Enhancing the sequential flamsa-treosulfan conditioning regimen with venetoclax – first results from the multicenter flamsaclax Phase I/II trial

Abstract Background: Sequential conditioning regimens are widely used to prepare patients with high-risk myeloid malignancies for allogeneic hematopoietic stem cell transplantation (alloHSCT). Venetoclax has been shown to act synergistically with hypomethylating agents (HMA) and conventional chemotherapy. Therefore, we initiated a Phase I/II trial to combine Venetoclax with the so-called FLAMSA-Treosulfan Regimen. Methods: Patients with high-risk MDS, CMML or low blast count AML were eligible if they were untreated or had received a maximum of 2 cycles HMA +/- Venetoclax. Using a classical 3+3 design, patients received escalating doses of Venetoclax starting on day -11, one day before a 4-day treatment with FLAMSA (day -10 to -7, Fludarabine 30 mg/m2/day, Amsacrine 100 mg/m2/day and Cytarabine 2 g/m2/day, 1 g/m2/day for patients older than 60 years). Venetoclax was given daily until the day after FLAMSA (day -6) followed by high-dose Treosulfan (3x 10 g/m2/day, day -5 to -3). Allogeneic peripheral blood stem cells were infused on day 0 and GvHD prophylaxis consisted of tacrolimus, mycophenolate mofetil and a total dose of 30 mg/kg ATG. Results: A total of 9 patients (3 female) at a median age of 62 years (range 56 - 69) were included in the phase I part of the study (6 MDS, 2 CMML, 1 AML, all having active disease and unfavorable biology). Three patients received a total daily dose of 200 mg, 3 of 400 mg, 2 of 800 mg and 1 of 1600 mg Venetoclax in combination with FLAMSA. Following the infusion of a median of 7.2 x 106 CD34+ cells (range 4.1 - 9.7 x 106) from matched (10/10) unrelated donors and G-CSF support, all patients engrafted. Neutrophil (> 500 per microliter) and platelet recovery (> 20,000 per microliter) was achieved in all patients after a median of 14 days (range 10 - 27) and 16 days (range 10 - 27), respectively. No dose limiting toxicity occurred. Adverse events included grade 3 to 4 hematotoxicity as well as gastrointestinal disorders, febrile neutropenia, infections and electrolyte imbalances typical for the early phase after alloHSCT. There was no VOD and no specific unexpected toxicity attributable to Venetoclax identified. No patient died. Best response during the first 3 months after alloHSCT was CR in all patients, 4 with incomplete donor chimerism. Acute GvHD was diagnosed in 8 patients (3x I°, 4x II°, 1x III°). Three patients relapsed and received salvage therapy resulting in CR in 2 patients so far. After a median follow up of 365 days (range 74 - 640), all patients are alive, 8 of 9 in CR. Three patients are affected by chronic GvHD — one each with mild, moderate, and severe manifestations. Conclusion: Smart conditioning using Venetoclax up to a daily dose of 800 mg in addition to FLAMSA-Treosulfan is safe. Hematopoietic reconstitution was not impaired and general toxicity of this sequential conditioning regimen was not increased. Early results are promising and the Phase II part of the FLAMSAClax study will continue to include patients up to a total number of 38.