Presence of TET2 Mutation Predicts A Higher Response Rate to Azacitidine In MDS and AML Post MDS

TET genes have been implicated in DNA demethylation in mammals (Thalihani, Science, 2009; Ito, Nature 2010) and the TET2 gene is mutated in 15–22% of MDS and AML (Kosmider et al. Blood 2009, Nibourel et al. Blood 2010). Azacitidine (AZA) is a hypomethylating agent providing about 50% of responses in MDS and AML with low blast count (Lancet Oncol 2009, JCO 2010). Routine clinical and biological variables can predict OS with AZA, but are poor predictors of response to AZA (Itzykson et al. ASH 2009, and other abstract submitted to ASH 2010), while no consensus genetic predictor of response has been reported so far.

In consecutive MDS (including RAEB-t and CMML) and AML post MDS (with >30% blasts) (AML/MDS) patients treated by AZA in 6 centers, we prospectively sequenced the TET2 gene from PBMC or BMNC DNA samples stored prior to AZA onset. Standard PCR and sequencing procedures were performed as previously described (Delhommeau et al, NEJM 2009), allowing detection of mutations in the entire coding sequence of the TET2 gene (exons 3 to 11). Patients were to receive AZA at the FDA/EMEA approved schedule (75mg/m²/d, 7d/4 weeks). Patients (pts) having received ≥ 1 cycle of AZA and who had bone marrow evaluation after ≥ 4 cycles, or who died or progressed before completion of 4 cycles were considered evaluable (the last 2 groups were considered as treatment failures). Responses were scored according to IWG 2006 criteria for MDS and to Cheson et al. (JCO 2003) for AML.

The study population included 103 pts: F/M: 36/67; median age 72 (range 43–91). Diagnosis at AZA onset was MDS in 89 (RAEB-1 n=20, RAEB-2 n=43, RAEB-t n=23, CMML-1 n=2, CMML-2 n=1; IPSS int-1 in 13, int-2 in 38, high in 36, undetermined in 2) and AML/MDS in 14 pts; 29 pts had previously been treated by LD AraC or intensive chemotherapy (IC). Cytogenetics according to IPSS was favorable in 48, intermediate in 20, unfavorable in 31, unknown in 4. 78 pts received the approved and 25 (24%) a reduced AZA schedule (mostly 75 mg/m² for 5 days every 4 weeks). Median number of cycles was 7 [range 1–39] and median follow-up was 18.2 months.

21 TET2 mutations were found in 17 (17%) pts, including 12 frameshift (all inducing a premature STOP codon), 6 non sense and 3 missense mutations. Predicted TET2 protein length was preserved in 3, and truncated in 14 pts, respectively.

Patients with mutated (MUT) TET2 had similar age, diagnosis, BM blast %, neutrophil and platelet counts as those with wild type (WT) TET2 (all p>0.3), but less frequent unfavorable cytogenetics (6% vs 37%, p=0.02) and a trend for higher WBC (p=0.12), lower Hb (p=0.11) and more pretreatment by LD AraC or IC (47% vs 24%, p=0.08) than WT TET2 pts. The 2 groups received AZA at similar schedules (p=0.4) for a median of 6 [1-39] cycles (TET2 WT) or 11 [4-34] cycles (TET2 MUT, p=0.01). Ten WT pts (vs 0 MUT) received <4 AZA cycles due to early progression (in 6 and early death in 4. Best response to AZA (excluding HI, due to inclusion of AML pts) was CR in 24, PR in 1, marrow CR (MDS)/CRi (AML) in 12, stable disease (SD) in 44, progression in 17 and early death in 4.

The overall response rate was 11/17 (CR n=7, marrow CR/CRi n= 4; 65%) in MUT TET2 pts, and 26/86 (CR n=17, PR n=1, marrow CR/CRi n=8; 30%) in WT TET2 pts (p=0.01). This difference remained significant after adjusting on cytogenetic risk and number of AZA cycles received (p=0.03). Median response duration was similar in the two groups (TET2 WT: 7.1 months, TET2 MUT: 9.2 months, p=0.7). An additional 15 pts (3 TET2 MUT and 12 TET2 WT) achieved SD with HI. Considering HI as response, including in AML pts, response was 14/17 (82%) in TET2 MUT pts vs 39/86 (45%) in TET2 WT pts (p=0.007).

Median OS was similar in TET2 WT (15.3 months) and TET2 MUT pts (16.2 months, p=0.4). Finally, response (excluding HI, ie. CR/PR/mCR) was 1/3 (33%) in the missense group vs 10/14 (71%) in pts with a predicted truncated TET2 protein.

In this cohort of MDS and AML/MDS, TET2 mutation was associated to higher response rate to AZA, independent of conventional cytogenetics and duration of AZA exposure, but had no influence on survival. Prediction of response by TET2 sequencing may thus complement prognostic factors of survival obtained by routine clinical and biological variables (Itzykson et al, other abstract submitted to ASH 2010). TET2 mediated chromatin changes may modulate the sensitivity of MDS to AZA, opening new perspectives in the understanding of AZA mode of action and novel therapeutic strategies.

Fenaux:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding. Fontenay:Celgene: Research Funding.