decitabine

Overview

Decitabine (5-aza-2’-deoxycytidine) is a cytosine nucleoside analog that is incorporated into DNA and irreversibly inhibits DNA methyltransferases (DNMT1, DNMT3A, DNMT3B), leading to global DNA hypomethylation and reactivation of silenced tumor suppressor genes. It is approved for MDS and used off-label in AML, particularly in older or unfit patients and those with TP53 mutations. The 10-day dosing schedule (20 mg/m²/day × 10 days per 28-day cycle) is more intensive than the standard 5-day schedule and was developed specifically to maximize epigenetic reprogramming.

Evidence in the corpus

  • In a single-arm prospective trial at Washington University in St. Louis (NCT01687400, N=116 total; discovery cohort n=84, extension cohort n=32), 10-day decitabine (20 mg/m²/day) achieved bone-marrow blast clearance in 53/116 (46%) of AML and MDS patients overall: 15 (13%) CR, 24 (21%) CRi, 14 (12%) mCR; cBioPortal study mnm_washu_2016 PMID:27959731
  • TP53 mutations are a positive predictor of decitabine response: 21/21 (100%) TP53-mutant patients achieved blast clearance vs 32/78 (41%) wild-type-TP53 patients (P<0.001); in the discovery cohort alone, 7/7 vs 15/32 (47%), P=0.02 PMID:27959731
  • Unfavorable-risk cytogenetics also predicted response: 29/43 (67%) with unfavorable karyotypes had blast clearance vs 24/71 (34%) intermediate/favorable-risk (P<0.001); 20/21 TP53-mutant patients had unfavorable karyotype PMID:27959731
  • Survival is not worsened by TP53 or unfavorable cytogenetics on this regimen: median OS 12.7 months (TP53-mutant) vs 15.4 months (wild-type-TP53), P=0.79; compared to only 4–6 months on conventional cytarabine-based induction in TP53-mutant AML PMID:27959731
  • Mutation clearance is universal but incomplete: only TP53 and SF3B1 mutations consistently dropped to VAF <5%; founding-clone VAF at maximum clearance ranged from 0.06% to 18.43% across the 20 best responders; all evaluable relapses arose from preexisting resistant subclones PMID:27959731
  • 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 from day 0 to day 10 was similar between responders and non-responders (P=0.19 by ANOVA) PMID:27959731
  • Allogeneic SCT had the largest survival effect: Cox stepwise regression — SCT vs no SCT, P<0.001; benefit not adversely affected by TP53 status; decitabine proposed as bridge to transplant in TP53-mutant ultra-high-risk AML/MDS PMID:27959731
  • Combined with panobinostat (10 mg three times weekly) in 3 patients in the 5-day decitabine extension cohort at WashU PMID:27959731

Resistance mechanisms

  • All evaluable relapses in the WashU trial arose from preexisting subclones that were already detectable before therapy; primary resistance was observed in 9/39 exome-sequenced patients who had resistant founding or subclonal architecture pre-treatment PMID:27959731
  • Mutation clearance was never complete in any tested patient; remissions are short-lived (typically <1 year); decitabine alone is not curative PMID:27959731

Cancer types (linked)

  • AML — primary indication; TP53-mutant AML has 100% response rate to 10-day decitabine; survival comparable to TP53-wild-type despite higher response.
  • MDS — transfusion-dependent MDS included in WashU trial; TP53 mutation trended toward decreased survival in MDS subset (P=0.08, underpowered).

Sources

  • PMID:27959731 — Welch et al. 2016, NEJM. WashU single-arm prospective trial of 10-day decitabine in AML/MDS (N=116); TP53 mutation as positive predictor of response; incomplete mutation clearance; SCT as dominant survival predictor.

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