Impact of <i>TP53</i> mutations and variant allelic frequency on survival in adults with newly diagnosed acute lymphoblastic leukemia.

Abstract

6544 Background: TP53 mutations are associated with poor outcomes in acute lymphoblastic leukemia (ALL); however, a variant allele frequency (VAF) cutoff (mutation burden) which may more accurately predict overall survival (OS) has not been identified. Methods: We retrospectively analyzed adult patients (pts) with newly diagnosed ALL with TP53 mutation status tested at diagnosis. The maximum log-rank test was used to evaluate the impact of TP53 VAF. Results: Among 654 pts, 115 (18%) harbored TP53 mutations. TP53 mutations were more common in B-cell ALL (19% vs. 6% in T-cell ALL, p=0.003), older age (61 vs. 45 years, p&lt;0.001), low hypodiploid/near-triploid (Ho-Tr) karyotype (98% vs. 10%, p&lt;0.001), and therapy-related ALL (20% vs. 9%, p&lt;0.001). 11 pts (10%) harbored ≥2 TP53 mutations. The median TP53 VAF was 42% (range, 1-94%) and was higher in pts with Ho-Tr karyotype (54%) compared to diploid karyotype (41%, p=0.02). TP53 -mutated ALL was associated with significantly inferior OS in pts ≥60 years of age (2-year OS 55% vs. 69%; p=0.03). In the older pts, TP53 VAF was associated with worse OS and the optimal cutoff was 45%. Among pts ≥60 years, TP53 VAF ≥45% had a 2-year OS of 37% compared to 71% for those with VAF &lt;45% (p=0.01), which was driven by higher rates of both relapse and non-relapse mortality. In older pts who received frontline inotuzumab ozogamicin (InO) and/or blinatumumab (Blina), TP53 VAF ≥45% remained a strong predictor of OS (2-year OS 37% vs. 75% for VAF &lt;45%; p=0.04). By multivariate analysis (MVA) in pts aged ≥60 years, TP53 VAF ≥45% (HR 1.8, 95% CI 1.0-3.2, p=0.03) and complex karyotype (HR 2.9, 95% CI 1.2-7.3, p=0.02) were associated with inferior OS, while frontline InO and/or Blina trended toward improved OS (HR 0.6, 95% CI 0.3-1.0, p=0.07). TP53 -mutated ALL was associated with a trend towards inferior OS in pts &lt;60 years of age (2-year OS 66% vs. 88%; p=0.06), despite higher rates of allo-SCT in pts with TP53 -mutated ALL (47% vs. 22% for TP53 wild type; p&lt;0.001). In these younger pts, TP53 VAF was not prognostic (2-year OS 72% vs. 61% for VAF ≥45% vs. &lt;45%; p=0.6). Outcomes were similar in younger pts with TP53 VAF≥45%, irrespective of allo-SCT status (2-year OS of 68% vs. 74% for those with VAF≥45% who underwent allo-SCT vs. those who did not; p=1.0). By MVA in younger pts, Ph-like was associated with worse OS (HR 2.1, 95% CI 1.3–3.1, p=0.002), while frontline InO and/or Blina significantly improved outcomes (HR 0.5, 95% CI 0.3–0.7, p&lt;0.001). Neither TP53 mutation status nor VAF impacted OS on MVA. Conclusions: TP53 mutations were associated with worse outcomes in both younger and older adults with ALL. VAF ≥45% can risk stratify pts aged ≥60 years but did not impact OS in younger pts. Incorporating frontline InO and/or Blina into therapy might improve outcomes of TP53 -mutated ALL.