dose; HDAT, HD cytarabine, daunorubicin, thioguanine; HR, high risk; ida, idarubicin; IL-2, interleukin 2; JPLSG, Japanese Paediatric Leukemia/Lymphoma Study Group; LAME, Leucémies Aigués Myéloblastiques de l'Enfant Cooperative Group; MAE, mitoxantrone, cytarabine, etoposide; midac, mitoxantrone, Ara-C; mitox, mitoxantrone; MP, mercaptopurine; MRC, Medical Research Council; MT, maintenance; NOPHO, Nordic Society of Paediatric Haematology and Oncology; POG, Pediatric Oncology Group; PPLLSG, Polish Pediatric Leukemia Lymphoma Study Group; PR, poor response; R, random assignment; R1, first randomization; R2, second randomization; SC, subcutaneously; SCT, stem-cell transplantation; SR, standard risk; tg, thioguanine.

aCreutzig U, et al: Leukemia 19:2030-2042, 2005.
bCreutzig U, et al: J Clin Oncol 24:4499-4506, 2006.
cEntz-Werle N, et al: Leukemia 19:2072-2081, 2005.
dSmith FO, et al: Leukemia 19:2054-2062, 2005.
eLange BJ, et al: Blood 111:1044-1053, 2008.
fCooper TM, et al: Cancer 118:761-769, 2012.
gKardos G, et al: Leukemia 19:2063-2071, 2005.
hHählen K, et al: Med Pediatr Oncol 35:251, 2001 (abstr).
iArmendariz H, et al: Leukemia 19:2139-2142, 2005.
jTaga T, et al: Jpn J Ped Hematol 17:346-351, 2011.
kPerel Y, et al: Leukemia 19:2082-2089, 2005.
lHann IM, et al. Blood 89:2311-2318, 1997.
mGibson BE, et al: Leukemia 19:2130-2138, 2005.
nLie SO, et al: Leukemia 19:2090-2100, 2005.
oHasle H, et al: Blood 120:978-984, 2012.
pRavindranath Y, et al: Leukemia 19:2101-2116, 2005.
qBecton D, et al: Blood 107:1315-1324, 2006.
rRibeiro RC, et al: Leukemia 19:2125-2129, 2005.
sCrews KR, et al: J Clin Oncol 20:4217-4224, 2002.
tRubnitz JE, et al: Lancet Oncol 11:543-552, 2010.

Fig A1.

An external file that holds a picture, illustration, etc.
Object name is zlj9991056760004.jpg

Distribution of additional cytogenic aberrations in patients with t(8;21) and full karyotype (n = 838). +4, gain of chromosome 4 (n = 21); +8, gain of chromosome 8 (n = 49); abn(7q), abnormalities of chromosome 7q (n = 41); del(9q), deletion of the long arm of chromosome 9 (n = 104); LOS, loss of sex chromosome (n = 381).

Fig A2.

An external file that holds a picture, illustration, etc.
Object name is zlj9991056760005.jpg

(A) Kaplan-Meier curves of event-free survival time: year of diagnosis. (B) Kaplan-Meier curves of overall survival: year of diagnosis.

Fig A3.

An external file that holds a picture, illustration, etc.
Object name is zlj9991056760006.jpg

(A) Kaplan-Meier curves of event-free survival for cKIT mutation. (B) Kaplan-Meier curves of event-free survival for RAS mutation.

Footnotes

See accompanying editorial on page 4238

The contents of this publication and methods used are solely the responsibility of the authors and do not necessarily represent the official views of the European Organisation for Research and Treatment of Cancer headquarters.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Presented in part at the 54th Annual Meeting of the American Society of Hematology (ASH), Atlanta, GA, December 8-11, 2012, and the 56th ASH Annual Meeting, San Francisco, CA, December 6-9, 2014.

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Disclosures provided by the authors are available with this article at www.jco.org.

AUTHOR CONTRIBUTIONS

Conception and design: Kim Klein, Gertjan Kaspers, Martin Zimmermann, Brenda Gibson

Administrative support: Kim Klein, Gertjan Kaspers, Ardine Reedijk, Susana Raimondi

Provision of study materials or patients: Kim Klein, Gertjan Kaspers, Christine J. Harrison, H. Berna Beverloo, Ardine Reedijk, Jacqueline Cloos, Andrea Pession, Dirk Reinhardt, Martin Zimmermann, Ursula Creutzig, Michael Dworzak, Todd Alonzo, Donna Johnston, Betsy Hirsch, Michal Zapotocky, Barbara De Moerloose, Alcira Fynn, Vincent Lee, Takashi Taga, Akio Tawa, Anne Auvrignon, Bernward Zeller, Erik Forestier, Carmen Salgado, Walentyna Balwierz, Alexander Popa, Jeffrey Rubnitz, Susana Raimondi, Brenda Gibson

Collection and assembly of data: Kim Klein, Gertjan Kaspers, Christine J. Harrison, H. Berna Beverloo, Ardine Reedijk, Jacqueline Cloos, Andrea Pession, Dirk Reinhardt, Martin Zimmermann, Ursula Creutzig, Michael Dworzak, Todd Alonzo, Donna Johnston, Betsy Hirsch, Michal Zapotocky, Barbara De Moerloose, Alcira Fynn, Vincent Lee, Takashi Taga, Akio Tawa, Anne Auvrignon, Bernward Zeller, Erik Forestier, Carmen Salgado, Walentyna Balwierz, Alexander Popa, Jeffrey Rubnitz, Susana Raimondi, Brenda Gibson

Data analysis and interpretation: Kim Klein, Gertjan Kaspers, Christine J. Harrison, H. Berna Beverloo, Ardine Reedijk, Mathilda Bongers, Jacqueline Cloos, Martin Zimmermann, Ursula Creutzig, Betsy Hirsch, Susana Raimondi

Manuscript writing: All authors

Final approval of manuscript: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Clinical Impact of Additional Cytogenetic Aberrations, cKIT and RAS Mutations, and Treatment Elements in Pediatric t(8;21)-AML: Results From an International Retrospective Study by the International Berlin-Frankfurt-Münster Study Group

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.

Kim Klein

No relationship to disclose

Gertjan Kaspers

Consulting or Advisory Role: Celgene, Boehringer Ingelheim, Galen Pharmaceuticals

Christine J. Harrison

No relationship to disclose

H. Berna Beverloo

No relationship to disclose

Ardine Reedijk

No relationship to disclose

Mathilda Bongers

Research Funding: GlaxtoSmithKline (Inst)

Jacqueline Cloos

Honoraria: Takeda

Travel, Accommodations, Expenses: Takeda Pharmaceuticals

Andrea Pession

No relationship to disclose

Dirk Reinhardt

No relationship to disclose

Martin Zimmermann

No relationship to disclose

Ursula Creutzig

No relationship to disclose

Michael Dworzak

Research Funding: Beckman Coulter

Todd Alonzo

No relationship to disclose

Donna Johnston

No relationship to disclose

Betsy Hirsch

No relationship to disclose

Michal Zapotocky

No relationship to disclose

Barbara De Moerloose

Travel, Accommodations, Expenses: Eusapharma

Alcira Fynn

No relationship to disclose

Vincent Lee

No relationship to disclose

Takashi Taga

No relationship to disclose

Akio Tawa

No relationship to disclose

Anne Auvrignon

No relationship to disclose

Bernward Zeller

No relationship to disclose

Erik Forestier

No relationship to disclose

Carmen Salgado

No relationship to disclose

Walentyna Balwierz

Consulting or Advisory Role: Pfizer

Travel, Accommodations, Expenses: Medac

Alexander Popa

No relationship to disclose

Jeffrey Rubnitz

No relationship to disclose

Susana Raimondi

No relationship to disclose

Brenda Gibson

Honoraria: Janssen Pharmaceutical Research and Development

Consulting or Advisory Role: Janssen Pharmaceutical Research and Development

Travel, Accommodations, Expenses: Jazzpharma, Medac

REFERENCES

1. Grimwade D, Walker H, Oliver F, et al. The importance of diagnostic cytogenetics on outcome in AML: Analysis of 1,612 patients entered into the MRC AML 10 trial—The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood. 1998;92:2322–2333. [PubMed]
2. Marcucci G, Mrozek K, Ruppert AS, et al. Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): A Cancer and Leukemia Group B study. J Clin Oncol. 2005;23:5705–5717. [PubMed]
3. Creutzig U, Zimmermann M, Bourquin JP, et al. Second induction with high-dose cytarabine and mitoxantrone: Different impact on pediatric AML patients with t(8;21) and with inv(16) Blood. 2011;118:5409–5415. [PubMed]
4. 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 uniformly according to trial AML-BFM 98. J Clin Oncol. 2010;28:2682–2689. [PubMed]
5. Martinez-Climent JA, Lane NJ, Rubin CM, et al. Clinical and prognostic significance of chromosomal abnormalities in childhood acute myeloid leukemia de novo. Leukemia. 1995;9:95–101. [PubMed]
6. Pession A, Masetti R, Rizzari C, et al. Results of the AIEOP AML 2002/01 multicenter prospective trial for the treatment of children with acute myeloid leukemia. Blood. 2013;122:170–178. [PubMed]
7. Chang M, Raimondi SC, Ravindranath Y, et al. Prognostic factors in children and adolescents with acute myeloid leukemia (excluding children with Down syndrome and acute promyelocytic leukemia): Univariate and recursive partitioning analysis of patients treated on Pediatric Oncology Group (POG) Study 8821. Leukemia. 2000;14:1201–1207. [PubMed]
8. Nguyen S, Leblanc T, Fenaux P, et al. A white blood cell index as the main prognostic factor in t(8;21) acute myeloid leukemia (AML): A survey of 161 cases from the French AML Intergroup. Blood. 2002;99:3517–3523. [PubMed]
9. Jung HA, Maeng CH, Park S, et al. Prognostic factor analysis in core-binding factor-positive acute myeloid leukemia. Anticancer Res. 2014;34:1037–1045. [PubMed]
10. Rege K, Swansbury GJ, Atra AA, et al. Disease features in acute myeloid leukemia with t(8;21)(q22;q22): Influence of age, secondary karyotype abnormalities, CD19 status, and extramedullary leukemia on survival. Leuk Lymphoma. 2000;40:67–77. [PubMed]
11. Rubnitz JE, Raimondi SC, Halbert AR, et al. Characteristics and outcome of t(8;21)-positive childhood acute myeloid leukemia: A single institution's experience. Leukemia. 2002;16:2072–2077. [PubMed]
12. Raimondi SC, Chang MN, Ravindranath Y, et al. Chromosomal abnormalities in 478 children with acute myeloid leukemia: Clinical characteristics and treatment outcome in a cooperative pediatric oncology group study-POG 8821. Blood. 1999;94:3707–3716. [PubMed]
13. Creutzig U, Zimmermann M, Bourquin JP, et al. Randomized trial comparing liposomal daunorubicin with idarubicin as induction for pediatric acute myeloid leukemia: Results from study AML-BFM 2004. Blood. 2013;122:37–43. [PubMed]
14. Willatt L, Morgan S, Shaffer LG, et al. ISCN 2009 an international system for human cytogenetic nomenclature. Hum Genet. 2009;126:603–604.
15. Bachas C, Schuurhuis GJ, Hollink IH, et al. High-frequency type I/II mutational shifts between diagnosis and relapse are associated with outcome in pediatric AML: Implications for personalized medicine. Blood. 2010;116:2752–2758. [PubMed]
16. Bachas C, Schuurhuis GJ, Reinhardt D, et al. Clinical relevance of molecular aberrations in paediatric acute myeloid leukaemia at first relapse. Br J Haematol. 2014;166:902–910. [PubMed]
17. Creutzig U, Ritter J, Schellong G. Identification of two risk groups in childhood acute myelogenous leukemia after therapy intensification in study AML-BFM-83 as compared with study AML-BFM-78. AML-BFM Study Group. Blood. 1990;75:1932–1940. [PubMed]
18. Creutzig U, van den Heuvel-Eibrink MM, Gibson B, et al. Diagnosis and management of acute myeloid leukemia in children and adolescents: Recommendations from an international expert panel. Blood. 2012;120:3187–3205. [PubMed]
19. Betts DR, Ammann RA, Hirt A, et al. The prognostic significance of cytogenetic aberrations in childhood acute myeloid leukaemia: A study of the Swiss Paediatric Oncology Group (SPOG) Eur J Haematol. 2007;78:468–476. [PubMed]
20. Schoch C, Haase D, Haferlach T, et al. Fifty-one patients with acute myeloid leukemia and translocation t(8;21)(q22;q22): An additional deletion in 9q is an adverse prognostic factor. Leukemia. 1996;10:1288–1295. [PubMed]
21. Gupta V, Minden MD, Yi QL, et al. Prognostic significance of trisomy 4 as the sole cytogenetic abnormality in acute myeloid leukemia. Leuk Res. 2003;27:983–991. [PubMed]
22. Nishii K, Usui E, Katayama N, et al. Characteristics of t(8;21) acute myeloid leukemia (AML) with additional chromosomal abnormality: Concomitant trisomy 4 may constitute a distinctive subtype of t(8;21) AML. Leukemia. 2003;17:731–737. [PubMed]
23. Shimada A, Taki T, Tabuchi K, et al. KIT mutations, and not FLT3 internal tandem duplication, are strongly associated with a poor prognosis in pediatric acute myeloid leukemia with t(8;21): A study of the Japanese Childhood AML Cooperative Study Group. Blood. 2006;107:1806–1809. [PubMed]
24. Boissel N, Leroy H, Brethon B, et al. Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML) Leukemia. 2006;20:965–970. [PubMed]
25. Manara E, Bisio V, Masetti R, et al. Core-binding factor acute myeloid leukemia in pediatric patients enrolled in the AIEOP AML 2002/01 trial: Screening and prognostic impact of c-KIT mutations. Leukemia. 2014;28:1132–1134. [PubMed]
26. Goemans BF, Zwaan CM, Miller M, et al. Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia. Leukemia. 2005;19:1536–1542. [PubMed]
27. Shih LY, Liang DC, Huang CF, et al. Cooperating mutations of receptor tyrosine kinases and Ras genes in childhood core-binding factor acute myeloid leukemia and a comparative analysis on paired diagnosis and relapse samples. Leukemia. 2008;22:303–307. [PubMed]
28. Pollard JA, Alonzo TA, Gerbing RB, et al. Prevalence and prognostic significance of KIT mutations in pediatric patients with core binding factor AML enrolled on serial pediatric cooperative trials for de novo AML. Blood. 2010;115:2372–2379. [PubMed]
29. Beghini A, Ripamonti CB, Cairoli R, et al. KIT activating mutations: Incidence in adult and pediatric acute myeloid leukemia, and identification of an internal tandem duplication. Haematologica. 2004;89:920–925. [PubMed]
30. Goemans BF, Zwaan CM, Cloos J, et al. FLT3 and KIT mutated pediatric acute myeloid leukemia (AML) samples are sensitive in vitro to the tyrosine kinase inhibitor SU11657. Leuk Res. 2010;34:1302–1307. [PubMed]
31. Visani G, Bernasconi P, Boni M, et al. The prognostic value of cytogenetics is reinforced by the kind of induction/consolidation therapy in influencing the outcome of acute myeloid leukemia: Analysis of 848 patients. Leukemia. 2001;15:903–909. [PubMed]
32. Byrd JC, Dodge RK, Carroll A, et al. Patients with t(8;21)(q22;q22) and acute myeloid leukemia have superior failure-free and overall survival when repetitive cycles of high-dose cytarabine are administered. J Clin Oncol. 1999;17:3767–3775. [PubMed]
33. Bloomfield CD, Lawrence D, Byrd JC, et al. Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res. 1998;58:4173–4179. [PubMed]
34. 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;27:4007–4013. [PubMed]
35. Lie SO, Abrahamsson J, Clausen N, et al. Treatment stratification based on initial in vivo response in acute myeloid leukaemia in children without Down's syndrome: Results of NOPHO-AML trials. Br J Haematol. 2003;122:217–225. [PubMed]
36. Klein K, Kaspers GJL. A review of liposomal daunorubicin in the treatment of acute leukemia. Oncol Hematol Rev. 2013;9:142–148.
37. Bishop JF, Lowenthal RM, Joshua D, et al. Etoposide in acute nonlymphocytic leukemia: Australian Leukemia Study Group. Blood. 1990;75:27–32. [PubMed]

Articles from Journal of Clinical Oncology are provided here courtesy of American Society of Clinical Oncology