Background: Acute myeloid leukemia (AML) remains a hard-to-treat disease. Except for molecularly defined subsets with relevant chemosensitivity, patients experience a high rate of induction failure and deaths due to the disease, having an expected 5-year survival probability below 30%. Inhibiting apoptosis with venetoclax (VEN) - a BH3 mimetic molecule - while administering chemotherapy containing high-dose of cytarabine, idarubicin, and fludarabine (V-FLAI) may improve the complete remission rate and overall survival. We hereby report the results of the planned interim analysis.

Methods: In this multicenter phase 1/2 trial, we investigated the safety and efficacy of 2 dosages of VEN in combination with FLAI (fludarabine 30 mg/sqm from day 1 to day 5, cytarabine 2000 mg/sqm from day 1 to day 5, and idarubicin 8 mg/sqm on days 1, 3 and 5) as first-line therapy for newly diagnosed ELN intermediate- or high-risk adult AML patients (NCT03455504). The study had a modified two-stage Simon's design; it was divided into 2 consecutive 6-patients safety run-in cohorts (SRI-C1 and SRI-C2), a Part 1 with 2 extension cohorts (P1-C1 and P1-C2), and a confirmatory cohort (Part 2). SRI-C1 tested the safety of VEN administered continuously at a daily dose of 400 mg in combination with FLAI; in SRI-C2 we escalated the dose of VEN up to 600 mg/day. After a positive safety review, patients were randomly allocated in P1-C1 and P1-C2 receiving FLAI in combination with VEN 400 mg or 600 mg, respectively. During the entire study, patients in partial response were allowed to receive a second induction at the same dosages; after V-FLAI induction, patients received center-specific cytarabine-based consolidation and allogeneic stem cell transplant (HSCT). VEN dose was under situations of concomitant posaconazole administration, discontinued until recovery for patients in remission at day 21 and during consolidation courses; post HSCT maintenance were not allowed.

Results: Here we report the results of SRI-C1, SRI-C2, P1-C1, and P1-C2 after a predefined interim analysis. Since February 2019, we enrolled 57 patients; 28 patients received V-FLAI with VEN 400 mg and 29 patients V-FLAI with VEN 600 mg. Overall, patients had a median age of 54 years (18 - 65); 37 patients (65%) were male; 32 (56%) and 25 (44%) were at intermediate- and high-risk according to ELN2017 category, respectively; 12 patients (21%) had secondary AML. Two/33 (6.5%) patients tested harbored IDH1 mutation, 7/35 (21%) IDH2 mutation, and 6/51 (12.2%) FLT3 mutation. Characteristics were well balanced between the 400 mg and 600 mg cohorts.

Complete remission was observed in 48/57 patients (84%). As for the primary endpoint, the complete remission rate was 22/28 (79%) in VEN 400 mg and 26/29 (90%) in VEN 600 mg arm; responses at induction are specified in table 1, 74% of patients were measurable residual disease (MRD) negative after induction (67% in ven 400 mg, and 78% in ven 600 mg arm). With a median follow-up of 10.5 months, 28 patients (49%) received HSCT in CR, of which 20 (80%) in MRD negative CR; median overall survival (OS) was not reached; probability of 12-month OS was 76% (71.5% for VEN 400 mg and 76.5% for VEN 600 mg. Median disease-free survival was not reached (figure 1).

No dose-limiting toxicity was observed in SRI-C1 or SRI-C2. Overall, within NCTCI grade 3+ adverse events (AE) infections were the most occurring AE; 30-day mortality and 60-day mortality were 1.8% and 5.3%, respectively. A prolonged time in aplasia (>30 days) was observed in patients receiving consolidation regimens with >10 g/sqm of cytarabine and/or >10 mg/sqm of idarubicin or equivalent. In transplanted patients, we did not observe instanced of graft failure or incidence of GVHD higher than expected.

No significant differences in terms of safety, complete remission, or survival were observed between the 400 mg and 600 mg arm.

Conclusions: V-FLAI administration was associated with a high and promising CR rate and prolonged OS duration in an intermediate- and high-risk population, without any safety signals. Preliminary MRD analysis revealed deep responses in most of the patients that translated to favorable 1-year survival. The confirmatory arm at the lower effective dosage (VEN 400 mg in combination with FLAI) with centralized MRD assessment is ongoing. Investigation of further escalation of VEN dosages together with optimization of exposure duration is warranted.

Figure 1
Figure 1
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Marconi:menarini/stemline: Honoraria, Speakers Bureau; astellas: Honoraria; servier: Honoraria; pfizer: Honoraria, Research Funding, Speakers Bureau; abbvie: Research Funding. Papayannidis:Abbvie: Honoraria; Amgen: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Blueprint: Honoraria; Incyte: Honoraria; GlaxoSmithKline: Honoraria; Bristol Myers Squibb: Honoraria. Martelli:Celgene: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Eusapharma: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lanza:Pfizer: Research Funding; Amgen: Consultancy; Alexion: Consultancy; Abbvie: Consultancy. Ciceri:Kite Pharma: Consultancy. Giaccone:Gilead: Honoraria; MSD: Honoraria; Novartis: Honoraria; MSD: Honoraria; MSD: Honoraria. La Sala:Roche: Consultancy. Bochicchio:werfen, Imstrumentation Laboratory: Consultancy, Honoraria. Saglio:Novartis: Speakers Bureau. Venditti:Janssen & Cylag: Honoraria; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; astrazeneca: Honoraria; abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Research Funding; Medac: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees. Vignetti:IQVIA, Dephaforum, AbbVie, Astrazeneca: Speakers Bureau. Martinelli:Jazz Pharmaceuticals: Consultancy; Roche: Consultancy; Pfizer: Consultancy, Speakers Bureau; Stemline: Consultancy; Abbvie: Consultancy; Astellas: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Incyte: Consultancy; Celgene/BMS: Consultancy, Speakers Bureau.

Venetoclax is registered in combination with azacytidine to treat elderly or unfit AML and to treat CLL. In the study, venetoclax is administered in combination with intensive chemotherapy to treat young and fit AML patients

Author notes

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Asterisk with author names denotes non-ASH members.

© 2022 by The American Society of Hematology
2022
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