TP53 mutations identify high-risk events for peripheral T-cell lymphoma treated with CHOP-based chemotherapy

Authors

William T. Johnson

Nivetha Ganesan

Zachary D. Epstein-Peterson

Alison J. Moskowitz

Robert N. Stuver

Ahmet Dogan

Nikolaus D. Schultz

Maria E. Arcila

Steven M. Horwitz

Doi

10.1182/bloodadvances.2023009953

PMID: 37078708 · DOI: 10.1182/bloodadvances.2023009953 · Journal: Blood Advances (2023)

TL;DR

Retrospective single-institution (MSK) study of 132 adults with nodal peripheral T-cell lymphoma (PTCL) treated with curative-intent CHOP-based chemotherapy and profiled on MSK-IMPACT. TP53 mutations and TP53/17p deletions were the only somatic aberrancies correlating with inferior progression-free survival (PFS); median PFS was 4.5 vs 10.5 months for TP53-mutated vs TP53-wildtype cases. CDKN2A deletions (n=9) correlated with inferior overall survival (OS) PMID:37078708.

Cohort & data

  • 132 adults with nodal PTCL (PTCL-NOS, AITL, PTCL-TFH, ALK+/− ALCL) plus EATL and MEITL, treated at MSK 2015–2020 with curative-intent CHOP-based chemotherapy and profiled on MSK-IMPACT (up to 500 genes; IMPACT341 / IMPACT410 / IMPACT468 depending on era) PMID:37078708.
  • Three analysis cohorts: entire cohort (N=132), complete clinical data (CCD, n=87), prospective (n=72).
  • Histology mix: AITL 47%, PTCL-NOS 27%, ALK− ALCL 11%, PTCL-TFH 7%, ALK+ ALCL 5%, MEITL 3%.
  • Regimens: CHOEP/EPOCH 45%, CHOP 30%, BV-CH(E)P 12%, CHOP + novel agent 13%.
  • Genetic data deposited in cBioPortal as study mtnn_msk_2022.

Key findings

  • Most frequently mutated genes across the cohort: TET2 52% (n=69), RHOA 30% (n=40), DNMT3A 19% (n=25), TP53 16% (n=21), IDH2 11% (n=15) PMID:37078708.
  • Most common CNAs: TP53 deletions 7% (n=9) and CDKN2A deletions 7% (n=9).
  • On multivariate analysis in the CCD cohort, clinical factors predicting inferior PFS were advanced-stage disease (HR 5.1) and bone marrow involvement. Somatic factors predicting inferior PFS were TP53 mutations (HR 3.1; 95% CI 1.4–6.8; P=.005) and TP53/17p deletions (HR 4.1; 95% CI 1.1–15.0; P=.03).
  • Median PFS: 4.5 months for TP53-mutated PTCL (n=21) vs 10.5 months for TP53-wildtype PTCL (n=111).
  • Of 21 TP53-mutated cases, 15 (71%) had no concurrent TP53/17p deletion; 6 (29%) were co-deleted.
  • No TP53 aberrancy correlated with inferior OS.
  • CDKN2A deletion correlated with inferior OS (HR 12.1; 95% CI 2.8–52.0; P<.001); median OS 17.6 months vs 56.7 months.
  • In AITL, 88% of RHOA mutations were the canonical G17V variant.
  • In MEITL (n=4), 3/4 (75%) had CDKN2A aberrancies.

Genes & alterations

  • TP53 — mutations in 16% (21/132); inferior PFS (HR 3.1, P=.005). TP53/17p deletions in a subset also inferior PFS (HR 4.1, P=.03). Neither correlated with OS.
  • CDKN2A — homozygous/heterozygous deletions in 7% (9/132); strong independent predictor of inferior OS (HR 12.1, P<.001). Enriched in MEITL (3/4 cases).
  • TET2 — most frequently mutated gene (52%), no independent prognostic effect reported.
  • RHOA — 30%; 88% of mutations in AITL were G17V.
  • DNMT3A — 19%.
  • IDH2 — 11%.
  • STAT3, FAT1, TP63 — additional recurrently altered genes profiled in subset analyses.

Clinical implications

  • TP53 mutation status identifies PTCL patients with markedly inferior PFS on CHOP-based induction and may warrant consideration of alternative induction or consolidation strategies and stratification in first-line randomized trials PMID:37078708.
  • CDKN2A deletion flags a rare but very high-risk subset for OS, particularly relevant in MEITL.
  • Authors explicitly state these findings warrant prospective confirmation.

Limitations & open questions

  • Single-institution retrospective design at a referral center; selection bias risk (hence three nested cohorts).
  • Small absolute numbers for some subsets (e.g., MEITL n=4, ALK+ ALCL n=6, CDKN2A-deleted n=9); HR confidence intervals are wide.
  • Targeted panel (MSK-IMPACT) rather than WES/WGS — non-panel drivers not assessed.
  • Heterogeneous CHOP-based regimens (CHOP, CHOEP/EPOCH, BV-CH(E)P, + novel agents) complicate treatment-specific inference.
  • Discordance between PFS and OS effect of TP53 is unexplained — possibly salvage therapy confounding.

Citations from this paper used in the wiki

  • “The only somatic genetic aberrancies correlating with inferior progression-free survival (PFS) were TP53 mutations and TP53/17p deletions.” (Abstract / Key Points)
  • “median PFS of 4.5 months for PTCL with a TP53 mutation (n=21) vs 10.5 months for PTCL without a TP53 mutation (n=111)” (Abstract)
  • “Although rare (n=9), CDKN2A-deleted PTCL correlated with inferior OS, with a median of 17.6 months vs 56.7 months” (Abstract)
  • “TP53 mutations (HR, 3.1; 95% CI, 1.4-6.8; P = .005) and TP53/17p deletions (HR, 4.1; 95% CI, 1.1-15.0; P = .03)” (Results, multivariate PFS)
  • “CDKN2A deletion (HR, 12.1; 95% CI, 2.8-52.0; P < .001)” (Results, multivariate OS)

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