Therapy Management and Outcomes in Newly Diagnosed Unfit AML Patients Receiving Venetoclax + HMA - Insights from a Prospective Real-World Study in Switzerland and Austria
Authors: Pabst Thomas , Lehmann Thomas , Pichler Petra , Machherndl-Spandl Sigrid , Gregor Michael , Goede Jeroen S. , Gerull Sabine , Mayer Daniel Maria , Lambert Jean-François , Germanier Catherine , Stüssi Georg 
Published: December 2024

Background
Patients (pts) with acute myeloid leukemia (AML) are often elderly and not fit for intensive chemotherapy (IC). The phase 3 VIALE-A study (DiNardo, NEJM 2020) evaluated the efficacy and safety of venetoclax (VEN) in combination with azacitidine (AZA) in AML pts ineligible for IC. Based on this study, VEN received approval in this indication, providing a treatment option for elderly and unfit AML pts. A more comprehensive understanding of dosing schemes, therapy management and outcomes in real-world setting is needed.
Methods
VALOR is a prospective, non-interventional, real-world study investigating treatment patterns, effectiveness, and safety of VEN+HMA/LDAC in newly diagnosed AML pts unfit for IC in Switzerland and Austria. 121 pts were enrolled between December 21, 2021 and November 14, 2023 to receive VEN-based treatments according to the local label. In this third interim analysis (data cut-off February 21, 2024), baseline data and treatment patterns including dosage adjustments, anti-infective management, quality of life (QoL) data as well as effectiveness and safety were documented.
Results
A total of 121 pts with de novo (71/121, 59%) or secondary AML (50/121, 41%) were treated with VEN-based combinations with a median follow-up of 3.5 months (range, 1.8-25.6). According to the ELN 2017 classification, 15.0 % had favorable, 19.5 % intermediate, and 53.1 % an unfavorable genetic risk. The median age was 75 years (range, 41-90), and the main reasons for ineligibility to IC were age, performance status and comorbidities. 51 (42.1 %) pts included in this study would not have been eligible for the VIALE-A trial, which includes 10 pts pretreated with hypomethylating agents (HMAs monotherapy) for a previous myelodysplastic syndrome.
Overall, 97.6 % of pts received VEN + AZA and 2.4 % received VEN + decitabine (DEC), 66% were hospitalized during the first treatment cycle. The median VEN-dosage was 265 mg/day, 259 mg/day and 200 mg/day in cycle 1,2 and 3 respectively. Daily dose reductions were mainly due to hematological (serious) adverse events ([S]AE) and pharmacological interactions. In following cycles, the median dose ranged from 260 to 300 mg/day. During the first two cycles, pts received VEN over a median period of 21 days (cycle 1 range, 1-37; cycle 2 range, 4-36), while in most cycles up to cycle 13 the median was 14 days/cycle. The duration of cycles varied between 28 and 35 days over the first 12 cycles. 90/121 (74%) pts received anti-infective agents during VEN treatment, most of them (85/90, 94%) initiated it during cycle 1.
A clinical response was reported for 73 pts, with 63/73 (86.3%) achieving CR/CRi. For 44 pts (36.4 %) a minimal residual disease (MRD) by FACS or qPCR was evaluable, 25/44 (56.8 %) pts achieved MRD negativity. First MRD negativity was achieved by 7 pts in cycle 1, 5 in cycle 2, 6 in cycle 3 and 5 in cycle 4. The last 2 pts achieved MRD negativity in cycle 5 and 6, respectively.
With a median follow-up of 3.5 months (range, 1.8-25.6) the median overall survival (OS) under VEN-based treatment was 13.5 months. The OS estimates for 6, 12, and 18 months were 74.3 %, 57.1 %, and 38,2 % respectively. In pts achieving vs. not achieving MRD negativity (&lt;10-3), the OS was 20.5 months vs. 13.2 months (p = 0.23). Of note, 8 pts received allogeneic stem cell transplantation (ASCT) after VEN+HMA treatment.
The 30 and 60-day mortality was 4.3 % and 11% respectively. The most common AEs were hematological toxicities (all grade/grade ≥3 neutropenia, thrombocytopenia, anemia and febrile neutropenia being 52.0%/47.2%, 48.8%/42.3%, 36.6%/31.7% and 24.4%/22.0% respectively) and infections (all grade/ grade ≥3 20.3 %/13.8%).
In general, QoL was improving with continuous therapy. Compared to cycle 1, the EQ-5D-5L index and the EORTC QLQ-C30 global health status score improved over the first 16 cycles. The global health status score improved already in cycle 2 with a change in score of 8.3 compared to cycle 1 and reached a maximum change in score of 20.8 at cycle 5.
Conclusion
In this prospective real-world study, the observed outcomes were consistent with those of VIALE-A, including in pts classified ineligible to this phase 3 trial. Dose modifications were mainly carried out by shortening VEN dose duration (days/cycle) or, in case of concomitant CYP3A4 inhibitors anti-infective use, by reducing the daily VEN dosage according to the guidelines. No new safety signals were observed in this interim analysis.