Venetoclax Plus High-Dose Cytarabine and Mitoxantrone As Feasible and Effective Novel Treatment for Relapsed AML: Results of the Phase-I SAL Relax Trial

Background Primary refractory disease and relapse remain the main obstacles for cure in AML. In fit patients, several salvage cytostatic options based on higher doses of cytarabine have been published, with complete remission (CR) rates ranging from 40 to 55%. As depth of remission is one of the main determinants of long-term prognosis and success of allogeneic hematopoietic cell transplantation (HCT), there is a need for more efficacious salvage regimens. The Bcl2 inhibitor venetoclax has demonstrated impressive antileukemic activity when combined with hypomethylating agents or low-dose cytarabine in newly diagnosed unfit AML patients. In the relapsed-refractory (r/r) setting, the combination induces CR rates of 20-40%. The SAL study group set up the RELAX trial in order to explore the combination of venetoclax with higher-dose cytarabine plus mitoxantrone (HAM).

Methods This is a phase-I/II trial combining 10 to 14 days of venetoclax plus mitoxantrone over 3 days with increasing doses of cytarabine. In the phase-I dose escalation part, patients with relapsed AML considered fit for intensive salvage treatment were treated in a 3+3 design in three dose cohorts. Venetoclax was given as a ramp-up over 3 days, followed by a fixed dose of 400 mg PO QD over a total period of 14 days, mitoxantrone 10 mg/m² IV fixed dose over three days. The cytarabine dose was 200 mg/m² continuous infusion over seven days in dose level 1, 500 mg/m² BID over 3 days in dose level 2, and 1000 mg/m² BID over 3 days in dose level 3. CYP3A inhibitors were not allowed in phase I, and patients did not receive G-CSF. Dose-limiting toxicities (DLT) were defined as any adverse event (AE) ≥ grade 3 related to venetoclax from day 1 to 28 and absence of blood count recovery above ANC 0.5x10⁹/L and PLT 25x10⁹/L by day 45 in patients achieving blast clearance. The trial is registered under NCT04330820. This research was supported by a grant from AbbVie Inc.

Results Between April 2020 and May 2022, 12 patients diagnosed with relapsed AML after intensive standard treatment were enrolled in the dose-escalation part. Median age was 56 years (range, 40-70). During study treatment, 57 adverse events CTCAE ≥3 were recorded, amongst them 21 (37%) of infectious origin. In addition, three patients suffered from grade 1-2 colitis. No DLT occurred in dose levels 1 and 2, but the first patient in cohort 3 did not show an adequate PLT recovery by the end of the hematological DLT period on day 45. Therefore, additional three patients were enrolled into dose level 3, and no DLT was observed. Based on these results, the maximum tolerated dose (MTD) was not reached and the combination of venetoclax 400 mg PO days 3-14 after ramp-up on days 1 to 3, cytarabine 1000 mg/m² IV BID days 4 to 6, mitoxantrone 10 mg/m² IV on days 6 to 8 could be shown to be safe and feasible. Remission assessment showed CR/CRi in 11/12 patients (92%). Utilizing a LAIP-based DfN MRD approach (Röhnert et al. Leukemia 2022), 3/10 (30%) evaluable patients were classified as MRD negative , whereas 5/8 (62.5%) evaluable patients by a conventional LAIP-based MRD approach (Köhnke et al. Haematologica 2019) were categorized as MRD negativie . The one refractory patient died of progressive disease after one month of follow-up. Postremission treatment in the 11 CR/CRi patients was allogeneic HCT in five patients. Of 11 patients in CR, nine are in ongoing CR/CRi, one died in CR from infectious complications after allogeneic HCT and one suffered from relapse and died of progressive disease.

Discussion The combination of venetoclax with higher doses of cytarabine and mitoxantrone (HAM) is well tolerated and led to complete remissions in 92% of patients with relapsed AML. Based on the results of the phase-I part, the following expansion part of the RELAX trial will explore tolerability and efficacy of dose level 3 in 42 patients with r/r disease.

Röllig:Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Amgen: Honoraria; BMS: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Servier: Consultancy. Fransecky:Pfizer: Consultancy, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau. Steffen:Jazz Pharmaceuticals: Other: Travel/Congress Participation Support; AbbVie: Other: Travel/Congress Participation Support. Schliemann:Roche: Consultancy; Astrazeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz: Consultancy, Research Funding; Novartis: Consultancy; Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; Pfizer: Consultancy. Alakel:Pfizer: Consultancy, Honoraria. Middeke:Abbvie: Membership on an entity's Board of Directors or advisory committees. Schetelig:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ruhnke:Beigene: Other.

venetoclax in combination with intensive chemotherapy in fit r/r AML patients