More Mutations, More Problems? Assessing Mutation Burden and Response to HMAs in MDS

Previous research has suggested that the presence of a TET2 mutation can predict which patients with myelodysplastic syndromes (MDS) are more likely to have a favorable response to hypomethylating agents (HMA; the standard of care for higher-risk MDS). However, a study presented by Guillermo Montalban-Bravo, MD, from the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, at the 2016 ASH Annual Meeting did not find that the presence of a TET2 mutation was significantly associated with an increased response rate to HMA.

Dr. Montalban-Bravo and researchers included 180 previously untreated patients (median age at diagnosis = 67 years; range = 20-88 years) with MDS (n=143; 79%) or chronic myelomonocytic leukemia (CMML; n=37; 21%) who were treated at the University of Texas MD Anderson Cancer Center. Using next-generation sequencing, the authors analyzed a panel of 28 genes (including ABL1, ASXL1, BRAF, DNMT3A, EGFR, EZH2, FLT3, GATA1, GATA2, HRAS, IDH1, IDH2, IKZF2, JAK2, KIT, KRAS, MDM2, MLL, MPL, MYD88, NOTCH1, NPM1, NRAS, PTPN11, RUNX1, TET2, TP53, and WT1) in patients’ samples collected prior to receiving HMA treatment.

Most patients (60%; n=108) had lower-risk MDS (based on the International Prognostic Scoring System [IPSS] low- and intermediate-1-risk criteria), while 40 percent (n=72) had higher-risk MDS (based on IPSS intermediate-2- and high-risk criteria). A majority of patients (n=87; 49%) had normal karyotype, while 20 percent (n=36) had complex karyotype.

Patients received the following HMAs: azacitidine monotherapy (n=60; 33%), decitabine monotherapy (n=55; 31%), or guadecitabine (SGI-110) or combination therapy (n=65; 36%).

The overall response rate (ORR) was 58 percent (n=105), including 37 percent (n=66) who achieved complete response (CR).

Sixty-eight percent of patients (n=123) had at least one detectable mutation, and the median number of mutations was one (range = 0-5 mutations). The most commonly detected mutations were TET2 (23%), TP53 (16%), and RUNX1 (12%).

Contradicting previous research, the presence of TET2 mutation was not significantly associated with an increased likelihood of response in this series (odds ratio [OR] = 1.32; 95% CI 0.64-2.70; p=0.453) or CR (OR=1.30; 95% CI 0.64-2.65; p=0.469). However, as has been reported by other investigators, the ASXL1 mutation was associated with a decreased chance of achieving CR (OR=0.30; 95% CI 0.10-0.93; p=0.037).

No differences in ORR were observed based on the presence of any mutation, but the number of mutations did significantly affect ORR and CR. Patients who had ≥3 detectable mutations had lower ORR (OR=0.29; 95% CI 0.10-0.88; p=0.028) and a decreased chance of achieving CR (OR=0.22; 95% CI 0.05-1.01; p=0.052).

Notably, TET2 mutations did not predict ORR (OR=1.83; 95% CI 0.78-4.25; p=0.163) or CR (OR=1.75; 95% CI 0.80-3.81; p=0.159) in patients with <3 mutations.

Over a median follow-up of 14.5 months (range = 2.4-101.3 months), patients who did not respond to HMA treatment had significantly shorter overall survival (OS; not reached [NR] for responders vs. 21.3 months for non-responders; hazard ratio [HR] = 1.68; 95% CI 1.03-2.73; p=0.037). Leukemia-free survival (LFS) was also decreased in those who did not achieve a response (NR vs. 34.3 months; HR=2.13; 95% CI 1.00-4.50; p=0.049).

CR was predictive of improved OS in patients with higher-risk MDS (median OS = NR vs. 14.6 months; p=0.046), but not for lower-risk patients (median OS = NR vs. 27.3 months; p=0.239). No significant differences in LFS were observed based on achievement of CR in both higher- (p=0.238) and lower-risk patients (p=0.453).

“The number of driver mutations may be a new biomarker to predict response to therapy with hypomethylating agents in patients with MDS and CMML,” the authors concluded. “Incorporating sequencing data at diagnosis may help predict response to therapy and patient outcomes.” However, because this was a single-center study, the results may not be generalizable and will need to be confirmed in larger studies.

Montalban-Bravo G, Pierola AA, Wang F, et al. Increased number of driver mutations is a predictor of response to hypomethylating agents in patients with myelodysplastic syndromes. Abstract #51. Presented at the 2016 ASH Annual Meeting, December 3, 2016; San Diego, California.