Safety, Tolerability and Efficacy of Crenolanib Administered Post Allogeneic Hematopoietic Stem Cell Transplant (HSCT) in Patients with FLT3 Mutant AML

Methods: Pts with FLT3 AML received crenolanib 42-90 days after undergoing allo-HSCT. Enrollment criteria included adequate engraftment with ANC ≥ 1,000/mL and platelets ≥ 25,000/mL, creatinine <1.5 x ULN and LFTS <2.0 ULN. Pts with active AML post-HSCT were excluded. Crenolanib was escalated from 60 mg BID, to 80 mg BID, to 80 mg TID in 1-month cycle increments. 5 pts received crenolanib 100 mg TID.

Results: Patient characteristics: From Sept 2015 to March 2020, 30 pts with a median age 53.5 (range 24-74, 6 pts > 60y) have been treated. Twenty-seven pts had de novo AML, 3 pts had secondary AML (2 prior MDS, 1 CMML). 24 had FLT3-ITD, 5 had FLT3-TKD and 1 had both ITD and TKD mutations. Six pts had cytogenetic abnormalities (2 with trisomy 8 and one each with DEK-NUP214, MLL-MLLT3, del 12p ETV6 rearrangement, and complex karyotype). Twenty pts were TKI pretreated (16 sorafenib, 2 quizartinib, 3 midostaurin, 2 gilteritinib). Twenty-two pts were in CR1, 5 in CR2, and 1 in CR3 at the time of HSCT (2 pts were transplanted with active AML). Eight pts had MRD prior to HSCT as assessed by multicolor flow cytometry.

Transplant details: Twenty-two pts received myeloablative conditioning, 8 received reduced intensity conditioning. Stem cell source was matched related in 12, matched unrelated in 14, and haploidentical in 4 patients.

Crenolanib tolerability: Safety of crenolanib was assessed in all 30 pts treated. There were no non-hematological grade 4 or 5 toxicities seen. Grade 3 toxicities of interest included diarrhea (2), ALT elevation (2), AST elevation (2), hypotension (2), creatinine elevation (1), herpes zoster (1), and rash (1). The most common adverse events observed were grade 1-2 nausea (60%), vomiting (43%), and diarrhea (40%). Four pts (13%) reported grade 1-2 ALT elevations. Two pts (7%) developed grade 1-2 shingles. Two pts (7%) developed facial edema. Two pts (7%) reported new or worsening GVHD on study.

Crenolanib administration: Ten pts stopped crenolanib within 28 days of enrollment due to early progression (6), facial edema (1) and pt preference (3). All 6 pts who progressed within 28 days had high risk factors including active AML at time of HSCT (2), MRD at time of HSCT (5), or haploidentical transplant (3). In retrospect, 4 of these 6 had lab values (LDH and platelets) suggesting a potential for relapsing disease at study entry.

Ten pts received crenolanib for more than 6 months, and 5 pts completed 2 full years of maintenance. Reasons for discontinuation within the first 6 months but beyond the first 28 days were AML relapse (2), patient preference (2), and 1 pt for each for facial swelling, prolonged cytopenia, depression, altered mental status, comorbidities and insurance issues. One patient remains on study.

Crenolanib Efficacy: A landmark analysis was performed for the 20 pts who received > 28 days of crenolanib (Fig 1). Seventeen pts (85%) remain alive and in remission. To date, 95% of the patients in landmark analysis population is remain alive and in remission, with a median follow-up of 35 months. Of the 3 pts with MRD at HSCT, all 3 remain alive and in remission. The 1 pt who received a haploidentical HSCT remains alive and in remission. Two pts relapsed at day 84 (IDH1+, FLT3-) and day 112 (FLT3+, during a crenolanib hold due to GVHD). One pt had an abdominal extramedullary relapse 10 months after stopping crenolanib due to prolonged drug hold for liver GVHD.

Conclusions: Crenolanib can be safely given at a dose of 80 mg TID or 100 mg BID in the post-HSCT setting. Patients who received at least 28 days of maintenance therapy had significantly reduced relapse rates and increased survival compared to historical rates for FLT3 mutant AML. Two randomized phase III trials have been initiated to investigate the efficacy of crenolanib with chemotherapy vs chemotherapy alone in R/R FLT3 mutated AML as well as crenolanib vs midostaurin following chemotherapy in newly diagnosed FLT3 mutated AML (NCT03250338, EudraCT 2017-001600-29; NCT03258931). Post HSCT crenolanib maintenance will be offered at 100 mg BID in both trials.