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Clinical Trial
. 2020 Jan 20;38(3):257-270.
doi: 10.1200/JCO.19.01053. Epub 2019 Dec 3.

Valproate and Retinoic Acid in Combination With Decitabine in Elderly Nonfit Patients With Acute Myeloid Leukemia: Results of a Multicenter, Randomized, 2 × 2, Phase II Trial

Michael Lübbert  1   2 , Olga Grishina  1 , Claudia Schmoor  1 , Richard F Schlenk  3   4 , Edgar Jost  5 , Martina Crysandt  5 , Michael Heuser  6 , Felicitas Thol  6 , Helmut R Salih  7 , Marcus M Schittenhelm  8 , Ulrich Germing  9 , Andrea Kuendgen  9   10 , Katharina S Götze  11   12 , Hans-Walter Lindemann  13 , Carsten Müller-Tidow  4   14   15 , Gerhard Heil  16 , Sebastian Scholl  17 , Gesine Bug  18   19 , Carsten Schwaenen  20   21 , Aristoteles Giagounidis  22 , Andreas Neubauer  23 , Jürgen Krauter  24 , Wolfram Brugger  25 , Maike De Wit  26 , Ralph Wäsch  1 , Heiko Becker  1   2 , Annette M May  1 , Justus Duyster  1   2 , Konstanze Döhner  3 , Arnold Ganser  6 , Björn Hackanson  1   27 , Hartmut Döhner  3 ; DECIDER Study Team
Affiliations
Clinical Trial

Valproate and Retinoic Acid in Combination With Decitabine in Elderly Nonfit Patients With Acute Myeloid Leukemia: Results of a Multicenter, Randomized, 2 × 2, Phase II Trial

Michael Lübbert et al. J Clin Oncol. .

Abstract

Purpose: DNA-hypomethylating agents are studied in combination with other epigenetic drugs, such as histone deacetylase inhibitors or differentiation inducers (eg, retinoids), in myeloid neoplasias. A randomized, phase II trial with a 2 × 2 factorial design was conducted to investigate the effects of the histone deacetylase inhibitor valproate and all-trans retinoic acid (ATRA) in treatment-naive elderly patients with acute myeloid leukemia (AML).

Patients and methods: Two hundred patients (median age, 76 years; range, 61-92 years) ineligible for induction chemotherapy received decitabine (20 mg/m2 intravenously, days 1 to 5) alone (n = 47) or in combination with valproate (n = 57), ATRA (n = 46), or valproate + ATRA (n = 50). The primary endpoint was objective response, defined as complete and partial remission, tested at a one-sided significance level of α = .10. Key secondary endpoints were overall survival, event-free survival, and progression-free survival and safety.

Results: The addition of ATRA resulted in a higher remission rate (21.9% with ATRA v 13.5% without ATRA; odds ratio, 1.80; 95% CI, 0.86 to 3.79; one-sided P = .06). For valproate, no effect was observed (17.8% with valproate v 17.2% without valproate; odds ratio, 1.06; 95% CI, 0.51 to 2.21; one-sided P = .44). Median overall survival was 8.2 months with ATRA v 5.1 months without ATRA (hazard ratio, 0.65; 95% CI, 0.48 to 0.89; two-sided P = .006). Improved survival was observed across risk groups, including patients with adverse cytogenetics, and was associated with longer response duration. With valproate, no survival difference was observed. Toxicities were predominantly hematologic, without relevant differences between the 4 arms.

Conclusion: The addition of ATRA to decitabine resulted in a higher remission rate and a clinically meaningful survival extension in these patients with difficult-to-treat disease, without added toxicity.

Trial registration: ClinicalTrials.gov NCT00867672.

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