Current Opinion in Hematology:
Myeloid disease: Edited by Martin S. Tallman
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
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: firstname.lastname@example.org
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.
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 . 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 . 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.
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  to less than 5% in older AML reports ; 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].
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 . 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 .
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 . 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 .
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 . 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 . 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).
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 , though not observed in a more recent study . 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.
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.
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).
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