Prognostic impact of the European LeukemiaNet standardized reporting system in older AML patients receiving stem cell transplantation after non-myeloablative conditioning

AML is a biologically heterogeneous disease with highly diverse patient outcomes. A reporting system has been developed by the European LeukemiaNet (ELN) to standardize AML classification.1 The prognostic impact of the four ELN genetic groups (favorable, intermediate-I, intermediate-II and adverse) has mainly been shown in two studies.2, 3 While patients within the favorable genetic group had the best outcome and patients within the adverse genetic group had the worst outcome, the prognosis for younger patients (<60 years) within the intermediate-II genetic group was superior compared to the intermediate-I genetic group. In older patients (60 years), the outcome was comparable between the two intermediate genetic groups.2, 3, 4 These studies focused predominantly on patients who did not receive a hematopoietic stem cell transplantation (HCT) in first CR.1, 2, 3

HCT is an important treatment option for AML patients for whom a suitable donor is available.5, 6 To date, only the study by Röllig et al.2 has analyzed the prognostic impact of the ELN genetic groups in a subgroup of 165 patients under 56 years receiving myeloablative conditioning (12 Gy TBI or busulfan (16 mg/kg) followed by cyclophosphamide (120 mg/kg)) HCT. For these patients, the authors observed no significant outcome differences between the favorable, intermediate-I and intermediate-II genetic groups, but a worse prognosis of the adverse genetic group. Another study by Oran et al.7 analyzed the prognostic impact of a modified ELN classification system—lacking information on NPM1 or CEBPA gene mutation status—in 423 AML patients (including 101 patients 60 years) who underwent HCT in first CR after various conditioning regimens. Here, the modified favorable risk and modified intermediate-II risk genetic groups had the best outcomes for both younger and older patients.

In the last decade, non-myeloablative (NMA) conditioning regimens for HCT have been used increasingly, since they allow patients to benefit from HCT, who are not eligible to receive myeloablative conditioning due to advanced age or comorbidities. NMA regimens are mainly immunosuppressive with low toxicity, and their therapeutic action is based almost exclusively on an immunological GvL effect. However, to our knowledge, studies analyzing the prognostic impact of the ELN standardized reporting system in AML patients receiving NMA-HCT have not been previously reported.

Here, we analyzed 159 older AML patients (60 years) with a median age of 66 years (range 60–76 years) diagnosed between May 2000 and December 2012 at our institution. All patients received NMA-HCT (2 Gy TBI with or without fludarabine) after cytarabine-based induction cycles (for further details, see Supplementary Information). Written informed consent for participation in these studies was obtained in accordance with the Declaration of Helsinki. Basic clinical and biological characteristics of the analyzed patients are shown in Table 1 and Supplementary Table S1. The median follow-up for patients alive was 2.9 years. Bone marrow or peripheral blood from the day of diagnosis was used for analyses. Cytogenetics were determined using standard techniques for banding and FISH. We analyzed the presence of FLT3-ITD (internal tandem duplication),8 and the mutation status of NPM1,9 as previously described, and that of the CEBPA gene (see Supplementary Information and Supplementary Table S2) and classified the patients into four genetic groups according to ELN recommendations.1

Table 1 Characteristics of 159 older AML patients treated with NMA-HCT

Patient distribution according to the ELN genetic groups was: 17.6% favorable (n=28), 22.0% intermediate-I (n=35), 24.5% intermediate-II (n=39) and 35.8% adverse (n=57; Figure 1a). The ELN genetic group distribution of our cohort was comparable to previously published data, for example, by Mrózek et al.3 for older patients (P=0.59; 20%, 19%, 30% and 31%, respectively, according to ELN genetic groups).

Figure 1
figure1

Distribution of the ELN genetic groups (a) and leukemia-free survival (b), cumulative incidence of relapse (c), and overall survival (d) according to the ELN genetic groups of 159 older AML patients (60 years) after NMA-HCT.

We observed a leukemia-free survival of 42.5% (95% confidence interval 34.4–52.6%), a cumulative incidence of relapse of 37.9% (95% confidence interval 29.1–46.6%) after 3 years, a median overall survival after NMA-HCT of 2.0 years and a 3-year overall survival of 46.5% (95% confidence interval 38.6–84.8%). These data are comparable with data from previous publications for TBI-based NMA conditioning regimens (see Supplementary Information).10, 11

We found a significantly different leukemia-free survival (P=0.031, Figure 1b), a trend for a different cumulative incidence of relapse (P=0.062, Figure 1c) and a significantly different overall survival (P=0.033, Figure 1d) by grouping AML patients according to the ELN classification system. Non-relapse mortality was not significantly different between the ELN genetic groups (P=0.56, Supplementary Figure S4). However, pairwise comparisons of overall survival among the ELN genetic groups yielded a significant difference only between the favorable and intermediate-II (P=0.01), and between the favorable and adverse (P=0.005) genetic groups. Notably, with the caveat of limited group sizes, no significant outcome differences were observed between the intermediate-I, intermediate-II and adverse genetic groups, suggesting that the ELN genetic grouping may have a reduced prognostic impact in NMA-HCT-treated AML patients compared to patients receiving a chemotherapy-based consolidation in first CR.2, 3 Interestingly, Röllig et al.2 detected no clear outcome differences between favorable, intermediate-I and intermediate-II genetic groups in their MAC-HCT patient set, while adverse genetic group patients had a significantly worse prognosis. Thus, HCT may reduce the prognostic impact of the ELN reporting system at AML diagnosis.

Since it has been recommended1 to report outcomes for specific subsets within each ELN genetic group, we analyzed those with a sufficient number of patients available (Supplementary Figures S1–S3).

The favorable genetic group consists of patients with a core-binding factor AML (t(8;21)(q22;q22) and inv(16)(p13.1q22), or t(16;16)(p13.1;q22)), a mutation in the gene CEBPA or a NPM1 mutation without FLT3-ITD (both with normal karyotype). In our cohort, no significant difference between the subsets was observed (Supplementary Figure S1). A significantly improved outcome within the favorable genetic group has been described for older patients with core-binding factor AML receiving a chemotherapy-based consolidation in first CR.2, 3 However, our set included only three patients with core-binding factor AML, preventing further analysis.

Similarly, no difference in outcome for the subsets was observed in the intermediate-I genetic group (Supplementary Figure S2). Interestingly, Mrózek et al.3 and several other publications described a significantly worse outcome for older patients with FLT3-ITD who were consolidated with chemotherapy in first CR.12, 13 In our cohort of NMA-HCT treated patients, we found no significant impact of the presence of a FLT3-ITD on outcome within the intermediate-I genetic group, similar to a previous report analyzing the FLT3-ITD status in patients receiving HCT.7, 13 However, the number of patients in the intermediate-I group was low (n=35), showing the need of further investigations of the impact of the presence of a FLT3-ITD in older NMA-HCT treated AML patients.

The adverse genetic group consists of several subsets, of which the complex karyotype is the largest. We found that the subsets within the adverse genetic group differed with regard to leukemia-free survival (P=0.03) and overall survival (P=0.04; Supplementary Figure S3). Patients with complex karyotype had the poorest prognosis within the adverse genetic group (data are shown in Supplementary Information). This is in concordance with data on older patients treated with chemotherapy in first CR, in which patients with complex karyotype also had the worst outcome within the adverse genetic group.2, 3, 4, 7 The second and third largest subsets in our cohort were patients with a monosomy 7, known to be the most frequent monosomy in AML, and loss of chromosome 5, respectively. Both aberrations have been described as negative prognosticators14, 15 in AML patients who for the most part did not receive HCT as consolidation in first CR. However, patients of both subsets treated with NMA-HCT showed an improved outcome compared to the complex karyotype within the adverse genetic group, which is similar to previous publications for older, transplanted patients.7

In conclusion, we observed outcome differences between the ELN genetic groups for AML patients receiving NMA-HCT, with patients within the favorable genetic group having the best prognosis. However, pairwise comparison revealed that only patients within the favorable genetic group performed better than patients in the intermediate-II or adverse genetic groups. The data presented here suggest that the ELN genetic grouping may have a reduced prognostic impact for patients receiving NMA-HCT as compared to those receiving a chemotherapy-based consolidation in first CR.

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Acknowledgements

MB was supported by an intramural scholarship of the medical faculty of the University of Leipzig (#990101-089). We thank Janet Bogardt, Annette Jilo and Dagmar Cron for assistance with collecting the AML patient samples. We thank Sabine Leiblein, Christel Müller, Evelin Hennig, Daniela Bretschneider, Christine Günther, Martina Pleß, Ulrike Bergmann and Rainer Krahl who helped to determine the cytogenetics and immunological analysis. Ines Kovacs, Scarlett Schwabe and Christine Günther assisted with material processing. Presented partly in abstract form at the 41st annual meeting of the European Society for Blood and Marrow Transplantation, Istanbul, Turkey, 24 March 2015; and at the ESH-EBMT Training Course on Hematopoietic Stem Cell Transplantation, Budapest, Hungary, 11–14 May 2016.

Author contributions

MB and SS designed and performed the experiments. KS performed the experiments. MB, MJ and SS analyzed and interpreted the data. TL, MC, GB, VV, WP and G-NF provided administrative and technical support. MB and SS wrote, and all authors reviewed and approved the manuscript. DN and SS supervised the study.

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Bill, M., Jentzsch, M., Grimm, J. et al. Prognostic impact of the European LeukemiaNet standardized reporting system in older AML patients receiving stem cell transplantation after non-myeloablative conditioning. Bone Marrow Transplant 52, 932–935 (2017). https://doi.org/10.1038/bmt.2017.42

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