Activity of Hypomethylating Agents in the Treatment of Therapy-Related Myelodysplastic Syndrome
Authors: Alfonso Pierola Ana , Montalban-Bravo Guillermo , Takahashi Koichi , Wang Feng , Xingzhi Song , Jabbour Elias J. , Kadia Tapan M. , Ravandi Farhad , Cortes Jorge E. , DiNardo Courtney D. , Daver Naval G. , Borthakur Gautam , Pemmaraju Naveen , Konopleva Marina , Bueso-Ramos Carlos E , Patel Keyur , Futreal Andrew , Pierce Sherry , Kantarjian Hagop M. , Garcia-Manero Guillermo 
Published: October 2019

Abstract

INTRODUCTION: Therapy-related myelodysplastic syndromes (t-MDS) are secondary malignancies that develop in patients who have received cytotoxic chemotherapy and/or radiation therapy for a primary cancer. t-MDS tend to have poor outcomes, with few available therapies and poor responses to conventional chemotherapies.
PATIENTS AND METHODS: 263 patients diagnosed with t-MDS and treated with hypomethylating agents (HMA) between July 2001 and December 2015 at a single institution were retrospectively reviewed. Clinical and demographic data were obtained from clinical records. Response was assessed by modified 2006 International Working Group (IWG) criteria. Statistical analyses were performed with the IBM SPSS Statistics 23.0 software. Overall survival (OS) and leukemia free survival (LFS) were defined as the time between treatment onset and death or leukemia (or last contact), respectively. Data were summarized using median, range, and percentage. Censored endpoints were estimated by the nonparametric Kaplan-Meier method and compared using the log-rank test. All tests were 2-sided with significance set at p<0.05.
RESULTS: Baseline characteristics are shown in Table 1. 56% of the patients were male. Median age at diagnosis was 66 years (range 13-87). According to the MDS International Prognostic Score System (IPSS), 17 patients (7%) belonged to the low risk group, 77 (29%) to the intermediate-1 risk group, 132 (50%) to the intermediate-2 risk group, and 34 (13%) to the high risk group. Following the Revised International Prognostic Score System (IPSS-R), 6 (2 %), 43 (16%), 20 (7%), 80 (30%), and 100 (38%) belonged to the very low, low, intermediate, high, and very high risk groups, respectively. Following the previously published scoring system for t-MDS, 57 (22%), 120 (46%), 63 (24%) belonged to the good, intermediate, and poor risk groups, respectively. The most common IPSS-R cytogenetic group was complex karyotype with more than 3 abnormalities, which was detected in 112 patients (43%), followed by the good risk group, which was present in 58 patients (22%). Next generation sequencing (NGS) analyzing a panel of 28 or 53 genes was available in 48 patients. The most frequent mutation observed was TP53 (present in 23 patients [48%]), followed by TET2 (present in 8 patients [7%]) and ASXL1 and DNMT3A (present in 3 patients each [6%]). Previous therapy received for the first neoplasm was chemotherapy alone in 123 patients (47%), radiotherapy alone in 27 (10%), or both in 111 patients (42%).
A total of 73 (28%) patients received azacitidine in monotherapy (AZA) for the treatment of their t-MDS, 97 (37%) decitabine in monotherapy (DAC), and 92 (35%) were treated with combinations. Overall response rate (ORR) was 52% (137/263), including 33% (87/263) complete response (CR). No difference in terms of OS were observed between those patients treated with AZA vs DAC in monotherapy (p=0.75). The median duration of response was 6 months (range 1-69 months). Median OS was 13 months (Fig. 1A), and transformation to AML occurred in 126 patients (47.9%). There were statistically significant OS differences between responders and non-responders: 17 vs. 9 months, respectively (p<0.01) (Fig.1B).
Univariate analysis revealed that concentration of hemoglobin (< 8 g/dl vs. ≥ 8 g/dl; p=0.003), number of platelets (<50x103/mm3 vs. ≥50x103/mm3; p< 0.001), presence of complex karyotype (p< 0.001), and presence of TP53 mutation (p=0.003) were all predictive of survival. After including all the significant factors in the univariate analysis in the multivariate model, only the presence of TP53 mutation was identified as independently associated with shorter survival in patients with t-MDS treated with HMA (HR[IC95%]: 3,44[1.53-7.34]) (Fig. 1C).
CONCLUSION: Despite the poor prognosis of patients with t-MDS (median OS 12 months), HMA are clinically effective in the treatment of those patients, providing an ORR of 52% with a CR rate of 33%. Better OS were observed in responders when compared to non-responders, as well as in those patients without TP53 mutations. These results need to be confirmed in a larger numbers of patients.

Disclosures
Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. DiNardo:Abbvie: Research Funding; Agios: Research Funding; Celgene: Research Funding; Daiichi Sankyo: Research Funding; Novartis: Research Funding. Konopleva:Calithera: Research Funding; Cellectis: Research Funding.