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C. Caprioli et al.
mosomes 5 and 7 or complex karyotypes in previous studies.9,21 To the best of our knowledge, this is the first report formally comparing outcomes of patients with de novo AML carrying this mutational profile and sAML (defined by clinical and/or cytogenetic criteria) on a large multi-center prospective cohort. Patients included in the study showed a broad age range representative of the real life population, were homogeneously treated with inten- sive chemotherapy within a prospective clinical trial and had a long duration of follow-up, which allowed to effec- tively study the prognostic relevance of CS mutations. As an additional feature, we evaluated the impact of alloHSCT in each AML category.
In keeping with previous observations, the identifica- tion of a CS-mutational signature revealed markedly high-risk features in about 18% of otherwise defined de novo AML patients in our study,9,14,15 which represents a significant proportion of the whole analyzed cohort, quite consistent with other studies.14,22 Apart from muta- tions in KMT2A-PTD, RUNX1 and ASXL1, we showed that also mutations in U2AF1 carry an independent prog- nostic impact; of note, the adverse significance of CS mutations was maintained independently from RUNX1 and U2AF1, suggesting that the full signature might be further evaluated for the assignment to the high-risk group of the European LeukemiaNet (ELN) stratification model.7 Based on these data, it remains unclear whether RUNX1-mutated AML, albeit constituting the most repre- sented subgroup within this category, accounts for a sep- arate clinical and prognostic entity.
In addition, we have highlighted that CS-AML more closely resembles sAML than de novo AML, in terms of clinical characteristics and outcomes. When considering OS, however, CS-AML stands as an intermediate catego- ry showing slightly but significantly better survival than sAML; this appears to be the consequence of the high rates of early chemoresistance and related mortality in sAML patients. A possible explanation for this difference resides in the negative impact of complex cytogenetics in the sAML group. Alternatively, this category might con- tain a mixture of both sAML and true de novo cases. As such, the role of the CS signature to accurately diagnose sAML remains not fully elucidated. However, from a practical point of view, the definition of CS-AML as a prognostically homogeneous group might be more clini- cally significant than a merely ontogenetic classification, as recently shown also for secondary-type mutations.23 In fact, since we observed a survival advantage in both sAML and CS-AML patients to whom alloHSCT was offered in first CR, patients with a CS molecular profile might be considered for intensive treatment strategies comprising rapid allocation to alloHSCT. The main chal- lenge in this setting, however, would be the improvement of remission rates and depth by means of innovative ther- apeutics, possibly overcoming the inherent long-term chemoresistance of CS-AML and extending the access to a potentially curative alloHSCT. In this regard, consider- ing the closer similitude between sAML and CS-AML might facilitate the optimization of available treatment
strategies as well as the design of dedicated clinical trials. Among potentially useful agents, CPX-351 has been recently approved by the Food and Drug Administration and European Medicines Agency specifically for the treat- ment of AML with MDS-related changes or therapy- related AML and might provide a similar benefit in fit CS- AML patients.4 Furthermore, in a large phase Ib trial the anti-BCL-2 agent venetoclax in association with hypomethylating agents has provided promising CR and survival rates even in sAML patients or AML with poor cytogenetics,5 while spliceosome modulators24,25 and DOT1L inhibitors26 may represent a rational candidate for functional targeting of CS-AML and are currently evaluat- ed in clinical trials involving myeloid neoplasms. Finally, in our dataset IDH2 mutations were reported in 20% of CS-AML patients, confirming previous observations14 and representing another potentially important therapeutic target in this population.27
The bottom line is that an accurate cytogenetic and molecular characterization is required at the diagnosis of AML, making it reasonable to wait for these data in order to perform the best treatment decision or enrollment into clinical trials; this approach has recently demonstrated to be safe in clinically stable patients.28 In this context, although conventional cytogenetics are still needed for a correct risk stratification,7 NGS technologies may over- come its limitations and long turnaround time,20 also pro- viding additional information with improved cost effec- tiveness.
In conclusion, we have assessed the impact of a CS- mutational signature on a large prospective cohort of AML patients employing a standardized, easily imple- mentable NGS method and highlighting the need to detect this signature at diagnosis for an accurate risk pre- diction, with potentially relevant implications for the clinical management of AML patients.
Disclosures
No conflicst of interest to disclose.
Contributions
CC, FL and AR designed the research, analyzed and inter- preted data, supervised the study and wrote the manuscript; FD, EO, TI, AG, GG, MF, DF, EA, ET, LDP, GR, EB, IC, MT, AMS, DM, PC, LC, FC, MB, ET, AG, BF, RB performed research and collected data; genetic studies were performed by RC, KB, LE, PZ, AM; SS and OS performed and supervised genetic studies, collaborated on data interpretation, revised the manuscript and approved the final version; CP analyzed and interpreted data, performed statistical analysis and wrote the manuscript. All authors revised the manuscript and approved the final version before submission.
Funding
This work was partially supported by grants from Agenzia Italiana del Farmaco (Rome, Italy, Project FARM6YMY2N/2006), Fondazione Guido Berlucchi-Onlus (Brescia, Italy, 2006), and Associazione Italiana per la Ricerca sul Cancro (grant IG 2016 n. 18568) to BF.
References
1. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neo-
plasms and acute leukemia. Blood.
2016;127(20):2391-2405.
2. Weinberg OK, Seetharam M, Ren L, et al.
Clinical characterization of acute myeloid leukemia with myel-odysplasia-related
changes as defined by the 2008 WHO clas- sification system. Blood. 2009;113(9):1906- 1908.
3. Naqvi K, Jabbour E, Bueso-Ramos C, et al. Implications of discrepancy in morphologic
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