Myeloablative fractionated busulfan conditioning regimen with sorafenib for allogeneic stem cell transplant in AML: Results of a phase 1/2 study.

6561 Background: Myeloablative conditioning for allogeneic stem cell transplant (allo-SCT) can be given safely to older patients by extending the duration of busulfan (Bu) administration. This allows the addition of agents like sorafenib for a 3-week period to synergize with the conditioning. Here, we studied 4 doses of sorafenib with myeloablative fludarabine and fractionated Bu (f-Bu) in a phase 1/2 study (NCT03247088). Methods: From 3/2018-9/2023, 59 AML patients 18-70 years old with 8/8-HLA matched donors were enrolled prospectively. Sorafenib dose finding was done in phase 1 with a Bayesian Model Averaging Continual Reassessment Method with target toxicity probability .30 and cohort size 3, with DLT defined as grade >3 regimen-related toxicity occurring on days -24 to 30. Subsample sizes were 3 patients at 200, 400, and 600mg, and 50 patients at the highest tolerated dose of 800mg (400mg bid), given daily on days -24 to -5. The f-Bu dose targeted an area under the concentration vs time curve of 20,000 ± 12% μmol.min, given over 3 weeks. The first 2 doses (80 mg/m2 each) were given outpatient on days -20 and -13. The last 4 pharmacokinetically guided doses were given inpatient after Flu 40mg/m2 on days -6 to -3. GVHD prophylaxis was cyclophosphamide 50mg/kg on days 3-4 and tacrolimus. Unrelated donor graft recipients also received MMF. All patients were eligible for sorafenib maintenance for 1 year post-transplant. 30 (51%) patients began this maintenance and 13 (21%) completed 1 year. Results: Median age was 53 years (range, 24-70). Disease status at SCT was CR1 in 42 (71%) patients, CRi in 6 (10%), and advanced disease in 11 (19%). 34 (58%) had ELN22 adverse risk disease, 31 (53%) were MRD+, 17 (29%) had FLT3 ITD, donor was unrelated in 37 (63%), and peripheral blood was the graft source in 53 (90%). The cohort’s 2-year overall survival (OS) was 74.9% (95% credible interval (CrI) 61.8-84.8%), with a median follow-up in 43 surviving patients of 2.2 years. A fitted Bayesian Weibull regression model for OS showed a higher risk of death with MRD+ disease (posterior mean HR = 3.13, 95% CrI 1.01–12.03) and age > 60 (posterior mean HR = 2.22, 95% CrI 0.76–6.91). No association was seen with OS or PFS and comorbidity score, remission status, or ELN22 risk group. Outcomes were similar in FLT3 ITD and wild type patients. Conclusions: The f-Bu regimen with sorafenib results in promising outcomes for AML patients. Clinical trial information: NCT03247088 . Outcomes (n=59). 1 year 2 years OS 86% 75% PFS 83% 69% Relapse 12% 22% NRM 10% 10% Percent Acute GVHD II-IV, day 100 36% Acute GVHD III-IV, day 100 3% Chronic GVHD, 2 years 14% Mod/Severe Chronic GVHD 9% Median (range) days Neutrophil Engraftment 15 (12-28) Platelet Engraftment 23 (14-164) T Cell Chimerism, day 30 100 (33-100) Myeloid Chimerism, day 30 100 (91-100) Grade 3-5 toxicity, day 100 (>10%) Events Percent Febrile Neutropenia 24 41% Bacterial infection 21 36% Pneumonitis/IPS 8 14% Rash 6 10%