Öz
Objective: Acute myeloid leukemia (AML) with TP53 mutations represents a distinct and high-risk molecular subgroup characterized by aggressive disease progression, chemoresistance, and poor survival outcomes. This study provides a single-center analysis of clinical characteristics, treatment responses, and survival outcomes in a real-world cohort of patients with TP53-mutated AML.
Material and Method: A retrospective observational study was conducted at Ankara Etlik City Hospital, analyzing nine patients diagnosed with TP53-mutated AML between January 2023 and January 2024. Patients were treated with intensive or less intensive induction regimens based on patient-related factors. Cytogenetic and molecular abnormalities were recorded, alongside treatment responses were assessed per the European Leukemia Net 2022 guidelines. The primary endpoint was overall survival.
Results: The median age at diagnosis was 65 years, with 55.5% female patients. Complex karyotypes were observed in 66.7% of cases, and multi-hit TP53 mutations were identified in two patients. A complete response was achieved in 75% of patients treated with intensive induction therapy (7+3), while a complete or partial response was achieved in 60% of patients receiving the azacitidine-venetoclax regimen. Six patients died within 12 months, predominantly due to infection, while the three surviving patients underwent for allogeneic hematopoietic stem cell transplantation (allo-HSCT). The median overall survival (OS) of the entire cohort was 9 months. Patients with TP53-mutated AML who underwent allo-HSCT exhibited significantly prolonged OS (p=0.01).
Conclusion: The prognosisof TP53-mutated AML remains particularly poor, highlighting an urgent need for the development of novel therapeutic approaches to improve patient outcomes. While allo-HSCT offers a potential survival benefit, effective bridging therapies and post-transplant management are critical for improving outcomes in this high-risk population
Anahtar Kelimeler
Acute myeloid leukemia stem cell transplantation survival TP53 mutation treatment
Etik Beyan
Per the principles outlined in the Declaration of Helsinki, the Institutional Review Board of the xxx Hospital reviewed and approved the study protocol (Date: 31-07-2024, Number: AEŞK-BADEK-2024-592).
Destekleyen Kurum
No relevant financial support.
Kaynakça
- Santini V, Stahl M, Sallman DA. TP53 Mutations in Acute Leukemias and Myelodysplastic Syndromes: Insights and Treatment Updates. Am Soc Clin Oncol Educ Book 2024;44(3):e432650.
- Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP. Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer 2009;9(12):862-873.
- Wong TN, Ramsingh G, Young AL et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature 2015;518(7540):552-555.
- Rücker FG, Schlenk RF, Bullinger L et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood 2012;119(9):2114-2121.
- Arber DA, Orazi A, Hasserjian RP et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood 2022;140(11):1200-1228.
- Khoury JD, Solary E, Abla O et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/ Dendritic Neoplasms. Leukemia 2022;36(7):1703-1719.
- Döhner H, Wei AH, Appelbaum FR et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 2022;140(12):1345-1377.
- Döhner H, Dolnik A, Tang L et al. Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conventional care. Leukemia 2018;32(12):2546-2557.
- Shin DY. TP53 Mutation in Acute Myeloid Leukemia: An Old Foe Revisited. Cancers (Basel) 2023;15(19):4816.
- Gannamani V, Baranwal A, Langer KJ et al. Impact of Wilms Tumor (WT1) Mutation on Relapse and Overall Survival in Acute Myeloid Leukemia Patients Following Allogenic Stem Cell Transplantation. Transplantation and Cellular Therapy, Official Publication of the American Society for Transplantation and Cellular Therapy 2024;30(2):112 - 113.
- Bowen D, Groves MJ, Burnett AK et al. TP53 gene mutation is frequent in patients with acute myeloid leukemia and complex karyotype, and is associated with very poor prognosis. Leukemia 2009;23(1):203-206.
- DiNardo CD, Jonas BA, Pullarkat V et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med 2020;383(7):617-629.
- Pollyea DA, Pratz KW, Wei AH et al. Outcomes in Patients with Poor-Risk Cytogenetics with or without TP53 Mutations Treated with Venetoclax and Azacitidine. Clin Cancer Res 2022;28(24):5272-5279.
- Sumransub N, Steinwand GK, Lee Y et al. TP53-Mutated Acute Myeloid Leukemia Patients Treated with Intensive Therapies Have Superior Outcomes: A Single Institution, Retrospective Study. Blood 2023;142(Supplement 1):1526.
- Badar T, Atallah E, Shallis RM et al. Outcomes of TP53-mutated AML with evolving frontline therapies: Impact of allogeneic stem cell transplantation on survival. Am J Hematol 2022;97(7):232-235.
Öz
Amaç: TP53 mutasyonlu akut myeloid lösemi (AML), agresif hastalık seyri, kemoterapi direnci ve kötü sağkalım sonuçlarıyla karakterize, yüksek riskli ve farklı bir moleküler alt grup olarak tanımlanır. Bu çalışma, TP53 mutasyonlu AML hastalarının klinik özelliklerini, tedavi yanıtlarını ve sağkalım sonuçlarını tek merkezden bir gerçek yaşam kohortunun analiziyle sunmaktadır.
Gereç ve Yöntem: Ocak 2023 ile Ocak 2024 tarihleri arasında Ankara Etlik Şehir Hastanesi’nde TP53 mutasyonlu AML tanısı alan dokuz hastanın verileri retrospektif gözlemsel bir çalışmayla incelendi. Hastalar, hasta ile ilgili faktörlere bağlı olarak yoğun veya yoğun olmayan indüksiyon rejimleriyle tedavi edildi. Sitogenetik ve moleküler anomaliler kaydedildi ve tedavi yanıtları Avrupa Lösemi Ağı (ELN) 2022 kılavuzuna göre değerlendirildi. Birincil sonlanım noktası genel sağkalım idi.
Bulgular: Tanı anındaki medyan yaş 65 olup, hastaların %55,5’i kadındı. Olguların %66,7’sinde kompleks karyotip gözlendi ve iki hastada çoklu-vuruş TP53 mutasyonları tespit edildi. Yoğun indüksiyon tedavisi (7+3) ile tedavi edilen hastaların %75’inde tam yanıta ulaşılırken, azasitidin-venetoklaks rejimi alan hastaların %60’ında tam veya kısmi yanıt elde edildi. Tanıdan sonraki 12 ay içinde altı hasta, çoğunlukla enfeksiyon nedeniyle hayatını kaybederken, hayatta kalan üç hasta allojeneik hematopoetik kök hücre nakli (AHKHN) yapılan hastalardı. Tüm kohortun ortanca genel sağkalımı 9 ay idi. AHKHN yapılan hastalarda genel sağkalım anlamlı şekilde daha uzundu (p=0,01).
Sonuç: TP53 mutasyonlu AML’nin prognozu halen son derece kötü olmaya devam etmektedir ve bu durum hasta sonuçlarını iyileştirmek için yeni tedavi yaklaşımlarının geliştirilmesine acil ihtiyaç duyulduğunu göstermektedir. AHKHN potansiyel bir sağkalım faydası sunsa da, etkili köprüleme tedavileri ve nakil sonrası yönetim, bu yüksek riskli popülasyonda sonuçların iyileştirilmesinde kritiktir.
Anahtar Kelimeler
Akut myeloid lösemi kök hücre nakli sağkalım tedavi TP53 mutasyonu
Kaynakça
- Santini V, Stahl M, Sallman DA. TP53 Mutations in Acute Leukemias and Myelodysplastic Syndromes: Insights and Treatment Updates. Am Soc Clin Oncol Educ Book 2024;44(3):e432650.
- Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP. Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer 2009;9(12):862-873.
- Wong TN, Ramsingh G, Young AL et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature 2015;518(7540):552-555.
- Rücker FG, Schlenk RF, Bullinger L et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood 2012;119(9):2114-2121.
- Arber DA, Orazi A, Hasserjian RP et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood 2022;140(11):1200-1228.
- Khoury JD, Solary E, Abla O et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/ Dendritic Neoplasms. Leukemia 2022;36(7):1703-1719.
- Döhner H, Wei AH, Appelbaum FR et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 2022;140(12):1345-1377.
- Döhner H, Dolnik A, Tang L et al. Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conventional care. Leukemia 2018;32(12):2546-2557.
- Shin DY. TP53 Mutation in Acute Myeloid Leukemia: An Old Foe Revisited. Cancers (Basel) 2023;15(19):4816.
- Gannamani V, Baranwal A, Langer KJ et al. Impact of Wilms Tumor (WT1) Mutation on Relapse and Overall Survival in Acute Myeloid Leukemia Patients Following Allogenic Stem Cell Transplantation. Transplantation and Cellular Therapy, Official Publication of the American Society for Transplantation and Cellular Therapy 2024;30(2):112 - 113.
- Bowen D, Groves MJ, Burnett AK et al. TP53 gene mutation is frequent in patients with acute myeloid leukemia and complex karyotype, and is associated with very poor prognosis. Leukemia 2009;23(1):203-206.
- DiNardo CD, Jonas BA, Pullarkat V et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med 2020;383(7):617-629.
- Pollyea DA, Pratz KW, Wei AH et al. Outcomes in Patients with Poor-Risk Cytogenetics with or without TP53 Mutations Treated with Venetoclax and Azacitidine. Clin Cancer Res 2022;28(24):5272-5279.
- Sumransub N, Steinwand GK, Lee Y et al. TP53-Mutated Acute Myeloid Leukemia Patients Treated with Intensive Therapies Have Superior Outcomes: A Single Institution, Retrospective Study. Blood 2023;142(Supplement 1):1526.
- Badar T, Atallah E, Shallis RM et al. Outcomes of TP53-mutated AML with evolving frontline therapies: Impact of allogeneic stem cell transplantation on survival. Am J Hematol 2022;97(7):232-235.
Ayrıntılar
| Birincil Dil | İngilizce |
|---|---|
| Konular | Hematoloji, İç Hastalıkları |
| Bölüm | Araştırma Makaleleri |
| Yazarlar | |
| Yayımlanma Tarihi | 23 Haziran 2025 |
| Gönderilme Tarihi | 29 Ocak 2025 |
| Kabul Tarihi | 5 Nisan 2025 |
| Yayımlandığı Sayı | Yıl 2025 Cilt: 7 Sayı: 2 |
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