Outcomes of TP53‐mutant acute myeloid leukemia with decitabine and venetoclax

Abstract

BACKGROUND: TP53 mutation (TP53 mut ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggest that TP53 mut confers resistance to venetoclax. The authors investigated the outcomes of patients with TP53 mut AML who were treated with a 10-day decitabine and venetoclax (DEC10-VEN) (ClinicalTrials.gov identifier NCT03404193). METHODS: Patients with newly diagnosed AML received decitabine 20 mg/m 2 for 10 days every 4 to 6 weeks for induction, followed by decitabine for 5 days after response. The venetoclax dose was 400 mg daily. TP53 mut was identified in bone marrow samples using next-generation sequencing, with sensitivity of 5%. Outcomes were analyzed according to European LeukemiaNet 2017 guidelines. RESULTS: Among 118 patients (median age, 72 years; age range, 49-89 years), 63 (53%) had secondary AML, 39 (33%) had AML with complex karyotype, and 35 (30%) had TP53 mut AML. The median TP53 variant allele frequency was 32% (interquartile range, 16%-65%), 8 patients (23%) had only a single TP53 mutation, 15 (43%) had multiple mutations, and 12 (34%) had mutation and deletion. Outcomes were significantly worse in patients who had TP53 mut AML compared with those who had wild-type TP53 AML, with an overall response rate of 66% vs 89% (P = .002), a complete response/complete response with incomplete hematologic recovery rate of 57% vs 77% (P = .029), and a 60-day mortality of 26% vs 4% (P < .001), respectively. Patients with TP53 mut versus wildtype TP53 had shorter overall survival at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95% CI, 2.44-8.93; P < .0001), and shorter relapse-free survival at 3.4 versus 18.9 months (hazard ratio, 4.80; 95% CI, 1.97-11.69; P < .0001), respectively. Outcomes with DEC10-VEN in patients with TP53 mut AML were comparable to historical results with 10-day decitabine alone. CONCLUSIONS: Patients with TP53 mut AML have lower response rates and shorter survival with DEC10-VEN.

Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)

“…The presence of this TP53 lesion is associated with resistance to apoptosis induced by DNA-damaging AML chemotherapy and relatively poor clinical outcomes [ 24 , 25 , 49 ]. Although treatment with hypomethylating agents with or without venetoclax are currently under investigation, none of these agents have overcome therapy resistance conferred by TP53 lesions and improved clinical outcomes [ 50 , 51 ]. A previous report had described MOLM13 cells into which TP53 mutations R175H and R248Q had been introduced along with null alleles [ 38 ].…”

The Current Understanding of and Treatment Paradigm for Newly-Diagnosed TP53-Mutated Acute Myeloid Leukemia

“…In contrast to the frequent cytogenetic abnormalities that are associated with mutated TP53, consistent co-mutations are not identified. In fact, mTP53-AML is noted to have statistically-significant decreased frequency of NPM1 (2-3%) and FLT3 mutations (2-7%) when compared with patients with TP53 wild type AML in which 30% of cases have these mutations, arguably the most commonly observed in AML [8,13,16,17,24]. The reasons for this lack of association are incompletely understood.…”

“…One of the largest retrospective analyses of 202 patients with mTP53 found that a mTP53 VAF cutoff of 40% was only predictive in intensivelytreated patients and not those treated less-intensively [25]. Conversely, other studies have shown no association at all between mTP53 VAF and median OS [16,24].…”

Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death

“…For subjects with primary or adaptive resistance to venetoclax-based therapy, median survival from treatment failure is only 2.4 months, highlighting the urgent and unmet need for more effective salvage options (6,(42)(43)(44). In this regard, it is now well-established that AML patients with TP53 mutation show much poorer outcomes with venetoclax based combination therapies (6,42,45) and our data confirm previous pre-clinical studies that showing venetoclax resistance in TP53 deficient AML cells (46,47). Importantly, ironomycin has equal efficacy in AML cells that are either replete or deficient for TP53 (Fig.…”