Study of Decitabine Alone or in Combination With Valproic Acid and All-trans Retinoic Acid in Acute Myeloid Leukemia
Summary
AML of the older patient constitutes a major unmet clinical need since the large majority will not be found eligible for induction chemotherapy. Reasons for this decision include host factors (comorbidities, reduced performance status, functional limitations due to age), leading to often poor tolerance of repeated chemotherapy courses and the unfavorable biology underlying this disease in older patients. Low dose Decitabine has shown very promising efficacy in high-risk MDS and is therefore a very promising approach also in older AML patients. Preliminary results from several centres have demonstrated excellent feasibility and good efficacy of this treatment. Therefore the investigators intend to investigate the effects of two drugs added onto low-dose Decitabine which have shown very promising synergistic effects in vitro and for which preliminary results indicate that the combination with low-dose Decitabine is very feasible.
Timeline
- Start
- 2011-08
- Primary completion
- 2015-02
- Completion
- 2016-02
Outcome
Mixed primary results
paper The primary endpoint was objective response, defined as complete and partial remission, tested at a one-sided significance level of α = .10. PMID 31794324 ↗
paper 21.9% with ATRA v 13.5% without ATRA; odds ratio, 1.80; 95% CI, 0.86 to 3.79; one-sided P = .06 PMID 31794324 ↗
paper 17.8% with valproate v 17.2% without valproate; odds ratio, 1.06; 95% CI, 0.51 to 2.21; one-sided P = .44 PMID 31794324 ↗
Publications
- Bresser H, Schmoor C, Grishina O, Pfeifer D, Thomas J, Rehman UU, Crysandt M, Jost E, Thol F, Heuser M, Gotze KS, Schlenk RF, Salih HR, Schittenhelm MM, Heil G, Schwaenen C, Muller-Tidow C, Brugger W, Kundgen A, de Wit M, Giagounidis A, Scholl S, Neubauer A, Krauter J, Bug G, May AM, Wasch R, Duyster J, Dohner K, Ganser A, Dohner H, Hackanson B, Becker H, Lubbert M. Impact of TP53 Mutation Status in Elderly AML Patients When Adding All-Trans Retinoic Acid or Valproic Acid to Decitabine. Eur J Haematol. 2025 Feb;114(2):231-237. doi: 10.1111/ejh.14304. Epub 2024 Oct 13.
- Thomas J, Rehman UU, Bresser H, Grishina O, Pfeifer D, Sollier E, Dohner K, Plass C, Becker H, Schmoor C, de Wit M, Lubbert M. Continued decitabine/all-trans retinoic acid treatment: extended complete remission in an elderly AML patient with multi-hit TP53 lesions and complex-monosomal karyotype. Clin Epigenetics. 2024 Sep 11;16(1):126. doi: 10.1186/s13148-024-01737-4.
- Duque-Afonso J, Veratti P, Rehman UU, Herzog H, Mitschke J, Greve G, Eble J, Berberich B, Thomas J, Pantic M, Waterhouse M, Gentile G, Heidenreich O, Miething C, Lubbert M. Identification of epigenetic modifiers essential for growth and survival of AML1/ETO-positive leukemia. Int J Cancer. 2024 Dec 1;155(11):2068-2079. doi: 10.1002/ijc.35134. Epub 2024 Aug 15.
- Javorniczky NR, Grishina O, Hund I, Pantic M, Pfeifer D, Schmoor C, Thomas J, Duyster J, Becker H, Lubbert M. Long-term decitabine/retinoic acid maintenance treatment in an elderly sAML patient with high-risk genetics. Clin Epigenetics. 2023 Nov 28;15(1):185. doi: 10.1186/s13148-023-01596-5.
- Lubbert M, Grishina O, Schmoor C, Schlenk RF, Jost E, Crysandt M, Heuser M, Thol F, Salih HR, Schittenhelm MM, Germing U, Kuendgen A, Gotze KS, Lindemann HW, Muller-Tidow C, Heil G, Scholl S, Bug G, Schwaenen C, Giagounidis A, Neubauer A, Krauter J, Brugger W, De Wit M, Wasch R, Becker H, May AM, Duyster J, Dohner K, Ganser A, Hackanson B, Dohner H; DECIDER Study Team. Valproate and Retinoic Acid in Combination With Decitabine in Elderly Nonfit Patients With Acute Myeloid Leukemia: Results of a Multicenter, Randomized, 2 x 2, Phase II Trial. J Clin Oncol. 2020 Jan 20;38(3):257-270. doi: 10.1200/JCO.19.01053. Epub 2019 Dec 3.
- Grishina O, Schmoor C, Dohner K, Hackanson B, Lubrich B, May AM, Cieslik C, Muller MJ, Lubbert M. DECIDER: prospective randomized multicenter phase II trial of low-dose decitabine (DAC) administered alone or in combination with the histone deacetylase inhibitor valproic acid (VPA) and all-trans retinoic acid (ATRA) in patients >60 years with acute myeloid leukemia who are ineligible for induction chemotherapy. BMC Cancer. 2015 May 26;15:430. doi: 10.1186/s12885-015-1432-5.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Subject | Decitabine | Small molecule | 20 mg/m2 | Intravenous |
| Subject | Tretinoin | Unknown | 45 mg/m2 | Oral |
| Subject | VPA | Unknown | — | Oral |