Full Doses of Crenolanib, a Type I FLT3 Inhibitor, Can be Safely Administered in AML Patients Post Allogeneic Stem Cell Transplant
Authors: Collins Robert , Kantarjian Hagop M. , Ravandi Farhad , Chen Jenny , Macaraeg Meghan , Urity Vinoo , Pond Blake , Ramachandran Abhijit , Cortes Jorge E. 
Published: October 2019

Abstract

Introduction:
Crenolanib besylate is a selective and potent type I tyrosine kinase inhibitor (TKI) of wild-type and mutant FMS-like tyrosine kinase 3 (FLT3). Crenolanib is being studied in patients with relapsed/refractory FLT3+ AML with FLT3-ITD and/or FLT3-D835 mutations. A total of 65 patients with relapsed/refractory AML have been treated with crenolanib. This retrospective analysis was done to assess whether full doses of crenolanib can be safely administered in the post allogeneic transplant setting (HSCT).
Methods:
Of the 65 patients treated with crenolanib, 16 patients (9 females and 7 males) had undergone HSCT prior to initiation of crenolanib. The median age was 51 years (range: 24-72). 15 patients had received salvage chemotherapies (median of 3 systemic therapies range: 1-5) following their recurrence post-transplant and prior to initiation of crenolanib. 11/16 patients also had prior exposure to FLT3 TKIs, including sorafenib (9 patients), ASP2215 (2 patients) and quizartinib (3 patients). The median time between allogeneic stem cell transplantation and initiation of crenolanib was 9 months (range, 1 to 69 months). One patient began maintenance crenolanib one month following transplant.
Crenolanib was initially given at a dose of 100 mg TID (7 patients) and subsequently escalated to a higher dose of 200 mg/m2 (9 patients). The highest total dose of crenolanib was 400 mg daily (2 patients). Patients were monitored for serious adverse events while on crenolanib, specifically for elevated liver transaminases and GI toxicities. Regular assessments of chemistry and hematologic laboratory values were performed to ensure safety of crenolanib in this patient population.
Results:
Crenolanib was well tolerated in the post-transplant setting and none of the 7 patients treated at 300 mg daily dose of crenolanib required dose reduction. Of the 9 patients treated at the higher dose of 200 mg/m2, 4 patients (total daily doses of 400, 360, 340 and 320 mg) did require dose reductions; no patients required drug discontinuation due to toxicities attributed to crenolanib. The pharmacokinetic profile in this patient population was consistent with that seen in all patients treated with crenolanib. For those patients who received crenolanib at 100mg TID, the median Cmax was 149 nM (range: 105-624 nM). Those patients who received crenolanib at 200mg/m2 had a median Cmax of 391 nM (range: 328-1497 nM).
Grade 1 and 2 nausea and vomiting were seen but were well controlled with standard anti-emetics, requiring no dose reductions or discontinuation. Two patients experienced grade 1 ALT and AST elevation and one patient experienced grade 1 ALT, AST and bilirubin elevation; no patient required dose interruption or reductions. The only grade 3 elevation of AST was attributed to GVHD and improved with treatment of GVHD and did not require crenolanib discontinuation. One patient developed grade 3 hyperbilirubinemia on day 53 of crenolanib. This patient had achieved a CRi on crenolanib and liver biopsy showed development of acute graft versus host disease. Following treatment of GVHD, the patient was able to restart crenolanib at 280 mg daily.
One patient received crenolanib maintenance in the immediate post-transplant setting. This patient was able to stay on crenolanib at a dose of 280 mg a day for 5 months with full recovery of neutrophils and platelet counts, and became transfusion independent.
Conclusion:
Post-transplant maintenance with a FLT3 inhibitor can potentially be beneficial in reducing post-transplant recurrence and improving overall outcomes. This retrospective study shows that crenolanib appears to be well-tolerated in patients with leukemia who have undergone a prior allogeneic transplant at the full therapeutic dose of 100 mg TID (300 mg daily). A formal study of crenolanib maintenance post-allogeneic stem cell transplantation has been initiated (NCT 02400255).

Disclosures
Chen: Arog Pharmaceuticals: Employment. Ramachandran:AROG Pharmaceuticals: Employment. Cortes:Teva: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.