A BCL-2 inhibitor is convincing in new studies in the first-line treatment of AML patients who are not suitable for intensive chemotherapy [1]. Hematologists Dr. Georgios Georgiou and Prof. Photis Beris assess the impact of these new data on the existing therapeutic landscape.
Acute myeloid leukemia (AML) predominantly affects elderly individuals, who are often unsuitable for standard intensive chemotherapy due to advanced age, frequent comorbidities, and unfavorable genetic characteristics [1]. Previously available alternatives such as low-dose cytarabine (LDAC) and the hypomethylating agents azacitidine and decitabine are more tolerable but do not achieve satisfactory remission rates [1]. Therefore, survival in these patients is particularly low and new, more effective approaches are urgently needed to improve the prognosis of this fragile patient population.
Based in part on the positive results of the VIALE-A trial, the highly selective BCL-2 inhibitor venetoclax was approved in December 2020 in combination with azacitidine, decitabine, or LDAC in adult patients with newly diagnosed AML for whom intensive chemotherapy is not an option(Box) [1, 2].
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VIALE-A: significantly prolonged OS and longer-lasting remissions with fewer blood transfusions [1]. The double-blind, multicenter, randomized phase III VIALE-A study evaluated the efficacy and safety of venetoclax in combination with azacitidine in 431 patients with a median age of 76 years. Thereby, venetoclax + azacitidine compared to placebo + azacitidine significantly prolonged median overall survival (mOS) and reduced mortality risk by 34 % after a median follow-up of 20.5 months (HR: 0.66; 95 % CI: 0.518 – 0.845; p < 0.001) can be observed. Remission duration was also longer with venetoclax + azacitidine (17.5 versus 13.4 months). Blood transfusion independence also increased significantly, with 59.8 % of patients no longer requiring red blood cell transfusion under venetoclax + azacitidine (versus 35.2 % under placebo + azacitidine) and 68.5 % no longer requiring platelet transfusion (versus 49.7 % under placebo + azacitidine). |
In this interview, hematologists Georgios Georgiou, MD, and Photis Beris, MD, PhD, explain the value of this new treatment option.
Georgios Georgiou, MD Prof. Photis Beris, MD
What is the significance of the approval of new targeted treatment options for elderly and fragile AML patients?
According to historical data, the survival time of patients who are not eligible for intensive chemotherapy is only about five months. New targeted therapies, which have recently been approved for AML patients older than 75 years or who are not suitable for intensive chemotherapy regardless of age, have shown extremely promising results in clinical trials. Examples include venetoclax in combination with LDAC or a hypomethylating agent. Other options, such as the hedgehog inhibitor glasdegib, are also in clinical trials but have not yet been approved in Switzerland.
How do you evaluate the efficacy data from the VIALE-A trial of venetoclax in combination with azacitidine?
This clinical trial establishes the combination treatment of venetoclax and azacitidine as a new standard of care for elderly and fragile AML patients. Common standard low-intensity therapies, such as azacitidine or decitabine, result in limited response with an expected median survival of nine to ten months and complete remission (CR/CRi) of less than 40 %. In the phase III VIALE-A trial, combination treatment with venetoclax and azacitidine achieved a median overall survival of 14.7 months, which was significantly superior to the mOS of 9.6 months with placebo + azacitidine. Venetoclax + azacitidine was also far superior in CR/CRi rate with 66.4 %, as placebo + azacitidine only achieved a CR/CRi rate of 28.3 %. Patients also responded more than twice as quickly to the combination treatment, within a median of 1.3 months, and were able to maintain this response longer, with a median response duration of 1.5 years.
How do you see the future role of venetoclax in the first-line treatment of AML?
The approval of venetoclax-based therapy for first-line treatment of elderly or unfit AML patients has led to a paradigm shift in our approach to the disease. Several clinical trials are currently underway evaluating venetoclax in various other combination therapies. However, even though these approaches appear highly interesting and promising, increased toxicity is to be expected with more intensive regimens. These should therefore be compared directly with venetoclax in combination with hypomethylating agents or LDAC.
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Sustained efficacy of the chemotherapy-free treatment regimen venetoclax plus rituximab in R/R CLL. Venetoclax has already been approved as monotherapy for CLL patients with a del(17p) or TP53 mutation after treatment failure under a B-cell receptor pathway inhibitor since May 2018 and in combination with rituximab after at least one prior therapy since November 2019 [2]. In the randomized, open-label phase III MURANO study, venetoclax + rituximab (VenR) significantly prolonged progression-free survival in R/R CLL patients compared to standard chemoimmunotherapy with bendamustine and rituximab (BR), and reduced the risk of progression by 81 % reduction (HR: 0,19; 95 % AI: 0,15 – 0.26; p < 0,0001) [3-5]. VenR was also superior in terms of overall survival (OS), achieving an estimated 5-year OS rate of 82.1 % (62,2 % under BR, HR: 0,40; 95 % AI: 0,26 – 0,62; p < 0,0001) [3]. |
This article was written with the financial support of AbbVie AG, alte Steinhauserstrasse 14, Cham.
Brief technical information VENCLYXTO®
CH-VNCAML-210034_10/2021
Contribution online since 03.11.2021
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