Page 21 - Haematologica March 2020

Editorials
This work confirms and expands upon the insights pub- lished in 2016 by Ng et al., showing the prognostic value of LSC gene expression signatures in an independent large cohort of AML patients. Here, Bill et al. apply the 17- gene LSC score to 934 de novo AML patients and report the association of the 17-gene LSC score with prognostic clinical parameters, specific AML mutations, and ELN risk classification.
Using unsorted pre-treatment bone marrow and/or peripheral blood specimens, the group conducted tran- scriptome analysis via RNA-sequencing. The 17-gene LSC score was calculated as the weighted sum of the nor- malized expression values of the 17 genes included in the signature panel defined by Ng et al. The scores derived were then divided into two groups using the median as the cutoff to define “17-genehigh” (more LSC-like) and “17- genelow” (less LSC-like) (Figure 1A, B).
Consistent with prior data, allocation into the 17-gene- high and 17-genelow groups correlated with known prognos- tic factors. 17-genelow patients were more often younger (age <60 years) and predominantly had favorable cytoge- netic profiles. Bill et al. also correlated the 17-gene score with known AML mutations.8 Favorable mutations in genes such as CEBPA, GATA2, and KIT were more fre- quent in patients with a 17-genelow score (Figure 1A) while unfavorable mutations in genes including ASXL1, RUNX1, and TP53 occurred more frequently in patients with a 17-genehigh score (Figure 1B). Patients with extremely high-risk EVI1 rearrangements inv(3)/t(3;3) were exclusively found in the 17-genehigh score group. With respect to mutation burden, more LSC-like AML harbored slightly more mutations, with a median of two among patients with a 17-genelow score and of three among those with a 17-genehigh score.
Next, Bill et al. assessed outcomes in the groups with 17-genelow and 17-genehigh scores. Both groups followed known associations for favorable and poor outcomes (complete remission rate, longer disease-free and overall survival) in, respectively, the younger (Figure 1C) and older cohorts of patients. In addition to validating the prognostic impact of the 17-gene LSC score in a large independent cohort and adding correlations with AML mutations, Bill et al. also compared the 17-gene LSC score to AML ELN risk stratification.8
When patients were classified according to the ELN stratification into Favorable-, Intermediate-, and Adverse- risk groups, there were significant differences in ELN risk distribution between the 17-genelow and 17-genehigh LSC score patients of different ages. In younger patients with a 17-genelow score, most (66%) were classified as having Favorable-risk, with 14% and 17% classified as having Intermediate- and Adverse-risk, respectively. However, younger patients with a 17-genehigh score were spread across the ELN classification: Adverse-risk (41%), Intermediate-risk (32%), and Favorable-risk (26%). In older patients with a 17-genelow score, only 36% were classified in the Favorable-risk group, while 24% had an Intermediate risk and 40% an Adverse risk. By compari- son, older patients with a 17-genehigh score clustered main- ly into the Adverse-risk group (63%), with fewer in the Intermediate- (18%), and Favorable-risk (18%) groups.
When assessing outcomes, the 17-gene LSC score failed to add significant prognostic information to ELN classifi- cation in older AML patients, in whom prognosis remains poor across prognostic groups with conventional chemotherapy.
Intriguingly, the data suggest that the 17-gene LSC score can provide additional prognostic value particularly for younger patients who may be currently misclassified as having a favorable risk. Younger patients with an ELN Favorable-risk classification with a high 17-gene LSC score (20% of ELN Favorable-risk patients) have a worse prognosis than would otherwise be expected from the ELN classification alone. This unexpectedly high-risk group of patients epitomizes the rationale for using refined prognostication schemes such as the 17-gene scor- ing tool, with the goal of tailoring first-line therapy more precisely and identifying populations of patients in need of prospective clinical trials.
The comprehensive RNA-sequencing approach described by Bill et al. does have some limitations. From a practical point of view, while pre-treatment cytogenetics as well as genomic profiling for mutations in specific genes have become standards of care for patients with AML, it is premature to recommend universal pre-treat- ment RNA-sequencing. Future studies in adult AML may validate the prognostic significance of pre-treatment pro- filing of a limited list of LSC-related genes using more tar- geted gene expression analysis, as was recently shown using Nanostring technology in pediatric AML.9
In a broader perspective, prognosis in any disease is shaped by the efficacy of available therapy. All patients evaluated in the current study by Bill et al. received cytarabine/anthracycline-based induction chemotherapy.8 Although AML prognosis has traditional- ly been evaluated in response to cytotoxic chemotherapy, the prognostic impact of ELN genetic risk classification and LSC gene expression signatures will need to be re- evaluated in the context of novel and more targeted ther- apeutics.
Recently, the BCL-2 inhibitor venetoclax in combina- tion with hypomethylating agents has become a new standard of care for adult patients with AML who are unfit, by virtue of age or comorbidities, to receive inten- sive chemotherapy.10 Although many patients still relapse, this combination shows activity in disease often refractory to standard induction chemotherapy, including secondary AML, therapy-related AML, and AML with high-risk cytogenetic and mutation profiles. One explana- tion for the relatively mutation-agnostic efficacy of vene- toclax + azacitidine is the combination’s suppression of oxidative phosphorylation and disruption of energy metabolism in LSC.11 The impact of LSC gene expression signatures on prognosis in patients treated with hypomethylating agents + venetoclax has yet to be deter- mined. Similarly, the impact of LSC gene expression sig- natures on prognosis in FLT3-mutated patients may also need to be re-evaluated, as more effective and specific FLT3 inhibitors enter clinical practice.12 In general, as more effective therapies are developed that target the fundamental biology of AML, prognostic factors and even post-remission therapies will need to be re-examined.
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