Background and Significance For many patients with AML and higher risk MDS, allogeneic hematopoietic stem cell translplantation (HSCT) is the only curative treatment. The introduction of reduced intensity conditioning (RIC) regimen has greatly increased the number of patients eligible for alloHSCT. While Fludarabine plus Busulfan (FluBu) is a very popular RIC regimen, data from a randomized controlled trial have demonstrated superior overall survival (OS) with Treosulfan (FluTreo) instead of Busulfan as alkylating agent (3 year OS 67 vs. 56%; Beelen et al., Am J Hematol, 2022). However, the favorable toxicity profile of RIC alloHSCT still comes at the price of a higher relapse risk as compared to myeloablatve conditioning (2 years relapse risk 6% higher; Alfaro Moya et al., Eur J Haematol, 2023). Since relapses remain the main cause of mortality after alloHSCT, there is an urgent need to reduce this risk. We hypothesized that the addition of the Bcl-2-Inhibitor Venetoclax to FluTreo RIC can enhance antileukemic efficacy, hence reducing the relapse risk, without adding relevant toxicity. Regarding toxicity, this expectation is based on the favorable safety profile of Venetoclax observed in the first line setting in elderly and comorbid patients, as well as on data from a phase I trial (Garcia et al., Blood Adv, 2021). The trial found a recommended phase II dose of 400 mg of Venetoclax for 7 days. Increased antileukemic activity is assumed based on preclinical data, showing synergism of Venetoclax with Fludarabine and alyklating agents in vitro (Valdez et al., Oncotarget, 2022). Taking into account the superiority of Treosulfan over Buslulfan, we also expect VenFluTreo to produce more favorable results than VenFluBu.

Study Design and Methods The trial VeStAL has the EU Trial Number (2025-521372-62-00). It is conducted as mononcentric, single-arrm phase II trial. General study design of this safety trial and analysis of the primary endpoint, overall survival at day 28 after alloHSCT, follows a Simon Optimal Design. This design includes 27 patients and tests the alternative hypothesis of rate of early mortality of 10% against a null hypothesis of an early mortality of 30% (5% one-sided probability of tye I error, 80% power). Stage 1 enrolls 6 patients. If ≤2 deaths within 28 days after alloHSCT are observed, the trial will be ended. Otherwise, stage 2 enrolls further 21 patients. DSMB-Meetings are held after 6 and 14 patients have reached the primary endpoint. The study meets its primary endpoint, if ≤4 deaths are observed within 28 days after alloHSCT. Enrolled are patients planned for alloHSCT (with peripheral blood stem cells) with AML, MDS/AML or higher risk MDS (ICC 2022), who present with a clinically controlled myeloid neoplasm. This is defined as having either responded to induction ± consolidation therapy (at least morphological leukemia free state) in cases with AML or MDS/AML or being treated with upfront alloHSCT in cases with MDS or MDS/AML. For patients with MDS, response to pre-treatment is not required. Excluded are patients with relapsed disease, extramedullary myeosarcoma, history of alloHSCT or patients who are scheduled for alloHSCT with bone marrow stem cells or with a haploidentical donor. Patients who are enrolled receive 7 days of Venetoclax ( day -8 to -2, 400 mg p.o.), 5 days of Fludarabine (day -6 to -2, 30 mg/m2i.v.) and 3 days of Treosulfan (day -4 to -2, 10 mg/m2i.v.). Immunosuppression and infusion of allogeneic stem cells on day 0 is performed according to standard of care and local practice. However, a minimum time interval of 54 hours (3 half lives) between the last dose of Venetoclax and infusion of allogeneic stem cells is to be adhered to. Patients are followed up until day 100. As mentioned above, the primary endpoint is overall survival on day 28 after alloHSCT. Since this is a safety trial, the key secondary endpoint is the incidence of AEs CTCAE Grade ≥4 until day 28. Further important secondary endpoints include rate of delayed engraftment on day 28 and overall survival, non-relapse mortality and cumulative incidence of relapse, as well as cumulative incidence of Grade III and IV GvHD on day 100. A scientific companion program includes spatial assessment of the bone marrow microenvironment under therapy and monitoring of chimerism via single nucleotide polymorphism using digital PCR. The study was submitted via CTIS on 30.07.2025 and will start enrollment early in 2026.

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2025
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