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ACUTE MYELOID LEUKEMIA

Prognostic implications of mono-hit and multi-hit TP53 alterations in patients with acute myeloid leukemia and higher risk myelodysplastic syndromes treated with azacitidine-based therapy

Leukemia volume 37, pages 240–243 (2023)Cite this article

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Mutations in TP53 confer an adverse prognosis in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) and are found in 10–15% of patients [1,2,3,4,5,6]. Outcomes of TP53 mutated AML and MDS patients also vary based on characteristics of the TP53 alterations and co-occurring genetic abnormalities [2, 6, 7]. Most recently, TP53 alterations have been formally included in AML and MDS classifications and risk stratification tools [4, 8, 9]. Both of the two recently published classifications of myeloid tumors proposed by the International Consensus Classification (ICC) and World Health Organization (WHO) introduced a novel MDS subcategory based on the presence and specific characteristics of TP53 mutations [8, 9]. Similarly, the molecular IPSS (IPSS-M) includes biallelic TP53 mutations as the most influential prognostic variable in the model [4].

However, recent data were conflicting regarding the prognostic impact of mono- vs bi-allelic TP53 mutation status [2, 6, 10]. It is important to note that cross-study comparisons are limited by differences in patient populations (e.g., MDS patients in Bernard et al. vs AML/MDS with excess blasts patients by Grob et al.) and treatment patterns, which results in uncertainty how the various results apply in different settings [6, 11]. To evaluate the prognostic implications of divergent classifications of TP53 mutation status, we analyzed a highly annotated genetic, clinical, and pathological dataset from 205 patients with previously untreated AML and higher risk (HR)-MDS who were uniformly treated with a hypomethylating agent (HMA)-based regimen and followed prospectively in the context of a clinical trial [12, 13]. In the FUSION AML-001 trial (NCT02775903), patients with intermediate, high, or very high risk IPSS-R MDS and older/unfit AML patients were randomized to azacitidine (AZA) + durvalumab or AZA monotherapy [12, 13]. As there was no difference in outcomes by treatment including among TP53 mutated patients, we combined AML and HR-MDS patients independent of treatment assignment [12, 13]. Responses were recorded per the International Working Group 2003 and 2006 criteria [14, 15]. Overall survival (OS) was assessed from the time of randomization.

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Fig. 1: Overall survival by TP53 mutation status.

Data availability

Original data are available from the corresponding author at request.

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Acknowledgements

AMZ is a Leukemia and Lymphoma Society Scholar in Clinical Research.

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Author notes

  1. These authors contributed equally: Amer M. Zeidan, Jan Philipp Bewersdorf.

Authors and Affiliations

  1. Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, Yale University, New Haven, CT, USA

    Amer M. Zeidan, Jan Philipp Bewersdorf, Rory M. Shallis & Stephanie Halene

  2. Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Jan Philipp Bewersdorf

  3. Bristol Myers Squibb, Princeton, NJ, USA

    Vanessa Hasle, Ethan Thompson, Daniel Lopes de Menezes, Shelonidta Rose, Isaac Boss & Brian Fox

  4. MLL Munich Leukemia Laboratory, Munich, Germany

    Torsten Haferlach

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Contributions

JPB, BF, and AMZ conceptualized the study. BF, VH, ET, and TH performed data analyses. JPB and AMZ wrote the initial manuscript draft. All authors interpreted data and contributed to subsequent drafts of the manuscript.

Corresponding author

Correspondence to Amer M. Zeidan.

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Competing interests

AMZ received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Cardiff oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. AMZ participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, and Tyme. AMZ served on clinical trial committees for Novartis, Abbvie, Gilead, BioCryst, Abbvie, ALX Oncology, Geron and Celgene/BMS. RMS participated in advisory boards, and/or had a consultancy with and received honoraria from Bristol Myers Squibb and Gilead Sciences, Inc; divested equity interest in Curis Oncology. IB, ET, BAF, VEH, and SR are employees of Celgene, a Bristol Myers Squibb company, and may be shareholders. SH has received research funding received honoraria from FORMA Therapeutics. TH is the owner of Munich Leukemia Laboratory. All other authors have no relevant conflicts of interest to declare.

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Zeidan, A.M., Bewersdorf, J.P., Hasle, V. et al. Prognostic implications of mono-hit and multi-hit TP53 alterations in patients with acute myeloid leukemia and higher risk myelodysplastic syndromes treated with azacitidine-based therapy. Leukemia 37, 240–243 (2023). https://doi.org/10.1038/s41375-022-01766-z

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