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Published on: October 15, 2018
TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients
Rafael Bejar1, Allegra Lord2, Kristen Stevenson3
1Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, La Jolla, CA;
Abstract:
Only a minority of myelodysplastic syndrome (MDS) patients respond to hypomethylating agents (HMAs), but strong predictors of response are unknown. We sequenced 40 recurrently mutated myeloid malignancy genes in tumor DNA from 213 MDS patients collected before treatment with azacitidine (AZA) or decitabine (DEC). Mutations were examined for association with response and overall survival. The overall response rate of 47% was not different between agents. Clonal TET2 mutations predicted response (odds ratio [OR] 1.99, P = .036) when subclones unlikely to be detected by Sanger sequencing (allele fraction <10%) were treated as wild-type (WT). Response rates were highest in the subset of TET2 mutant patients without clonal ASXL1 mutations (OR 3.65, P = .009). Mutations of TP53 (hazard ratio [HR] 2.01, P = .002) and PTPN11 (HR 3.26, P = .006) were associated with shorter overall survival but not drug response. Murine-competitive bone marrow transplantation followed by treatment with AZA demonstrated that Tet2-null cells have an engraftment advantage over Tet2-WT cells. AZA significantly decreased this advantage for Tet2-null cells (P = .002) but not Tet2-WT cells (P = .212). Overall, Tet2 loss appears to sensitize cells to treatment with AZA in vivo, and TET2 mutations can identify patients more likely to respond to HMAs.
Insights
TET2 mutations predict response to hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS). Tet2 loss sensitizes cells to azacitidine (AZA) treatment, identifying patients likely to benefit from HMAs.
Area of Science:
- Hematology
- Oncology
- Genetics
Background:
- Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell disorders.
- Only a minority of MDS patients respond to hypomethylating agents (HMAs).
- Predictors of HMA response in MDS remain largely unknown.
Purpose of the Study:
- To identify genetic predictors of response to azacitidine (AZA) or decitabine (DEC) in myelodysplastic syndrome (MDS) patients.
- To investigate the association of mutations in recurrently mutated myeloid malignancy genes with HMA response and overall survival.
- To explore the in vivo effect of Tet2 loss on HMA treatment efficacy.
Main Methods:
- Sequencing of 40 recurrently mutated myeloid malignancy genes in 213 MDS patients before HMA treatment.
- Analysis of mutation associations with overall response rate (ORR) and overall survival (OS).
- Murine-competitive bone marrow transplantation models to assess Tet2-null and Tet2-WT cell behavior with AZA treatment.
Main Results:
- The overall response rate to HMAs was 47%, with no significant difference between AZA and DEC.
- Clonal TET2 mutations were associated with a higher likelihood of response (OR 1.99, P = .036).
- TP53 and PTPN11 mutations correlated with shorter overall survival (HR 2.01, P = .002 and HR 3.26, P = .006, respectively), but not drug response.
- Tet2-null cells showed an engraftment advantage in vivo, which was significantly decreased by AZA treatment (P = .002).
Conclusions:
- TET2 mutations are a significant predictor of response to HMAs in MDS patients.
- Tet2 loss sensitizes cells to AZA treatment in vivo, suggesting a mechanism for improved response.
- Identifying TET2 mutations can help select MDS patients who are more likely to benefit from HMA therapy.
