Quizartinib with Decitabine +/- Venetoclax Is Highly Active in Patients (Pts) with FLT3-ITD Mutated (mut) Acute Myeloid Leukemia (AML): Clinical Report and Signaling Cytof Profiling from a Phase IB/II Trial

• Published in: Blood 2020-11, Vol.136 (Supplement 1), p.19-20
• Main Authors: Yilmaz, Musa, Kantarjian, Hagop M., Muftuoglu, Muharrem, Kadia, Tapan M., Konopleva, Marina, Borthakur, Gautam, DiNardo, Courtney D., Pemmaraju, Naveen, Short, Nicholas J., Alvarado, Yesid, Montalban Bravo, Guillermo, Jurisprudencia, Carissa, Pike, Allison M., Ohanian, Maro, Jabbour, Elias, Garcia-Manero, Guillermo, Ruvolo, Vivian, Ravandi, Farhad, Andreeff, Michael, Daver, Naval
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2020-142687

Background: Single-agent gilteritinib and quizartinib (quiz) met their primary endpoints of improved overall survival (OS) in relapsed/refractory (R/R) FLT3-mut AML in phase III studies, but CRc durations were short (4-11 months). Quiz demonstrated potent synergy with venetoclax (VEN) (a BCL-2 inhibitor) in AML cell lines and PDX models (Mali et al. Haematologica 2020). Methods: Newly diagnosed or R/R AML with ECOG ≤2, and adequate organ function were eligible. The protocol initially evaluated safety of the doublet of decitabine (DAC) plus quiz regardless of FLT3 status [Fig 1A]. After the first 10 pts were treated on the doublet, the protocol was amended to add VEN (triplet) in a safety dose escalation lead in [Fig 1B]. CRc criteria were as published in the phase III ADMIRAL and QUANTUM-R studies. Results: 21 pts including DAC10 + quiz (phase 1: N=10) and DAC10 + VEN + quiz (phase IB/II: n=11) were evaluable at the time of this report (Table 1). DAC10 + Quiz Of 10 pts treated with DAC10 + quiz (Table 1), CRc rate was 40% (1 CRp and 3 CRi). No FLT3 R/R WT (n=3) pts responded. Four of 7 FLT3-ITD mut pts (1 frontline and 5/6 R/R, who had all received ≥1 FLT3 TKI) achieved CRc (57%), with 3/6 FLT3-PCR negative at response. 1 pt experienced QTcF prolongation > 500 msec on quiz 40mg/day (resolved after holding quiz with no clinical cardiac events). Grade 3/4 toxicities in >/= 2 pts, irrespective of attribution, included infection (12), neutropenic fever (3), mucositis (3), diarrhea (2), and prolonged QTcF >450 (2). With a median (med) follow-up (f/u) of 12 months (mos), the med OS was 5.7 months in the 6 R/R FLT3-mut pts (Fig 2A). Three of 4 CRc pts proceeded to allogeneic stem cell transplantation (ASCT) and 2 were alive in remission at last f/u. DAC10 + VEN + Quiz Of 11 enrolled pts (Table 2), 10 treated prior to July 1 2020 were evaluable. CRc achieved in 9/10 (90%) (1 CR, 3 CRp, 5 CRi) with 5/9 responders FLT3-PCR negative. Excluding the 1 frontline evaluable pt, 8 of 9 R/R FLT3-ITD (88% with ≥1 prior FLT3 TKIs) pts achieved CRc. No pts developed a DLT with 30 mg/day quiz, however with the 40mg/day quiz 2 pts developed hematologic DLT (grade ≥3 neutropenia with a /=2 pts, irrespective of attribution, included infection (7) and neutropenic fever (4). No QTcF prolongations >500msec noted. 60-day mortality was 0. With a med f/u of