First-in-human trial of siltuximab in combination with standard induction chemotherapy in patients with acute myeloid leukemia: The Phase 1 siltuxilam study.

Abstract Background: Numerous studies have pointed out the pathological role of deregulated expression of Interleukin-6 (IL-6) in cancers. In acute myeloid leukemia (AML), IL-6 promotes chemo-resistance and correlates with poor prognosis. One explanation is that AML cells express IL-6 receptor (R) and self-produce IL-6 at once, favouring blast proliferation and survival. Therefore, IL-6 blockade may represent a new promising therapeutic strategy for AML. Here, we have tested Siltuximab (Siltux), an anti-IL-6 antibody approved for the treatment of multicentric Castleman's disease in the US and Europe at a dose of 11 mg/Kg per injection, in combination with a standard AML induction chemotherapy. Methods: The aim of this investigator-initiated single-centre phase 1 trial was to determine the maximum tolerated dose (MTD) of Siltux in combination with a standard intensive AML induction. According to a continual reassessment method, three escalating doses of intravenous (IV) Siltux (7, 9 and 11 mg/kg) were tested. Siltux was administered at day (d) 8 after the end of a standard AML induction chemotherapy (IV idarubicine 8 mg/m2 d1 to d5 + IV cytarabine 100 mg/m2 d1 to d7). All adults (aged ≥ 18 years old (yo)) with an Eastern Cooperative Oncology Group performance status of 0–2 and with a newly diagnosed (excluding patients with a favourable risk according to ELN-2022 classification if <60 yo) or a relapsed/refractory (R/R) AML were eligible. Twelve patients (pts) had to be included. Serious adverse events (SAE) were recorded and toxicity was evaluated using NCI CTCAE version 5.0 toxicity criteria up to 45 days after Siltux injection. Responses were defined according to ELN-2022 criteria being evaluated between d30/d45 of induction. Also, FLT3 Ligand and IL-6 plasma levels were assessed. All pts gave informed consent. The trial is registered at ClinicalTrials.gov, NCT05697510. Results: Patients: From March 2023 to June 2024, 13 pts were enrolled but 12 were eventually treated as required. Indeed, one pt was excluded from the study and replaced because he did not receive Siltux due to neurological complications during induction. The characteristics of the 12 pts at inclusion were as follows: median age: 66.5 yo, male n= 6, median white blood count: 2.7 Giga/L (1.3 – 4.4), newly diagnosed (ND) AML n=10, R/R AML n=2. Among the 10 ND AML pts, all were classified as adverse-risk (ELN-2022 classification), 6 had complex karyotype and 6 had secondary AML, including 2 who had been already treated for myelodysplastic syndrome (azacitidine and upfront allo-HCT). One R/R AML had received low-dose aracytine + venetoclax in first line and had a normal karyotype with RUNX1 mutation at relapse. The other one has been treated intensively and consolidated with an allotransplant 2 years before the relapse and still had MLL rearrangement at this time. Safety: Two patients received Siltux at the dose of 7 mg/kg, 2 at 9 mg/kg, and 8 at 11 mg/kg. One patient (level 3) died (8%) at d20 of induction due to a non-documented sepsis while being refractory (43% of circulating blasts). The 30-day and 60-day mortality rates were both 8.3%. No SAE and death were linked to Siltux. Thus, there was no dose limiting toxicity at level 1, level 2 and level 3, and MTD was not reached. Response and consolidation: Overall response rate (CR/CRh/CRi/MLFS) was 67% (n=8) (34%/8%/8%/17%), this being 70 % (n=7/10) in ND AML, 67% (n=4/6) for AML with complex karyotype, 50% (n=3/6) for secondary AML and 50% (n=1/2) for R/R AML. Among responders, 5 out of 8 (62%) reached MRD-Flow negativity, 6/8 were consolidated with chemotherapy (AZA n= 4, AZA+ LDAC+ida n=1, IDAC n=1) and 4/8 received allo-HCT including 1 in MLFS just after induction. In non-responders, 1/4 received allo-HCT while in partial response. Survivals: At last follow-up (July 2025), 2 pts/8 have relapsed (25%) and 7/12 have died (58%). With a median follow-up of 222 days, 1-y overall and leukemia-free survivals were estimated at 35% (14-87%) and 29% (8.9-92%), respectively. FLT3 ligand and IL-6 dosages: this is on-going, results and correlation with outcomes will be presented at the meeting. Conclusions: This phase 1 first-in-human study showed that the addition of Siltux at d8 of a standard AML intensive induction is safe and provides relatively good response rate in a very high-risk AML population. We now recommend a dose of 11 mg/kg of Siltux given at d8 of intensive AML induction for further phase 2/3 studies.