-Author name in bold denotes the presenting author
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663 Decitabine Plus All-Trans Retinoic Acid Versus Decitabine Monotherapy for Myelodysplastic Syndromes with Excess Blasts: A Multicentre, Randomized Controlled TrialClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 637. Myelodysplastic Syndromes: Clinical and Epidemiological: Treatment and Prognostication of MDS
Hematology Disease Topics & Pathways:
Research, Clinical trials, Clinical Research
Sunday, December 8, 2024: 5:00 PM

Hongyan Tong, PhD1,2,3,4, Xinping Zhou1,2,3,5*, Yanjuan Lin6*, Yan Gao7*, Zheng Ge, MD, PhD8, Huang Li9*, Jin Zhang10*, Hai Cheng11*, Guifang Ouyang12*, Fanjun Meng13*, Yulu Tian14*, Yuemin Kuang15*, Fengping Zhou16*, Lixia Sheng12*, Weimei Jin5*, Gaixiang Xu1,2,3,4*, Liya Ma1,2,3,4*, Li Ye1,2,3,17*, Chen Mei5*, Jian Li18* and Jie Jin, M.D.2,19,20,21

1Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, China
2Zhejiang University Cancer Center, Hangzhou, China
3Zhejiang Provincial Clinical Research Center for Hematological disorders, Hangzhou, China
4Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
5Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
6Department of Hematology, Fujian Medical University Union Hospital, Fuzhou, China
7Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao, CHN
8Jiangsu Provincial People’s Hospital, Nanjing, China
9Department of Hematology, The Affiliated Jinhua Hospital of Wenzhou Medical University, Wenzhou, China
10Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
11Department of Hematology, The Affiliated Hospotal of Xuzhou Medical College, Xuzhou, China
12Department of Hematology, The First Affiliated Hospital of Ningbo University, Ningbo, China
13Department of Hematology, The Affiliated Hospital of Qingdao University,, Qiangdao, China
14Department of Hematology, Zhongda Hospital, Institute of Hematology Southeast University, School of Medicine, Southeast University,, Nanjing, China
15Department of Hematology, The Affiliated Jinhua Hospital of Wenzhou Medical University, Jinhua, China
16Department of Hematology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
17Department of Hematology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
18Clinical Research Center, Ruijin Hospital Affiliated To Shanghai Jiao Tong Unive, Shanghai, China
19Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
20Zhejiang Provincial Clinical Research Center For Hematological disorders, Hangzhou, China
21Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou, China

Background: Hypomethylating agents (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 (Br J Cancer. 2023). 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 multicenter, open-label, randomized controlled trial, adult patients (≥18 years of age) with morphologically confirmed MDS-EB-1 or MDS-EB-2, as defined by the World Health Organization classification (WHO 2016), were eligible. Patients were randomized 1:1 to receive either oral ATRA plus DEC or DEC monotherapy. Each treatment cycle lasted for 28 days, and treatment was planned for at least four cycles. For each cycle, all patients received 20 mg/m2 intravenous decitabine on the first 5 days. For the first 4 cycles, patients in the ATRA group also received oral ATRA at 25 mg/m2/day in 2 divided daily doses throughout the 28-day cycle. Starting from the fifth cycle, ATRA was given at 25 mg/m2/day only for the first 14 days of the 28-day cycle. Treatment continued until disease progression, unacceptable toxicity, or patient decision to withdraw from the trial. The primary end point was the overall response, including complete remission, partial remission, bone marrow complete remission and hematologic improvement. Key secondary endpoints were mCR, HI, overall survival (OS), and progress free survival (PFS). Response was assessed within 4 treatment cycles in a modified intent-to-treat (mITT) population that included all patients who received at least one dose of the assigned treatment. This trial is registered at the Chinese Clinical Trial Registry (ChiCTR1800018307).

Results: 227 patients were randomly allocated into either DEC plus ATRA (n=113) or DEC monotherapy (n=114). The mITT population included 223 patients (median age: 62 years; 78 women). Disease subtype was MDS-EB-1 in 108 (48%) patients and MDS-EB-2 in 115 (52%) patients. The median number of decitabine cycles was 4 (range, 1-17) in the ATRA group and 3 (range, 1-20) in the decitabine group. The ORR was 78% (86/110) in the ATRA group versus 51% (58/113) in the decitabine group (odds ratio 3.40; 95% CI 1.90-6.09; P<0.001). The ATRA group also had higher CR rate (23% [25/110] versus 12% [14/1130]; odds ratio 2.05; 95% CI 1.02-4.25; P=0.042), CR+mCR rate (72% [79/110] versus 49%[55/113]; odds ratio 2.69; 95% CI 1.54-4.68; P<0.001), and CR+PR+HI rate (48% [53/110]versus 34% [ 38/113]; odds ratio 1.84; 95% CI 1.07-3.15; P=0.027). With the median follow-up of 30.1 months, progression-free survival (PFS) was 14.9 months in the ATRA group versus 10.5 months in the decitabine group (hazard ratio 0.70; 95% CI 0.51 - 0.97; P =0.032). The two groups did not differ in time to AML transformation (18.9 versus 15.8 months; hazard ratio 0.81; 95% CI 0.58-1.14; p=0.221) and OS (23.0 versus 19.3 months; hazard ratio 0.77, 95% CI 0.54-1.09; p=0.137). The rate of hematological treatment-emergent serious adverse events was 86% (94/110) in the ATRA group versus 80% (90/113) in the decitabine group (p=0.254). The rate of non-hematological treatment-emergent serious adverse events was 35% (38/110) in the ATRA group versus 23% (26/113) in the decitabine group (p=0.057).

Conclusion: Treatment with decitabine plus ATRA resulted in higher ORR and prolonged PFS than decitabine monotherapy in patients with MDS-EB. This combination may be a new treatment option for MDS-EB patients.

Disclosures: No relevant conflicts of interest to declare.

OffLabel Disclosure: All-trans retinoic acid (ATRA) induces blast differentiation in acute promyelocytic leukemia (APL) and is recommended for treatment of APL patients. ATRA is not highly effective in AML except in the presence of the PML-RARA fusion protein. However preclinical studies indicated that HMA may render AML cells more sensitive to ATRA. Reciprocally, ATRA could potentiate the cytotoxic effects of decitabine.

*signifies non-member of ASH