Acute Leukemia

Impact of IKZF1 deletions on long-term outcomes of allo-SCT following imatinib-based chemotherapy in adult Philadelphia chromosome-positive ALL

Abstract

We investigated the prognostic relevance of IKZF1 deletions in 118 adult Ph-positive ALL patients who had minimal residual disease (MRD) data under a uniform treatment of allo-SCT following first-line imatinib-based chemotherapy. IKZF1 deletions were identified in 93 patients (78.8%). IKZF1-deleted patients had a lower proportion of early-stable molecular responders compared with wild-type patients (28.0 vs 56.0%, P=0.028). After a median follow-up of 72 months, IKZF1-deleted patients had a trend for higher cumulative incidence of relapse (CIR) (38.0 vs 13.3%, P=0.052), particularly in a subgroup of early-stable molecular responders (n=40; 21.4 vs 0%, P=0.088), but comparable disease-free survival to wild-type patients. Patients with biallelic-null deletions showed higher CIR (74.6 vs 13.3%, P=0.003) and lower disease-free survival (20.0 vs 67.5%, P=0.022) than wild-type patients. In multivariate analysis, MRD kinetics were closely related to outcomes, while neither IKZF1 deletions nor their functional subtypes retained an independent statistical power. Within the limitation of sample size, however, considering both the negative impact of IKZF1 deletions on MRD kinetics and a trend for relationship between IKZF1 deletions and relapse in early-stable molecular responders, IKZF1 deletions may have a potentially additive effect on unfavorable prognosis in a specific MRD-based subgroup of adult Ph-positive ALL transplants.

Introduction

Despite the introduction of tyrosine kinase inhibitors (TKIs) markedly improving overall prognosis of adult Philadelphia chromosome-positive ALL (Ph-positive ALL), a substantial proportion of transplanted and nearly all non-transplanted patients died as a result of disease progression.1, 2, 3, 4, 5, 6, 7, 8, 9, 10 Consequently, patients at the highest risk of relapse are likely to benefit from the identification of new criteria that enable prediction of patient outcome. Following the use of TKIs, quantitative minimal residual disease (MRD) monitoring during treatment has become a major tool to assess molecular response and to evaluate risk of impending relapse.11, 12, 13, 14, 15 Of importance, individual MRD-based differences in response to TKI-based chemotherapy and prognosis indicate a substantial biological and clinical heterogeneity in patients with Ph-positive ALL. This emphasizes the need for new prognostic markers on the basis of MRD kinetics and co-operating genetic lesions, other than BCR-ABL1, for identification of patients with a high risk of relapse.

Several genetic abnormalities in key pathways have been identified by genome-wide approaches in B-cell precursor ALL (BCP-ALL), including lymphoid differentiation, cell-cycle regulation, tumor suppression and drug responsiveness.16, 17, 18 Among these abnormalities, deletions of the IKZF1 gene, which encodes the lymphoid transcription factor Ikaros, have received the most attention due to their frequency in BCP-ALL, particularly Ph-positive ALL (approximately 70%).19, 20, 21, 22, 23, 24, 25 Using different sample composition and treatment protocols in a chemotherapy setting, several studies have shown that IKZF1 deletions were significantly associated with an increased relapse rate and poor outcome in childhood BCP-ALL.26, 27, 28, 29, 30, 31 This predictive value is frequently independent of other known risk factors, suggesting that testing for IKZF1 status at time of diagnosis is warranted. However, limited information is available on their associations in adult ALL. Moreover, the prognostic value of IKZF1 deletions in an allo-SCT setting following TKI-based chemotherapy has not been reported in adult Ph-positive ALL.

This study aimed to investigate the prognostic relevance of IKZF1 deletions in a homogenous cohort of adult Ph-positive ALL patients who received allo-SCT following two courses of first-line imatinib-based chemotherapy. Strengths of this analysis include prospectively determined quantitative MRD data in all subjects, sufficient follow-up duration and restriction to a single disease subtype with a uniform pre- and post-transplant treatment strategy.

Patients and methods

Patients

Between September 2000 and December 2011, 118 patients (median age, 36 years (range, 16–64 years)) were enrolled in this study. All had newly diagnosed Ph-positive ALL and received a uniform treatment protocol of allo-SCT following two courses of first-line imatinib-based chemotherapy,2, 14, 15 and had data on both IKZF1 deletions and prospectively determined quantitative MRD kinetics. A total of 48 patients were excluded because of old age (65 years; n=12), patient’s refusal (n=4), deaths during the first course of imatinib-based chemotherapy (n=8), transplants receiving only one course of imatinib-based chemotherapy (n=4), deaths during the second course of imatinib-based chemotherapy (n=5), lack of donors (n=10) and poor-quality DNA or RNA (n=5) (Figure 1). All patients in this study provided written informed consent for clinical and molecular analyses, and the study protocol was approved by the institutional review board of The Catholic University of Korea. This study was conducted in accordance with the Declaration of Helsinki. Data were analyzed in June 2014.

Figure 1
figure1

Flow chart of the patients included in this study.

Conditioning regimen and GVHD prophylaxis

As previously described,2, 14, 15, 32, 33, 34, 35 all patients received SCT from a fully matched sibling or suitably matched (2-allele mismatched) unrelated donor after completion of two courses of imatinib-based chemotherapy. A myeloablative conditioning regimen consisted of TBI (13.2 Gy) and CY (120 mg/kg). Patients aged 50 years or those with co-morbid conditions were given an identical reduced-intensity conditioning regimen consisting of fludarabine (150 mg/m2) and melphalan (140 mg/m2). GVHD prophylaxis was attempted by administering calcineurin inhibitor (CYA for sibling transplants and tacrolimus for unrelated transplants) and methotrexate. No prophylactic imatinib administration was planned after SCT.

Detection of IKZF1 deletions

IKZF1 deletions were investigated by multiplex ligation-dependent probe amplification (MLPA) using a SALSA MLPA P202-B1 kit (MRC-Holland, Amsterdam, The Netherlands) according to the manufacturer’s instructions. A total of 200 ng of genomic DNA was used in each MLPA reaction. Probe mix and hybridization buffer (MRC-Holland) were added in equal amounts to the genomic DNA followed by heat denaturation and overnight hybridization of probes at 60 °C. Subsequently, ligation was performed, and ligation products were amplified by PCR using a 6-FAM fluorophore-labeled primer set (MRC-Holland). Amplification products were quantified and identified by capillary electrophoresis on an ABI 3130 DNA analyzer (Applied Biosystems, Foster City, CA, USA). The resulting peak intensities were normalized to manufacturer’s control probes and to normal DNA as a reference. An intensity ratio of between 0.7 and 1.3 was considered to represent a normal copy number (wild type), a ratio between 0.3 and 0.7 a monoallelic deletion and a ratio of <0.3 a biallelic deletion. We classified patients with IKZF1 deletions into three functional subtypes based on quantities and localizations of Ikaros proteins: (1) dominant-negative deletions (deletions involving at least exons 4–7 (Δ4–7), which lead to the expression of dominant-negative Ikaros isoform due to the loss of DNA binding domains; Δ4–7 deletions and/or monoallelic-null deletions), (2) haploinsufficient deletions (monoallelic-null deletions of the whole gene (complete deletions) or partial deletions affecting exon 2 or exon 8, which lead to haploinsufficiency with reduced protein levels of Ikaros) and (3) biallelic-null deletions (deletions of two null alleles, which lead to the absence of Ikaros protein).19, 20, 21, 22, 24, 25

MRD monitoring

MRD monitoring for BCR-ABL1 transcripts was centrally evaluated by RQ-PCR (4.5 log sensitivity) through handling of BM samples from all patients (Research Institute of Molecular Genetics, The Catholic University of Korea, Seoul, Korea). Details of methods for MRD assessment were previously described.15 The quantity of BCR-ABL1 transcripts was normalized for ABL1 expression, and the ratio of BCR-ABL1 to ABL1 was expressed as a percentage according to international scale for p210BCR-ABL1 and log reduction from the standardized pooled baseline for p190BCR-ABL1. Major molecular response (MMR) was defined as a ratio of BCR-ABL1 to ABL1 of 0.1% on the international scale for p210BCR-ABL1 or a reduction in BCR-ABL1 transcript level by at least 3-log from the standardized pooled baseline value for p190BCR-ABL1. Complete molecular response (MR4.5) was defined as undetectable levels of BCR-ABL1 transcript. On the basis of MRD quality and its kinetics by the end of two courses of imatinib-based chemotherapy, we stratified patients into three subgroups: (1) early-stable molecular responders (patients showing early and persistent MMR or MR4.5), (2) late molecular responders (patients showing a conversion of MRD levels from no MMR to MMR or MR4.5) and (3) poor molecular responders (patients showing persistent or increased MRD levels of >0.1% (for p210BCR-ABL1) or <3-log reduction (for p190BCR-ABL1)).

Statistical analysis

Curves for disease-free survival (DFS) and OS were plotted using the Kaplan–Meier method and compared using the log-rank test. Relapse and non-relapse mortality were calculated using cumulative incidence estimates and compared using the Gray test. Prognostic significances of covariates affecting DFS and OS were determined using the Cox proportional hazards model. Factors were considered to be significant if they had an associated P-value of <0.05, using two-tailed significance testing. Prognostic significances of covariates affecting relapse and non-relapse mortality were determined using the proportional hazards model for subdistribution of a competing risk.

Results

Patient characteristics

IKZF1 deletions were identified in 93 of 118 patients (78.8%) (Table 1). Among 93 patients carrying IKZF1 deletions, 45 patients (48.4%) had dominant-negative deletions, 38 (40.8%) had haploinsufficient deletions (13 complete deletions, 12 Δ2–7 deletions, 9 Δ2–8 deletions, 2 Δ4–8 deletions and 2 Δ2–3 deletions) and 10 (10.8%) had biallelic-null deletions. The frequency and patterns of IKZF1 deletions did not differ between patients aged <50 years and those aged 50 years. The main clinical and biological features for patients are summarized in Table 2. All characteristics at the time of diagnosis and transplantation were comparable between the two groups. The median follow-up duration for surviving transplants was 72 months (range, 20–152 months).

Table 1 Frequency and patterns of IKZF1 deletions at diagnosis
Table 2 Patient characteristics

Association of IKZF1 deletions and molecular response to imatinib-based chemotherapy

IKZF1 deletions were significantly associated with MRD level and its kinetics by the end of two courses of pre-transplant imatinib-based chemotherapy (Table 3). In detail, at the end of the first course of imatinib-based chemotherapy, 28 (30.1%) of 93 IKZF1-deleted patients had MMR (n=16) or MR4.5 (n=12), while 14 (56.0%) of 25 wild-type patients had at least MMR (9 MMR and 5 MR4.5) (P=0.016). However, this association was not dominant at the end of the second course of imatinib-based chemotherapy (P=0.426). Among 42 patients with MMR or MR4.5 after the first course of imatinib-based chemotherapy (28 IKZF1-deleted and 14 wild-type), 40 patients (26 IKZF1-deleted and 14 wild-type) remained in a stable molecular response at the end of the second course of imatinib-based chemotherapy; two IKZF1-deleted patients relapsed with an increase in MRD level. In addition, 42 patients (37 IKZF1-deleted and 5 wild-type) without MMR post-first course of imatinib-based chemotherapy achieved new MMR or MR4.5 at this time point. Overall, on the basis of speed of good molecular response and its persistence, IKZF1 status was significantly associated with MRD kinetics by the end of the second course of imatinib-based chemotherapy. IKZF1-deleted patients had a lower proportion of early-stable molecular responders compared with wild-type patients (28.0 vs 56.0%, P=0.028).

Table 3 Association of IKZF1 deletions and molecular response to imatinib-based chemotherapy

Outcomes according to IKZF1 deletions and their functional subtypes: univariate analysis

At the time of analysis, 71 patients (54 IKZF1-deleted and 17 wild-type) were alive, and 65 of them (48 IKZF1-deleted and 17 wild-type) remained in sustained CR. Forty-seven patients had died of causes other than leukemic relapse (n=17; 12 IKZF1-deleted and 5 wild-type) or disease progression (n=30; 27 IKZF1-deleted and 3 wild-type). Only 3 of 25 wild-type patients relapsed (at 3, 4 and 9 months after SCT, respectively), while 33 of 93 IKZF1-deleted patients relapsed at a median of 9 months after SCT (range, 2–87 months). IKZF1-deleted patients showed a trend for higher cumulative incidence of relapse (CIR) compared with wild-type patients (38.0±5.4% vs 13.3±7.1% at 6 years, P=0.052). However, there was no significant difference in non-relapse mortality (14.5±3.9% vs 21.8±8.7%), DFS (52.1±5.2% vs 67.5±9.5%) and OS (57.7±5.3% vs 67.5±9.5%) at 6 years between the two groups (Table 4; Figure 2).

Table 4 Overall transplantation outcomes
Figure 2
figure2

Influence of IKZF1 deletions on transplantation outcomes in all patients (IKZF1-deleted vs wild-type). (a) CIR. (b) Cumulative incidence of non-relapse mortality. (c) DFS rate. (d) OS rate.

We further analyzed the impact of IKZF1 deletions on CIR and DFS according to MRD kinetics (Figure 3). Within the cohort of early-stable molecular responders (n=40; 26 IKZF1-deleted and 14 wild-type), IKZF1-deleted patients showed a trend for higher CIR compared with wild-type patients (21.4±8.7% vs 0% at 6 years, P=0.088). Interestingly, none of 14 wild-type patients relapsed in contrast to 5 of 26 IKZF1-deleted patients. In terms of DFS, however, no significant difference was observed between the two groups (68.0±9.4% vs 85.1±9.7%). In a subgroup of late molecular responders (n=42; 37 IKZF1-deleted and 5 wild-type) and poor molecular responders (n=36; 30 IKZF1-deleted and 6 wild-type), respectively, no significant differences were found in CIR and DFS between IKZF1-deleted and wild-type patients.

Figure 3
figure3

Influence of IKZF1 deletions on CIR and DFS according to MRD kinetics. CIR and DFS rate in (a, d) early-stable molecular responders (n=40; 26 IKZF1-deleted and 14 wild-type), (b, e) late molecular responders (n=42; 37 IKZF1-deleted and 5 wild-type) and (c, f) poor molecular responders (n=36; 30 IKZF1-deleted and 6 wild-type), respectively.

In a pairwise comparison of transplantation outcomes according to functional subtypes of IKZF1 deletions, patients with biallelic-null deletions showed higher CIR (74.6±15.5% vs 13.3±7.1% at 6 years, P=0.003) and lower DFS (20.0±12.6% vs 67.5±9.5% at 6 years, P=0.022) compared with wild-type patients. In contrast, patients harboring dominant-negative or haploinsufficient subtypes showed no significant difference in CIR (34.5±7.2% for dominant-negative, 34.0±8.9% for haploinsufficient) and DFS (60.0±7.3% for dominant-negative, 50.5±8.6% for haploinsufficient) at 6 years compared with wild-type patients (Figure 4).

Figure 4
figure4

Transplantation outcomes according to functional subtypes of IKZF1 deletions (dominant-negative vs haploinsufficient vs biallelic-null vs wild-type). (a) CIR. (b) DFS rate.

Multivariate analysis of independent variables affecting transplantation outcomes

In univariate analysis, potential factors predicting relapse risk were IKZF1 status (wild-type vs deletions; P=0.052), functional subtypes of IKZF1 deletions (wild-type vs dominant-negative vs haploinsufficient vs biallelic-null; P=0.003), MRD kinetics (early-stable molecular responders vs late molecular responders vs poor molecular responders; P<0.001), acute GVHD (positive vs negative; P=0.088) and chronic GVHD (positive vs negative; P<0.001). No significant effect of age, presenting leukocyte count, cytogenetics or transcript subtype on CIR was shown. Multivariate analysis showed that the most powerful factor predicting relapse risk was MRD kinetics (Table 5). CIR at 6 years was significantly higher for poor molecular responders (hazard ratio (HR), 7.41; 95% confidence interval [CI], 2.76–19.88; P<0.001) than early-stable molecular responders, while no difference was found between early-stable molecular responders and late molecular responders. An absence of chronic GVHD was also found to be associated with higher CIR (HR, 4.65; 95% CI, 2.15–10.04; P<0.001). Multivariate analysis of several potential factors (functional subtypes of IKZF1 deletions, MRD kinetics, and chronic GVHD) showed that factors independently associated with lower DFS were poor molecular responders (HR, 4.18; 95% CI, 1.96–8.90; P<0.001) and an absence of chronic GVHD (HR, 2.88; 95% CI, 1.56–5.32; P=0.001). Neither IKZF1 deletions nor their functional subtypes showed statistical power in multivariate analysis (Table 5).

Table 5 Multivariate analysis of independent variables affecting transplantation outcomesa

Discussion

This study was the first to examine the prognostic relevance of IKZF1 deletions by analyzing long-term transplantation outcomes of adult Ph-positive ALL patients who had quantitative MRD data under a uniform first-line imatinib-based chemotherapy. IKZF1 deletions were identified in 93 of 118 patients (78.8%), which is within range of other cohorts.19, 20, 21, 22, 23, 24, 25, 36, 37 In this cohort of patients, on the basis of speed of good molecular response and its persistence in response to imatinib-based chemotherapy, IKZF1 status was significantly associated with MRD kinetics. IKZF1-deleted patients had a lower proportion of early-stable molecular responders compared with wild-type patients. When correlating IKZF1 deletions and transplantation outcomes, we found that IKZF1-deleted patients had a trend for higher CIR than wild-type patients, particularly in a subgroup of patients with an early-stable molecular response. In multivariate analysis including both IKZF1 deletions and MRD status as a covariate, poor molecular responders had higher CIR and lower DFS, while IKZF1 deletions did not have an independent statistical power. However, our results should be interpreted with caution because of the limitation of sample size (especially in the limited sample size of wild-type patients; n=25) and potential selection biases of our cohort. These limitations did not allow us draw firm conclusions on the independent prognostic role of IKZF1 deletions beyond MRD kinetics. Considering both negative impact of IKZF1 deletions on MRD kinetics during the pre-transplant imatinib-based chemotherapy courses and an interesting trend for relationship between IKZF1 deletions and post-transplant relapse risk, particularly in early-stable molecular responders, IKZF1 deletions may rather have a potentially additive effect on unfavorable prognosis in a specific MRD-based subgroup of adult Ph-positive ALL transplants.

In the only one report to date about the impact of IKZF1 deletions on treatment outcome in adult Ph-positive ALL, the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) group found that IKZF1-deleted patients (n=52; 63%) showed higher CIR (69.1 vs 40.4% at 2 years, P=0.0103) and lower DFS (30.9 vs 53.9% at 2 years, P=0.0229) compared with wild-type patients (n=31) in univariate analysis.37 However, in their multivariate analysis, IKZF1 deletions retained their prognostic impact on DFS (P=0.0425) but not on CIR. A major reason for the difference between results from the GIMEMA group and ours could be explained by a lack of analysis of the relationship between MRD and IKZF1 deletions in the GIMEMA study. Most studies in the TKI era include quantitative MRD monitoring for BCR-ABL1 transcript, with results demonstrating its importance as an independent prognostic factor.11, 12, 13, 14, 15 Our results showed that IKZF1 deletions did not have an independent adverse effect on the prognosis of adult Ph-positive ALL transplants, when including both IKZF1 deletions and prospectively determined MRD status as a covariate in our analysis. In contrast, Mullighan et al.26 identified a strong association between IKZF1 deletions and MRD levels in two independent cohorts of childhood BCP-ALL. Moreover, the relationship between IKZF1 status and treatment outcomes was independent of age, presenting leukocyte count, cytogenetic subtype and MRD level. Recently, Waanders et al.38 suggested that a combination of IKZF1 deletions and MRD status is a better predictor of relapse than each marker alone, and risk stratification may be improved by integration of IKZF1 and MRD status in uniformly treated childhood BCP-ALL. Therefore, further larger studies are warranted to verify whether IKZF1 deletions are independently useful for risk stratification, regardless of MRD status in adult Ph-positive ALL. Additional factors for consideration are differences in treatment protocols (heterogenous protocols including chemotherapy alone, TKI alone or TKI-based chemotherapy vs homogenous protocol of imatinib-based chemotherapy followed by allo-SCT), population composition (mainly non-transplants vs transplants), detection method of IKZF1 deletions (SNP microarray vs MLPA), follow-up duration (14.8 months vs 72 months) and center effects (multicenter vs single center).

Recently, van der Veer et al.36 investigated the prognostic role of IKZF1 deletions in 191 childhood Ph-positive ALL patients before TKI (pre-TKI) and after the introduction of imatinib. In the pre-TKI cohort, IKZF1-deleted patients had higher CIR (57.2 vs 20.9% at 4 years, P=0.026) and lower DFS (30.0 vs 57.5% at 4 years, P=0.013) compared with wild-type patients. After the introduction of imatinib, however, the prognostic power of IKZF1 deletions depended on early clinical response. They showed that IKZF1 deletions correlated with an unfavorable outcome in imatinib-treated patients with an early-good clinical response (DFS at 4 years; 55.5% for IKZF1-deleted vs 75.0% for wild-type, P=0.05), while no significant association between IKZF1 deletions and poor outcome was found in a subgroup of patients with a poor clinical response. They provided a rationale to potentially avoid SCT, thereby reducing TRM, in IKZF1 wild-type patients with an early-good clinical response to imatinib. Similarly, when analyzing the impact of IKZF1 deletions on CIR and DFS according to MRD kinetics, we found an interesting trend for association between IKZF1 deletions and CIR in a subgroup of patients with an early-stable molecular response; no relapses occurred in wild-type patients. However, in a subgroup of late molecular responders and poor molecular responders, respectively, no significant differences were found in CIR and DFS between IKZF1-deleted and wild-type patients. Taken together, these findings suggest that the prognostic impact of IKZF1 deletions could be different in a specific MRD-based subgroup of patients.

IKZF1 deletions are not homogenous in terms of functional consequence. Our results suggest a possibility of outcome heterogeneity according to functional subtypes of IKZF1 deletions. Patients with biallelic-null deletions showed higher CIR and lower DFS, while those harboring dominant-negative or haploinsufficient subtypes showed no difference compared with wild-type patients. However, the difference was not statistically significant in multivariate analysis. In a recent study on childhood Ph-positive ALL,36 IKZF1 haploinsufficient patients showed an unfavorable outcome compared with wild-type patients. Moorman et al.39 also suggested that a poor outcome associated with IKZF1 deletions was not linked to the expression of dominant-negative subtype but to other subtypes in adult Ph-negative ALL. However, due to adverse effects in the less-frequent subgroup of patients, further studies are required to verify whether a distinct subtype of IKZF1 deletions has a different biology and its association with different clinical outcomes.

In summary, our data support a negative impact of IKZF1 deletions on molecular response to imatinib-based chemotherapy, indicating that the detection of IKZF1 deletions as a routine screening assay is likely to be useful in identifying a subgroup of patients with an early-stable molecular response. Although the limited sample size of our cohort prevented a solid conclusion on the prognostic impact of IKZF1 deletions and their functional subtypes on transplantation outcomes irrespective of MRD kinetics, a trend for association between IKZF1 deletions and CIR in a subgroup of early-stable molecular responders suggests that IKZF1 deletions may have a potentially additive effect on unfavorable prognosis in a specific MRD-based subgroup of adult Ph-positive ALL transplants. Further studies on larger cohorts of adult Ph-positive ALL are needed to elucidate the mutual effect of IKZF1 deletions and MRD status on long-term outcomes and to understand how IKZF1 deletions functionally interact with other co-existing genetic alternations. If this is verified then it would be interesting to study whether an alternative, IKZF1- and MRD-based therapeutic approach modifies overall transplantation outcomes for a specific subgroup of patients with adult Ph-positive ALL (for example, reduced-intensity transplantation for wild-type patients with an early-stable molecular response or early and prolonged use of more potent TKIs for IKZF1-deleted patients or poor molecular responders).

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Acknowledgements

This study was supported by a grant of the Korea Health technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A120175). Statistical analyses performed in this article were advised by the Catholic Medical Center Clinical Research Coordinating Center.

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Correspondence to S Lee.

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Kim, M., Park, J., Kim, D. et al. Impact of IKZF1 deletions on long-term outcomes of allo-SCT following imatinib-based chemotherapy in adult Philadelphia chromosome-positive ALL. Bone Marrow Transplant 50, 354–362 (2015) doi:10.1038/bmt.2014.281

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