High Expression Levels of the ETS-Related Gene, ERG, Predict Adverse Outcome and Improve Molecular Risk-Based Classification of Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study
To validate ERG overexpression as an adverse predictor and assess its prognostic value in the context of other molecular markers in cytogenetically normal (CN) -acute myeloid leukemia (AML).
Seventy-six adult patients with primary CN-AML, younger than 60 years and treated on Cancer and Leukemia Group B (CALGB) trial 19808, were evaluated for ERG expression by quantitative reverse transcriptase polymerase chain reaction. They were then combined with 72 patients enrolled onto CALGB 9621 for analyses that included other molecular markers.
Similar to patients enrolled onto CALGB 9621, high ERG expressers on CALGB 19808 had fewer complete remissions (CRs; P = .03) and worse event-free survival (EFS; P = .016) than low ERG expressers. In the combined set, high expressers (n = 55) had fewer CRs (P = .004) and shorter EFS (P < .001) than low expressers (n = 93). High ERG predicted failure to achieve CR (P = .004) after adjusting for BAALC expression (P = .04) and age (P = .008), and EFS (P = .004) after adjusting for FLT3 internal tandem duplication (ITD; P < .001). Among patients without FLT3-ITD (FLT3-ITD negative), only high ERG predicted shorter EFS (P = .001). Among NPM1-mutated (NPM1 positive) patients, high ERG predicted shorter EFS (P = .003), after adjusting for FLT3-ITD (P < .001). When all three markers were considered together, in the favorable FLT3-ITD–negative/NPM1-positive subset, high ERG was the only factor predicting shorter EFS (P = .002).
We validated ERG overexpression as an adverse predictor in CN-AML. Moreover, by using ERG expression levels, we improved the previously proposed molecular-risk classification of CN-AML based on the presence or absence of FLT3-ITD and NPM1 mutations, given that we identified subsets with different outcome among FLT3-ITD–negative, NPM1-positive, and FLT3-ITD–negative/NPM1-positive patients.
Acute myeloid leukemia (AML) with normal cytogenetics has been considered an intermediate-risk group, with five-year survival rates varying between 24% and 42%.1 This difference in clinical outcome reported across studies is likely related to the genomic heterogeneity of this cytogenetic subgroup in which several molecular markers have been proven prognostic.1 Among these, FLT3 internal tandem duplication (FLT3-ITD), MLL partial tandem duplication (MLL-PTD), and high BAALC expression have been shown to influence adversely the clinical outcome, whereas mutations of the NPM1 and CEBPA genes have been associated with a favorable prognosis.1-7 Furthermore, when considered in combination, these markers may become even better predictors. Indeed, patients with mutations in the NPM1 gene (NPM1 positive) and no FLT3-ITD (FLT3-ITD negative) have been shown to have a superior outcome to FLT3-ITD–negative patients with no NPM1 mutations (NPM1 negative) and those harboring FLT3-ITD (FLT3-ITD positive).3,4,8
ETS-related gene (ERG) and other members of the ETS family are downstream effectors of signaling transduction pathways involved in the regulation of cell proliferation, differentiation, and apoptosis.9-11 Cytogenetic or molecular rearrangements involving ERG, which is located at chromosome band 21q22, have been found in AML, Ewing sarcoma, and prostate cancer.10,12,13 ERG is also overexpressed frequently in AML patients with complex karyotypes and cryptic amplification of chromosome 21,14 and cytogenetically normal (CN) -AML patients with high levels of expression of this gene have been reported previously to have a poor clinical outcome.15 More recently, it has been shown that ERG overexpression also negatively influences the outcome of patients with other types of malignancies (ie, T-cell acute lymphoblastic leukemia and prostate cancer).16,17
To date, however, only one study on the prognostic significance of ERG in CN-AML has been reported.15 Therefore, we sought to validate the prognostic significance of ERG by analyzing an independent set of uniformly treated patients with CN-AML. Consistent with the prior report, we show here that higher levels of ERG expression are associated with significantly worse outcome. Furthermore, we show that when combined with other known prognostic markers, ERG expression can improve the molecular risk-based stratification of patients with CN-AML.
A total of 148 adult patients younger than 60 years with untreated primary (de novo) CN-AML were included in this study. Seventy-six patients enrolled onto the Cancer and Leukemia Group B (CALGB) treatment protocol 1980818 were newly analyzed for ERG expression by real-time reverse transcriptase polymerase chain reaction (RT-PCR). The outcome of these patients was evaluated according to ERG expression levels. To explore the impact of ERG expression in the context of other markers, these patients were then combined with a previously reported group of 72 patients enrolled onto a similar treatment protocol, CALGB 9621.15
Pretreatment cytogenetic analyses of bone marrow (BM) were performed by CALGB-approved institutional cytogenetic laboratories as part of CALGB 8461, a prospective cytogenetic companion, and were reviewed centrally, as reported previously.19 To be considered cytogenetically normal, at least 20 metaphase cells had to be analyzed and the karyotype found to be normal in each case. The presence or absence of the FLT3-ITD,20 MLL-PTD,7 and mutations in the NPM1 gene,3 and BAALC expression levels6 were also determined centrally in pretreatment samples as described previously. Written informed consent for participation in these studies was obtained from all patients.
Patients enrolled onto CALGB 19808 were randomly assigned to receive induction chemotherapy with cytarabine, daunorubicin, and etoposide with or without PSC-833 (also called valspodar), a multidrug resistance protein inhibitor.18 On achievement of complete remission (CR), all patients (regardless of the type of induction received) were assigned to intensification with high-dose cytarabine and etoposide for stem-cell mobilization followed by myeloablative treatment with busulfan and etoposide supported by autologous peripheral-blood stem-cell transplantation (APSCT). Patients unable to receive APSCT received two additional cycles of high-dose cytarabine. Patients enrolled onto CALGB 9621 were treated similarly to those enrolled onto CALGB 19808, as reported previously.21
Mononuclear cells from pretreatment blood were enriched by Ficoll-Hypaque gradient and cryopreserved in liquid nitrogen until they were thawed at 37°C for this analysis. Total RNA extraction, complementary DNA synthesis from 2 μg total RNA, real-time RT-PCR amplification, construction of standard curves for quantification of ERG and the internal control ABL, and calculation of ERG copy number normalized to ABL copy number were performed as previously reported.15
CR was defined as recovery of morphologically normal BM and blood counts (ie, neutrophils ≥ 1,500/μL and platelets ≥ 100,000/μL), and no circulating leukemic blasts or evidence of extramedullary leukemia. Relapse was defined by ≥ 5% BM blasts, circulating leukemic blasts, or development of extramedullary leukemia. Event-free survival (EFS) was defined as the interval from the date on study until removal from study because of failure to achieve CR, relapse, or death as a result of any cause (whichever occurred first); patients alive and disease free at last follow-up were censored. Disease-free survival (DFS) was measured from the date of CR until date of relapse or death, regardless of cause; patients alive at last follow-up were censored.
The main objective of this study was to evaluate the predictive value of ERG expression on clinical outcome. The negative impact of ERG expression reported previously in patients treated on CALGB 9621 was first validated independently in patients treated on CALGB 19808. For these patients, the median ERG/ABL copy number value was chosen to define the low and high ERG expressers. This cutoff was based on the trend for EFS of patients divided in quartiles by ERG level values; patients in quartiles 1 and 2 had a better outcome than patients in quartiles 3 and 4 (P = .049, test for trend22). There were no statistically significant differences in CR rates or EFS for patients enrolled onto CALGB 9621 or onto CALGB 19808 who were analyzed for ERG expression compared with those who were not analyzed for ERG expression.
To address the prognostic value of ERG expression levels in the context of the presence or absence of other molecular prognostic markers (ie, FLT3-ITD, NPM1 mutation, MLL-PTD, and BAALC overexpression), high and low ERG expressers on CALGB 19808 were combined with the previously reported high and low ERG expressers on CALGB 9621, respectively, and analyzed for outcome. Pretreatment clinical features were compared between the two groups using Fisher's two-sided exact and Wilcoxon rank sum tests for categoric and continuous variables, respectively. To analyze factors related to the probability of achieving CR, a logistic regression model was constructed using a limited backward selection procedure. Variables considered in the model were those significant at α = .20 from the univariable models. Variables remaining in the final model for CR were significant at α = .05. Odds ratios and 95% CIs were obtained to describe the odds of achieving a CR for significant prognostic factors.
Estimated probabilities of EFS and DFS were calculated using the Kaplan-Meier method, and the log-rank test evaluated differences between survival distributions. Proportional hazards models were constructed for survival end points, using a limited backward selection procedure. Variables considered in the model were those significant at α = .20 from the univariable models. Variables remaining in the final models were significant at α = .05. The proportional hazards assumption was checked individually for each variable entered in the multivariable analyses. Estimates for hazard ratios and corresponding 95% CIs were obtained for each significant prognostic factor. All analyses were performed by the CALGB Statistical Center.
Within the group of patients enrolled onto CALGB 19808, high ERG expressers differed from the low expressers in that they were more frequently FLT3-ITD positive (P = .001) and had higher WBC counts (P < .001; Table 1). The high ERG group had a significantly lower CR rate compared with the low ERG group (79% v 97%; P = .03) and, with a median follow-up of 2.9 years (range, 1.7 to 5.4 years) for patients who did not have an event, a significantly worse EFS (median, 0.8 v 3.4 years; P = .016; Fig 1A). Estimated 2-year EFS rates for the high and low expressers were 29% and 53%, respectively.
These results confirmed those obtained in 72 patients with CN-AML enrolled onto CALGB 9621. In that set of patients, we also observed significantly different CR rates for patients with high ERG expression compared with those with low expression (65% v 89%; P = .03), when levels of this marker were measured against the internal control ABL (unpublished data). Furthermore, with a median follow-up of 7.1 years (range, 5.8 to 8.9 years) for patients who did not have an event, the median EFS duration for the high ERG expressers on CALGB 9621 was 0.5 years compared with 2.5 years for the low ERG expressers (P = .001), and the estimated 2-year EFS rates were 24% and 51%, respectively (Fig 1B).
Having validated the prognostic impact of levels of ERG expression in two independent sets of patients, next we assessed its predictive value when other molecular markers were taken into account. To achieve this goal, we combined patients identified as high or low expressers on CALGB 19808 with those identified as high or low expressers on CALGB 9621, respectively.15 In these newly formed groups, 93 patients were categorized as low and 55 patients were categorized as high ERG expressers.
At diagnosis, high expressers had higher WBC (P = .001), a lower incidence of gum infiltration (P = .006), higher incidence of FLT3-ITD (P = .003), and a trend toward more often having high expression of BAALC (P = .08; Appendix Table A1, online only). High expressers had a lower CR rate (74% v 92%) compared with low expressers (P = .004). In a multivariable analysis, high ERG expression status independently predicted failure to achieve CR (P = .004), after adjusting for BAALC expression (P = .04) and age (P = .008). High expressers had 5.7 times the odds of not achieving CR compared with the low expressers (Table 2).
With a median follow-up of 5.8 years for patients who did not have an event (range, 1.7 to 8.9 years), high expressers also had shorter EFS (P < .001) than low expressers. In a multivariable analysis, high ERG expression independently predicted worse EFS (P = .004) after adjusting for FLT3-ITD status (P < .001; Table 2). When we analyzed patients who received APSCT after achievement of CR, there was also a significant difference in EFS duration (P < .0001) between the low and high ERG expresser groups, and the expected 2-year EFS rates were 71% and 34%, respectively. When stratifying by FLT3-ITD status, we observed no difference in EFS among FLT3-ITD–positive patients according to ERG expression levels (P = .31), whereas in the FLT3-ITD–negative subset, high ERG expressers had a worse EFS than low expressers (median, 1.3 years v not reached; P < .001), with estimated 2-year EFS rates of 35% and 65%, respectively (Fig 2A and 2B). In a multivariable analysis limited to the FLT3-ITD–negative subset, high ERG expression was the only factor that predicted for worse EFS (P = .001) and conferred a 2.8 times higher risk of an event compared with low ERG expression (Table 2).
NPM1 mutations were present in 68% of the patients and were distributed similarly among the high and low ERG groups (73% v 67%; P = .46). Within the subset of NPM1 mutated (NPM1 positive) patients, high ERG expressers had a worse EFS than low expressers (median, 0.7 years v not reached; P < .001), with estimated 2-year EFS rates of 25% and 55%, respectively (Fig 2C). In contrast, the outcome of both ERG expression groups with NPM1-negative status was similarly poor (P = .29; Fig 2D), but the number of patients in this group was too small to draw definitive conclusions (Appendix Fig A1, online only). In a multivariable analysis of NPM1-positive patients, ERG expression levels independently predicted EFS duration (P = .003), after adjusting for FLT3-ITD status (P < .001; Table 2).
It has been shown previously that being both NPM1 positive and FLT3-ITD negative constitutes an independent favorable prognostic factor in CN-AML. Several groups have found that FLT3-ITD–negative/NPM1-positive patients have a significantly better outcome than the FLT3-ITD–negative/NPM1-negative and FLT3-ITD-positive patients.3,4,8 Thus, we tested whether determining ERG expression levels could improve the previously reported prognostic stratification based on the combined NPM1 mutation and FLT3-ITD status.3,4,8 We found that in the FLT3-ITD–negative/NPM1-positive subset, high ERG expressers had worse EFS (median, 1.6 years v not reached; P < .001) and DFS (median, 1.7 years v not reached; P = .003) than low expressers, with estimated 2-year EFS rates of 36% and 72% and DFS rates of 42% and 74%, respectively (Fig 3). In contrast, ERG expression had no significant prognostic impact on the FLT3-ITD–negative/NPM1-negative subset (data not shown). Among FLT3-ITD–negative/NPM1-positive patients, ERG status was the only independent predictor for EFS (P = .002; Table 2) and DFS (P = .003). In this subset, high ERG expressers had a 3.8 times higher risk of an adverse event (ie, failure to achieve CR, relapse, or death) than low expressers (Table 2).
We report here the first independent validation of ERG overexpression as a negative prognostic marker in CN-AML. We have been able to show that high ERG expression predicts failure to achieve CR and shorter EFS in independent cohorts of patients treated on two separate, albeit similar, treatment protocols. These results support ERG expression as an additional and valuable predictor for clinical outcome in patients with CN-AML, and are consistent with reports in other types of cancer (ie, T-cell acute lymphoblastic leukemia and prostate cancer), showing that high levels of ERG expression identify aggressive malignant phenotypes.16,17 To take full advantage of the predictive value of ERG expression, future larger studies in these different diseases will be necessary to establish a standardized method of quantification and define absolute cut points that would allow prospective classification of patients as high or low ERG expressers.
Given that two or more genetic alterations can be present simultaneously in CN-AML patients, part of the validation process of a newly discovered predictor is to prove that it can maintain an independent prognostic value when assessed against other molecular markers. One of the limitations of this type of approach, however, often lies in the small number of patients available for subset analyses. Therefore, we combined patients with CN-AML enrolled onto CALGB 9621 and 19808 treatment protocols and investigated the prognostic value of ERG expression once FLT3-ITD, MLL-PTD, and NPM1 mutations and high BAALC expression were taken into account (Fig 4). Using this approach, our data support the existence of a complex prognostic network constituted by these markers. First, we observed that levels of ERG expression affected the outcome of only FLT3-ITD–negative patients, but not that of FLT3-ITD–positive patients. This is consistent with the notion that patients harboring FLT3-ITD have a dismal prognosis and are relatively unaffected by the presence or absence of other prognostic markers. In contrast, FLT3-ITD–negative patients seem to constitute a more heterogeneous prognostic group, consisting of subsets with different outcomes that can be identified on additional molecular characterization. Second, we showed that expression levels of ERG also influenced the outcome of the NPM1-positive subset only, whereas the prognosis of the NPM1-negative subset seemed not to be affected, although too few patients were analyzed to draw definitive conclusions (Fig A1). Finally, when we tested whether ERG expression could improve the previously proposed molecular risk classification of CN-AML based on a combined FLT3-ITD and NPM1 mutation status,3,4,8 we identified a subset of patients (ie, FLT3-ITD negative/NPM1 positive/low ERG) with a favorable prognosis, with an estimated 2-year EFS rate exceeding 70% (Fig A1).
Our data reinforce the view that from a molecular standpoint, CN-AML is a heterogeneous disease. We have proposed previously a prioritized schema that stratifies patients with CN-AML to risk-adapted therapies based on molecular markers.1 In light of the information derived from the current work, we can now integrate ERG expression levels into this schema. Our data indicate that FLT3-ITD–negative/NPM1-positive patients, considered to have a favorable prognosis,3,4,8 can be separated into prognostic subsets based on expression levels of ERG. FLT3-ITD–negative/NPM1-positive/low ERG patients are likely to benefit from high-dose cytarabine and APSCT-based therapies as administered in CALGB 9621 and 19808. In contrast, FLT3-ITD–negative/NPM1-negative/high ERG patients perhaps should be considered for alternative and/or more aggressive treatments, given that their estimated 2-year EFS is less than 40% (Fig A1). Likewise, CN-AML patients with FLT3-ITD who have a poor prognosis should be considered for clinical trials investigating compounds that directly inhibit FLT3 tyrosine kinase activity or for allogeneic SCT, although a definitive role for the latter in first CR remains to be established.23,24
The author(s) indicated no potential conflicts of interest.
Conception and design: Guido Marcucci, Clara D. Bloomfield
Financial support: Clara D. Bloomfield
Administrative support: Guido Marcucci, Richard A. Larson, Clara D. Bloomfield
Provision of study materials or patients: Bayard L. Powell, Jonathan E. Kolitz, Richard A. Larson, Clara D. Bloomfield
Collection and assembly of data: Kati Maharry, Susan P. Whitman, Tamara Vukosavljevic, Peter Paschka, Christian Langer, Claudia D. Baldus, Andrew J. Carroll
Data analysis and interpretation: Guido Marcucci, Kati Maharry, Susan P. Whitman, Krzysztof Mrózek, Clara D. Bloomfield
Manuscript writing: Guido Marcucci, Krzysztof Mrózek, Clara D. Bloomfield
Final approval of manuscript: Guido Marcucci, Kati Maharry, Susan P. Whitman, Tamara Vukosavljevic, Peter Paschka, Christian Langer, Krzysztof Mrózek, Claudia D. Baldus, Andrew J. Carroll, Bayard L. Powell, Jonathan E. Kolitz, Richard A. Larson, Clara D. Bloomfield
|Characteristic||Low ERG (n = 38)||High ERG (n = 38)||P|
|No. of Patients||%||No. of Patients||%|
|Platelet count, × 109/L||.28|
|WBC count, × 109/L||< .001|
|Percentage of BM blasts||.32|
|Percentage of PB blasts||.46|
|Consolidation treatment, received APSCT||22||58||25||66||.42|
|Percent relapsed (relapse rate)||49||70||.09|
|95% CI||36 to 67||16 to 44|
Abbreviations: CALGB, Cancer and Leukemia Group B; BM, bone marrow; PB, peripheral blood, FLT3-ITD, internal tandem duplication of the FLT3 gene; MLL-PTD, partial tandem duplication of the MLL gene; ADE, cytarabine, daunorubicin, and etoposide; ADEP, cytarabine, daunorubicin, etoposide, and valspodar; APSCT, autologous peripheral-blood stem-cell transplantation; CR, complete remission; EFS, event-free survival.
|End Point||Patient Group||Variables in Final Models||OR||HR||95% CI||P|
|CR*||All patients||ERG expression, low v high||5.7||1.8 to 18.8||.004|
|BAALC expression, low v high||3.6||1.1 to 11.9||.04|
|Age||0.91||0.85 to 0.98||.008|
|EFS†||All patients||ERG expression, high v low||1.9||1.2 to 2.9||.004|
|FLT3-ITD, positive v negative||2.3||1.5 to 3.6||< .001|
|EFS‡||FLT3-ITD negative||ERG expression, high v low||2.8||1.5 to 5.1||.001|
|EFS§||NPM1 positive||ERG expression, high v low||2.2||1.3 to 3.8||.003|
|FLT3-ITD, positive v negative||2.5||1.5 to 4.4||< .001|
|EFS‖||FLT3-ITD negative/NPM1 positive||ERG expression, high v low||3.8||1.7 to 8.8||.002|
NOTE. ORs < 1 mean lower CR rate for the higher values of the continuous variables. ORs > 1 mean higher CR rate for the first category listed for categorical variables. HRs > 1 indicate higher risk for an event for the first category listed.
Abbreviations: CALGB, Cancer and Leukemia Group B; OR, odds ratio; HR, hazard ratio; CR, complete remission; EFS, event-free survival; FLT3-ITD, internal tandem duplication of the FLT3 gene; FLT3-ITD negative, patients without FLT3-ITD; NPM1 positive, patients with mutations of the NPM1 gene.
*Variables considered for model inclusion were ERG expression (low v high), FLT3-ITD (positive v negative), BAALC expression (low v high), age, log-transformed WBC count, and sex.
†Variables considered for model inclusion were ERG expression (low v high), FLT3-ITD (positive v negative), BAALC expression (low v high), log-transformed WBC count, and gum hypertrophy.
‡Variables considered for model inclusion were ERG expression (low v high), BAALC expression (low v high), log-transformed WBC count, lymphadenopathy, and gum hypertrophy.
§Variables considered for model inclusion were ERG expression (low v high), BAALC expression (low v high), log-transformed WBC count, platelets, percentage of blood blasts, and gum hypertrophy.
‖Variables considered for model inclusion were ERG expression (low v high), lymphadenopathy, and gum hypertrophy.
|Characteristic||Low ERG (n = 93)||High ERG (n = 55)||P|
|No. of Patients||%||No. of Patients||%|
|Percentage of males||49||40||.31|
|Platelets, × 109/L||.20|
|WBC count, × 109/L||.001|
|Percentage of BM blasts||.21|
|Percentage of PB blasts||.56|
|FLT3-ITD status||5 unknown||1 unknown||.003|
|NPM1 status||3 unknown||.46|
|BAALC expression||14 unknown||1 unknown||.08|
|Consolidation treatment, received APSCT||52||60||32||78||.59|
|Percentage relapsed (relapse rate)||48||73||.008|
|95% CI||41 to 61||16 to 39|
Abbreviations: CALGB, Cancer and Leukemia Group B; BM, bone marrow; PB, peripheral blood; FLT3-ITD, internal tandem duplication of the FLT3 gene; MLL-PTD, partial tandem duplication of the MLL gene; ADE, cytarabine, daunorubicin, and etoposide; ADEP, cytarabine, daunorubicin, etoposide, and valspodar; APSCT, autologous peripheral-blood stem-cell transplantation; CR, complete remission; EFS, event-free survival.
published online ahead of print at www.jco.org on June 18, 2007.
Supported by National Cancer Institute (Bethesda, MD) Grants No. CA101140, CA77658, CA102031, CA31946, CA09512, CA16058, CA98933, CA90469, CA96887, and CA089341, and the Coleman Leukemia Research Foundation.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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