Decitabine Plus All-Trans Retinoic Acid Versus Decitabine Monotherapy for Myelodysplastic Syndromes with Excess Blasts: A Multicentre, Randomized Controlled Trial

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.

No relevant conflicts of interest to declare.

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.