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539 Combination of Decitabine and ATRA in Newly Diagnosed Myelodysplastic Syndromes Subtype EB—Interim Analysis of a Multicenter, Randomized, Open-Label Trial

Program: Oral and Poster Abstracts
Type: Oral
Session: 637. Myelodysplastic Syndromes – Clinical and Epidemiological: Treatment of HIgh Risk and Relapsed/Refractory Myelodysplastic Syndrome
Hematology Disease Topics & Pathways:
Clinical Trials, Clinical Research, Clinically Relevant, Therapies
Sunday, December 12, 2021: 5:30 PM

Xinping Zhou1*, Fanjun Meng2*, Yanjuan Lin3*, Zheng Ge, MD, PhD4, Yuemin Kuang5*, Lu Wang6*, Jin Zhang7*, Hai Cheng, M.D.8*, Yan Gao9*, Yulu Tian10*, Li Huang11*, Jie Jin, PhD12 and Hongyan Tong, MD13*

1Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
2The Affiliated Hospital of Qingdao University, Qingdao, China
3Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, China
4Department of Hematology, Zhongda Hospital, Southeast University Medical School, Nanjing, China
5Jinhua people’s hospital, Hangzhou, China
6Department of Hematology, The first affiliated hospital, Zhejiang university school of medicine, Hangzhou, China
7Sir Run Run Shaw Hospital, School of Medicine, Zhejiang university, Hangzhou, China
8Affiliated Hospital of Xuzhou Medical University, xuzhou, China
9The Affiliated Hospital of Qingdao University, QINGDAO, CHN
10Department of Hematology, Institute of Hematology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
11Jinhua People's Hospital, Jinhua, China
12First Affiliated Hospital Zhejiang Univ. School of Med., Hangzhou, China
13Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China

Background: HMAs are mainstay treatment of higher-risk myelodysplastic syndromes (MDS). However, clinical outcomes of patients treated with decitabine (DEC) monotherapy were far from satisfactory with an overall response rate (ORR) of 33%-55.4% and an overall survival (OS) of 17.7-22 months. Some clinical researches reported that the addition of all-trans retinoic acid (ATRA) to DEC increased response rate and prolonged survival of MDS and elderly acute myeloid leukemia (AML) patients. Our data showed ATRA enhanced the cytotoxic effect of DEC on MDS via activating RARα-Nrf2 complex (2021 EHA abstract EP891). These findings suggested that addition of ATRA to DEC in treatment-naive patients may improve response rate based on the synergetic function. We therefore conducted a study of combination of DEC and ATRA in MDS subtype excessive blasts (EB) patients.

Methods: In this randomized, multicenter, open-label trial, patients with newly diagnosed MDS subtype EB based on the 2016 WHO classification from 7 different tertiary medical centers in China were included. Patients were randomized 1:1 to receive either oral ATRA (25mg/m2/day on days 1-28) plus DEC (20 mg/m2 daily on days 1-5) or DEC monotherapy(Figure 1). The primary endpoint was overall response rate ORR, defined as complete remission (CR), partial remission (PR), marrow complete remission (mCR), or hematological improvement (HI). Key secondary endpoints were mCR, HI, overall survival (OS), and progress free survival (PFS). Response was assessed after completion of four cycles of treatment. For patients who bridged to allo-HSCT later on and did not complete four cycles of treatments, response was defined as best response ever observed before receiving allo-HSCT. Here, we report results of the interim analysis.

Results: Between May 2018 and July 2021, 165 patients were randomly allocated into either DEC plus ATRA (n=82) or DEC monotherapy (n=83). 63.6% of patients were male and 36.4% were female, with a median age of 62 years (range, 19 to 81 years). 38.8% of patients had EB1 and 61.2% had EB2. As of July 31, 2021, 126 patients were available for the assessment of treatment results.

After a median follow up of 9.6 months, median number of courses on treatment was 4 courses (range, 1-14), 61 in DEC plus ATRA arm and 65 in DEC arm . OR was achieved in 85.2% of DEC plus ATRA patients compared to 56.9% in DEC monotherapy (p<0.001). mCR rate was 73.8% in patients treated with DEC plus ATRA and 53.8% in those with DEC monotherapy (p=0.02). HI rate was 63.9% and 44.6% in patients with DEC plus ATRA and DEC monotherapy, respectively (p=0.03). The median OS and PFS were 18.8 months and 13.5 months for DEC plus ATRA arms, 19.2 months and 13.0 months for in DEC arm, respectively.

72.7% patients developed at least one adverse event (AE) during the trial, 73.3% in the DEC plus ATRA arm and 72.0% in DEC arm, respectively. Grade 3/4 Hematological toxicity occurred in 73.68 % of DEC plus ATRA arm and 76.92 % of DEC arm. Hyperlipidemia occurred in 31 patients in DEC plus ATRA arm (3.2% grade 3/4), and 18 (no grade 3/4) in DEC arm (p<0.001). Incidence of headache was higher in DEC plus ATRA arm (14.7% vs 4.0% in DEC arm, respectively, p<0.001). No other statistically significant differences were observed in the incidence of treatment-related AEs between the two groups. No early death occurred.

Conclusion: Combination of DEC and ATRA achieved an OR rate of 85.2% in MDS subtype EB. Enrollment is ongoing to assess its efficacy and safety in treating EB. This therapy may be a new treatment option for EB subjects.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH