AVALON: The Italian cohort study on real‐life efficacy of hypomethylating agents plus venetoclax in newly diagnosed or relapsed/refractory patients with acute myeloid leukemia

Abstract

Background: Venetoclax in combination with hypomethylating agents (HMA) is revolutionizing the therapy of acute myeloid leukemia (AML). However, evidence on large sets of patients is lacking, especially in relapsed or refractory leukemia. Methods:AVALON is a multicentric cohort study that was conducted in Italy on patients with AML who received venetoclax-based therapies from 2015 to 2020.The study was approved by the ethics committee of the participating institution and was conducted in accordance with the Declaration of Helsinki. The effectiveness and toxicity of venetoclax + HMA in 190 (43 newly diagnosed, 68 refractory, and 79 relapsed) patients with AML are reported here. Results:In the newly diagnosed AML, the overall response rate and survival confirmed the brilliant results demonstrated in VIALE-A. In the relapsed or refractory AML, the combination demonstrated a surprisingly complete remission rate (44.1% in refractory and 39.7% in relapsed evaluable patients) and conferred to treated patients a good expectation of survival. Toxicities were overall manageable, and most incidents occurred in the first 60 days of therapy. Infections were confirmed as the most common nonhematologic adverse event.Conclusions: Real-life data show that the combination of venetoclax and HMA offers an expectation of remission and long-term survival to elderly, newly diagnosed patients, and to relapsed or chemoresistant AML, increasing the chance of cure through a TODISCO ET AL.-993 different mechanism of action. The venetoclax + HMA combination is expected to constitute the base for triplet combinations and integration of target therapies. Our data contribute to ameliorate the understanding of venetoclax + HMA effectiveness and toxicities in real life.

Development of a scoring system for predicting primary resistance to venetoclax plus hypomethylating agents (HMAs) in acute myeloid leukemia patients

“…Although the ND and R/R AML patients were included our cohort, the ORR rate was still as high as 70.0%. The ORR rate of ND AML patients (70.1%) observed in our cohort was slightly higher than those reported recently in the multicentric cohort of AVALON study (65.1%) 28 . For R/R AML patients, the ORR in the AVALON study was 46.3% (68/147), compared with 60% in our study.…”

“…The ORR rate of ND AML patients (70.1%) observed in our cohort was slightly higher than those reported recently in the multicentric cohort of AVALON study (65.1%). 28 For R/R AML patients, the ORR in the AVALON study was 46.3% (68/147), compared with 60% in our study. However, given the small proportion of elderly patients (age ≥60) (22.6% of our study vs 66.3% of AVALON) and the low rate of secondary AML (11.8% of our study vs. 32.6% of AVALON), this may largely explain the higher ORR in our cohort.…”

Venetoclax‐based therapy for relapsed or refractory acute myeloid leukaemia following intensive induction chemotherapy

“…Thus, patients may be highly selected according to characteristics, that is, cytogenetic risk, associated with response to therapy. For example, only 1/3 had adverse risk factors at R/R compared with 35%–66% in the aforementioned studies 30–33 . Additionally, our study population is younger since we selected patients with R/R after front‐line intensive chemotherapy, which may also affect response rates and OS.…”

“…Comparing our results with other studies on R/R AML, we find numerically higher response rates and better survival. The largest studies to date are the Italian AVALON multicentre study, 30 the Spanish PETHEMA registry study, 31 and two single‐centre studies from Memorial Sloan Kettering Cancer Center 35 and City of Hope Medical Center 32 . Jointly, these studies report outcome of 374 patients with R/R AML with a median age ranging from 59 to 68 years treated primarily with venetoclax combined with low‐intensity backbone.…”

“…32 Jointly, these studies report outcome of 374 patients with R/R AML with a median age ranging from 59 to 68 years treated primarily with venetoclax combined with low-intensity backbone. The reported ORRs range between 31% and 46% 30,31,33 and CRc-rates range from 18% to 46% [30][31][32][33] with a median OS ranging from 3.4 to 7.8 months. [30][31][32][33] Additionally, a Chinese multicentre study including 150 younger (median age 54) patients with R/R AML reported an ORR and CRc of 56.2% and 43.3%, respectively, and a median OS of 10 months.…”