TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Authors

John S. Welch

Allegra A. Petti

Christopher A. Miller

Catrina C. Fronick

Michelle O’Laughlin

Robert S. Fulton

Richard K. Wilson

Jack D. Baty

Eric J. Duncavage

Bevan Tandon

Yi-Shan Lee

Lukas D. Wartman

Geoffrey L. Uy

Armin Ghobadi

Michael H. Tomasson

Iskra Pusic

Rizwan Romee

Todd A. Fehniger

Keith E. Stockerl-Goldstein

Ravi Vij

Stephen T. Oh

Camille N. Abboud

Amanda F. Cashen

Mark A. Schroeder

Meagan A. Jacoby

Sharon E. Heath

Kierstin Luber

Megan R. Janke

Andrew Hantel

Niloufer Khan

Madina J. Sukhanova

Randall W. Knoebel

Wendy Stock

Timothy A. Graubert

Matthew J. Walter

Peter Westervelt

Daniel C. Link

John F. DiPersio

Timothy J. Ley

Doi

10.1056/NEJMoa1605949

PMID: 27959731 · DOI: 10.1056/NEJMoa1605949 · Journal: New England Journal of Medicine (2016)

TL;DR

Welch and colleagues prospectively treated 84 adults with AML or MDS on a single-institution trial of decitabine (20 mg/m²/day on days 1–10 of 28-day cycles) at Washington University in St. Louis, with an extension cohort of 32 additional patients (combined N=116). Enhanced exome and amplicon-panel sequencing revealed that all 21 patients with TP53 mutations achieved bone-marrow blast clearance (<5%) versus 32 of 78 wild-type-TP53 patients (100% vs 41%, P<0.001), and patients with unfavorable-risk cytogenetics had higher response rates than intermediate/favorable-risk patients (67% vs 34%, P<0.001). Despite these high response rates, mutation clearance was never complete, remissions were short-lived, and overall survival in TP53-mutant patients (median 12.7 months) was similar to wild-type-TP53 patients (15.4 months, P=0.79) — outcomes notably better than the 4–6 month survival typically seen with cytotoxic induction in TP53-mutant AML.

Cohort & data

  • Trial: Single-arm, prospective trial at Washington University in St. Louis (March 2013 – November 2015), ClinicalTrials.gov NCT01687400; cBioPortal study mnm_washu_2016.
  • Enrollment groups: AML ≥60 yr, relapsed AML, or transfusion-dependent MDS; ECOG performance status ≤2.
  • Discovery cohort: 84 patients on the WashU 10-day decitabine protocol.
  • Extension cohort: 32 additional patients — 24 with relapsed AML who received 10-day decitabine at the University of Chicago (2005–2010), and 8 patients on a 5-day decitabine schedule at WashU (5 single-agent, 3 combined with panobinostat 10 mg three times weekly).
  • Combined cohort: 116 patients total; 99 had any-type sequencing performed.
  • Sequencing assays:
  • Comparator dataset: TCGA AML cohort (laml_tcga_pub) used to benchmark the spectrum of TP53 mutations and methylation patterns.
  • Data deposition: Exome data in dbGaP (phs000159); methylation arrays in GEO (GSE80762).

Key findings

  • Overall response (combined N=116): 53/116 (46%) achieved bone-marrow blast clearance (<5% blasts): 15 (13%) complete remission (CR), 24 (21%) CR with incomplete count recovery (CRi), 14 (12%) morphologic CR (mCR with or without hematologic improvement). Partial response 9 (8%), stable disease 23 (20%), progressive disease 19 (16%).
  • TP53 mutations are a positive predictor of decitabine response: 21 of 21 (100%) TP53-mutant patients achieved blast clearance vs 32 of 78 (41%) wild-type-TP53 patients (P<0.001). In the discovery cohort alone, 7/7 TP53-mutant patients responded vs 15/32 (47%) without TP53 mutations (P=0.02).
  • Unfavorable cytogenetics also predicted response: 29/43 (67%) with unfavorable-risk karyotypes had blast clearance vs 24/71 (34%) with intermediate/favorable risk (P<0.001). 20 of 21 TP53-mutant patients had an unfavorable-risk karyotype.
  • Mutation clearance is universal but incomplete: Across 54 patients with serial sequencing (median 4 timepoints/patient), only TP53 and SF3B1 mutations consistently dropped to variant allele frequency (VAF) <5%; founding-clone VAF at maximum clearance still ranged from 0.06% to 18.43% in the 20 best responders. Bone-marrow blast clearance preceded mutation reduction in 15/54 patients.
  • Survival is not worsened by TP53 or unfavorable cytogenetics on this regimen: Median overall survival 12.7 mo (TP53-mutant) vs 15.4 mo (wild-type-TP53), P=0.79; 11.6 mo (unfavorable-risk) vs 10 mo (intermediate/favorable-risk), P=0.29. By contrast, conventional anthracycline+cytarabine induction in TP53-mutant AML yields median survival of only 4–6 months.
  • Subclonal architecture and resistance: Differential decitabine sensitivity within subclones was observed in 11/39 exome-sequenced patients — 2 had sensitive subclones inside a resistant founding clone, 9 had primary-resistant subclones. All 9 evaluable relapses involved outgrowth of a preexisting subclone (often detectable pre-therapy).
  • Pharmacology and methylation are not predictive: Steady-state plasma decitabine on day 4 of cycle 1 did not correlate with response. Reduction in CpG methylcytosine content from day 0 to day 10 of cycle 1 was similar between responders and non-responders and between TP53-mutant and wild-type-TP53 patients (P=0.19 across response groups by ANOVA). No TP53-driven methylation signature could be identified in either this cohort or the TCGA AML cohort.
  • Allogeneic SCT had the largest survival effect: Cox stepwise regression — transplantation vs no transplantation, P<0.001 — and benefit was not adversely affected by TP53 status.
  • Clonal-hematopoiesis (“rising clones”) in remission: 7/22 responders developed nonleukemic rising clones; 2 carried mutations in DNMT3A or PPM1D. No correlation with incomplete count recovery (P=0.36).
  • Toxic effects: 128 grade 3–5 events in cycles 1–2; 93 (in 56 patients) were febrile neutropenia/infection. 8 treatment-related deaths (6 infection, 1 acute kidney injury, 1 cardiac arrest).

Genes & alterations

  • TP53 — somatic mutations in the founding clone identified in 21/99 sequenced patients; 100% achieved bone-marrow blast clearance with 10-day decitabine. Spectrum (missense dominant, hotspot distribution) was indistinguishable from the TCGA AML cohort. One additional patient (Patient 1080) had TP53 LOH and add(17)(p13) by cytogenetics without a detectable coding-sequence mutation.
  • SF3B1 — alongside TP53, the only other gene whose mutations consistently cleared to VAF <5% with decitabine therapy.
  • DNMT3A — frequently mutated; persisted in remission in some patients and appeared in nonleukemic rising clones consistent with clonal hematopoiesis of indeterminate potential. Did not predict response in this trial.
  • PPM1D — appeared in nonleukemic rising clones of remission patients (clonal hematopoiesis).
  • IDH1, IDH2, TET2 — covered by both the 264-gene and 8-gene panels; previously hypothesized to predict hypomethylating-agent response but not validated as predictive in this study.
  • ASXL1, SRSF2, U2AF1 — included in the 8-gene amplicon panel and observed in the cohort; not reported as predictive of decitabine response.
  • RUNX1 — listed among genes implicated in age-related clonal hematopoiesis but data on its presence in remission rising clones was not assessed in this study.

Clinical implications

  • 10-day decitabine cycles offer a clinically meaningful response option for AML and MDS patients with TP53 mutations and/or unfavorable-risk cytogenetics — populations whose response and survival on conventional anthracycline+cytarabine induction are uniformly poor (CR rates 20–30%, median survival 4–6 months).
  • Authors propose decitabine as a candidate up-front strategy or bridge to allogeneic stem-cell transplantation in TP53-mutant ultra-high-risk AML/MDS, pending prospective validation.
  • Decitabine alone is not curative: remissions are short-lived (typically <1 year), mutation clearance is incomplete in every tested patient, and resistant subclones reliably emerge at relapse. Authors advise against using single-agent decitabine as definitive therapy.
  • Routine pharmacokinetic monitoring (steady-state plasma decitabine) and global methylation-change measurements do not appear to be useful response biomarkers — neither correlated with clinical response.
  • TP53 mutation status (whether by amplicon panel or exome) is the single most informative pre-treatment predictor identified.

Limitations & open questions

  • Single-arm, uncontrolled, single-institution trial with a heterogeneous extension cohort (different protocols, dosing schedules, and time periods) — survival comparisons are post-hoc and lack a randomized comparator.
  • Mechanism of TP53-decitabine sensitivity is unknown. No canonical TP53-driven methylation signature could be identified in either this cohort or laml_tcga_pub. Authors speculate about cell-intrinsic epigenetic priming versus non-cell-intrinsic mechanisms (e.g., endogenous-retrovirus reactivation, regulatory-T-cell modulation).
  • Subclonal sensitivity rules are not yet defined. Both sensitive and resistant subclones occurred within the same patients, but no genetic correlate of subclonal sensitivity emerged in this sample size.
  • Durability problem unresolved. Even patients with TP53 mutations and complete clinical responses retained measurable founding-clone VAF, and all evaluable relapses arose from preexisting subclones — strategies to deepen clearance (e.g., combination therapy, consolidation) are an open question.
  • MDS subset signal: TP53 mutations showed a trend toward decreased survival among MDS patients but not AML (P=0.08), suggesting disease context may matter; underpowered to confirm.
  • Limited data on rising-clone genes: RUNX1, UNC5C, RRN3P2, and SCAMP5 (clonal-hematopoiesis genes) were not specifically assayed in remission samples.

Citations from this paper used in the wiki

  • “Surprisingly, all 7 patients with TP53 mutations had a response with bone marrow blast clearance, as compared with 15 of 32 patients without TP53 mutations (47%) (P=0.02).” (discovery cohort, p. 7)
  • “We observed TP53 mutations in 14 of 60 patients: 14 of 14 had blast clearance … and 17 of 46 patients with wild-type TP53 had blast clearance (P<0.001).” (extension cohort, p. 7)
  • “Mutations in only two genes (TP53 and SF3B1) had consistent, rapid reductions in variant allele frequency to levels of less than 5%.” (mutation clearance, p. 6)
  • “Median survival, 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53, P=0.79.” (survival, p. 8)
  • “Bone marrow blast clearance (complete remission, complete remission with incomplete count recovery, or morphologic complete remission) in 29 of 43 patients with karyotypes associated with unfavorable risk (67%) versus 24 of 71 patients with karyotypes associated with intermediate or favorable risk (34%) … in 21 of 21 patients with TP53 mutations (100%) versus 32 of 78 patients with wild-type TP53 (41%).” (Discussion, p. 8)
  • “Decitabine did not clear all leukemia-specific mutations in any patient tested … the short durations of remission are due to incomplete clearance of leukemia cells bearing the pathogenetically relevant driver mutations.” (Discussion, p. 9)
  • “Eight treatment-related deaths were due to infection (in 6 patients), acute kidney injury (in 1 patient), or cardiac arrest (in 1 patient).” (toxicity, p. 5)

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