Impact of Next-Generation Sequencing on Treatment Choices for Patients with Acute Myeloid Leukemia

INTRODUCTION: Until recently, therapy options for patients with acute myeloid leukemia (AML) were limited. This is changing due to advent of CLIA-approved next generation sequencing (NGS) panels and development of multiple new anti-leukemia agents. Examples are the recent approval of a FLT3 and IDH2 inhibitors. Multiple other targeted agents are currently being studied in clinical trials for AML. The aim of our study was to evaluate the impact of a NGS panel on the clinical practice at a major clinical trial research center. We report the experience in 1171 patients with AML who had a NGS panel evaluation as part of their clinical care during 2012-2015.

METHODS : We included all AML patients for whom an NGS-based analysis for the detection of somatic mutations in the coding sequence of a total of 28 or 53 genes was performed between October 2012 and October 2015. Clinical and demographic data were obtained from clinical records. 17 genes ( ALK, CSF1R, FGFR1, FGFR2, FGFR3, FLT3, IDH1, IDH2, JAK2, KDR, KRAS, NPM1, NRAS, PDGFRA, PRPN11, RET and TP53) were considered potentially actionable due to the possibility to be targeted with established or investigational therapies, either directly or indirectly. Statistical analyses were performed with the IBM SPSS Statistics 23.0 software.

RESULTS: A total of 732 patients (62.5%) were evaluated using the 28 gene panel and 439 patients (37.5%) using the 53 gene panel. 36% of patients were evaluated frontline (n=421), 27.6% during treatment (n=313) and 37.4% (n=437) at relapse. The median time to inform the results were 9 days (range 2-90). Median age at AML diagnosis was 62 years (range 10-92). Baseline characteristics are shown in Table 1.

881 patients (75%) had at least one detectable mutation: 669 (57.1%) on a potential actionable gene and 502 (42.9%) on non-actionable genes. The most frequently potentially actionable mutation was IDH2 (n=196; 16.7%), followed by TP53 (N=174; 14.9%), NPM1 (n=163; 13.9%), NRAS (n=129; 11.0%), IDH1 (n=116; 9.9%) and KRAS (n=66; 5.6%), present on more than 5% of the patients. The frequency of all identified mutations is shown in Fig. 1A.

A total of 421 patients (36.0%) were evaluated at initial diagnosis, with 404 patients subsequently starting therapy for their AML. 277 (65.8%) of these had potentially targetable alterations, and only 5 (1.8%) of these patients were treated with a targeted agent. 437 patients (37.4%) patients were evaluated at the time of relapse/refractory with 388 patients (88.6%) starting new therapy. 281 (72.4%) of these treated patients had a targetable mutation and 46 (16.4%) of them were treated with a target agent. Therefore, considering only patients with an actionable mutation, patients with relapse/refractory AML were more likely to receive targeted therapy than those at diagnosis (16.4% vs 1.8%, p<0.001). Considering different time points, the probability of receiving a target therapy for those patients with actionable mutations was 3.4% for the period 2012-2013, 5.7% in 2014 and 13.5% in 2015 (p<0.001) (Fig.1B).

The 614 remaining patients (91.8%) never received a targeted therapy. 9.5% of these patients (n=58) never return to the institution after the mutation analysis and 16.6% (n=102) responded to another therapy. For the remaining 434 patients, documentation of discussion of enrollment in a clinical trial was present on 82.9% (n=358): 85.8% (n=307) enrolled in a clinical trial not involving actionable mutations and 10.1% (n=36) were not eligible owing to poor status or other causes.

CONCLUSION: NGS technologies can be used to identify a significant proportion of patients (57%) with potentially actionable mutations. However, until 2015, only a small proportion of patients (8.2%) with AML and actionable alterations were treated with targeted therapy. Relapse/refractory patients were more likely to receive targeted agents than those at initial diagnosis. Possible reasons are: 1) delays in NGS results and physicians not willing to wait to start treatment; 2) presumption that standard therapies may be better than investigational target agents. Personalized medicine based on mutation profiles in AML remains an area under development, but a dramatic increase in the proportion of patients treated with a target agent were observed in 4 years. The results of current clinical trials may change the way we treat these patients.

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