Outcomes of Adults Treated with a Hypomethylating Agent Plus Venetoclax for Relapsed/Refractory Acute Myeloid Leukemia: A Multicenter Retrospective Study

BACKGROUND: Despite recent advances in treatment options for relapsed/refractory (R/R) acute myeloid leukemia (AML), prognosis remains poor for patients who do not proceed to allogeneic stem cell transplant. In the frontline setting, the combination of a hypomethylating agent with venetoclax (HMA + ven) has emerged as a new standard of care for adults who are unfit for intensive chemotherapy. However, data on response rates with HMA + ven in the R/R setting is limited. In this multicenter retrospective analysis, we sought to estimate the response rate associated with HMA + ven as salvage therapy for R/R AML and to explore predictors of response.

METHODS: We conducted a multicenter retrospective study through COMMAND (Consortium on Myeloid Malignancies and Neoplastic Diseases), a collaboration involving 10 academic institutions. A total of 93 patients treated with HMA + ven for R/R AML at 3 sites (University of Pittsburgh Medical Center, Yale, Mayo Clinic Florida) were evaluated. We summarized clinical characteristics of the study population using descriptive statistics. We reported the best response at any point after starting therapy by summarizing complete remission (CR) rate, CR with incomplete count recovery (CRi) rate and rate of CR + CRi + morphologic leukemia free state (MLFS) by frequency (percentage) and its exact 95% confidence interval (CI). The association of CR rate with continuous variables was examined using t-tests for normally distributed variables and Wilcoxon rank sum tests for non-normally distributed variables, as well as Fisher's exact test for categorical variables. Overall survival (OS), defined as the time from start of HMA + ven to death from any cause or the last follow-up, was analyzed by the Kaplan-Meier method, and the median OS was calculated along with its 95% CI.

RESULTS: Among the 93 patients in our analysis, 63% (n=59) received azacitidine + ven and 37% (n=34) received decitabine + ven. Median age at AML diagnosis was 61 years (IQR 54-69). Most patients had de novo AML (59%, n=55), followed by 31% (n=29) with secondary AML and 10% (n=9) with therapy-related AML. The distribution of cytogenetic/molecular abnormalities was as follows: 61% (n=57) with complex cytogenetics, 10% (n=10) with FLT3 mutation (ITD or TKD), 9% (n=8) with NPM1 mutation, 35% (n=33) with TP53 mutation, and 19% (n=18) with IDH1/ IDH2 mutation. Among a subset of 25 patients for whom data on lines of therapy prior to HMA + ven was available, 28% (n=7) received 1 prior line of therapy, 44% (n=11) received 2 prior lines and 28% (n=7) received 3 prior lines. The median time from diagnosis to start of salvage therapy with HMA + ven was 15 months (IQR 2-17 months).

Of 75 evaluable patients, 26 achieved a CR, for a CR rate of 35% (95% CI 24-47%). The MRD-negative CR rate was 24% (95% CI 15-35%, n=18) and the MRD-positive CR rate was 11% (95% CI 5-20%, n=8). The CRi rate was 4% (95% CI 1-11%, n=3), and the rate of CR + CRi + MLFS was 47% (95% CI 35-59%, n=35). Median OS was 8 months (95% CI 6-10 months), and 1-year and 2-year OS rates were 33% and 16%, respectively. There were no associations between CR rate and cytogenetic/molecular profile or type of AML. Age was associated with CR rate (median [IQR] age at HMA + ven in patients who achieved a CR was 65 [61-72] years versus 58 [48-69] years in patients who did not achieve a CR, p=0.05).

CONCULSIONS: In this multicenter retrospective analysis, CR and OS rates with HMA + ven were comparable to historical CR rates reported with other regimens used to treat R/R AML. We did not find an association between CR rate and cytogenetic/molecular profile or type of AML, suggesting that HMA + ven can be used broadly in this setting. Further prospective studies are needed to determine populations that may benefit most from this regimen and additional outcomes such as time to response and duration of response that may guide clinical decision making.

Shallis:Bristol Myers Squibb and Gilead Sciences, Inc: Honoraria; Gilead Sciences, Inc.: Honoraria. Im:CTI Biopharma: Consultancy; Incyte: Research Funding; Abbvie: Consultancy.