Outcomes of TP53-Mutant Acute Myeloid Leukemia with Venetoclax and Decitabine

Background: TP53 mutation (TP53^mut) confers adverse prognosis in acute myeloid leukemia (AML) with limited response to chemotherapy. 10-day decitabine (DEC) regimen has shown high efficacy in TP53^mut AML (Welch et al. NEJM 2016). We hypothesized that adding venetoclax (VEN) to 10-day DEC may further improve outcomes in high-risk AML (NCT03404193). However, preclinical data suggests that TP53^mut confers resistance to VEN in AML (Nechiporuk et al. Cancer Discov. 2019). Herein, we investigated outcomes of patients (pt) with TP53^mut AML who received frontline therapy on this prospective trial of 10-day DEC and VEN (DEC10-VEN).

Methods: Patients 60 years of age and older with newly diagnosed previously untreated AML were treated with DEC 20 mg/m² for 10 days every 4 to 6 weeks for induction followed by DEC for 5 days after CR/CRi. VEN dose was 400 mg daily or equivalent. Reduction of VEN duration was allowed in cases of cytopenias and/or myelosuppression. TP53^mut was assessed in bone marrow samples using a PCR-based 81-gene Next Generation Sequencing panel targeting the entire coding regions. A MiSeq platform (Illumina, San Diego, CA, USA) was used with an analytical sensitivity established at 5% mutant reads in a background of wild type reads. Full protocol of the study has been published previously (DiNardo et al. Lancet Haematol. 2020. In press).

Results: Between January 2018 and April 2020, 121 pts received frontline therapy with DEC10-VEN on this trial. The median age of the cohort was 72 yrs (range 49-89), 34 (28%) pts had ECOG performance status ≥2 and 81 (67%) pts had ELN adverse risk AML. 37 (31%) pts had TP53^mut. Pts with TP53^mut were more likely to have therapy-related AML (t-AML) in 43% pts compared to 11% in pts with TP53 wild type (TP53^WT, p<.001), adverse ELN cytogenetic risk in 92% compared to 27% in pts with TP53^WT (p<.001), and less frequently have co-mutations in NPM1^mut (3%), RUNX1^mut (5%) and ASXL1^mut (5%), compared to patients with TP53^WT with NPM1^mut (32%, p<.001), RUNX1^mut (24%, p=.002), and ASXL1^mut (24%, p=.002), respectively. 22% of pts with TP53^mut had received prior therapy for an antecedent hematological disorder, as compared to 24% in TP53^WT (p= .793). Baseline characteristics of the pts is shown in Table 1.

The rate of CR/CRi in the whole cohort was 69% (n=84) with negative measurable residual disease (MRD) by flow cytometry (FCM) in 42% pts (n=51). Pts with TP53^mut had a lower rate of CR at 35% compared to 57% in pts with TP53^WT (p=.026), lower rate of CR/CRi at 54% vs. 76% in pts with TP53^WT (p=.015), and lower rate of MRD negativity by FCM in 19% compared to 52% in TP53^WT AML (p=.001, Table 2). The median time to response in TP53^mut pts was 1.2 mo (IQR 1.0-1.4) and in TP53^WT pts was 1.7 mo (IQR 1.2-2.8) and median number of cycles to response for both groups were 1 cycle (IQR 1-2; p=.259). The 60-day mortality was higher in the TP53^mut pts at 27% (n=10/37) compared to 2% in TP53^WT pts (n=2/84, p<.001), all due to refractory disease in TP53^mut pts. No pts in TP53^mut group underwent stem-cell transplantation (SCT) after response compared to 16 (100%) pts in TP53^WT group.

Median overall survival (OS) was 5.2 months (mo) in pts with TP53^mut compared to 19.4 mo in TP53^WT AML (hazard ratio [HR] 4.68, 95% CI 2.50, 8.78, p <.001, Fig. 1). This survival difference of pts with TP53^mut compared to wild type was significant after adjustment for other variables including age, gender, ECOG performance status, secondary AML including t-AML and AML history of antecedent hematologic disorder, NPM1^mut, RUNX1^mut and ASXL1^mut, with an adjusted HR 5.41, 95% CI 2.76, 19.61, p<.001. TP53^mut pts who achieved CR had a median OS of 9.6 mo compared to CRi pts with median OS of 5.6 mo. Median duration of response (DOR) of CR/CRi in TP53^mut AML was shorter compared to TP53^WT with median CR/CRi DOR of 3.5 mo vs NR, HR 5.89, 95% CI 2.09, 16.6, p<.001 (Fig. 2). TP53^mut pts who achieved CR had a median DOR of 7.0 mo compared to CRi pts with median OS of 2.5 mo (p= .009).

Conclusion: TP53^mut is associated with inferior response with shorter response duration, higher MRD positivity and inferior survival outcomes in pts with AML receiving frontline therapy with VEN and DEC. Novel therapies are needed to overcome TP53-mediated resistance to VEN with hypomethylating agents in AML.