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244 TP53 Mutations in Myeloproliferative Neoplasms: Context-Dependent Evaluation of Prognostic Relevance

Program: Oral and Poster Abstracts
Type: Oral
Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Personalized and Molecular Approaches in Myeloproliferative Neoplasms: Risk Stratification and Therapeutic Implications
Hematology Disease Topics & Pathways:
MPN, Chronic Myeloid Malignancies, Diseases, Myeloid Malignancies
Saturday, December 7, 2024: 2:45 PM

Ayalew Tefferi, MD1, Maymona Abdelmagid, MD2*, Giuseppe Gaetano Loscocco3*, Kebede Begna, MD2, Aref Al-Kali, MD1, James M. Foran, MD4, Jeanne Palmer, MD5, Talha Badar, MD6, Mrinal M. Patnaik, MD, MBBS7, Kaaren K. Reichard, MD8, Rong He, MD9, Cinthya Zepeda Mendoza, PhD2*, Mithun V Shah, M.D., Ph.D.1, Attilio Orazi, MD10*, Daniel A. Arber, MD11, Animesh D. Pardanani, MBBS, PhD2, Alessandro M. Vannucchi, MD, PhD12, Devendra Hiwase, MD, MBBS, PhD, FRACP, FRCPA13, Naseema Gangat, MBBS1 and Paola Guglielmelli, MD14

1Division of Hematology, Mayo Clinic, Rochester, MN
2Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
3Department of Experimental and Clinical Hematology, Centro di Ricerca e Innovazione Malattie Mieloproliferative (CRIMM), AOU Careggi, University of Florence, Florence, Italy
4Division of Hematology & Medical Oncology, Mayo Clinic, Jacksonville, FL
5Mayo Clinic - Arizona, Scottsdale, AZ
6Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL
7Mayo Clinic, Rochester, MN
8Department of Pathology, Mayo Clinic, Rochester, MN
9Division of Hematopathology, Mayo Clinic, Rochester, MN
10Texas Tech University Health Sciences Center, El Paso
11University of Chicago, Chicago, IL
12Department of Clinical and Experimental Medicine, University of Florence, Florence, Italy
13Royal Adelaide Hospital, Adelaide, SA, Australia
14Department of Experimental and Clinical Medicine, Centro di Ricerca e Innovazione Malattie Mieloproliferative (CRIMM), AOU Careggi, University of Florence, Florence, Italy

Background

The prognostic relevance of TP53 mutations (TP53MT) in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) has been extensively studied and the information accessed for defining the new International Consensus Classification (ICC) category of “myeloid neoplasms with mutated TP53” (Blood 2022;140:1200). The latter designation requires ≥10% TP53 variant allele frequency (VAF) for AML and MDS/AML and in case of MDS, multi-hit TP53 or ≥10% VAF associated with complex karyotype (CK). We examined the prognostic relevance of TP53MT in myeloproliferative neoplasms (MPN), specified by subtype and disease stage.

Methods

The current study was conducted under an institutional review board approved minimum risk protocol. Additional informative cases from the University of Florence, Italy and the South Australian Myeloid Neoplasm Registry were included. Diagnostic criteria and assignment of TP53 allelic state were according to the ICC. Next-generation sequencing (NGS) and cytogenetic studies were performed according to institutional standard protocols. Conventional statistical methods were employed. Survival analyses were censored for allogeneic stem cell transplantation (ASCT) and were calculated from the time of first detection of TP53MT.

Results

115 patients with MPN and documented pathogenic TP53MT were considered (median age 68.5 years). ICC-defined subtype designations, at time of TP53MT detection, were polycythemia vera (PV) or essential thrombocythemia (ET) (N=9), chronic phase myelofibrosis (MF-CP; N=63), accelerated phase MPN (MPN-AP; N=16), and blast phase MPN (MPN-BP; N=27). Driver mutation distribution was JAK2 64%, CALR 18%, MPL 8%, and triple-negative 10%. Karyotype was monosomal (MK) in 42%, CK 9%, and normal (NK) 35%. Frequent co-mutations were ASXL1 (28%), TET2 (14%), and SRSF2 (14%). TP53MT were classified as ICC-defined multihit in 67 (58%) cases; karyotype in the latter was MK (58%), CK (16%), non-MK/CK (13%), or NK (13%). TP53 VAF was ≥50% in 27 (24%) patients and <10% in 25 (22%). TP53MT included one (N=96) or ≥2 (N=19). MPN subtype- and stage-specific distributions for multihit TP53MT were 91% for MPN-BP, 88% MPN-AP, 44% MF-CP, and 0% ET/PV.

In order to examine disease subtype- and stage-specific prognostic contribution of TP53MT, the study population was divided into 10 operational groups: 1) PV/ET non-multihit/non-MK/CK (N=8; VAF range 3-32%); 2) MF-CP non-multihit/non-MK/CK with TP53MT VAF <10% (N=10); 3) MF-CP non-multihit VAF ≥10% and non-MK/CK (N=11); 4) PV/ET/MF-CP non-multihit with MK/CK (N=5); 5) MF-CP multihit/non-MK/CK (N=8); 6) MF-CP multihit and MK/CK (N=20); 7) MPN-BP/AP non-multihit/non-MK/CK (N=2); 8) MPN-BP/AP non-multihit with MK/CK (N=2); 9) MPN-BP/AP multihit/non-MK/CK (N=9); and 10) MPN-BP/AP multihit with MK/CK (N=30). The corresponding median survivals were “not reached”, 55, 42, 6, 18, 10, “not reached”, 4, 4, and 6 months (p<0.01).

Survival was similar between groups 1, 2, and 3 (p>0.2 for all comparisons) now referred to as “PV/ET/MF-CP non-multihit/non-MK/CK (N=39)”. Survival was similarly dismal for groups 8, 9, and 10 (p values > 0.3 for all comparisons) now referred to as “MPN-BP/AP with or without multihit TP53MT or MK/CK (N=43)”. Survival was also similar between groups 4, 5, and 6 (p values >3 for all comparisons) now referred to as “PV/ET/MF-CP with multihit TP53MT or MK/CK (N=33)”. The three consolidated groups were subsequently compared for survival that showed a significantly worse outcome for “MPN-BP/AP with or without multihit TP53MT or MK/CK” with median survival of 4 months, compared to 12 months for “PV/ET/MF-CP with multihit TP53MT or MK/CK” (HR 2.3; 95% CI; 1.3-3.9) and 55 months for “PV/ET/MF-CP non-multihit/non-MK/CK” (10.9; 95% CI 5.3-22.4); survival in the latter two groups was also significantly different, in favor of PV/ET/MF-CP non-multihit/non-MK/CK (HR 4.8; 95% CI 2.3-10.1).

Conclusions: The presence of multi-hit TP53MT or MK/CK, in MF-CP, and possibly in ET/PV, warrants their inclusion in the ICC category of “myeloid neoplasms with mutated TP53”. By contrast, non-multihit TP53MT in ET/PV/MF-CP, regardless of VAF and in the absence of MK/CK, does not appear to compromise short-term survival. The observations from the current study also suggest a prognostic hierarchy with blast percentage being the most unfavorable, followed by MK/CK and multihit TP53MT.

Disclosures: Begna: Novartis: Membership on an entity's Board of Directors or advisory committees. Badar: Takeda: Other: advisory board ; Morphosys: Other: Advisory Board; pfizer: Other: Advisory board. Patnaik: Solu therapeutics: Research Funding; Polaris: Research Funding; StemLine: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Research Funding; Epigenetix: Research Funding. Vannucchi: Incyte: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Blueprint: Consultancy, Speakers Bureau; AOP: Consultancy, Speakers Bureau. Hiwase: Abbvie: Honoraria; Astella Pharma: Honoraria; Otsuka: Honoraria. Gangat: Agios: Other: Advisory Board; DISC Medicine: Consultancy, Other: Advisory Board . Guglielmelli: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AOP: Honoraria; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH