Conditioning with alkylating agents, cytarabine, cladribine, hypomethylating agents, and venetoclax (ARCHIVE) for upfront allogeneic stem cell transplantation in patients with active Acute Myeloid Leukemia or myelodysplastic syndrome with increased blasts-2 Free

BACKGROUND Consolidation with allogeneic stem cell transplantation (alloSCT) after bridging therapies remains the cornerstone for relapsed/refractory (R/R) or newly diagnosed, poor-risk acute myeloid leukemia (AML) patients. Despite the improving efficacy of remission-inducing regimens, a proportion of patients become ineligible for alloSCT due to refractory disease or toxicity. Herein, we report an investigational conditioning regimen with alkylating agents, cytarabine, cladribine, hypomethylating agents, and venetoclax (ARCHIVE) in patients with active AML or MDS-IB2 proceeding to upfront alloSCT without conventional bridging therapies.

METHODS This was an observational single-center study. Treatment and data collection were approved by Vilnius University Hospital Santaros Klinikos Hematology Board and Vilnius Regional Biomedical Research Ethics Committee. The patients were older than 18 years and had AML or MDS-IB2 with >5% blasts and/or extramedullary disease.

ARCHIVE conditioning consisted of cytarabine 500 or 1000 mg/m², cladribine 5 mg/m² on days -8, -7, -6, -5, -4, venetoclax 600 mg/d and decitabine 20 mg/m² / azacitidine 75 mg/m² on days -8, -7, -6, -5, -4, -3, -2. The backbone alkylating agent was either busulfan (3.2 mg/kg on days -3 and/or -2) or melphalan (100 mg/m2 on day -2 in patients with previous busulfan exposure), whereas thiotepa (5 or 10 mg/kg on day -3 or -4) was added to busulfan or melphalan in individual cases. Gilteritinib 120 mg/d was given until day -2 in FLT3-mutated AML patients. Peripheral blood stem cell grafts were used in all cases with the target CD34+ dose of 7 mln/kg. GVHD prophylaxis consisted of post-transplant cyclophosphamide 40 mg/kg on days +3 and +4, cyclosporine A (from day -1 and continued individually with tapering from day +70, target concentration 200-400 mcg/l), and mycophenolate mofetil 3 g/d (days 0-30).

We collected baseline patient characteristics, disease-related factors, CR + CRp rate at day +30 after alloSCT, MRD negativity rate (by multiparameter flow cytometry and PCR), engraftment rate, grade 3-5 non-hematological toxicity (CTCAE v5.0), OS, and RFS.

RESULTS 25 patients (16 female) were enrolled in the study, 20 (80 %) with AML and 5 (20 %) with MDS-IB2. The median age was 57 (23-70), 18 patients had ECOG 0-1 status (72 %), and 7 patients had ECOG 2 (28 %). Twenty-one patients (84 %) had R/R disease, and 4 (16 %) were newly diagnosed. ELN 2022 poor risk genomics were identified in 80 % (20/25). The median number of previous therapies in R/R cases was 1 (1-8). Patients were previously exposed to venetoclax (52 %, 13/25), FLT3 inhibitors (12 %, 3/25), revumenib (8 %, 2/25), and BCR-ABL1 inhibitors (4 %, 1/25). Twenty-eight percent (7/25) had been previously allotransplanted (one patient with 3 prior alloSCTs). The median blast count prior to ARCHIVE was 13% (0-85).

Dose-escalated cytarabine (1000 mg/m²) and Gilteritinib were used in 16 % (4/25) of patients. Thiotepa was added to busulfan or melphalan in 80 % (20/25). Matched sibling, matched unrelated, mismatched unrelated, and haploidentical donors were used in 8 % (2/25), 28 % (7/25), 8 % (2/25), and 56 % (14/25), respectively.

The CR + CRp rate at day 30 post alloSCT was 96 % (23/24) with all responders successfully engrafting. One patient died prior to the disease evaluation, and 1 patient had leukemia regrowth. MRD negativity was achieved in 91 % (20/22) of MRD-evaluable responders. The median time to neutrophil recovery (>1x10⁹/l) was 16 (13-27) days after the stem cell infusion and 25 (19-35) days after the start of the conditioning.

Grade 3-5 infectious complications were confirmed in 88 % (22/25). Grade 3-4 mucositis was reported in 40 % (10/25). Eight percent (2/25) had been diagnosed with veno-occlusive disease. Grade 3-4 acute GVHD was diagnosed in 16 % (4/25). Secondary graft failure was confirmed in 4 % (1/25). Day 30 mortality rate was 8 % (2/25).

At the data cut-off (August 1st, 2025), 20 patients are alive and in CR, with no confirmed relapses. There were 5 deaths due to infectious complications (4) and GVHD (1). After the median follow-up of 5 months, the median OS and RFS were not reached.

CONCLUSIONS The early results of the investigational ARCHIVE conditioning with upfront alloSCT demonstrate promising efficacy in poor-risk newly diagnosed or R/R AML or MDS-IB2 patients. Nevertheless, the treatment is associated with high rates of severe infectious and conventional alloSCT-associated complications.