Clinical implications of TP53 mutations (TP53MT) in patients (pts) with higher risk Myelodysplastic Syndromes (HR-MDS) treated with hypomethylating agents (HMA) and allogeneic hematopoietic transplantation (allo-HCT): An analysis from the international consortium of MDS (icMDS) validate database
Abstract
Abstract Introduction TP53MT are associated with poor outcomes in MDS, especially in the context of biallelic MT. We have previously reported on outcomes of pts with HR-MDS with TP53MT who received HMA in the VALIDATE dataset (Kewan T et al, ASH 2023). Here we provide expanded analyses focusing on outcomes post allo-HCT, and we explore the prognostic significance of different classification methods for biallelic TP53MT. Methods The VALIDATE database includes 4,732 pts with MDS who received HMA-based frontline therapy from 32 international centers in 9 countries. For this study, only pts with HR-MDS with molecular data at time of diagnosis were included. Biallelic TP53MT status was assessed using three classification schemes: WHO 2022, ICC 2022, and a VAF-based Cleveland Clinic Foundation (CCF) method.1TP53 copy neutral loss of heterozygosity (CN-LOH) was evaluable in 386 pts (118 had TP53MT). Treatment responses were evaluated using IWG 2023 criteria (Zeidan A et al, Blood 2023). Composite complete remission (cCR) was defined as CR+CRbi+CRuni+CRh+CRequivalent. We calculated OS from time of HMA initiation to date of death or last follow up. Unsupervised clustering (MOSAIC framework) was applied to identify molecular subgroups within the TP53MT cohort. The study was funded by an independent grant from Abbvie. Results A total of 1,485 pts were included. Median age was 69 years (IQR: 62–76), with 66% male pts. Median bone marrow blast was 7%, and 28% had a complex karyotype. Treatment regimens included azacitidine (68%), decitabine (15%), HMA/Venetoclax (8%), and other HMA combinations (9%); 34% underwent allo-HCT. Overall, 392 (26%) had TP53MT with 430 TP53 mutations (missense: 316; truncating: 89). Biallelic TP53MT % varied by classification: 72% (WHO), 84% (ICC), and 85% (CCF). Compared to TP53 wild-type (TP53WT) pts, pts with TP53MT had worse OS (median: 11.5 vs. 23.9 months [mo], p< 0.001), were younger (68 vs. 70 years, p=0.039), and had lower counts at diagnosis. Complex karyotype (81% vs. 14%) and chromosomal abnormalities were more frequent in TP53MT pts. Pts with TP53MT also had fewer co-mutations in other genes. Response to HMA was evaluable in 1,094 pts: cCR and CR were 32% and 13%, respectively. TP53MT pts had higher cCR (39% vs. 29%, p=0.001) than TP53WT, but similar CR rates (16% vs. 12%, p=0.093). According to WHO 2022, biallelic TP53MT had higher CR rates than monoallelic TP53MT (18% vs. 8%, p=0.03), but similar cCR. ICC and CCF classifications did not differentiate response rates. Median OS did not differ by TP53MT allelic status using WHO or ICC definitions. However, using the CCF method, pts with biallelic TP53MT had shorter OS than monoallelic TP53MT (10.4 vs. 17.2 mo, p=0.038). In multivariable models adjusted for age, gender, and allo-HCT, only the CCF-defined biallelic TP53MT group had significantly worse OS (HR: 1.6; 95% CI: 1.1–2.4). TP53MT pts undergoing allo-HCT had improved OS regardless of allelic status. Median OS for TP53MT pts with allo-HCT was 18.9 vs. 9.2 mo without all-HCT. This benefit was observed across WHO, ICC, and CCF classifications. However, a TP53MT VAF ≥19% predicted worse OS even post allo-HCT (14.6 vs. 47.1 mo, p<0.001). At 1 year, the survival rate was 78% (95%CI: 69-89%) in TP53MT pts who underwent allo-HCT and had cCR vs. 68% (95%CI: 55-84%) in pts who did not have cCR. However, 1 year survival rate was significantly higher for pts with TP53MT who did not have allo-HCT and achieved cCR (60%, 95%CI: 48-76%) vs. no cCR (26%, 95%CI: 20-35%). Unsupervised clustering of 335 TP53MT pts identified 9 molecular clusters (MCs). MC2, characterized by low TP53MT VAF (median 17%), fewer co-mutations, and frequent del17p, was associated with significantly improved OS (17.9 mo) and predicted favorable outcome (HR for death: 0.6; 95% CI: 0.4–0.8). Other clusters were enriched for adverse features (e.g., high VAF, multi-hit TP53MT).Conclusions The CCF method appears to best classify biallelic TP53MT pts with worse survival in the absence of accurate assessment of LOH status. Treatment response per IWG 2023 for TP53MT pts was associated with OS only in non-transplanted pts. Allo-HCT improved survival across TP53MT subsets, but TP53 VAF ≥19% at diagnosis remained a strong negative prognostic factor. Integrative clustering revealed a less aggresive molecular subset among TP53MT pts, suggesting refined risk stratification may guide therapy in this high-risk population. Ref: 1.Bahaj et al. J Hematol Oncol 2023.
Article Details
Authors (58)
Tariq Kewan
1Cleveland Clinic, Department of Translational Hematology and Oncology Research, Cleveland, United States
Jan Philipp Bewersdorf
Luca Lanino
3Yale University, New Haven, United States
Ondrej Blaha
5Yale University, School of Public Health, Yale Center for Analytical Sciences, New Haven, United States
Jessica Stempel
5Yale University, School of Public Health, Yale Center for Analytical Sciences, New Haven, United States
Najla Al Ali
9Moffitt Cancer Center, Department of Malignant Hematology, Tampa, United States
Amy DeZern
1Johns Hopkins University School of Medicine, Oncology, Baltimore, United States
Mikkael Sekeres
13Sylvester Cancer Center, University of Miami Health System, Miami, United States
Geoffrey Uy
18Washington University School of Medicine, Saint Louis, United States
Samuel Urrutia
10Washington University School of Medicine, Saint Louis, United States
Hetty Carraway
1Cleveland Clinic, Internal Medicine, Cleveland, United States
Pinkal Desai
Elizabeth Griffiths
8Roswell Park Comprehensive Cancer Center, Buffalo, United States
Eytan Stein
3Memorial Sloan Kettering Cancer Center, Medicine, New York, United States
Andrew Brunner
3Dana-Farber Cancer Institute, Boston, United States
Christine McMahon
2University of Colorado School of Medicine, Division of Hematology, Aurora, United States
Rory Shallis
1H. Lee Moffitt Cancer Center, Tampa, United States
Joshua Zeidner
5University of North Carolina, Chapel Hill, United States
Michael Savona
7Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, United States
Namrata Chandhok
9Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States
Constantine Logothetis
10Washington University School of Medicine, Saint Louis, United States
Aram Bidikian
3Yale University, Department of Internal Medicine, Section of Hematology, New Haven, United States
Theodore Getz
3Yale University, Department of Internal Medicine, Section of Hematology, New Haven, United States
Gail Roboz
3Weill Cornell Medicine and The New York Presbyterian Hospital, New York, United States
Benjamin Rolles
1Brigham and Women's Hospital, Harvard Medical School, Division of Hematology, Department of Medicine, Boston, United States
Eunice Wang
13Roswell Park Comprehensive Cancer Center, Buffalo, United States
Amyah Harris
11Harvard Medical School, Division of Hematology/Oncology, Massachusetts General Hospital, Boston, United States
Maria Amaya
2University of Colorado School of Medicine, Division of Hematology, Aurora, United States
Hayley Hawkins
17Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States
Somedeb Ball
2Vanderbilt University School of Medicine, Division of Hematology and Oncology, Nashville, United States
Justin Grenet
12Weill Cornell Medicine, New York City, United States
Zhuoer Xie
Moffitt Cancer Center, Tampa, Florida, United States
Yazan Madanat
Yasmin Abaza
19Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Division of Hematology and Oncology, Leukemia Program, Chicago, United States
Talha Badar
Mayo Clinic, Jacksonville, Florida, United States
Jaclynn Campos
20Mayo Clinic, Division of Hematology-Oncology, Jacksonville, United States
Torsten Haferlach
7Munich Leukemia Laboratory, Munich, Germany
Jaroslaw Maciejewski
1Department of Translational Hematology and Oncology Research, Cleveland, United States
Anoop Enjeti
22Calvary Mater Hospital, Australia and Australasian Leukaemia and LymphomaGroup (ALLG), Department of Haematology, Newcastle, Australia
Kamal Al-Rabi
25King Hussein Cancer Center, Amman, Jordan
Khalid Halahleh
10Department of Internal Medicine, Adult BMT Program, King Hussein Cancer Center, Amman, Jordan
Devendra Hiwase
24The Royal Adelaide Hospital, Department of Haematology, Adelaide, Australia
Maria Diez-Campelo
11Hospital Clínico Universitario de Salamanca, Salamanca, Spain
David Valcárcel
Claudia Haferlach
8Munich Leukemia Laboratory, Munich, Germany
Lisa Pleyer
Ioannis Kotsianidis
29Department of Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
Vassiliki Pappa
2University General Hospital Attikon, Second Department of Internal Medicine and Research Institute, Athens, Greece
Valeria Santini
7DMSC University of Florence, AOUC, MDS Unit, Hematology, Florence, Italy
Angela Consagra
30University of Florence, MDS Unit, Hematology, AOU Careggi - Department of Experimental and Clinical Medicine, Florence, Italy
Aref Al-Kali
1Mayo Clinic, Division of Hematology, Department of Medicine, Rochester, United States
Seishi Ogawa
Yasuhito Nannya
Rami Komrokji
Moffitt Cancer Cancer and Research Institute, Tampa, Florida, United States
Maximilian Stahl
Matteo Della Porta
1IRCCS Humanitas Research Hospital, AI Center, Rozzano, Italy
David Sallman
Moffitt Cancer Cancer and Research Institute, Tampa, Florida, United States
Amer Zeidan
18Yale School of Medicine - Yale Cancer Center, New Haven, United States