Outcome of Patients with Acute Myeloid Leukemia Following Failure of Front-Line Venetoclax Plus Hypomethylating Agent Therapy

Introduction Venetoclax (Ven) in combination with hypomethylating agents (HMA) is FDA-approved for elderly/unfit acute myeloid leukemia (AML) patients. In the Phase 3 VIALE-A study, complete remission (CR) with or without count recovery (CRi) was documented in 66.4% of previously untreated AML patients receiving Ven+HMA, however, disease progression or relapse occurred in 42% of cases (NEJM, 2020). The clinical outcomes of AML patients with lack or loss of response to front-line Ven+HMA are not well-studied. Accordingly, in the current study, our primary objective was to describe outcomes of patients with AML following failure of front-line Ven+HMA therapy and identify clinical and molecular predictors of survival.

Methods Patients with AML who received front-line Ven+HMA outside clinical trials at the Mayo Clinic between 2018 and 2020 were retrospectively recruited after institutional review board approval. Cytogenetic and molecular studies were performed at the time of AML diagnosis by conventional karyotype, and next-generation sequencing (42-gene panel), respectively. All patients received either azacitidine 75 mg/m2 days 1-7 or decitabine 20 mg/m2 days 1-5 with Ven dose adjusted based on azole antifungal prophylaxis. Bone marrow biopsy was obtained after either cycle 1 or 2 based on treating physician discretion with response assessed according to the 2017 European Leukemia Net (ELN) criteria. Treatment failure was defined as inability to achieve CR/CRi (refractory) or loss of CR/CRi (relapse).

ResultsPatient characteristics

71 of 103 (69%) patients with treatment-naïve AML (median age; 74 years, range 37-91; 70% males; 61% de novo, 23% secondary, 17% therapy-related) were either refractory (n=43, 61%) or relapsed (n=28, 39%) following Ven+HMA. ELN cytogenetic risk included intermediate (48%, n=34) or adverse (49%, n=35). Mutations involved TP53 in 23 patients (32%), ASXL1 in 12 (17%), IDH1/2 in 11 (16%), FLT3 in 10 (14%), N/KRAS in 9 (13%) and NPM1 in 7 (10%). A comparison of clinical characteristics of refractory vs relapsed patients revealed similarities in age (median age; 73 vs 76 years, p=0.6), secondary/therapy-related AML (44% vs 32%, p=0.5), ELN adverse cytogenetics (53% vs 43%, p=0.7), FLT3 (16% vs 11%, p=0.5), NPM1 (9% vs 11%, p=0.8), IDH1/2 (14% vs 18%, p=0.7), and N/KRAS mutations (14% vs 11%, p=0.7). On the other hand, patients refractory to Ven+HMA were more likely to harbor TP53 mutations (40% vs 21%, p=0.1) while ASXL1 mutations were predominant in relapsed patients (32% vs 6%, p=0.01)

Treatment

45 of 71 (63%) patients received decitabine and the remainder azacitidine with median Ven dose of 200 mg (range, 50-400 mg) for a median of 3 cycles as front-line therapy. After Ven+HMA failure, therapy was pursued in 11 of 71 (15%) patients with gilteritinib (n=6), ivosidenib (n=2), Ven+Gilteritinib (n=1), CPX-351 (n=1), and IMGN 632 clinical trial (n=1). 3 patients (27%) achieved CR with one patient receiving allogeneic transplant.

Survival

At a median follow-up of 6 months (range; 1-40 months), 66 patients (93%) have died from disease progression. Median overall survival (mOS) was 5.9 months (95% CI, 2.7-14.1 months). On univariate analysis, predictors of inferior survival included age (p=0.02), refractory vs relapsed following Ven+HMA (3.1 months vs 11.2 months, p=0.002), ELN adverse cytogenetic risk (5.4 vs 6.6 months, p=0.04), presence of TP53 (3.2 vs 6.6 months, p=0.006), and K/NRAS mutations (4.1 vs 6.3 months, p=0.007) and absence of IDH1/2 mutations (5.7 vs 14.1 months, p=0.13). On multivariable analysis, presence of K/NRAS (HR 3.7, 95% CI 1.6-8.1, p=0.002), and TP53 mutations (HR 2.6, 95% CI 1.5-4.7, p=0.001) and refractory to Ven+HMA (HR 2.1, 95% CI 1.3-3.5, p=0.004) remained significant. Accordingly, a three-tiered model was generated, 2 points for K/NRAS mutations, 1 point each for TP53 mutation and refractory to Ven+HMA, resulting in high (≥ 2 points, n=24; mOS, 2.9 months), intermediate (1 point, n=28; mOS, 6.2 months) and low risk (0 points, n=19; mOS, 15.2 months) categories (p<0.0001) (Figure).

Conclusion The current study identifies presence of TP53 and K/NRAS mutations as predictors of inferior survival in patients with AML relapsed or refractory to front-line Ven+HMA. Additionally, we propose a practical three-tiered survival model based on TP53 and K/NRAS mutations and refractoriness to Ven+HMA.

Al-Kali:Astex: Other: research support to institution. Mangaonkar:Bristol Myers Squibb: Research Funding. Litzow:Abbvie: Research Funding; Amgen: Research Funding; Astellas: Research Funding; Novartis: Research Funding; Syndax: Research Funding; Jazz: Consultancy; Actinium: Research Funding; Pluristem: Research Funding; Biosight: Other: Data Monitoring Board. Shah:Astellas: Research Funding; Celgene: Research Funding; Marker Therapeutics: Research Funding. Patnaik:Kura Oncology, Stemline Therapeutics: Research Funding.