Emerging molecular studies have identified a subgroup of patients with unfavorable core-binding factor-positive (CBF)-AML who should be treated by intensified post-remission treatments. We analyzed 264 adults with CBF-AML from 2002 to 2011, and focused on 206 patients who achieved CR after standard ‘3+7’ induction chemotherapy. Patients who achieved CR with an available donor were treated with allogeneic hematopoietic SCT (allo-HSCT, n=115) and the rest were treated with autologous (auto) HSCT (n=72) or chemotherapy alone (n=19). OS was not significantly different between CBFβ/MYH11 (n=62) and RUNX1/RUNX1T1 (n=144), and auto-HSCT showed favorable OS compared with allo-HSCT or chemotherapy alone. Cytogenetic analysis identified that inv(16) without trisomy had a favorable OS and t(8;21) with additional chromosomes had an unfavorable OS, but multivariate analysis revealed those were NS. Patients with c-kit mutation showed inferior OS. For transplanted patients, residual post-transplant CBF-minimal residual disease quantitative PCR with higher WT1 expression at D+60 showed the worst OS with a higher incidence of relapse. Conclusively, we found that unfavorable CBF-AML can be defined with risk stratification using cytogenetic and molecular studies, and a careful risk-adapted treatment approach using frontline transplantation with novel therapies should be evaluated for this particular risk subgroup.
Core-binding factor (CBF)-positive AML is regarded as a favorable group with a high CR rate, and is generally treated by repeated high-dose cytarabine chemotherapy, sometimes followed by autologous hematopoietic SCT (auto-HSCT).1, 2, 3, 4 Allogeneic (allo)-HSCT has been generally used only for relapsed CBF-AML and has shown similar survival outcomes compared with the frontline allo-HSCT in the first CR status.5 However, some CBF-AML cases are difficult to manage owing to relapse after remission.5, 6, 7 In addition to the poor prognostic factors already reported in CBF-AML,6, 8, 9 emerging molecular markers have also been identified for prediction of the unfavorable CBF-AML subgroup, who should be treated by intensified treatments such as frontline auto-HSCT or allo-HSCT.10, 11, 12, 13, 14, 15
First, cytogenetic analyses can be focused. Additional chromosomal abnormality (that is, deletion of 9q or complex karyotype) within t(8;21)7,8 and several trisomies or residual normal metaphases within inv(16) have been analyzed,16,17 although National Comprehensive Cancer Network (NCCN) or Medical Research Council (MRC) guidelines have stated that other cytogenetic abnormalities in addition to CBF-AML do not alter the risk status.3,4 Second, several molecular markers are important for estimating residual disease and relapse prediction. CBF-AML has good representative molecular markers—RUNX1/RUNX1T1 and CBFβ/MYH11—for minimal residual disease (MRD), which can be measured by quantitative PCR (qPCR).18 The c-kit and FLT3-ITD mutations have been reported as poor prognostic indicators,10, 11, 12, 13, 14 and recently, the expression of Wilms’ tumor gene 1 (WT1) and brain and acute leukemia, cytoplasmic (BAALC) were also evaluated in CBF-AML.19
In this study, we found that CBF-AML can be further stratified according to cytogenetic and molecular studies, and we tried to identify unfavorable CBF-AML cases that should be treated with more intensified treatments, including HSCT or maintenance therapy. Finally, we suggest an appropriate combination of molecular markers for estimating MRD, which can be predictive for relapse.
Materials and methods
Diagnosis of patients with CBF-AML
This single-center retrospective study included 264 adult patients with CBF-AML with a median age of 39 years (range: 18–89 years) from 2002 to 2011. The research was conducted in accordance with the Institutional Review Board guidelines of the Catholic Medical Center and the principles of the Declaration of Helsinki. We confirmed all CBF-AML with chromosomal analysis and additional reverse transcriptase PCR (RT–PCR) and/or qPCR. For the detection of karyotypes, all samples were BM cells and at least 20 metaphases were analyzed by the GTG banding method after 24 or 48 h of unsynchronized culture. The International System for Cytogenetic Nomenclature was used as a guideline for classification.20 There were 193 patients with t(8;21)(q22;q22.3) and 71 patients with inv(16)(q13.1q22) or t(16;16)(p13.1;q22); all the patients were identified by the RT-PCR results for RUNX1/RUNX1T1 and CBFβ/MYH11. We subdivided patients according to the combination of additional chromosomal abnormalities (for example, monosomy, trisomy, deletion, addition and translocation and so on), total number of chromosomal abnormalities and the normal karyotype (NK) mosaicism for risk stratification. Chromosomal abnormality, which can be considered as a malignant clone, should include at least two metaphases, and we used ⩾1 copy of residual normal metaphase as the determinant for presence of a NK mosaicism.16,21 Also, we tried to identify the presence of additional chromosomal abnormalities known as the adverse-risk group (for example, monosomal karyotype or mixed lineage leukemia (11q23) abnormalities).
All the molecular studies were performed from the BM samples at the time of initial diagnosis and at post-induction, post-consolidation and pre- and post-HSCT (D+60) periods. RUNX1/RUNX1T1 and CBFβ/MYH11, the representative MRD markers for CBF-AML, were detected by the multiplex RT-PCR screening assay using the HemaVision Kit (DNA Technology, Risskov, Denmark), and quantification of both was performed using the qPCR method. BAALC and WT1 expression was measured by qPCR (BAALC and WT1 ProfileQuant kit, Ipsogen, Marseille, France). The qPCR level represented the ratios of RUNX1/RUNX1T1, CBFβ/MYH11, BAALC and WT1 expression normalized to expression of the reference gene, ABL1 (1.0 × 104) as previously reported.19,22 To determine the significant cutoff level, we used the receiver operation characteristic curve. The most significant cutoff level of both BAALC and WT1 expression was available at post HSCT, and the value was around the 65th percentile for BAALC expression (1.0, P=0.016) and the 60th percentile for WT1 expression (0.015, P=0.004). The FLT3-ITD mutation was detected using a multiplex allele-specific RT-PCR (ABSOULTE FLT3 TKD/ITD RT-PCR, BioSewoom Inc., Seoul, Korea), and the c-kit mutation was detected by melting curve analysis using RT-PCR (Real-Q C-KIT screening kit and D816muta-ID kit, Biosewoom Inc.), which can detect the c-kit mutation located at Asp816 (D816) and Asn822 (N822K) in exon 17.
Treatments and patient selection
Except 15 untreated patients, 217 were treated with standard chemotherapy and 32 were treated with reduced-intensity chemotherapy. Among 217 patients treated with standard chemotherapy, 178 patients (129 in the RUNX1/RUNX1T1 subgroup and 49 in the CBFβ/MYH11 subgroup) were treated according to our standard protocol, consisting of ‘3+7’ idarubicin plus N4-behenoyl-1-β-D-arabinofuranosyl cytosine.23 The other 39 patients (26 in the RUNX1/RUNX1T1 subgroup and 13 in the CBFβ/MYH11 subgroup) were treated with ‘3+7’ idarubicin plus cytosine arabinoside (ARA-C). Finally, 206 (94.9%) patients who achieved CR after standard induction chemotherapy were selected for analysis.
After CR achievement, one or two consolidation chemotherapies were administered; otherwise, patients were treated with re-induction chemotherapy. Our standard consolidation chemotherapy consisted of ‘3+5’ mitoxantrone (12 mg/m2 i.v.) plus an intermediate-dose of ARA-C (1.0 g/m2 i.v. b.i.d.) or idarubicin (12 mg/m2) plus an intermediate-dose of ARA-C, which were alternatively applied. Post-remission treatment strategy for CBF-AML at the Catholic BMT Center was based on the transplantation procedures. If an available donor was found during consolidation, patients were treated with allo-HSCT. We administered a reduced-intensity conditioning regimen, consisting of busulfex (6.4 mg/kg) and fludarabine (150 mg/m2) with 400 cGy of TBI. However, for patients categorized as high-risk for relapse (including initial hyperleukocytosis, additional chromosomal abnormalities and mutation of c-kit), we considered a myeloablative conditioning regimen consisting of CY (120 mg/kg) combined with 1320 cGy of TBI or busulfex (12.8 mg/kg). If the patient did not have an available donor, we provided auto-HSCT with a myeloablative conditioning regimen consisting of ARA-C (9 g/m2), melphalan (100 mg/m2) and 1200 cGy of TBI after two cycles of consolidation.24 The rest of the patients finished treatments with three cycles of consolidation chemotherapies.
All categorical variables were compared by χ2-analysis, and continuous variables were assessed with the Student’s t-test and one-way analysis of variance. OS and EFS rates were calculated using Kaplan–Meier survival analysis, and the log-rank test was used to evaluate differences between survival distributions. OS represents the proportion of people who were alive at a specified time from the date of diagnosis, and was associated with death due to any cause. EFS indicates the proportion of people who remained alive or free of disease at a specified time from the date of first CR achievement, and the events that were counted included death, relapse and loss to follow-up with hopeless status due to disease or treatment complications. Non-relapse mortality (NRM) and cumulative incidence of relapse (CIR) were calculated by cumulative incidence estimation treating relapse and non-relapse deaths as competing risks for NRM and CIR, and compared using the Gray test.25 Multivariate analyses using the Cox proportional regression model were used to calculate the survival hazard ratio. All statistical analyses were performed using the SAS software (ver. 9.2, SAS Institute Inc., Cary, NC, USA) and the ‘R’ software (ver. 2.15.1, R Foundation for Statistical Computing, Vienna, Austria, 2012). Statistical significance was set at a P-value <0.05.
Baseline characteristics and outcomes according to post-remission treatments
We focused on the 206 patients who achieved CR after standard ‘3+7’ induction chemotherapy and they were treated with allo- or auto-HSCT or chemotherapy alone according to the donor availability. Among the three treatment groups, the chemotherapy group consisted of older patients (median: 44.5 years) compared with the transplantation groups (P=0.002), and there was a lower proportion of patients with positive c-kit mutation in the auto-HSCT group (P=0.026). Table 1 shows the baseline characteristics with the proportion of the patient number according to the post-remission treatments.
The median follow-up duration for surviving patients was 61.8 months (range: 7.7–135.7) and outcomes according to the post-remission treatments are displayed in Figure 1. Our treatment results showed that 5-year OS for auto-HSCT, allo-HSCT and chemotherapy was 72%, 61% and 40%, respectively, and 5-year EFS was 68%, 61% and 40%, respectively. Transplantation strategy showed superior OS (P<0.001) and EFS (P=0.001) compared with chemotherapy alone. However, OS and EFS was similar between the two transplantation settings (P=0.182 and P=0.433, respectively; Figure 1a). Figure 1b shows OS and EFS according to the treatments; each was subdivided into the two subgroups of CBFβ/MYH11 and RUNX1/RUNX1T1. Although there were no significant statistical differences, CBFβ/MYH11 treated with allo-HSCT and RUNX1/RUNX1T1 treated with auto-HSCT showed favorable clinical outcomes. The chemotherapy group showed higher CIR rate (P=0.006) followed by auto-HSCT with marginal significance (P=0.054), compared with the results of allo-HSCT. In contrast, auto-HSCT showed the lowest NRM rate (4.1% (n=3) in auto-HSCT vs 24.3% (n=28) in allo-HSCT; P=0.004), which resulted in similar or slightly favorable outcomes of auto-HSCT compared with allo-HSCT (Figure 1c). In the auto-HSCT subgroup, two patients died of pneumonia sepsis and one died of organ failure followed by veno-occlusive disease. In the allo-HSCT subgroup, 12 patients died of GVHD, 12 died of infection, 3 died of organ failure followed by acute kidney injury or veno-occlusive disease and 1 died of thrombotic microangiopathy.
Survival outcomes according to the cytogenetic and molecular studies
We calculated OS curves for the cytogenetic subgroups of CBF-AML (Supplementary Figure 1). Although the CBFβ/MYH11 showed significantly superior OS compared with the RUNX1/RUNX1T1 subgroup (P=0.032) in the entire CBF-AML group, the result was NS (P=0.173) among the patients who achieved CR after standard induction chemotherapy (n=206). Within inv(16), trisomy was the most frequently found additional chromosomal abnormality followed by some deletions and translocations. Within t(8;21), X- or Y-chromosome loss was the most frequently found abnormality, and 25% of the X- or Y-chromosome loss also accompanied several trisomies, deletions and translocations. There were only two monosomies within t(8;21), and there was no case of 11q23 rearrangement in both CBF-AML subgroups. In the case of inv(16) or t(16;16), additional trisomy (n=14) showed inferior OS (P=0.080) compared with the same group without any trisomy (n=48), which showed the most favorable OS. Our data revealed that two or more additional chromosomal abnormalities combined with t(8;21) (n=11) showed the worst OS (P=0.001). The t(8;21) with sole X-chromosome loss (n=15) also showed adverse effects on OS with marginal significance (P=0.054), and this abnormality was distributed in the group of t(8;21) with 0~1 additional chromosomal abnormalities (n=88) for final analysis. Our study showed that sole Y-chromosome loss (n=45) showed favorable OS among the patients with t(8;21). Conclusively, aside from t(8;21) with two or more additional abnormalities, which showed the worst OS, other subgroups showed similar OS. Only in the inv(16) or t(16;16) subgroup, did NK mosaicism (n=13) show favorable OS (P=0.021) and EFS (P=0.025), but multivariate analysis revealed that it was NS.
Analysis of c-kit mutation was performed only in 69 patients (positive in 24 (34.8%) patients) and 137 patients diagnosed before 2008 were not assessed for c-kit mutation. CBF-AML with c-kit mutation showed poorer OS than patients without c-kit mutation (P=0.002, Figure 2a). The c-kit mutation was applied for each karyotype of CBF-AML, and the survival curves for the four subgroups are presented in Figure 2b. RUNX1/RUNX1T1 with c-kit mutation showed the worst OS (P=0.006) and CBFβ/MYH11 with c-kit mutation also showed poorer OS (P=0.045) compared with CBFβ/MYH11 without c-kit mutation. After chemotherapy, we serially checked qPCR for RUNX1/RUNX1T1 and CBFβ/MYH11 (CBF-MRD), and BAALC, and WT1 expression was also checked. Figure 2c shows that CBF-MRD qPCR reduction greater than 3-log after induction chemotherapy was a good predictive marker for favorable OS (P=0.001), and Figure 2d shows that undetected levels of CBF-MRD after final treatment was also a good predictive marker for better OS. As previously reported,19 we once again identified that post-HSCT WT1 and BAALC expression could be an additional marker for MRD (Figures 2e and f). We found that WT1 and BAALC expression correlated with each other, and we used only WT1 expression for combinatorial MRD analysis because the discrimination power of WT1 was greater than that of BAALC expression.
In the case of expression at diagnosis, we previously reported that only higher BAALC expression (upper 25% level) showed poorer OS and EFS with higher incidence of relapse19 and these results were also confirmed in the current study.
MRD monitoring after HSCT
As most of the patients were treated with transplantation, post-transplantation CBF-MRD qPCR and WT1 expression were concomitantly analyzed for OS and CIR rates. We first identified that when the post-HSCT CBF-MRD was not detected after HSCT, the patients (n=39) showed no relapse with favorable OS. Next, lower WT1 expression at the post-HSCT period was also considered as a favorable factor for OS (P=0.018) and lower CIR rate (P=0.019). We finally divided the patients into four subgroups, according to the combination of the post-HSCT CBF-MRD and WT1 expression, and calculated OS and CIR rate (Figure 3a). Detectable post-HSCT CBF-MRD with higher WT1 expression (⩾0.015) showed the worst OS with higher CIR rate (P<0.001). We also identified that the combinatorial post-HSCT molecular assay was also applicable to both c-kit-positive and c-kit-negative groups with similar results (Figure 3b).
All the results were multivariately adjusted in Table 2. Older age (⩾40 years) adversely affected OS, EFS, NRM and CIR rates, and the c-kit mutation also showed poor outcomes for OS, EFS and NRM rates, but not for CIR. Higher BAALC expression at diagnosis also showed poor outcomes for OS, EFS and CIR rates. Cytogenetic stratification was not statistically significant, except for t(8;21) with additional abnormalities, which showed marginal significance for worse OS (P=0.055). In treating CBF-AML, allo-HSCT showed higher NRM (P=0.063), but showed significantly lower CIR rate than auto-HSCT (P=0.028). Combinatorial marker analysis using CBF-MRD qPCR and WT1 expression was also significantly predictive for OS, EFS and CIR rates.
Integrative prognostic-risk scoring for CBF-AML
On the basis of the result of the current study and the previous report from our center,19 the univariate Cox proportional hazard model was used for OS using candidate prognostic markers. Parameters with P<0.05 in univariate analysis for OS were included in the risk score, and the objectives were age, c-kit mutation, diagnostic BAALC expression and two or more additional chromosomal abnormalities (Table 3). Those were also evaluated in the multivariate analysis presented in Table 2. Patients with 0–1, 2–3, 4–7 points were assigned to the low-, intermediate- and high-risk groups, respectively. The curves plotted for OS and CIR are presented in Figure 4.
In this study focusing on CBF-AML, we suggested a risk stratification using age, c-kit mutation, diagnostic BAALC expression and two or more additional chromosomal abnormalities. Furthermore, we identified a good combinatorial marker using CBF-MRD qPCR and WT1 expression for reasonable MRD detection after final treatments. The treatment strategy for adult AML in our healthcare center is mainly based on auto- or allo-HSCT, which has not been generally considered as a standard for favorable-risk AML. Therefore, the results of unfavorable prognostic markers in this study might not be widely applied, especially for CBF-AML treated with repeated high-dose ARA-C chemotherapy alone. However, several centers already reported considerably higher incidence of relapse (45–58%) after chemotherapy alone,5,7 and the other reported exclusively superior OS and DFS of allo-HSCT in treating CBF-AML.26 In a recent report, 3-year OS after allo-HSCT in second CR was 48%.27 Although this OS rate is higher than the 30% of non-CBF-AML in second CR,5 frontline auto-HSCT or allo-HSCT should be reconsidered for CBF-AML with adverse-risk factors and when the CBF-MRD qPCR is not properly reduced to an acceptable level after treatments. Given this point of view, our data can be a reference for future prospective studies that implicate frontline HSCT for CBF-AML.
Our frontline transplantation strategy for CBF-AML showed reasonable OS and EFS (70% for 5-year OS and 66% for 5-year EFS) compared with previous large studies.3,7,8 Our data revealed that auto-HSCT showed relatively good survival outcomes with the lowest NRM rate compared with allo-HSCT. Our strategy included only a small proportion of patients treated with chemotherapy alone, and the median age of the group was significantly older. Therefore, comparative analysis between transplantation and chemotherapy was not reasonable. Our study showed that t(8;21) showed significantly lower CR rate and inferior OS compared with inv(16) like previous reports.6, 7, 8 But among the patients who achieved CR after standard induction chemotherapy, the results were NS. Therefore, those results lead us to intensify the induction or consolidation chemotherapy for t(8;21) to improve the CR rate and survival outcomes.
We determined that cytogenetic stratification for CBF-AML might be helpful for prediction of unfavorable outcomes. In the current study, two or more chromosomal abnormalities combined with t(8;21) or any trisomy combined with inv(16) showed trends toward inferior OS, and NK mosaicism combined with inv(16) showed a favorable OS, but the results were not statistically significant in multivariate analysis. Previously, several studies have mentioned additional chromosomal abnormalities or deletion of 9q combined with t(8;21), and trisomy 8 or trisomy 22 combined with inv(16).7,8,28 But no definite results were reported and guidelines are still showing footnotes that CBF-AML maintain its favorable-risk property irrespective of additional cytogenetic abnormalities.3,4 Recently, residual normal metaphases were discussed in CBF-AML, but the data were also controversial.16,17
Molecular analysis including c-kit mutation and CBF-MRD qPCR monitoring after treatments showed good prognostic values comparable to previous reports.10, 11, 12, 13, 14,18,29,30 Most of them used more log-reduction or lower level of CBF-MRD qPCR after consolidation therapy for prediction of lower relapse and superior survival outcome, and one of them showed possible use of peripheral blood for detection.18 We also showed a powerful role of CBF-MRD qPCR, and our unique approach using WT1 expression could be additionally considered for prediction of relapse and survival outcomes. Previous reports have shown that WT1 expression in peripheral blood showed good correlation with BM, and higher WT1 expression without proper log-reduction after chemotherapy showed poor clinical outcomes in adult AML.22,31, 32, 33, 34 Recently, we also reported the utility of WT1 in the CBF-AML.19 Although the results of this study originated from the HSCT strategy, we expect that using CBF-MRD qPCR and WT1 can be similarly evaluated in the setting of chemotherapy alone. Furthermore, in this group with higher-risk of relapse, WT1-associated cytotoxic T-lymphocyte therapy or vaccination may be used in near future.35, 36, 37
Contrary to the expectations associated with the c-kit mutation,12, 13, 14 our data showed a higher NRM rate rather than higher CIR rate after HSCT (Table 2). This might be caused by a higher proportion of allo-HSCT using myeloablative conditioning regimen producing higher therapy-related mortality, which was mainly conducted in c-kit-positive AML. With regard to these findings, we may have to change our strategy to a more stratified approach using chemotherapy alone or auto-HSCT or allo-HSCT with reduced-intensity conditioning regimen. In addition, the poor prognosis of c-kit mutation should be overcome by innovative therapeutic strategies using protein tyrosine kinase inhibitors (that is, imatinib,38, 39, 40 PKC412,41, 42, 43 and SU541644, 45, 46, 47).
Our results did not originate from a prospective clinical trial; therefore, they should be interpreted with caution. Considering the relatively favorable prognosis of CBF-AML, our treatment strategy should be modified to reduce therapy-related mortality. Nevertheless, as no prospective study has established a role of transplantation in CBF-AML, the current study may encourage the use of frontline transplantation for an unfavorable subgroup defined by molecular cytogenetics. In conclusion, we suggest the use of cytogenetics and molecular markers to find out unfavorable CBF-AML and a risk-adapted approach using transplantation might be re-evaluated in this particular risk subgroup.
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This study was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (1020370).
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on Bone Marrow Transplantation website
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Yoon, J., Kim, H., Kim, J. et al. Identification of molecular and cytogenetic risk factors for unfavorable core-binding factor-positive adult AML with post-remission treatment outcome analysis including transplantation. Bone Marrow Transplant 49, 1466–1474 (2014). https://doi.org/10.1038/bmt.2014.180
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