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Clinical Trial
. 2025 Feb;114(2):231-237.
doi: 10.1111/ejh.14304. Epub 2024 Oct 13.

Impact of TP53 Mutation Status in Elderly AML Patients When Adding All-Trans Retinoic Acid or Valproic Acid to Decitabine

Helena Bresser  1 , Claudia Schmoor  2 , Olga Grishina  2 , Dietmar Pfeifer  1 , Johanna Thomas  1 , Usama-Ur Rehman  1 , Martina Crysandt  3 , Edgar Jost  3 , Felicitas Thol  4 , Michael Heuser  4 , Katharina S Götze  5   6 , Richard F Schlenk  7   8 , Helmut R Salih  9 , Marcus M Schittenhelm  9   10 , Gerhard Heil  11 , Carsten Schwaenen  12 , Carsten Müller-Tidow  7   13 , Wolfram Brugger  14 , Andrea Kündgen  15   16 , Maike de Wit  17 , Aristoteles Giagounidis  18 , Sebastian Scholl  19 , Andreas Neubauer  20 , Jürgen Krauter  21 , Gesine Bug  22   23 , Annette M May  24   25 , Ralph Wäsch  1 , Justus Duyster  1   26 , Konstanze Döhner  27 , Arnold Ganser  4 , Hartmut Döhner  27 , Björn Hackanson  28 , Heiko Becker  1   26 , Michael Lübbert  1   26
Affiliations
Clinical Trial

Impact of TP53 Mutation Status in Elderly AML Patients When Adding All-Trans Retinoic Acid or Valproic Acid to Decitabine

Helena Bresser et al. Eur J Haematol. 2025 Feb.

Abstract

In a randomized phase II trial (AMLSG 14-09, NCT00867672) of elderly, newly diagnosed AML patients, ATRA combined with decitabine (DEC) significantly improved the overall response rate (ORR) and survival also in patients with adverse-risk genetics, without adding toxicity. We performed a post hoc analysis to determine the predictive impact of TP53 status. Despite a nominally higher ORR, the clinically meaningful survival benefit when adding ATRA to DEC was diminished, but not completely negated, in TP53-mutated patients. Indeed, 2 out of 14 TP53-mutated patients (14%) randomized to a DEC + ATRA-containing regimen lived for > 36 months. Further studies of ATRA combined with hypomethylating agents appear warranted in non-M3 AML patients ineligible for HMA/venetoclax therapy. Trial Registration: ClinicalTrials.gov identifier: NCT00867672.

Keywords: TP53; AML; ATRA; HMA; epigenetics.

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Conflict of interest statement

Crysandt

Incyte: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Thol

Abbvie: Honoraria; Pfizer: Honoraria; Astellas: Honoraria; Novartis: Honoraria; BMS/Celgene: Honoraria, Research Funding; Jazz: Honoraria.

Heuser

Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolremo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; BergenBio: Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; Astellas: Research Funding.

Götze

Abbvie: Advisory Board; BMS/Celgene: Advisory Board, Research Funding.

Schlenk

Agios: Honoraria; Astellas: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Abbvie: Honoraria; Hexal: Honoraria; Neovio Biotech: Honoraria; Novartis: Honoraria; Pfizer: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding; AstraZeneca: Research Funding; Boehringer Ingelheim: Research Funding.

Salih

Synimmune GmbH: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Celgene: Honoraria; BMS: Honoraria.

Schittenhelm

Takeda: advisory board; Astellas: advisory board; BMS: advisory board; University of Tuebingen: Patents & Royalties: patent for ASPP2k.

Müller‐Tidow

Pfizer: Research Funding; Janssen: Consultancy, Research Funding; Bioline: Research Funding; Astellas: lecture fees. Germing: speakers honorarium: BMS, Novartis, Janssen: speakers honorarium; BMS, Novartis, Abbvie, Jazz: institutional research report; BMS: Advice.

Giagounidis

Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Bug: Novartis: Support of Investigator‐Initiated Trial to my Institution; Jazz, Gilead, Novartis, BMS, Pfizer: Honoraria; Jazz, Neovii: Travel Grants.

Wäsch

Amgen: Consultancy, Honoraria; Pfizer: Consultancy; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy.

Döhner

Jazz Roche: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Advisory Board; Agios and Astex: Research Funding; Abbvie: Consultancy, Honoraria; Janssen: Honoraria, Advisory Board; Astellas: Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Ganser

Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria.

Döhner

Astellas: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Berlin‐Chemie: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Ulm University Hospital: Current Employment; Jazz: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; GEMoaB: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding.

Hackanson

Roche: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Boehringer‐Ingelheim: Consultancy, Honoraria; MSD: Consultancy, Honoraria. Becker: BMS: Honoraria; Pierre Fabre Pharma: Honoraria; Servier: Honoraria; MSD: Honoraria; Novartis: Honoraria; Lilly: Honoraria; GSK: Honoraria.

Lübbert

Advisory Board: AbbVie, Astex, Otsuka, Syros; Research funding to our institution: Janssen‐Cilag; Research support with study drug: Cheplapharm (ATRA), Imago (Bomedemstat) OffLabel Disclosure: ATRA, in non‐M3 AML valproic acid, in non‐M3 AML.

Figures

FIGURE 1
FIGURE 1
Impact of TP53 mutational status in the DECIDER trial. (A) Overall survival rates of 168 pts. treated on the DECIDER trial, TP53 WT (blue curve: n = 129), TP53 MUT (red curve: n = 39), unadjusted (Kaplan–Meier method), and adjusted for ATRA, VPA, ECOG, HCT‐CI, LDH, Hb (Cox model). (B) Objective response rates (ORR: complete remission with or without complete hematologic recovery, partial remission) of pts. with TP53 WT or TP53 MUT receiving DEC with or without ATRA. (C) Prolonged survival of pts. treated in the DECIDER trial, with (red) or without (green) the addition of ATRA. Shown are pts. with wildtype (WT; n = 19) or mutated (MUT; n = 4) TP53, who lived > 2 years, 14.7% and 10.2%, respectively. This criterion was met by 5/58 WT pts. treated without ATRA (8.6%) and 14/71 WT pts. treated with ATRA (19.7%) as well as 2/25 MUT pts. treated without ATRA (8.0%) and 2/14 MUT pts. treated with ATRA (14.2%). (D) Effect of add‐on treatment (ATRA or VPA added to DEC) on overall survival in pts. with TP53 WT or TP53 MUT, estimated as hazard ratios with 95% confidence intervals. ATRA: all‐trans retinoic acid; DEC: decitabine; VPA: valproic acid.
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