Acute Leukemias

Prognostic significance of 11q23 aberrations in adult acute myeloid leukemia and the role of allogeneic stem cell transplantation

Abstract

The clinical features and outcomes of 148 patients with acute myeloid leukemia (AML) and 11q23 chromosomal abnormalities were compared with those of 2640 patients with non-11q23 AML. Patients with t(9;11) ), t(6;11) or other 11q23 balanced translocations (t(11;v)(q23;v)) presented at a younger age and with higher percentage of bone marrow blasts. Unbalanced 11q23 abnormalities were commonly associated with deletions of chromosomes 5q, 7q and/or complex karyotypes. In multivariate analysis, when compared with patients with non-11q23 AML and unfavorable-risk karyotype, there was a significant difference in overall survival (OS) for patients with t(9;11) (P=0.004), whereas there were no differences in OS for patients with t(6;11) (P=0.62), t(11;19) (P=0.20) and unbalanced 11q23 aberrations (P=0.85) or t(11;v)(q23;v) (P=0.59), indicating that t(9;11) has an independent intermediate prognostic significance, with all others being poor prognostic factors for OS; this was further confirmed by comparing them with patients with non-11q23 AML and intermediate-risk karyotype. Using intention-to treat analysis based on donor availability, we also noted that allogeneic stem cell transplant in first remission had a significant benefit toward improving OS (P<0.001) and relapse-free survival (P<0.001) in patients with AML and 11q23 abnormalities.

Introduction

Cytogenetic abnormalities in leukemia cells are strongly associated with distinct clinical subgroups and are predictive of both clinical features and therapeutic outcome.1, 2, 3, 4 Recurrent cytogenetic abnormalities in chromosome 11q23 involving the mixed-lineage leukemia (MLL) gene have been observed in 3–4% of adult patients with acute myeloid leukemia (AML), in 3–7% of adults with acute lymphoblastic leukemia5 and at even higher rate in infant leukemia.6, 7 To date, >60 translocation partner genes of 11q23 have been identified.8

MLL encodes a histone methyltransferase that is critical for maintaining gene expression during embryonic development and hematopoiesis. MLL gene translocations generate chimeric MLL fusion proteins that directly bind to DNA and positively regulate gene transcription. These events result in aberrant expression of downstream MLL targets, including the HOX gene, thereby leading to leukemic transformation.8, 9 Recent studies have shown that the prognosis of 11q23/MLL AML is heterogeneous depending on the 11q23 fusion partner.10, 11 In addition, the prognosis of AML with 11q23 abnormalities with the same translocation partner differs between adults and children.10, 11, 12, 13 As a result, in the 2008 edition of the World Health Organization classification of myeloid neoplasms, the category of AML with 11q23/MLL abnormalities was revised to focus on AML with t(9;11) (p22;q23)/MLLT3-MLL, with the notation that rearrangements of MLL with other fusion partners need to be specified on AML diagnosis.14

As adult AML cases with11q23 abnormalities are rare, the clinical features and prognostic significance of the abnormalities other than t(9;11) are not well known. To our knowledge, the prognostic significance of unbalanced 11q23 aberrations has only been reported in one small study.15 The prognostic impact of additional chromosomal abnormalities in patients with 11q23 aberrations is also not clear. The existing information about this subgroup is based on data from only a few clinical trials with potential for selection bias. Furthermore, information on the potential therapeutic role of allogeneic stem cell transplantation (allo-SCT) in this subgroup is scarce, as most of the published studies involved groups that were too small to allow definitive conclusions.16, 17

In this study, to characterize their clinical features, assess their outcomes in response to therapy and evaluate the significance of allo-SCT performed at first complete remission (CR1), we retrospectively analyzed the data from 148 adult patients with newly diagnosed 11q23 AML between January 1990 and February 2011 who were treated at our institution. We clearly demonstrate that t(6;11), t(11;19), unbalanced 11q23 aberrations and t(11;v)(q23;v) are independent poor prognostic factors whereas patients with t(9;11) have intermediate-risk disease. We also demonstrate that allo-SCT in CR1 has a significant benefit for improving overall survival (OS) and relapse-free survival (RFS) for patients with AML and 11q23 abnormalities.

Patients and methods

Patients

We searched the database of the Department of leukemia at the University of Texas - MD Anderson Cancer Center. Between January 1990 and February 2011, 2788 consecutive patients with newly diagnosed AML with available cytogenetic analysis were identified and were the subject of this study (excluding patients with acute promyelocytic leukemia, and those with core binding factor leukemia with t(16;16)/inv(16) or t(8;21)). On initial diagnosis, 148 of the 2788 patients had 11q23 abnormalities detected by conventional cytogenetic analysis; these were confirmed by fluorescence in situ hybridization analysis in 29 patients. AML with MLL partial tandem duplications was not included in this study as it is considered as a distinct entity.14 The remaining 2640 patients were defined as having non-11q23 AML. Among the patients with 11q23 AML, 144 (97%) underwent chemotherapy regimens consisting of high-dose ara-C (1 g/m2 per dose) alone (n=3) or plus idarubicin (n=85), plus fludarabine (n=20), or plus other agents such as clofarabine, topotecan, troxacitabine or liposomal daunorubicin (n=20); non-high-dose ara-C (<1 g/m2 per dose) plus daunorubicin or clofarabine (n=9); 7 patients had other non-ara-C-based regimens. Among the 2640 non-11q23 reference group, 131 patients received supportive treatment only (5%). In all, 1838 patients received high-dose ara-C-based regimens (70%), 297 patients received non-high-dose ara-C-based regimens (11%) and 374 patients received other non-ara-C-based regimens (14%). All patients were treated on prevailing clinical trials and gave written informed consent to participate. This study was further approved by the Institutional Review Board at The University of Texas MD Anderson Cancer Center.

Subgroups of 11q23 abnormalities

The 11q23 abnormalities were classified into five groups. Group (A): t(9;11) (n=65; 44%) included t(9;11)(p22;q23) (n=58) and t(9;11)(p21;q23). Group (B): t(6;11) (n=12; 8%) included t(6;11)(q27;q23). Group (C): t(11;19) (n=18; 12%) included 12 cases with t(11;19)(q23;p13), 3 with t(11;19) (q23;p13.3), 2 with t(11;19)(q23;p13.1) and 1 with t(11q23;p13.2). Group (D): unbalanced 11q23 aberrations (n=41; 28%) included del(11)(q23) (n=32) and add(11)(q23), inv11q23, or dic11q23 (n=9). Group (E): t(11;v)(q23;v) (n=12; 8%) comprised of other balanced 11q23 translocations, including two patients each with t(10;11) and t(11;17), and one each with t(11;15), t(7;11), t(X;11), dic(11;12), t(3;11), t(11;22), t(4;11) and t(11;11). These distributions are similar to those reported in previous studies,18, 19 with the exception of a relatively lower frequency of t(10;11). In addition, the frequency of unbalanced 11q23 aberrations was relatively higher in our study. Cases of non-11q23 AML were grouped into two cytogenetic-risk categories (intermediate and unfavorable) according to the European LeukemiaNet criteria.1 The outcomes and clinical features of the cases in the five 11q23 AML subgroups were compared with those of the non-11q23 AML cases.

Statistical analysis and definitions

CR, OS, event-free survival (EFS) and RFS were defined on the basis of criteria recommended by the International Working Group.20 A Wilcoxon rank-sum test was used to make pairwise comparisons of continuous variables between cytogenetic subgroups, and a Kruskal–Wallis test was used to compare continuous variables among more than two subgroups. Categorical variables were compared using Fisher’s exact test. The Bonferroni method was used to adjust the type I error when multiple comparisons were used. The Kaplan–Meier method was used to estimate the time-to-event variables. Log-rank tests were conducted to compare the survival among the various cytogenetic subgroups. Cox proportional hazards models were used to evaluate the ability of the covariates to predict the time-to-event variables. For each fitted Cox regression model, nonsignificant variables in univariate analyses were eliminated in a step-down manner using a P-value cutoff of P=0.05. All computations were carried out using SAS software version 9.1 (SAS Institute Inc., Cary, NC, USA) and S-Plus software version 8.04 (TIBCO Software Inc., Palo Alto, CA, USA).

Results

Incidence and clinical characteristics of 11q23 AML

The frequency of 11q23 AML within intermediate and unfavorable cytogenetic-risk AML was 5.3% (148/2788). Among the 2640 patients with non-11q23 AML, 1679 had intermediate-risk cytogenetics and 961 had unfavorable-risk cytogenetics. Among the 148 patients with 11q23 AML, 78 (52%) had de novo AML, and 58 (40%) had therapy-related AML (t-AML); in 12 (8%) patients the disease was secondary to a prior myelodysplastic syndrome or myeloproliferative neoplasm (secondary AML, s-AML).

The median age of patients with 11q23 AML was 54 years (range, 17–84 years), and 61 (41%) patients were male. Of note, 60 of 148 (41%) cases were classified as the French–American–British (FAB) classification M5 (FAB-M5), and 32 (22%) were classified as M4 (FAB-M4). The presenting features of various 11q23/MLL AML subgroups are shown in Table 1. Patients with t(9;11), t(6;11) and t(11;v)(q23;v) presented at a younger age (P<0.001, =0.002, and <0.001, respectively) and had a higher percentage of bone marrow blasts (P<0.001, <0.001 and =0.04, respectively) at diagnosis than those in the non-11q23 reference group. As multiple tests were conducted in comparison with the reference group (unfavorable or intermediate), the Bonferroni method was used to adjust for the type I error with significance level being 0.01. Proportion of patients with FAB-M5 was higher among patients with all 11q23 AML subgroups than in the reference group (P<0.001). Patients with t(9;11) were more likely to be female (69%) than the non-11q23 reference group (41%; P<0.001). Patients with t(9;11) were more likely to have t-AML and/or s-AML compared with those with non-11q23 AML (P=0.008),21 whereas patient with t(6;11) commonly presented with de novo AML (P=0.007). No differences in white blood cell counts, platelet counts, hemoglobin levels, FAB-M4 incidence were observed between the 11q23 subgroups and the non-11q23 reference group (Table 1).

Table 1 Patient characteristics, response and outcomes by comparison of five 11q23 subgroups with non-11q23 reference group

Del(5q)/-5, del(7q)/-7, complex karyotypes and additional trisomy 8 with 11q23 abnormalities

The incidence of additional cytogenetic abnormalities including del5/5q−, del7/7q− and/or complex karyotypes was significantly higher in patients with unbalanced 11q23 aberrations than in the non-11q23 reference group (P<0.001), whereas the incidence of these additional abnormalities was significantly lower in patients with t(9;11) (P=0.008) and t(11;19) (P=0.006) than in the non-11q23 reference group. The incidence of additional trisomy 8 was higher in patients with t(9;11) and unbalanced 11q23 aberrations) than in the non-11q23 reference group (P=0.003 and 0.02, respectively).

Treatment response and clinical outcome

The median follow-up time in all patients (n=2788) was 5 years. The overall CR rate for the 144 patients with 11q23 aberrations who received induction chemotherapy was 68% (n=98). The median OS time in the 11q23 AML group and the non-11q23 AML reference group was 8.5 months (95% confidence interval, 6.4–11.9 months) and 9.5 months (95% confidence interval, 9.0–10.2 months), respectively (P=0.32; data not shown). Patients with t(9;11) had OS and EFS similar to intermediate non-11q23 reference group, whereas all other 11q23 groups (data not shown) had OS and EFS comparable to unfavorable non-11q23 reference group (Figure 1).

Figure 1
figure1

(a) OS by comparison of 11q23 subgroups with non-11q23 reference groups. (b) EFS by comparison of 11q23 subgroups with non-11q23 reference groups.

The 5-year OS rates and EFS rates were shown in Table 1. The OS rate was lower in patients who had 11q23 AML with del(5q)/-5, del(7q)/-7, and/or complex karyotypes than in those without del(5q)/-5, del(7q)/-7, and/or complex karyotypes (P<0.001; Figure 2). There was no significant difference in OS rates between patients who had11q23 AML with additional trisomy 8 and those without additional trisomy 8 (P=0.96, data not shown).

Figure 2
figure2

OS for 11q23 AML patients with or without del5/5q−, del7/7q− and/or complex karyotype.

Risk factor analysis

To determine the prognostic impact of each11q23 subgroup, we used Cox regression models when age, sex, race, white blood cell counts, platelet counts, hemoglobin levels, lactate dehydrogenase, percentage of bone marrow blasts, type of AML (de novo vs t-AML/s-AML), type of treatment, performance status and the five 11q23 subgroups were considered. Cytogenetic abnormalities were excluded because of overlap with five 11q23 subgroups. The nonsignificant variables (P-value>0.05) in the univariate Cox analyses were excluded in the multivariate model. Using the unfavorable non-11q23 AML as the reference group, the multivariate Cox analysis revealed that only t(9;11) was an independent intermediate-risk factor for OS (hazard ratio (HR)=0.61; P=0.004). There was no significant difference in OS when patients with intermediate non-11q23 were used as the reference group (HR=1.10; P=0.53), further confirming that t(9;11) was an intermediate cytogenetic-risk factor. Similar results were observed for EFS when patients with unfavorable or intermediate-risk non-11q23 AML were used as the reference group (HR=0.52; P<0.001 and HR=1.04; P=0.80, respectively).

In multivariate analysis, there was no significant difference in OS in group t(6;11), t(11;19), unbalanced 11q23, or t(11;v)(q23;v) group (HR=1.17, 0.72, 0.97 and 0.84, respectively; P=0.62, 0.20, 0.85 and 0.59, respectively; Table 2) when compared with patients with unfavorable non-11q23 AML, indicating they were independent poor prognostic factors for OS. These were further confirmed by comparing with patients with intermediate non-11q23 AML. Of note, the presence of t(11;19) and t(11;v)(q23;v) was a marginally significant factor for poor OS (P=0.07; Table 2) when patients with intermediate non-11q23 AML were used as reference group. Similar results were observed for EFS when patients with unfavorable non-11q23 AML were used as the reference group (Table 2). Of note, when compared with patients with intermediate non-11q23 AML, only t(6;11) and unbalanced 11q23 aberrations were independent poor prognostic features for EFS (HR=2.00, P=0.02 and HR=1.58, P=0.005, respectively).

Table 2 Multivariate analysis of prognosis of five 11q23 subgroups

Molecular abnormalities in cases of 11q23 AML

Evaluation for mutations of RAS, FLT3 and NPM1 genes were performed routinely, as a part of the patient assessment, at the time of initial presentation in a limited number of the patients. Evaluation for other well-described gene aberrations were not performed. The incidence of RAS mutations was slightly higher in the 11q23 AML group than in the non-11q23 AML reference group (21.8% (12/55) and 18.3% (203/1112), respectively (P=0.48)). However, FLT3-ITD mutations were detected in 4.8% (3/63) and 16.1% (226/1406; P=0.01) of the 11q23 and non-11q23 groups, respectively; FLT3-D835 mutations were detected in 6.4% (4/63) and 5.0% (70/1405; P=0.55), respectively; and NPM1 mutations were detected in 2.9% (1/35) and 20.7% (114/552; P<0.001), respectively. These results are consistent with other reports, thereby indicating that 11q23 AML often harbors gene mutations involved in the RAS pathway,22 whereas mutations in FLT3 and NPM1 are uncommon.22, 23, 24

Role of allo-SCT in post remission consolidation at CR1

Of the 98 AML patients with 11q23 abnormalities who achieved CR after induction chemotherapy. Donor availability for four patients is unknown. Among remaining 94 patients, 55 patients had no donor or were not screened for donor, 39 patients (41%) had donor available. Patient characteristics by donor vs non-donor were shown in Table 3. The clinical characteristics of the patients with donor vs non-donor were well balanced except patient age, bone marrow blast and 11q23 aberrations. Of 39 patients, 24 underwent allo-SCT (16 from related donors, 4 from unrelated donors, 3 cord blood and 1 from a haploidentical donor) in CR1.The conditioning regimens consisted of fludarabine plus busulfan (n=14), fludarabine plus melphalan (n=8), Total body irradiation plus etoposide and cyclophosphamide (n=1), or unknown regimen (n=1). The median time from CR1 to SCT was 3 months (range, 1–27 months). Patients who underwent allo-SCT at CR1 (n=39) had a significantly longer OS (P<0.001) and RFS (P<0.001) than those who did not undergo allo-SCT at CR1 (n=55; Figures 3a and b). This superior outcome was also evident when considering only patients with t(9;11) (Figures 3c and d). Multivariate analysis using allo-SCT as a time-dependent covariable after controlling for other risk factors as described above revealed a significant positive impact of allo-SCT at CR1 on OS (HR=0.56; P=0.02) and RFS (HR=0.51; P=0.01; data not shown).

Table 3 Patient characteristics and outcomes by donor availability in first remission
Figure 3
figure3

(a) OS by donor availability at first CR (all patients with 11q23). (b) RFS by donor availability at first CR (all patients with 11q23). (c) OS by donor availability (patients with t(9;11) only). (d) RFS by donor availability (patients with t(9;11) only).

Discussion

The results of this study of a large cohort of patients confirm that AML with t(9;11) is indeed a distinct entity with a better clinical outcome than AML with other 11q23 abnormalities. In multivariate analysis, t(9;11) was the only independent predictor of survival with the OS and EFS of these patients being comparable to those of patients with intermediate cytogenetic risk (HR1.10 and 1.04, respectively; Table 2). These results are in agreement with those reported in previous studies of 47 adult patients with de novo AML by the Cancer and Leukemia Group B19 and of 180 adult patients with AML by the German AML Intergroup17 and in a more recent study by the Medical Research Council, which showed that the prognosis of these patients was better than that of patients with other balanced t(11q23).4 Our data conflict with another study of 54 adult patients with AML that demonstrated no significant difference in prognosis between cases with t(9;11) (n=19) and cases with other balanced t(11q23) (unfavorable prognosis).18 The reasons for the potential superior outcome of patients with t(9;11) compared with those with other MLL translocations are unknown and may be related to the differences of proteins encoded by MLL fusion genes derived from various translocations. Of note, t(9;11) is more commonly associated with t-AML/s-AML, but has the highest OS rate among 11q23 AML subgroups and non-11q23 AML reference group, this could be due to t(9;11) being less associated with del(5q)/-5, del(7q)/-7 and/or complex karyotype and also suggests that, at least in this population, t-AML/s-AML is a weak prognostic factor.25

In our study, patients with t(6;11), like those with t(9;11), presented at a younger age and with a higher percentage of bone marrow blasts than patients with non-11q23. However, t(6;11) was shown to be an independent poor prognostic feature in adult AML (Table 2). Adverse outcomes of patients with t(6;11) have been reported in pediatric AML12 and adult AML by Cancer and Leukemia Group B16 and the German AML Intergroup.17 Given the dismal outcomes of these patients, clinical trials using novel strategies should be encouraged for this group.

Group t(11;19) had the lowest incidence of del5/5q−, del7/7q− and/or complex karyotypes (6%) among 11q23 subgroups and the non-11q23 reference group, and is not commonly associated with t-AML/s-AML. However, t(11;19) was also identified as an independent adverse prognostic feature in adult AML, a finding that is consistent with the results reported in the majority of other such studies,17, 18, 26 but that conflicts with the findings of a recent study by the Medical Research Council.4

The various other unbalanced 11q23 aberrations were the second most common 11q23 abnormalities, and the majority of the cases in this group had del(11)(q23). This group was commonly associated with del5/5q−, del7/7q− and/or complex karyotypes and a poor prognosis. Del(11)(q23) and inv11q23 aberrations have been described involving the human MLL gene and several translocation partner genes have been identified for each of them.27, 28, 29, 30, 31 The prognostic significance of unbalanced 11q23 aberrations was first reported in a smaller study.15 In this study, we confirmed that the presence of unbalanced 11q23 aberrations is an independent poor prognostic factor. The subset of cases with other balanced translocations involving 11q23 was small, and the prognosis of this group was similar to that of the patients with unfavorable risk in the non-11q23 reference group.

In this study of allo-SCT for AML patients with 11q23 abnormalities, we demonstrated that all-SCT in CR1 results in sustained remission and long-term survival for approximately 40% of patients. Allo-SCT significantly improved OS and RFS compared with no allo-SCT. A majority of AML patients with 11q23 abnormalities who received consolidation with chemotherapy relapsed and died within a year and 5-year OS and RFS is 13% and 10%, respectively. We also observe that there is a plateau in the OS and RFS curves, suggesting the allo-SCT could be a curative for these rare diseases. In multivariate analysis, we revealed a significant impact of allo-SCT in CR1 on OS (P=0.02) and RFS (P=0.01) in patients with 11q23 aberrations. In the last decade, the number of allo-SCT has increased significantly.32 In a recent study of 3638 patients with AML using meta-analysis, investigators revealed a significant survival benefit of allo-SCT from matched sibling donor for AML patients with unfavorable cytogenetic-risk groups.33 Two other studies showed that allo-SCT from human leukocyte antigen-matched unrelated donor and marched sibling donor yield similar clinical outcomes in patients with high-risk AML.34, 35 Our results are in line with these studies, but contradict a recent report of 49 patients with AML and 11q23 abnormalities who received allo-SCT at CR1, in which allo-SCT had only a borderline significant impact on OS.17

In summary, we found characteristic differences among patients with different 11q23 aberrations, which may suggest differences in etiology; we confirmed that in adult AML, t(9;11) is an intermediate-risk factor, whereas, t(6;11), t(11;19), unbalanced11q23 aberrations, and t(11;v)(q23;v) all had dismal outcomes; the presence of del5/5q−, del7/7q− and/or complex karyotypes confers a poorer prognosis in patients with 11q23 AML. Most importantly, we revealed that allo-SCT provides significant OS and RFS benefits for patients with 11q23 AML in CR1. Innovative treatment strategies should be investigated in adults with these cytogenetic abnormalities.

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Correspondence to F Ravandi.

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Chen, Y., Kantarjian, H., Pierce, S. et al. Prognostic significance of 11q23 aberrations in adult acute myeloid leukemia and the role of allogeneic stem cell transplantation. Leukemia 27, 836–842 (2013). https://doi.org/10.1038/leu.2012.319

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Keywords

  • AML
  • 11q23 cytogenetic abnormalities
  • complete remission
  • prognosis
  • allogeneic stem cell transplantation

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