Post-remission immunotherapy with vididencel for a measurable residual disease defined high-risk sub-group of adult patients with Acute Myeloid Leukemia in first complete hematological remission: Updated results of the european advance II study demonstrate robust safety, relapse-free and overall survival benefit.

Abstract Background Despite the approval of multiple novel therapies and substantial improvements in allogeneic stem cell transplantation for the treatment of acute myeloid leukemia, the long-term clinical outcomes remain poor. Herein, we report the results of a phase 2 trial testing vididencel, an allogeneic immunotherapy, in patients aged 18 years or more, with newly diagnosed AML who achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi) following conventional intensive chemotherapy but demonstrated measurable residual disease (MRD). Vididencel expresses myeloid antigens such as WT1, PRAME and RHAMM, and has been found to be safe and potentially effective in phase 1 studies in patients with AML with low tumor burden (Janssen L, et al, HemaSphere 2023, 7(11): p e968). Methods Twenty evaluable patients with MRD-positive AML (all risk categories by ELN 2017) in CR/CRi and ineligible for an allogeneic stem cell transplant at inclusion, received four biweekly doses of vididencel administered intradermally followed by two booster doses at week 14 and 18. Bone marrow aspirates were obtained for genomic analysis (NGS) at baseline (analysis performed prospectively or post-hoc) and peripheral blood samples were drawn on day 1, 3, 42, 44, week 11, 18, 20 and 32; peripheral blood mononuclear cells were cryopreserved for functional T-cell responses by IFNy ELISPOT to myeloid antigens. The primary endpoint of the trial was MRD conversion, and the secondary endpoints assessed vididencel-induced immune response (VIR), relapse-free survival (RFS) and overall survival (OS). Statistical analysis was performed in JMP18. MRD assessment was conducted in the various Europeans centers of recruitment using standardized ELN methodologies by flow cytometry (FC), qPCR and NGS. Results. Following a median follow-up of 47.8 months, median RFS and OS have not been reached, with 4-year OS 66.5% (42.5%-82.3%) and estimated 5-year OS 61% (34.8-79.3%); the estimated 5-year OS for patients younger than 63 years, (median age at study inclusion was 63 years with range 34 – 76 years), was 100%, compared with 35% for patients older than 63 years. The 4-year RFS was 54.9% (31.4-83.3%) and the estimated 5-year RFS 50.5% (26.3-7.5%). In total, 5 of 20 (25%) patients have completed 5-year follow-up alive and 7 patients (35%) are still in follow-up. Six patients relapsed clinically within 32 weeks of entry into the trial; 7 patients remained stable and MRD-positive, and 5 patients converted from MRD-positive to MRD-negative; 2 patients demonstrated at least a 10x reduction in MRD levels. Genomic analysis revealed DNMT3A mutations in 6 of 20 patients, with 1 patient relapsing, 1 patient converting to MRD-negative and the remainder remained stable; 3 of 7 patients with MRD response had additional mutations at baseline: TET2 (1 pt; alive at 41 months); KIT1 (1 pt; alive at 50 months), ASXL1 and SRSF2 (1 pt; converted to MRD-negative but relapsed and died after 30 months), TET2 and TP53 (1 pt; relapse at 12 months; alive at 54 months), SRSF2, RUNX1 and PPM1D (1 pt; relapse at 7 months and died after 30 months), TET2 and PHF6 (1 pt; relapse after 2.5 months and died after 10 months); SRSF2 and JAK2 (1 pt; relapse after 4.6 months and died after 14.6 months). Most patients (85%) showed a VIR and 35% demonstrated a MRD response, with conversion to MRD-negative in 5 patients. Responding patients were characterized by a more immune competent profile with higher B cells and lower CD8+LAG3+ cells at baseline. Seventeen of 20 patients showed a T-cell response to either WT1, PRAME and/or RHAMM that correlated with MRD conversion and improved survival. Conclusion Post remission therapy with vididencel for MRD-positive AML patients in CR/CRi was associated with T-cell responses which correlate with long-term RFS and OS at a median follow-up of 47.8 months. The treatment was well tolerated, with injection site reactions as the principal treatment-related adverse event. Vididencel is now being assessed as post-remission/maintenance therapy in a randomized phase IIb study in high-risk AML (AMLM22/D4).