Venetoclax with Hypomethylating Agents in Newly Diagnosed Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis of Survival Data from Real-World Studies

Abstract

In recent years, the association of venetoclax (VEN) with hypomethylating agents (HMAs) significantly improved the outcome of patients with newly diagnosed acute myeloid leukemia (AML) who were unfit for intensive chemotherapy and became the standard of care after the publication of the pivotal RCT VIALE-A. However, it is still not clear to what extent the results observed in the VIALE-A apply to a real-world setting. For this reason, we carried out a systematic review and meta-analysis of real-world studies on newly diagnosed patients with AML, ineligible for intensive induction chemotherapy, receiving first-line VEN+HMA. We then compared their results in term of survival with those from the VIALE-A. Kaplan-Meier curves were extracted from all included studies and individual survival data was reconstructed. We then estimated a pooled survival curve and compared it with the results of the VIALE-A using the log-rank test. We also conducted a secondary analysis including only studies considering VEN plus azacytidine (AZA) as treatment, as this was the schedule originally used in the VIALE-A. Nineteen real-world studies met the inclusion criteria and were included in the systematic review. Most of them reported a worse survival than the VIALE-A. The pooled survival curve was similar to that reported in the VIALE-A during the first three months of treatment but diverged thereafter (p-value = 0.0001). The pooled median survival among the real-world studies was 9.37 months (95%CI 8.81–10.5), substantially lower than that reported in the VIALE-A (14.7 months; 95%CI 11.9–18.7). Results slightly increased when the analysis was restricted to the studies using VEN+AZA as treatment (median survival: 11.5 months; 95%CI 10.2–14.8). Survival of newly diagnosed AML patients treated with VEN+HMAs in a real-world setting seems to be lower than previously reported in the VIALE-A, while the effect of VEN+AZA is more in line with expected results. Future studies are needed to evaluate whether this apparent discrepancy is due to the different characteristics of enrolled patients or to a non-optimal adherence to therapy, and whether alternative regimens can provide better results in terms of safety and effectiveness.

Real-Life Multicenter Experience of Venetoclax in Combination with Hypomethylating Agents in Previously Untreated Adult Patients with Acute Myeloid Leukemia in Greece

“…The CCR rate of HMA-venetoclax in our study was 86.8%, confirming the previously reported good outcomes [7]. Even though recent meta-analyses for HMA-venetoclax in newly diagnosed AML in a real-life setting indicate lower OS [10], in our cohort, the median OS of patients older than 75 years was 22.9 months, even higher than VIALE-A survival of 17.5 months [7]. When only younger patients were included, OS exceeded 2 years (33.8 months).…”

“…These results were confirmed with a CR + CRi rate of 66.4% in VIALE-A, and full approval was obtained [7]. Following this, the combination of HMAs with venetoclax has been increasingly used over the last 3 years as a first-line treatment for patients non-eligible for intensive chemotherapy and allogeneic stem-cell transplantation (all-SCT) [8], translating into accumulating real-world data [9][10][11][12][13][14].…”

No impact of time from diagnosis to treatment on survival in newly diagnosed AML treated with venetoclax-based regimens

“…patients with advanced kidney, liver or heart problems, chronic lung disease or advanced diabetes). Consequently, our data is in line with reported median overall survival rates of between 9 and 13 months in several real-world analyses and a meta-analysis including 1134 patients that showed a pooled median survival time of 9.4 months (23)(24)(25)(26)(27). Outside of prospective, controlled, randomised clinical trials (RCTs), it is suspected that reduced safety monitoring and bone marrow assessments as well as decreased treatment adherence may contribute to impaired prognosis as well as distortion of e cacy parameters, such as response rates, and RFS (23)(24)(25)(26)28).…”

Monocytic Differentiation in Acute Myeloid Leukemia Cells: Diagnostic Criteria, Biological Heterogeneity, Mitochondrial Metabolism, Resistance to and Induction by Targeted Therapies

“…However, it should be emphasized that the differentiation-associated resistance is an important, but not the only, mechanism of venetoclax resistance. The main observations with regards to monocytic differentiation and venetoclax resistance are summarized in Table 4 and are discussed in detail in this main section [ 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 ].…”