Patterns of Molecular Response to and Relapse After Combination of Sorafenib, Idarubicin, and Cytarabine in Patients with Newly Diagnosed FLT3-Mutant Acute Myeloid Leukemia (AML).
Authors: Al-Kali Aref , Jones Dan , Cortes Jorge , Faderl Stefan , Ao Xue , Garcia-Manero Guillermo , Borthakur Gautam , Konopleva Marina , Brandt Mark , Andreeff Michael , Kantarjian Hagop , Ravandi Farhad 
Published: October 2019

Abstract 2079

Poster Board II-56

Background:

Sorafenib is an orally active multi-kinase inhibitor with potent activity against FLT3 and the Raf/ERK/MEK pathway, Significant clinical activity of sorafenib in patients (pts) with AML and FLT3 mutation has been reported anecdotally and in phase I trials. We have reported the results of a clinical trial in which sorafenib 400 mg po bid ×7 days, was combined with cytarabine 1.5 gm/m2 iv over 24 hours daily × 4 (× 3 for pts over 60) and Idarubicin 12 mg/m2 iv daily × 3 (ASH 2008, abstract 768) in pts younger than 65 with AML. Pts achieving CR received up to 5 cycles of consolidation with Idarubicin 8 mg/m2 iv × 2 and cytarabine 0.75 gm/m2 iv daily × 3 in addition to continuous Sorafenib 400 mg po bid × 28 days (cycle=4-6 weeks). Maintenance with Sorafenib 400 mg bid would continue for up to a year after consolidation. In in-vitro culture studies, exposure of AML cell lines to sorafenib induces kinase domain (KD) resistant mutations Aim: To determine the pattern of molecular response and relapse in pts with mutated FLT3 receiving this regimen. Methods: FLT3 internal tandem duplication (ITD) and codon 835/836 KD point mutation status were determined in DNA from initial, post-induction, follow-up, and relapse bone marrow samples by a PCR-based method with an analytical sensitivity of 1-2%. FLT3 allele burden was determined by ratios of the area under the PCR amplicon peak. Flow cytometry was used to track the levels of residual leukemic blasts. In addition relapsed samples were analyzed for KD mutations in FLT3 exons 16, 17, 20 and 21 using PCR-based Sanger sequencing of genomic DNA. Results: Eighteen pts (median age 54 years, range 20-65) with newly diagnosed AML and mutated FLT3 were treated in this phase II study. Fifteen pts had FLT3-ITD, 2 had FLT3-TKD, and 1 had both with 5 pts having low FLT3 mutant burden (present in <25% of the blasts). 17/18 pts achieved a morphological CR/CRp (94%) and one achieved PR (had CNS involvement, not evaluable for response at the time of report). CR/CRp was achieved after 1 course of induction in 16 pts and after 2 courses in 1 pt. In samples analyzed post-induction (approximately, day 30), 10 pts had no molecularly detectable disease, 6 showed partial regression of the FLT3 mutated clone, and 2 showed molecularly persistent disease with no preferential regression of the mutated clone. Ten pts have relapsed after a median follow-up of 9 months (range, 1 -16 Months) with a median CR duration of 8.8 months (range, 1 - 9.5 months).The degree of regression of mutated FLT3 clone at day 30 did not predict relapse. At relapse, one pt had persistent loss of the mutated FLT3 clone with the others having clones identical to the diagnosis specimens. Bone marrow specimens at the time of relapse from 6 of 10 pts were examined for the presence of new mutations in exon 16, 17, 20 and 21 of FLT3 gene; none were identified. Twelve pts proceeded to an allogeneic stem cell transplant; 5 in CR1, and 7 after relapse. Four pts have died with a median overall survival of 12.7 months (range, 1 to 14.8). Three of four deceased pts had a high FLT3 mutant burden. Conclusions: Induction therapy with Sorafenib, Idarubicin, and Cytarabine is effective in reducing the mutated clone in pts with mutated FLT3 but does not universally eradicate it. Continuous therapy with sorafenib in induction may potentially be beneficial in further reducing the leukemic clone; however, the extent of suppression of the clone post-induction is not predictive of relapse. No secondary FLT3 mutations were found in the evaluated pts at relapse suggesting factors other than mutations conferring resistance to sorafenib may be important.

Disclosures:

Off Label Use: Sorafenib is a multikinase inhibitor approved for hepatocelular carcinoma and renal cell carcinoma. Sorafenib has shown in vitro activity against FLT3 mutated leukemia cells. This study is to proof this concept that sorafenib will increase the response rate in FLT3 positive AML patients, which is off-label use.. Ravandi:Bayer & Onyx: Consultancy, Honoraria.