Page 247 - Haematologica Vol. 110 - January 2025

LETTER TO THE EDITOR
Prognostic stratification in venetoclax-based acute myeloid leukemia treatments: the molecular prognostic risk signature tested in a real-world setting
Genotype-based stratification models used in acute myeloid leukemia (AML), such as the European LeukemiaNet (ELN) 2022 risk classification,1 have been developed based on patients treated in a conventional intensive chemotherapy setting and their performance in outcome prediction for patients treated with venetoclax-based combinations is un- satisfactory. Bataller et al.2 recently reported a single-center, retrospective study in patients with newly diagnosed (ND) AML treated with venetoclax and hypomethylating agents - either included in, or outside, a clinical trial - aiming to validate the molecular prognostic risk signature (mPRS) developed by Döhner et al. using mutational data from the phase Ib trial (NCT02203773) and the pivotal phase III VI- ALE-A trial.3 In the particular study patients were allocated, according to the mutational status of four genes, to a lower benefit (TP53mut), an intermediate benefit (FLT3-ITDmut or N/KRASmut) or a higher benefit (none of the above) group.3 The construction of this model stemmed from evidence that refractoriness and adaptive resistance to venetoclax are largely attributable to the presence and/or emergence of clones harboring the aforementioned mutations.4 In the study by Bataller et al., mPRS effectively stratified treat- ment-naïve AML patients into the three risk groups with statistically significant differences in median overall survival (OS) and event-free survival (EFS).2 A different stratification model for relapsed/refractory (R/R) AML patients treated with venetoclax-based combinations, proposed by Krüger et al.,5 stratifies patients into three risk groups based on the mutation profile of eight genes, resulting in favorable (STAG2mut, BCORmut or SF3B1mut), adverse (TP53mut, any FLT- 3mut, CBLmut, PTPN11mut or NF1mut) and intermediate (none of the above) risk categories.
We set out to assess the reproducibility of those observations in ND AML patients and also to extend the analysis to R/R patients in our institutional, real-world cohort of patients receiving venetoclax-based combinations from January 2015 to December 2023. The study was approved by the local institutional review board. Written informed consent was obtained in accordance with the Declaration of Helsinki. The performance of different stratification models was assessed and compared using Harrell’s concordance index (C-index). We identified 89 R/R and 61 ND patients; their clinical char- acteristics are summarized in Online Supplementary Table S1. The partner drug was azacitidine in 129 (86%), decitabine in eight (6%) and low-dose cytarabine in 12 (8%) patients. According to the mPRS stratification model in the ND co- hort, 35 (57%), 16 (26%) and 10 (17%) patients were allocat-
ed to the higher-, intermediate- and lower-benefit group, respectively. The overall response rate, which included patients experiencing complete remission (CR) and CR with incomplete hematological recovery (CRi), was 77%, 19% and 40% (P<0.001), respectively. When using the ELN 2022 risk stratification model, the overall response rate was 54%, 37% and 57% in the favorable, intermediate and adverse categories, and the difference was not statistically significant (P=0.593). Among patients in CR or CRi with available minimal residual disease data, 11/24 (46%) in the higher-, 0/2 (0%) in the intermediate- and 0/3 (0%) in the lower-benefit mPRS groups were negative for minimal re- sidual disease (P=0.157).
We then compared the predictive power of the mPRS model and the ELN 2022 classification system for OS and EFS. The median OS was 30, 11 and 4 months in the higher-, intermediate- and lower-benefit groups according to the mPRS model (P<0.001; C-index=0.69) (Figure 1A, D) and not reached, 27 and 11 months for the favorable, intermediate and adverse ELN 2022 categories, respectively (P=0.177; C-index=0.590). The median EFS was 13, 1 and 2 months for the mPRS groups (P<0.001; C-index=0.70) (Figure 2A, D) and 25, 1 and 6 months for the ELN 2022 categories (P=0.088; C-index=0.49). The mPRS versus ELN 2022 clas- sification system Z-score was 2.22 (P=0.030) (Figure 1D) for OS and 4.4 for EFS (P<0.001) (Figure 2D). In keeping with the observations by Döhner et al.3 and Bataller et al.,2 mPRS outperformed the ELN 2022 classification system in ND AML patients.
We then set our focus on R/R patients receiving veneto- clax-based lower intensity salvage treatments and repeat- ed the above analyses in this setting. Forty-eight (54%), 31 (35%) and ten (11%) of the patients were stratified into the higher-, intermediate- and lower-benefit groups, re- spectively. The overall response rate was 73%, 48% and 20% in the three groups (P=0.003) and 80%, 52% and 58% in the favorable, intermediate and adverse ELN 2022 risk categories (P=0.147). In the relapsed subcohort, the overall response rate was 68%, 50% and 33% in the three mPRS groups (P=0.361) and 71%, 40% and 63%, in the three ELN 2022 categories (P=0.032). In the refractory subcohort, the overall response rate was 69%, 44% and 14% in the mPRS groups (P=0.051) and 100% and 43% in the intermediate and adverse categories when using the ELN 2022 risk stratification (P=0.197). Among patients of the R/R cohort in composite CR with available minimal residual disease data, 18/35 (51%) in the higher-, 6/15 (40%) in the interme-
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