Real World Experience with Venetoclax-Based Therapy in Acute Myeloid Leukemia in the Czech Republic

Background: Venetoclax (VEN) in combination with azacitidine (AZA) has become a standard treatment for patients (pts) with newly diagnosed (ND) acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. Here, we present a retrospective study of real-world efficacy of AZA/VEN therapy in AML across seven centers in the Czech Republic.

Patients and methods: Patients (n = 162) were newly diagnosed with AML between 2020 and 2023. The median age was 72 years (40-98), all previously untreated, 11% (18/162) secondary AML from MDS, 9% (14/162) therapy-related AML and 80% (130/162) had de novo AML. Prognosis according to European LeukemiaNet 2022 was favorable in 16% (27/162) of pts, intermediate in 33% (53/162), adverse in 47% (77/162) of pts, it was not specified in 4% (6/162) of pts. Treatment was considered palliative or non-intensive according to the physician's decision. In most patients, 89% (144/162), treatment was started with standard AZA/VEN regimen (7 + 28; i.e., AZA 75mg/m² for 7 days + VEN for 28 days), and 74% (120/162) pts received reduced dose of venetoclax (100 mg or 200 mg) with azole antifungal prophylaxis. The median OS interval was calculated since the start of VEN treatment. Overall response rate was evaluated as complete composite remission (CCR, CR + CRi + CRh + MLFS).

Results: The palliative treatment cohort consisted of 52 elderly pts with median ECOG 2 (0-3), 85% (44/52) of them started with standard AZA/VEN regimen (7 + 28), 15% (8/52) with reduced regimen (AZA 7 days, VEN 14 days), respectively. ORR was evaluated in 81% (42/52) of pts, 67% (28/42) reached CCR, respectively 68% (19/28) CR, 25% (7/28) CRi, 7% (2/28) MLFS. MRD negative CR assessed by RT-PCR was reached in 3 out of 28 of pts. At the time of analysis, the median OS was 5 (0-32.9) months, day 30 and day 60 mortality of 12% (6/52) and 21% (11/52), respectively. The median OS of patients who achieved CCR was 11.6 (1.8-32.9) months.

The non-intensively treated cohort consisted of 110 pts with median ECOG 1 (0-4), 91% (100/110) of them started with standard AZA/VEN (7+28), 9% (10/110) of pts with reduced regimen (7+14). ORR was evaluated in 108 pts, in whom 80% (86/108) reached CCR, respectively 77% (66/86) CR, 16% (14/86) CRi, 5% (4/86) CRh, 2% (2/86) MLFS. MDR negative CR was reached in 30% of responded pts (26/86) based on RT- PCR (18/26) and flow cytometry (8/26). The median OS was 12.6 (0-37.2) months, day 30 and day 60 mortality of 5 % (6/110) and 10 % (11/110), respectively. The median OS of patients who achieved CCR was 16.0 (1.5-37.2) months. Allogeneic transplantation was performed in 23% (25/110) of pts and the median OS was not reached in this group.

Overall, 19% (30/162) pts achieved MRD negativity with a median of 3 (1-11) administered cycles and in these pts median OS was not reached. Patients with TP53 mutation achieved CR in 48% (10/21), all within the first 3 cycles, the median OS was 5.5 (0-17.5) months. The median OS of patients with TP53 mutation who achieved CR was 12.0 (1.8-17.5) months. In 11% (8/73) of pts in CR, the treatment was stopped by mutual agreement, 75% (6/8) of patients were low risk according to ELN 2022 and at the same time MRD negative according to RT-PCR, median of administered cycles was 8 (6-22). In 88% (7/8) CR lasted with a median follow-up of 21.0 (15.6-32.9) months.

Conclusions: Combination of AZA/VEN is highly effective regimen for AML. Our real-world data showed comparable outcomes with available published trial data (C.D. DiNardo, 2020) ORR 67% and 80% in palliatively and non-intensively treated pts, respectively. In younger patients unfit for intensive chemotherapy at diagnosis, the AZA/VEN regimen has comparable efficacy to standard induction regimens, and low toxicity due to gradual improvement of the condition allows such patients to undergo allogeneic transplantation. In palliative patients, median OS was affected by short follow-up time (5 mth) and higher 60-days mortality. Data suggests that TP53 patients benefit from treatment if they achieve a CR within the first 3 cycles. Stopping AZA/VEN treatment in low-risk MRD negative patients does not worsen overall survival, whether it will be associated with a permanent response remains to be seen.

Hajek:AbbVie: Consultancy; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy; PharmaMar: Consultancy, Research Funding; Takeda: Consultancy, Research Funding.