General AML|FLT3|TET2

TET2E2S is a favorable prognostic factor for cytogenetically normal AML: A French Study

The prognosis of patients with Cytogenetic Normal (CN) Acute Myeloid Leukemia (AML) is uncertain and the ideal post-remission therapy for this group of patients remains unclear. Some genes in AML are abnormally spliced and these alternatively spliced genes are likely to have potential prognostic, diagnostic and therapeutic implications. Mutations in Tet Methylcytosine Dioxygenase 2 (TET2), a dioxygenase, occurs in AML and its impact on patient outcomes has been contradictory hence the rationale for this study.

Aminetou Mint Mohamed from the Claude Bernard University Lyon 1, France and colleagues published results from their retrospective study, which investigated the importance of TET2 exon deregulation in CN-AML patients treated with Intensive Chemotherapy (IC) in Leukemia Research in January 2017.

In order to gain an insight into the clinical importance of TET2 exon deregulation in AML, the authors investigated the role of TET2 Exon 2 Skipping (TET2E2S) in CN-AML patients (n = 219). Patients were split into three cohorts; discovery cohort (median age = 56, n = 99), validation cohort (median age = 57, n = 57) and AML unsuitable for IC (median age = 74, n = 34). The discovery cohort and validation cohort were further divided into two categories based on their TET2E2S value; TET2E2Shigh and TET2E2Slow patients.  

The key results are:
  • In the discovery cohort, significantly lower Complete Remission (CR) in TET2E2Shigh (25/42) compared to TET2E2Slow (51/57); 59% vs 89%, P = 0.001
  • In the discovery cohort, 5- year Cumulative Incidence of Relapse (CIR) in TET2E2Shigh was significantly lower compared to TET2E2Slow; 21% vs 75%, < 0.0001
  • In the discovery cohort, 5- year Disease Free Survival (DFS) was significantly longer in TET2E2Shigh patients compared to TET2E2Slow patients; 52% vs 12%, P = 0.0007 
  • Age (HR = 2.24, P = 0.004), cytogenetics (HR = 2.67, P = 0.003) and TET2E2S (HR = 0.38, P = 0.003) were independent prognostic factors for DFS
  • In the validation cohort, TET2E2Shigh patients were significantly younger than TET2E2Slow patients; P = 0.027
  • In the validation cohort, 2- year CIR in TET2E2Shigh was significantly lower compared to TET2E2Slow; 4% vs 80%, P < 0.0001
  • In the validation cohort, 2- year DFS was significantly longer in TET2E2Shigh patients compared to TET2E2Slow patients; 88% vs 19%, P < 0.0001 
  • In the validation cohort, 2- year Event Free Survival (EFS) was significantly longer in TET2E2Shigh patients compared to TET2E2Slow patients; 75% vs 14%, < 0.0001 
  • In the validation cohort, 2- year Overall Survival (OS) was significantly longer in TET2E2Shigh patients compared to TET2E2Slow patients; 77% vs 38%, P = 0.0002 
  • TET2E2S (HR = 0.088, P < 0.0001) and FLT3-ITD (HR = 1.949, P =0.069) were independent prognostic factors for DFS and EFS
  • TET2E2S was a sole prognostic factor for OS; HR = 0.277, P < 0.001
  • In patients that was unsuitable for IC, there was no prognostic impact for TET2E2S

In summation, this is the first study to link the clinical outcomes of intensively treated CN-AML patients with TET2 mRNA splicing. However, the authors noted that their findings would require further confirmations in prospective studies due to the retrospective nature of their study.

High levels of TET2E2S was found to prolong survival and reduce relapse in intensively treated CN-AML patients. Additionally, the findings of this study suggests that TET2E2S can predict against relapse in CN-AML patients. The authors concluded by suggesting that assessing levels of TET2E2S in CN-AML patients could permit a better assessment of disease severity thereby improving patient management and survival outcomes in this subgroup of patients.

Abstract

In AML, approximately one-third of expressed genes are abnormally spliced, including aberrant TET2 exon 2 expression. In a discovery cohort (n = 99), TET2 exon 2 skipping (TET2E2S) was found positively associated with a significant reduction in the cumulative incidence of relapse (CIR). Age, cytogenetics, and TET2E2S were independent prognostic factors for disease-free survival (DFS), and favorable effects on outcomes predominated in cytogenetic normal (CN)-AML and younger patients. Using the same cutoff in a validation cohort of 86 CN-AML patients, TET2E2Shigh patients were found to be younger than TET2low patients without a difference in the rate of complete remission. However, TET2E2Shigh patients exhibited a significantly lower CIR (p < 10−4). TET2E2S and FLT3-ITD, but not age or NPM1 mutation status were independent prognostic factors for DFS and event-free survival (EFS), while TET2E2S was the sole prognostic factor that we identified for overall survival (OS). In both the intermediate-1 and favorable ELN genetic categories, TET2E2S remained significantly associated with prolonged survival. There was no correlation between TET2E2S status and outcomes in 34 additional AML patients who were unfit for IC. Therefore our results suggest that assessments of TET2 exon 2 splicing status might improve risk stratification in CN-AML patients treated with IC.

References
  1. Mohamed A M. et al. TET2 exon 2 skipping is an independent favorable prognostic factor for cytogenetically normal acute myelogenous leukemia (AML): TET2 exon 2 skipping in AML. Leukemia Research. Epub 2017 Jan 16. DOI: 10.1016/j.leukres.2017.01.012.