Page 250 - Haematologica Vol. 110 - January 2025

LETTER TO THE EDITOR
diate- and 2/2 (100%) in the lower-benefit mPRS groups were negative for minimal residual disease (P=0.268). The actualization rate of hematopoietic stem cell transplanta- tion differed in the three mPRS categories, with borderline statistical significance (90%, 67% and 63%, respectively; P=0.064). The median OS of R/R patients was 24, 9 and 6 months in the higher-, intermediate- and lower-benefit groups according to the mPRS (P=0.011; C-index=0.61) (Figure 1B, D); the median EFS was 15, 6 and 1 months, respectively (P<0.001; C-index=0.63) (Figure 2B, D). Sim- ilar figures for median OS using ELN 2022 categorization were 46, 11 and 11 months for favorable, intermediate and adverse risk categories (P=0.091; C-index=0.54) and 46, 9 and 6 months for median EFS, respectively (P=0.024; C-index=0.58). The mPRS versus ELN 2022 Z-score was 1.20 (P=0.220) for OS and 1.00 (P=0.310) for EFS. Compa- rable results were obtained by censoring at the time of hematopoietic stem cell transplantation.
We then evaluated the goodness of fit for outcome pre- diction of the model independently developed by Krüger et al. in our R/R cohort. The mutational frequencies of the genes that are included in Krüger’s algorithm in our series are shown in Online Supplementary Table S1. Ac- cording to the model, eight (9%), 51 (57%) and 30 (34%) patients were allocated to the favorable, intermediate and adverse groups, with respective overall response rates of 88%, 71% and 40% (P=0.006). The median OS was 37, 14 and 9 months for the favorable, intermediate and adverse categories according to the model (P=0.061; C-index 0.58) (Figure 1C, D); the median EFS was 15, 6 and 1 month, respectively (P<0.001; C-index 0.64) (Figure 2C, D). This risk stratification model exhibited slightly better perfor- mance than the ELN 2022 classification system, but not the mPRS model. In detail, the Z-score for OS was 0.59 for Krüger’s model versus the ELN 2022 model (P=0.550) and -0.81 versus the mPRS (P=0.410) (Figure 1D).
Finally, we evaluated the performance of the mPRS mod- el in the entire cohort of patients treated with veneto- clax-based regimens (Online Supplementary Figure S1). The median OS was 30, 9 and 6 months in the higher, intermediate and lower benefit groups according to mPRS (P<0.001; C-index=0.64) and 46, 14 and 11 months for fa- vorable, intermediate, and adverse ELN 2022 categories (P=0.016; C-index=0.56). The median EFS was 15, 3 and 1 months in the mPRS groups (P<0.001; C-index=0.66) and 46, 6 and 6 months in the ELN 2022 categories (P=0.013; C-index=0.55). The calculated Z-score for mPRS versus ELN 2022 was 2.28 (P=0.020) and 3.21 (P=0.001) for OS and EFS, respectively, in the entire cohort of venetoclax-treated patients, confirming the better performance of the mPRS model for predicting OS and EFS.
As venetoclax-based regimens are steadily taking the lead in the management of elderly/unfit patients, it soon be- came apparent that conventional stratification algorithms (e.g., the ELN 2022 risk stratification) have shortcomings
in effectively predicting clinical outcomes in such a ther- apeutic context. In fact, susceptibility and resistance to venetoclax and conventional intensive therapy are be- lieved to originate through different mechanisms. As a consequence, there is an unmet need for stratification model(s) that could provide a reliable tool for clinicians to inform their decisions and to facilitate communication with patients and families. The recently developed mPRS model holds the promise of being able to effectively inform prognosis in ND patients, but whether it is also accurate in R/R settings remains unclear. Furthermore, the purpose of venetoclax-based treatment in the two clinical settings (ND and R/R) often differs, as do the relative populations of patients. The former context generally involves elderly/ unfit patients with the primary aim of prolonging survival and the observed inadequacy at estimating initial response does not diminish the utility of mPRS. Conversely, in the R/R setting, venetoclax provides an effective and less toxic bridge to transplant, and the performance of prediction models needs to be measured accordingly. Furthermore, the observed variability in genotypic groups from different models (e.g., mPRS, Krüger) likely reflects the inadequacy of conventional bulk sequencing to capture the dynamics of subclones, their varying dominance, and sensitivity to venetoclax-based therapies.
Overall, our data from a real-world setting confirm the goodness of mPRS in terms of OS and EFS prediction in the ND setting, where it clearly identifies three distinct prognostic groups, and suggest its potential role also for R/R patients, at least for the prediction of the likelihood of response, which is of paramount importance in this subset. The mPRS model might, therefore, be suitably used in clinical practice for all patients receiving veneto- clax-based regimens and - together with already validated criteria to assess the fitness6 - could be used to guide the choice between different therapeutic strategies for AML patients. This notwithstanding, further efforts are warranted to develop and validate new models to predict response to venetoclax-based regimens in larger series, specifically for R/R patients who are treated with the in- tent of bridging to stem cell transplantation; otherwise, in the case of a predicted unfavorable outcome, these patients might be more suitably addressed to agents in clinical development.
Authors
Gaia Ciolli,1 Matteo Piccini,1 Francesco Mannelli,1,2 Giacomo Gianfaldoni,1 Barbara Scappini,1 Laura Fasano,1 Francesca Crupi,1 Elisa Quinti,1 Andrea Pasquini,1 Jessica Caroprese,1 Giada Rotunno,2 Fabiana Pancani,2 Leonardo Signori,2 Chiara Maccari,2 Fiorenza I. Vanderwert,2 Paola Guglielmelli1,2 and Alessandro M. Vannucchi1,2
1Hematology Department, Azienda Ospedaliero-Universitaria
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