Evaluation of Venetoclax Duration in Venetoclax-Azacitidine Regimen for Untreated Acute Myeloid Leukemia: Real World Experience from Hokkaido Leukemia Net
Authors: Kanaya Minoru , Onozawa Masahiro , Matsukawa Toshihiro , Miyashita Naoki , Fujii Fumiaki , Yoshida Shota , Nagai Jun , Aiba Masayuki , Hidaka Daisuke , Hashiguchi Junichi , Senjo Hajime , Igarashi Tetsuyuki , Chiba Masahiro , Yamamoto Satoshi , Shimizu Taku , Ishio Takashi , Yokoyama Shota , Ebata Ko , Iyama Satoshi , Oyake Tatsuo , Kondo Takeshi , Teshima Takanori 
Published: December 2024

Aims: Venetoclax-Azacitidine (Ven-Aza) is the current standard regimen for newly diagnosed acute myeloid leukemia (AML) patients who are ineligible for intensive chemotherapy. In real-world settings, Ven is often administered for less than 28 days to avoid severe cytopenia, febrile neutropenia (FN), and serious infections. A small retrospective study by a single institution within the Hokkaido Leukemia Net (HLN) suggested that a 14-day administration of Ven may reduce the risk of complications while maintaining similar efficacy to the 28-day regimen (Aiba M, et al. Ann Hematol. 2023). To evaluate the significance of the shortened duration of Ven, we analyzed a larger cohort of newly diagnosed AML patients with Ven-Aza in the HLN.

Methods: We retrospectively analyzed 100 Japanese patients (median age: 74 [47 - 91]) with untreated AML who were initially treated by Ven-Aza from 14 institutes in the HLN between May 2021 and December 2023. The duration of Ven exposure was divided into three groups: 14 ± 3 days (Ven 14, n = 31), 21 ± 3 days (Ven 21, n = 51), and 28 ± 3 days (Ven 28, n = 18). Aza 75 mg/m2 was administered from day 1 to day 7, and the Ven dose was adjusted based on azole anti-fungal prophylaxis (median Ven dose: 200 mg, [50-400 mg]). Composite CR (CRc; CR + CRi) rate in the 1st cycle was compared to the three groups (Ven 14 vs Ven 21 vs Ven 28). In order to perform a fair comparison of CRc rate in the three groups, we stratified patients with our novel risk stratification for Ven-Aza (Miyashita N, et al. Br J Haematol. 2024), which categorized as follows: NPM-1or IDH1/2 or DNMT3 mutations were “Ven-sensitive”; complex karyotype (CK)/TP53 mutations without Ven-sensitive mutations were “unfavorable”; and other mutations were “intermediate”. In addition to CRc rate, overall survival (OS), frequency of FN and grade 4 neutropenia (less than 500/μl), and occurrence of documented infection in the 1st cycle was assessed. This study conformed to the principles of the Declaration of Helsinki and was approved by the ethics committee at Hokkaido University Hospital.

Results: The median follow-up period was 166 days [13-636]. CRc rates for Ven 14, Ven 21, and Ven 28 were not significantly different: 67.7%, 51.0%, and 38.9%, respectively. According to our risk stratification system, CRc rates in the Ven-sensitive group were 83.3% (10/12), 71.4% (10/14), and 83.3% (5/6) in Ven 14/21/28, respectively. CRc rates in the intermediate risk group for Ven 14/21/28 were 61.5% (8/13), 45.6% (10/22), and 25.0% (1/4), respectively. In the unfavorable group, CRc rates were 50.0% (3/6), 40.0% (6/15), and 12.5% (1/8). No statistical significance of CRc rate was observed among Ven14/21/28, stratified by the HLN risk classification.

The difference of OS was not statistically significant among Ven 14/21/28: unreached, 430 days, and 328 days, respectively. In terms of the safety profile, the frequency of grade 4 neutropenia, FN, and documented infection in Ven 14/21/28 were as follows: grade 4 neutropenia - 67.7%, 78.4%, and 50.0%; FN - 54.8%, 47.1%, and 38.9%; documented infection - 25.8%, 11.7%, and 16.7%. There were no significant differences in these adverse events. The duration of grade 4 neutropenia was also assessed with no statistical distinction among the groups: median 29 days [21-57] in Ven 14, median 32 days [24-52] in Ven 21, and median 33 days [20-63] in Ven 28.

Conclusions: In line with previous literature from the Mayo Clinic (Karrar O, et al. Am J Hematol. 2024), the shorter duration of Ven in the Ven-Aza regimen for newly diagnosed AML in the HLN cohort did not affect patient outcomes, including CRc rate, OS, grade 4 neutropenia, FN, and infection. We demonstrated that a shorter duration of Ven (14 or 21 days) could be effective and safe for the East Asian cohorts as well. Ven 14 showed a trend toward relatively longer survival than Ven 28, though not statistically significant. Moreover, in high-risk patients with CK/TP53 mutations in our stratification, Ven 14 and 21 tended to show relatively higher CRc rates than conventional Ven 28 (not statistically significant), indicating that shorter Ven duration was potentially still effective for high-risk patients. Economic benefits could also motivate the shorter Ven duration. This is retrospective data, which might contain physician's' intentions to modify Ven duration according to the patients' condition. Therefore, a prospective randomized study comparing Ven 14 and Ven 28 is needed.