Clinical Benefit of Crenolanib, with or without Salvage Chemotherapy, in Multiply Relapsed, FLT3 Mutant AML Patients after Prior Treatment with Gilteritinib
Authors: Goldberg Aaron D , Geyer Mark B. , Kell Jonathan , Di Bona Eros , Pardee Timothy S. , Bhave Rupali , Grunwald Michael R. , Marconi Giovanni , Wang Yijia , Pathan Asif , Messahel Boo 
Published: November 2020

Background: Gilteritinib monotherapy provides a CR/CRh rate of 34% and a median event-free survival of 2.3 months in relapsed FLT3 mutant AML. Many AML patients (pts) who relapse after gilteritinib still express mutant FLT3 receptor and could potentially respond to FLT3 inhibition. Crenolanib is a type I, pan-FLT3 inhibitor which can be given as monotherapy or combined at full doses with standard salvage chemotherapy.
Methods: We here report our experience with 7 consecutive pts who received crenolanib on compassionate basis after progressing on gilteritinib. IRB/local ethics approval was obtained prior to treatment for each pt and all pts signed informed consent forms.
Results: Prior Treatment history: From Sep 2019 to July 2020, 7 consecutive pts with multiply relapsed FLT3-mutant AML who received compassionate use crenolanib after progressing on gilteritinib were identified. Four pts had relapsed after allogeneic HSCT (one pt had undergone two HSCT) and the other 3 were primary refractory despite multiple prior lines of therapy (range 2-5, median 4).
Clinical presentation: At the time of treatment all pts had bone-marrow infiltration or greater than 20% circulating blasts. 1 pt did not undergo BM assessment prior to salvage chemotherapy and crenolanib but had 87% circulating blasts in the peripheral blood. One pt had cranial nerve palsy due to leukemic meningitis, another pt had extramedullary relapse in spleen and lymph nodes. Five pts had FLT3-ITD (1 of whom also had the gate-keeper FLT3-F691L mutations); 1 had FLT3-D835 and 1 had both FLT3-ITD and TKD.
Crenolanib treatment: Crenolanib at 100mg TID was administered with intensive salvage therapy in 3 pts (FLAG-IDA in 2, HiDAC in 1). In the other 4 pts crenolanib was given with a palliative intent (with decitabine in 2, with azacytidine in 1 and as monotherapy in 1).
Tolerability of crenolanib: Crenolanib has been clinically well tolerated, with mild nausea and vomiting reported in 3 pts which was controlled by antiemetics without causing any drug interruptions. Two pts had elevated transaminases (which resolved as concomitant medications were discontinued). There were no cardiac toxicities, pericardial effusion, fluid retention or weight gain.
Response to crenolanib: At the time of this abstract, 5 of the 7 pts remain on crenolanib from a period of 18-160 days. Six of 7 pts reported clinical benefit with crenolanib.
Of the 3 pts being treated with curative intent, the pt with extramedullary disease in the spleen and lymph nodes had complete resolution of her AML by PET scan. She also had exhibited clearance of bone-marrow blasts with full count recovery and became FLT3 negative. The pt with FLT3-F691 mutation and cranial nerve palsy due to CNS leukemia had clearance of CNS blasts and improvement in cranial nerve function after HIDAC, crenolanib, and intrathecal cytarabine; this patient achieved morphologic leukemia free state and FLT3 negativity in the BM. A 22-year-old pt treated with FLAG-IDA has only received 18 days of crenolanib at time of data cutoff. All pts treated with curative intent continue on crenolanib.
Of the 4 pts treated with palliative intent, the pt with mutant TP53 had no benefit following crenolanib and azacytidine and died within two months. One patient, who had had two prior HSCTs, had 90% reduction in circulating blasts with azacytidine + crenolanib, but chose to discontinue treatment after 9 days. The other 2 pts continue on crenolanib 2 and 5 months after starting treatment.
Conclusion: With the widespread availability of gilteritinib, more pts are now in need of treatment options after gilteritinib refractoriness or treatment failure. These pts often have resistant clones due to either acquisition of the gate-keeper FLT3-F691 mutation or RAS mutant clones. In this consecutive case series of 7 post-gilteritinib pts, treated in US and Europe, crenolanib can be given at full doses in combination with intensive salvage chemotherapy or decitabine/azacitidine. The individual-patient-level experience suggests crenolanib could effectively clear FLT3-ITD and variant FLT3-TKD mutations in pts progressing from multiple lines of treatment including gilteritinib. Clinical trials combining crenolanib with salvage chemotherapy in relapsed and refractory AML with FLT3 mutations are ongoing. More information about crenolanib compassionate use program is available by emailing compassionate@arogpharma.com.

Disclosures
Goldberg: Celgene: Consultancy; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aptose: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Aprea: Research Funding; AROG: Research Funding; Celularity: Research Funding; Dava Oncology: Honoraria; Pfizer: Research Funding. Geyer:Amgen: Research Funding. Pardee:Rafael Pharmaceuticals: Consultancy; AbbVie: Consultancy; Genentech, Inc.: Consultancy; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Research Funding; Rafael: Research Funding; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Pharmacyclics: Speakers Bureau. Grunwald:Cardinal Health: Consultancy; Amgen: Consultancy; Amgen: Consultancy; Agios: Consultancy; Merck: Consultancy; Merck: Consultancy; Abbvie: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Abbvie: Consultancy; Abbvie: Consultancy; Trovagene: Consultancy; Daiichi Sankyo: Consultancy; Incyte: Consultancy, Research Funding; Celgene: Consultancy; Incyte: Consultancy, Research Funding; Astellas: Consultancy; Astellas: Consultancy; Astellas: Consultancy; Genentech/Roche: Research Funding; Premier: Consultancy; Premier: Consultancy; Janssen: Research Funding; Genentech/Roche: Research Funding; Genentech/Roche: Research Funding; Forma Therapeutics: Research Funding; Merck: Research Funding; Janssen: Research Funding; Forma Therapeutics: Research Funding; Forma Therapeutics: Research Funding; Trovagene: Consultancy; Premier: Consultancy; Merck: Consultancy; Daiichi Sankyo: Consultancy; Trovagene: Consultancy; Incyte: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Consultancy; Celgene: Consultancy; Cardinal Health: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Cardinal Health: Consultancy. Wang:Arog Pharmaceuticals: Current Employment. Pathan:Arog Pharmaceuticals: Current Employment. Messahel:AROG Pharmaceuticals: Current Employment.