Share this article on:

Core binding factor acute myeloid leukemia (CBF-AML): is high-dose Ara-C (HDAC) consolidation as effective as you think?

Dombret, Hervéa; Preudhomme, Claudeb; Boissel, Nicolasa

Current Opinion in Hematology: March 2009 - Volume 16 - Issue 2 - p 92–97
doi: 10.1097/MOH.0b013e3283257b18
Myeloid disease: Edited by Martin S. Tallman

Purpose of review Core binding factor acute myeloid leukemia (CBF-AML) corresponds to two distinct subtypes of AML characterized by recurrent favorable chromosome translocations, namely t(8;21) and inv(16)/t(16;16). Given the relatively good outcome of patients with CBF-AML, when treated with intensive chemotherapy including high-dose cytarabine, they are generally not considered as candidates for intensification with allogeneic stem cell transplantation in the first complete remission. The optimal treatment strategy (place of stem cell transplantation, best postremission chemotherapy, role of targeted agents) remains, however, to be defined in these patients.

Recent findings The biological and prognostic heterogeneity of both CBF-AML subtypes, including gene mutation and gene expression profiles as well as molecular response to therapy, has been recently described.

Summary These new insights in the heterogeneity of CBF-AML suggest that a tailored approach might be preferred to a unique predefined strategy to treat these patients.

aDepartment of Hematology, Hôpital Saint-Louis (AP-HP), Paris, France

bLaboratory of Hematology, Hôpital Claude Hurriez, CHRU Lille, France

Correspondence to Professor Hervé Dombret, Hôpital Saint-Louis (AP-HP), University Paris 7 – Institut Universitaire d'Hematologie, 1 Avenue Claude Vellefaux, 75010 Paris, France Tel: +33 1 4249 9643; fax: +33 1 4249 9345; e-mail:

Back to Top | Article Outline


Core binding factor acute myeloid leukemia (CBF-AML) is a distinct subset of AML originally defined by recurrent balanced chromosomal abnormalities disrupting genes encoding the subunits of the CBF transcription factor. The first described reciprocal translocation t(8;21)(q22;q22) disrupts the RUNX1/AML1 gene that encodes subunit alpha of the CBF, creating a chimeric fusion gene AML1-ETO[1]. The presence of AML1-ETO fusion gene and protein is associated with AML-M2 in the French–American–British (FAB) classification even if representing approximately only 20–25% of this FAB subtype. The second type of recurrent CBF abnormalities disrupts the CBFB gene that encodes subunit beta of the CBF, creating a chimeric fusion gene CBFB-MYH11[2]. Both inv(16)(p13;q32) and its less common variant t(16;16)(p13;q32) lead to this CBFB-MYH11 fusion. Cytogenetically, CBFB rearrangements might be less readily identified, especially in karyotypes of suboptimal quality. The presence of CBFB-MYH11 fusion gene and protein is more closely associated with the AML-M4eo subtype of the FAB classification corresponding to acute myelomonocytic leukemia with abnormal marrow eosinophils. In both CBF-AML subtypes, these class II mutations are responsible for the hematopoietic differentiation blockage and considered as primary leukemogenic events, even if it has been demonstrated in animal models that they are not sufficient to induce AML by themselves [3,4]. Associated class I mutations conferring a proliferative and survival advantage to transformed cells are required, some of them such as KIT, RAS, or FLT3 mutations having been identified. Overall, the incidence of CBF-AML is around 15%, both t(8;21) and inv(16)/t(16;16) subtypes accounting for approximately half of cases.

Back to Top | Article Outline

Clinical characteristics of core binding factor acute myeloid leukemia

Both CBF-AML subtypes display the following characteristics: their association with a younger age, with an incidence ranging from approximately 20% with two-thirds of t(8;21) cases in pediatric AML reports [5] to less than 5% in older AML reports [6]; their ability to be diagnosed and monitored using quite sensitive real-time quantitative polymerase chain reactions (RQ-PCR) targeting AML1-ETO and CBFB-MYH11 fusion transcripts, respectively; and their relative good prognosis leading most cooperative groups to restrict the favorable cytogenetic subset to CBF-AML [7–9].

Patients with t(8;21) AML often presented with a mild hyperleucocytosis made of abnormal maturing granulocytes arising from the leukemic clone. In cases associated with marked maturation ability, the percentage of marrow blasts may be lowered to less than 30%. Leukemic cells usually express the B-cell CD19 antigen, with a typical HLA-DR+ CD34+ CD117+ CD19+ TdT+ immunophenotype and a frequent coexpression of the CD56 antigen. Expression of this latter adhesion molecule has been associated with the occurrence of extramedullary granulocytic sarcomas, which are particularly frequent in this AML subset. The majority of t(8;21) AML cases have at least one additional chromosome anomaly, loss of a sex chromosome (−Y in men and −X in women), and deletion in the long arm of chromosome 9 being the most frequent.

Patients with inv(16)/t(16;16) AML are more frequently white and less frequently African–American than those with t(8;21) AML [10,11]. They have a higher percentage of marrow blasts and white blood cell count (WBC) with more frequent splenomegaly, lymphadenopathy, gingival hypertrophy, as well as skin, pulmonary, or central nervous system (CNS) involvement. Additional chromosome anomalies are less frequent, the most common being +22, +8, +21, and deletion of 7q.

Finally, CBF-AML, especially inv(16) AML, has been reported in therapy-related AML series [12,13], and there are some anecdotic reports of inv(16) in BCR-ABL positive chronic myelogeneous leukemia in blast phase [14,15].

Back to Top | Article Outline

Treatment outcome

There is absolutely no doubt that patients with CBF-AML have a favorable prognosis when compared with other AML patients or to those with cytogenetically normal AML. For a long period of time, all large AML cooperative groups consistently report this finding. Complete remission rate is usually 90% or more, which is significantly higher than in other AML subtypes even after adjustment on age. Lower relapse incidences contribute to longer disease-free survival (DFS) and overall survival (OS) and to higher long-term cure rate [7–9,16]. Amazingly, this relatively favorable outcome, now between 60 and 70% long-term OS, has been simultaneously reached by all cooperative groups through various treatment intensification approaches, raising now the issue of the best treatment that should be offered to these patients.

The first issue is whether therapy of both CBF-AML subtypes should be discussed together or separately. In most reports, relapse and survival curves of t(8;21) and inv(16)/t(16;16) patients closely superimpose. One study suggested, however, that t(8;21) patients had a shorter OS than inv(16)/t(16;16) patients after adjustment on other prognostic factors in a multivariate analysis [10]. Several studies also reported shorter postrelapse survival in t(8;21) as compared with inv(16)/t(16;16) patients, suggesting a lower response to salvage treatment in t(8;21) AML patients [10,11,17].

The second issue concerns complete remission induction. Is standard 3 + 7 anthracycline/cytarabine (Ara-C) combination the best induction option for CBF-AML patients? Yes, if one assumes that 90% complete remission rate is high enough. Maybe not, if one believes that alternative or reinforced induction combinations might improve molecular response levels and be associated with lower relapse rates? Earlier studies testing the introduction of high-dose Ara-C (HDAC) during the first induction course did not provide specific information about this specific AML patient subset [18,19]. In the German double-induction TAD-TAD (TAD: cytarabine, daunorubicine, 6-thioguanine), TAD-HAM (HAM: high-dose cytarabine, mitoxantrone), and HAM-HAM studies, a beneficial effect of intensified induction chemotherapy was mainly reported in high-risk patients [20–22]. Reinforced timed-sequential induction has been randomly tested in children by the Children's Cancer Group (CCG) and in adults by the Acute Leukemia French Association (ALFA) [23,24]. Fifty-three children and 56 adults with CBF-AML were enrolled, respectively, but again no specific information was given for CBF-AML patients. The potential superiority of a timed-sequential induction containing intermediate-dose Ara-C over a standard 3 + 7 induction is thus currently prospectively evaluated in the CBF-2006 trial conducted by the French AML Intergroup. Finally and interestingly, the adjunction of gemtuzumab ozogamicin to standard chemotherapy has been recently reported as associated with a marked benefit in CBF-AML patients in the large British AML-15 study [25].

The third and most discussed issue concerns the optimal postremission treatment. The role of allogeneic stem cell transplantation (SCT) in the first complete remission has been studied through four so-called ‘donor versus no-donor’ studies [26–28,29••]. An overview of these results has been presented in the most recently published study from the Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research (HOVON-SAKK) cooperative group [29••]. Despite some methodological issues related to the genetic randomization concept and its use, the conclusion is that once complete remission has been achieved, CBF-AML patients tended to have longer DFS and OS in the no-donor as compared with the donor group. Even if the difference did not reach the statistically significant level, most groups are now indicating allogeneic SCT in the second rather than the first complete remission in these patients, mainly because of the morbidity associated with allogeneic transplantation. A recent retrospective comparison confirmed that cytarabine-based chemotherapy is associated with results at least similar or even better than human leukocyte antigen (HLA)-matched sibling SCT in the first complete remission [30]. A retrospective study from the ALFA group showed that donor availability remained a positive factor for survival after first relapse in these CBF-AML patients [31].

The role of autologous SCT in the first complete remission has not been specifically studied in the subset of CBF-AML patients. Associated with much lower procedure-related morbidity and mortality than allogeneic SCT, autologous SCT remains obviously an option to consolidate the first complete remission in these patients. Interestingly, a recent survey from the European Bone Marrow Transplantation (EBMT) showed no difference in outcome between the autologous and the allogeneic procedures in CBF-AML patients, based on retrospective registry analysis [32•].

In AML, in general, most consolidation chemotherapy strategies now include at least one and more frequently repeated cycles based on HDAC. HDAC may be used in combination with other drugs or administered alone according to the Cancer and Leukemia Group B (CALGB) schedule [33]. The incorporation of HDAC as part of postremission therapy has been demonstrated as particularly beneficial to CBF-AML patients, with a higher gain in outcome when using repeated HDAC cycles as opposed to one cycle only [34–37]. However, no available randomized study has demonstrated that several HDAC cycles yield better results than other intensive postremission approaches, such as autologous SCT eventually preceded by one HDAC cycle for instance. A recent Australian study prospectively compared high-dose versus standard-dose cytarabine given with idarubicin and etoposide (ICE versus IcE) as postremission cycles in AML in general, but after HDAC-containing induction. In this study, the outcome of 33 patients with CBF-AML randomized for postremission therapy did not seem to differ between both arms [38]. Our group has recently conducted a postremission ALFA-9802 trial in which patients reaching complete remission after an intensified timed-sequential induction were randomized to receive either the original CALGB schedule based on four HDAC courses or one intensive timed-sequential course, including etoposide, mitoxantrone and intermediate-dose cytarabine (EMA). A total of 51 patients with CBF-AML were randomized, and no difference in outcome was observed between the two postremission arms (unpublished data).

Back to Top | Article Outline

Prognostic heterogeneity of core binding factor acute myeloid leukemia patients

One of the most interesting observations that have recently emerged is the heterogeneity of CBF-AML. Some factors associated with significant prognostic values within this specific CBF-AML subtype were known for a long time. Advanced age, higher WBC or granulocyte count, as well as CD56 expression or granulocytic sarcoma in t(8;21) patients have been reported as clinical bad-prognostic factors [10,11,17,39–46]. Cytogenetically, the presence of associated trisomy 22 seems to confer a better prognosis in inv(16)/t(16;16) AML patients whereas loss of the sex chromosome Y might be a bad-prognostic factor in men with t(8;21) AML [10,17]. Additional deletion in the long arm of chromosome 9 has also been reported as a potential adverse factor in t(8;21) AML patients [47], though not observed in a more recent study [11]. Some other observations suggest that t(8;21) or inv(16)/t(16;16) might not have the same favorable value when found in the context of a complex karyotype, even if low numbers of such patients preclude any formal demonstration at the present time.

Three more recent lines of evidence also support the biological heterogeneity of this subset of so-called CBF-AML, beyond the fact that there are already two CBF alteration subtypes. The first observation is the incidence of cooperating class I gene mutations in CBF diseases. The second observation is their heterogeneity shown in gene or micro-RNA expression profiles. The third observation is the variability of early molecular response to therapy. How these three observations might be correlated or related to the clinical covariates mentioned above remains, however, to be determined.

Three genes encoding tyrosine kinase receptor or molecule, that is, KIT, RAS, and FLT3, have been found as frequently mutated in both CBF-AML subtypes. Mutations of KIT and RAS appear to be relatively specific of these CBF diseases. KIT mutations are exceptionally observed in non-CBF leukemias, whereas their incidence may reach 30–40% in CBF-AML series [48–58]. RAS mutations seem to be particularly frequent in inv(16)/t(16;16) AML with reported incidence up to 36% [51,59]. More importantly, the presence of such class I mutations has been relatively consistently reported to be associated with a higher incidence of relapse and a worse outcome in CBF-AML patients.

After initial reports showing that gene expression profiles (GEPs) may identify specific signatures for both CBF-AML subtypes [60–63], recent studies focused on the heterogeneity of CBF leukemias with the attempt to develop outcome predictors [64••,65••]. Specific micro-RNA signatures have also been recently reported for both CNF-AML subtypes [66••].

Molecular monitoring of minimal residual disease (MRD) using the fusion transcripts as specific markers also underline the heterogeneity of these diseases in regard to their response to initial therapy. Several studies have reported significant impact of initial MRD response on the outcome of patients with either t(8;21) or inv(16)/t(16;16) AML [67–72,73•,74•]. As baseline expression level might vary among patients, log-reduction after either induction or consolidation courses is usually taken into account.

One therapeutic consequence of this CBF-AML heterogeneity could be to evaluate the effect of new drugs targeting tyrosine kinase mutations, either as single agents in patients with molecular relapse or front-line in combination with conventional chemotherapy. Another intervention could be to reoffer allogeneic SCT to patients at higher risk of relapse, based for instance on mutation screening, GEP, or MRD levels. In the ongoing CBF-2006 trial from the French AML Intergroup, patients with MRD reduction less than 3 logs after the first consolidation cycle are candidates for SCT in the first complete remission. Correlations with mutation and GEPs are being evaluated. Dasatinib second-generation tyrosine kinase inhibitor targeting KIT is evaluated as single agent in patients with poor molecular response and no donor as well as in those with molecular relapse.

Back to Top | Article Outline


With respect to their biological heterogeneity, CBF-AML still represents a very good model to develop tailored therapeutic approaches in AML patients. Incorporation of new biological tools in treatment decision-making at the individual patient level, including gene mutation and expression profiles as well as MRD monitoring, should allow to improve the overall outcome of patients with CBF-AML.

Back to Top | Article Outline

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 151–152).

1 Erickson P, Gao J, Chang KS, et al. Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt. Blood 1992; 80:1825–1831.
2 Liu P, Tarle SA, Hajra A, et al. Fusion between transcription factor CBF beta/PEBP2 beta and a myosin heavy chain in acute myeloid leukemia. Science 1993; 261:1041–1044.
3 Speck NA, Gilliland DG. Core-binding factors in haematopoiesis and leukaemias. Nat Rev Cancer 2002; 2:502–513.
4 Downing JR. The core-binding factor leukemias: lessons learned from murine models. Curr Opin Gen Dev 2003; 13:48–54.
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 between 1981 and 2000. Leukemia 2005; 19:2101–2116.
6 Grimwade D, Walker H, Harrison G, et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 2001; 98:1312–1320.
7 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.
8 Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000; 96:4075–4083.
9 Byrd JC, Mrózek K, Dodge RK, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002; 100:4325–4336.
10 Marcucci G, Mrózek 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.
11 Appelbaum FR, Kopecky KJ, Tallman MS, et al. The clinical spectrum of adult acute myeloid leukaemia associated with core binding factor translocations. Br J Haematol 2006; 135:165–173.
12 Quesnel B, Kantarjian H, Bjergaard JP, et al. Therapy-related acute myeloid leukemia with t(8;21), inv(16), and t(8;16): a report on 25 cases and review of the literature. J Clin Oncol 1993; 11:2370–2379.
13 Andersen MK, Johansson B, Larsen SO, Pedersen-Bjergaard J. Chromosomal abnormalities in secondary MDS and AML. Relationship to drugs and radiation with specific emphasis on the balanced rearrangements. Haematologica 1998; 83:483–488.
14 Merzianu M, Medeiros LJ, Cortes J, et al. inv(16)(p13q22) in chronic myelogenous leukemia in blast phase: a clinicopathologic, cytogenetic, and molecular study of five cases. Am J Clin Pathol 2005; 124:807–814.
15 Wu Y, Slovak ML, Snyder DS, Arber DA. Coexistence of inversion 16 and the Philadelphia chromosome in acute and chronic myeloid leukemias: report of six cases and review of literature. Am J Clin Pathol 2006; 125:260–266.
16 Yanada M, Garcia-Manero G, Borthakur G, et al. Potential cure of acute myeloid leukemia: analysis of 1069 consecutive patients in first complete remission. Cancer 2007; 110:2756–2760.
17 Schlenk RF, Benner A, Krauter J, et al. Individual patient data-based meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol 2004; 22:3741–3750.
18 Bishop JF, Matthews JP, Young GA, et al. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 1996; 87:1710–2177.
19 Weick JK, Kopecky KJ, Appelbaum FR, et al. A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood 1996; 88:2841–2851.
20 Büchner T, Hiddemann W, Wörmann B, et al. Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group. Blood 1999; 93:4116–4124.
21 Büchner T, Hiddemann W, Berdel WE, et al. 6-Thioguanine, cytarabine, and daunorubicin (TAD) and high-dose cytarabine and mitoxantrone (HAM) for induction, TAD for consolidation, and either prolonged maintenance by reduced monthly TAD or TAD-HAM-TAD and one course of intensive consolidation by sequential HAM in adult patients at all ages with de novo acute myeloid leukemia (AML): a randomized trial of the German AML Cooperative Group. J Clin Oncol 2003; 21:4496–4504.
22 Büchner T, Berdel WE, Schoch C, et al. Double induction containing either two courses or one course of high-dose cytarabine plus mitoxantrone and postremission therapy by either autologous stem-cell transplantation or by prolonged maintenance for acute myeloid leukemia. J Clin Oncol 2006; 24:2480–2489.
23 Woods WG, Kobrinsky N, Buckley JD, et al. Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia: a report from the Children's Cancer Group. Blood 1996; 87:4979–4989.
24 Castaigne S, Chevret S, Archimbaud E, et al. Randomized comparison of double induction and timed-sequential induction to a ‘3 + 7’ induction in adults with AML: long-term analysis of the Acute Leukemia French Association (ALFA) 9000 study. Blood 2004; 104:2467–2474.
25 Burnett AK, Kell WJ, Goldstone AH, et al. The addition of gemtuzumab ozogamicin to induction chemotherapy for AML improves disease free survival without extra toxicity: preliminary analysis of 1115 patients in the MRC AML15 trial. Blood 2006; 108:13a.
26 Burnett AK, Wheatley K, Goldstone AH, et al. The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: results of the UK MRC AML 10 trial. Br J Haematol 2002; 118:385–400.
27 Suciu S, Mandelli F, De Witte T, et al. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEMA AML-10 trial. Blood 2003; 102:1232–1240.
28 Jourdan E, Boiron J-M, Dastugue N, et al. Early allogeneic stem-cell transplantation for young adults with acute myeloblastic leukemia in first complete remission: an intent-to-treat long-term analysis of the BGMT experience. J Clin Oncol 2005; 23:7676–7684.
29•• Cornelissen JJ, van Putten WLJ, Verdonck LF, et al. Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom? Blood 2007; 109:3658–3666. The above article shows the results of HOVON donor versus no-donor study, including a meta-analysis with the three other British Medical Research Council (MRC), European Organisation for Research and Treatment of Cancer/Gruppo Italiano Malattie Ematologiche dell'Adulto (EORTC/GIMEMA), and Bordeaux Grenoble Marseille Toulouse (BGMT)] donor versus no-donor studies.
30 Schlenk RF, Pasquini MC, Pérez WS, et al. HLA-identical sibling allogeneic transplants versus chemotherapy in acute myelogenous leukemia with t(8;21) in first complete remission: collaborative study between the German AML Intergroup and CIBMTR. Biol Blood Marrow Transplant 2008; 14:187–196.
31 de Labarthe A, Pautas C, Thomas X, et al. Allogeneic stem cell transplantation in second rather than first complete remission in selected patients with good-risk acute myeloid leukemia. Bone Marrow Transplant 2005; 35:767–773.
32• Gorin N-C, Labopin M, Frassoni F, et al. Identical outcome after autologous or allogeneic genoidentical hematopoietic stem-cell transplantation in first remission of acute myelocytic leukemia carrying inversion 16 or t(8;21): a retrospective study from the European Cooperative Group for Blood and Marrow Transplantation. J Clin Oncol 2008; 26:3183–3188. The largest report on autologous transplantation in CBF-AML patients.
33 Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 1994; 331:896–903.
34 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.
35 Bloomfield CD, Ruppert AS, Mrózek K, et al. Core binding factor acute myeloid leukemia. Cancer and Leukemia Group B (CALGB) Study 8461. Ann Hematol 2004; 83(Suppl 1):S84–S85.
36 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.
37 Byrd JC, Ruppert AS, Mrózek K, et al. Repetitive cycles of high-dose cytarabine benefit patients with acute myeloid leukemia and inv(16)(p13q22) or t(16;16)(p13;q22): results from CALGB 8461. J Clin Oncol 2004; 22:1087–1094.
38 Bradstock KF, Matthews JP, Lowenthal RM, et al. A randomized trial of high-versus conventional-dose cytarabine in consolidation chemotherapy for adult de novo acute myeloid leukemia in first remission after induction therapy containing high-dose cytarabine. Blood 2005; 105:481–488.
39 O'Brien S, Kantarjian HM, Keating M, et al. Association of granulocytosis with poor prognosis in patients with acute myelogenous leukemia and translocation of chromosomes 8 and 21. J Clin Oncol 1989; 7:1081–1086.
40 Tallman MS, Hakimian D, Shaw JM, et al. Granulocytic sarcoma is associated with the 8;21 translocation in acute myeloid leukemia. J Clin Oncol 1993; 11:690–697.
41 Baer MR, Stewart CC, Lawrence D, et al. Expression of the neural cell adhesion molecule CD56 is associated with short remission duration and survival in acute myeloid leukemia with t(8;21)(q22;q22). Blood 1997; 90:1643–1648.
42 Byrd JC, Weiss RB, Arthur DC, et al. Extramedullary leukemia adversely affects hematologic complete remission rate and overall survival in patients with t(8;21)(q22;q22): results from Cancer and Leukemia Group B 8461. J Clin Oncol 1997; 15:466–475.
43 Daniels JT, Davis BJ, Houde-McGrail L, Byrd JC. Clonal selection of CD56+ t(8;21) AML blasts: further suggestion of the adverse clinical significance of this biological marker? Br J Haematol 1999; 107:381–383.
44 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.
45 Delaunay J, Vey N, Leblanc T, et al. Prognosis of inv(16)/t(16;16) acute myeloid leukemia (AML): a survey of 110 cases from the French AML Intergroup. Blood 2003; 102:462–469.
46 Narimatsu H, Yokozawa T, Iida H, et al. Clinical characteristics and outcomes in patients with t(8;21) acute myeloid leukemia in Japan. Leukemia 2008; 22:428–432.
47 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.
48 Beghini A, Peterlongo P, Ripamonti CB, et al. C-kit mutations in core binding factor leukemias. Blood 2000; 95:726–727.
49 Care RS, Valk PJM, Goodeve AC, et al. Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias. Br J Haematol 2003; 121:775–777.
50 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.
51 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.
52 Schnittger S, Kohl TM, Haferlach T, et al. KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood 2006; 107:1791–1799.
53 Cairoli R, Beghini A, Grillo G, et al. Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. Blood 2006; 107:3463–3468.
54 Cairoli R, Beghini A, Ripamonti CB, et al. Prevalence and prognostic impact of KIT mutations in acute myeloid leukaemia with inv(16). A retrospective study. Blood 2007; 110:1021a–1022a.
55 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.
56 Shimada A, Ichikawa H, Taki T, et al. Low frequency of KIT gene mutation in pediatric acute myeloid leukemia with inv(16)(p13q22): a study of the Japanese Childhood AML Cooperative Study Group. Int J Hematol 2007; 86:289–290.
57 Paschka P, Marcucci G, Ruppert AS, et al. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J Clin Oncol 2006; 24:3904–3911.
58 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.
59 Bacher U, Haferlach T, Schoch C, et al. Implications of NRAS mutations in AML: a study of 2502 patients. Blood 2006; 107:3847–3853.
60 Schoch C, Kohlmann A, Schnittger S, et al. Acute myeloid leukemias with reciprocal rearrangements can be distinguished by specific gene expression profiles. Proc Natl Acad Sci U S A 2002; 99:10008–10013.
61 Bullinger L, Dohner K, Bair E, et al. Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med 2004; 350:1605–1616.
62 Valk PJ, Verhaak RG, Beijen MA, et al. Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 2004; 350:1617–1628.
63 Haferlach T, Kohlmann A, Schnittger S, et al. Global approach to the diagnosis of leukemia using gene expression profiling. Blood 2005; 106:1189–1198.
64•• Bullinger L, Rücker FG, Kurz S, et al. Gene-expression profiling identifies distinct subclasses of core binding factor acute myeloid leukemia. Blood 2007; 110:1291–1300. A study which shows CBF-AML GEP heterogeneity.
65•• Paschka P, Radmacher MD, Marcucci G, et al. Gene expression profiling improves outcome prediction in adult core binding factor (CBF) acute myeloid leukemia (AML): a Cancer and Leukemia Group B (CALGB) study. J Clin Oncol 2007; 25:359a. A very interesting study using gene expression profiling as a prognostic tool in CBF-AML patients.
66•• Jongen-Lavrencic M, Sun SM, Dijkstra MK, et al. MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia. Blood 2008; 111:5078–5085. The first large study of microRNA expression profiling in AML.
67 Morschhauser F, Cayuela JM, Martini S, et al. Evaluation of minimal residual disease using reverse-transcription polymerase chain reaction in t(8;21) acute myeloid leukemia: a multicenter study of 51 patients. J Clin Oncol 2000; 18:788–794.
68 Guerrasio A, Pilatrino C, De Micheli D, et al. Assessment of minimal residual disease (MRD) in CBFbeta/MYH11-positive acute myeloid leukemias by qualitative and quantitative RT-PCR amplification of fusion transcripts. Leukemia 2002; 16:1176–1181.
69 Krauter J, Gorlich K, Ottmann O, et al. Prognostic value of minimal residual disease quantification by real-time reverse transcriptase polymerase chain reaction in patients with core binding factor leukemias. J Clin Oncol 2003; 21:4413–4422.
70 Schnittger S, Weisser M, Schoch C, et al. New score predicting for prognosis in PML-RARA+, AML1-ETO+, or CBFBMYH11+ acute myeloid leukemia based on quantification of fusion transcripts. Blood 2003; 102:2746–2755.
71 Leroy H, de Botton S, Grardel-Duflos N, et al. Prognostic value of real-time quantitative PCR (RQ-PCR) in AML with t(8;21). Leukemia 2005; 19:367–372.
72 Perea G, Lasa A, Aventín A, et al. Prognostic value of minimal residual disease (MRD) in acute myeloid leukemia (AML) with favorable cytogenetics [t(8;21) and inv(16)]. Leukemia 2006; 20:87–94.
73• Weisser M, Haferlach C, Hiddemann W, Schnittger S. The quality of molecular response to chemotherapy is predictive for the outcome of AML1-ETO-positive AML and is independent of pretreatment risk factors. Leukemia 2007; 21:1177–1182. A recent report on the impact of MRD level in t(8;21) AML patients.
74• Narimatsu H, Iino M, Ichihashi T, et al. Clinical significance of minimal residual disease in patients with t(8;21) acute myeloid leukemia in Japan. Int J Hematol 2008; 88:154–158. doi: 10.1007/s12185-008-0108-1. Another recent report on the impact of MRD level in t(8;21) AML patients.

acute myeloid leukemia; core binding factor; gene expression profiling; KIT mutations; minimal residual disease

© 2009 Lippincott Williams & Wilkins, Inc.