Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Musa Yilmaz , Muharrem Muftuoglu , Hagop M. Kantarjian , Courtney Denton Dinardo , Tapan M. Kadia , Marina Konopleva , Gautam Borthakur , Naveen Pemmaraju , Nicholas James Short , Yesid Alvarado Valero , Abhishek Maiti , Lucia Masarova , Guillermo Montalban Bravo , Sanam Loghavi , Steven Mitchell Kornblau , Elias Jabbour , Guillermo Garcia-Manero , Farhad Ravandi , Michael Andreeff , Naval Guastad Daver
Background: QUIZ, a potent 2nd generation FLT3 inhibitor (FLT3i) demonstrated synergy with VEN in AML cell lines and PDX models (Mali Haematologica 2020). We evaluated the safety and efficacy of DAC + VEN + QUIZ triplet in patients with newly diagnosed (ineligible for intensive induction chemotherapy) or relapsed/refractory (R/R; up to 5 prior chemotherapies) FLT3 ITD mutated AML. Methods: All pts received 10 days of DAC (20 mg/m2) in Cycle 1. Pts underwent day 14 bone marrow (BM) biopsy, and VEN (400 mg/day starting from day1) was put on hold in pts with BM blasts ≤ 5% or aplasia. Those with day14 BM blast >5% continued VEN for 21 days during cycle 1. In subsequent cycles, DAC was reduced to 5 days. QUIZ (30 or 40 mg/day) was administered daily continuously. Results: Overall, 28 pts were enrolled and evaluable at the time of this report. Of the 23 pts with R/R AML (median 3 [range 1-5] prior therapies, 78% with ≥1 prior FLT3i including prior gilteritinib (GILT) in 70%, and 39% had a prior ASCT), 78% achieved CRc (3 CR, 15 CRi) with 6/16 and 5/18 responders FLT3-PCR and multicolor flow cytometry (MFC) negative, respectively. Pts with RAS/MAPK mutations had the lowest response rates (Table). Interestingly, no emergent TKD mutations were noted at relapse after the triplet but 3/8 evaluable pts had emergent RAS/MAPK mutations. 60-day mortality rate was 5%. Of 5 patients with newly diagnosed AML (median age 69), all achieved CRc (2 CR, 3 CRi) with 4/5 and 2/4 responders FLT3-PCR and MFC negative, respectively. 60-day mortality was 0. 2 pts developed hematologic DLT with 40 mg/day QUIZ dose (grade 4 neutropenia with a <5% cellular BM lasting ≥42 days). Hence, QUIZ 30 mg/day dose was determined as RP2D for the triplet. Grade 3/4 non-hematologic toxicities included lung infections (42%) and neutropenic fever (30%). No QTcF prolongations >480 msec were noted. With a median follow-up (f/u) of 13 months, the median OS was 7.6 months in R/R cohort (1-year OS of 30%). 8/18 responding R/R pts (including 5/8 prior GILT exposed pts) underwent ASCT with a median OS of 19 vs 8 months in those who underwent ASCT versus not (p=0.26). Of the 5 frontline responding pts median OS was 14.5 months, 2 were alive in CR, 1 died in CR1 post-ASCT, 2 died due to relapsed disease at the last f/u. Conclusions: DAC + VEN + QUIZ is active in R/R FLT3-ITD mutated AML pts, with CRc rates of 78% and the median OS of 7.6 months. Interestingly, RAS/MAPK mutations but not emergent TKD mutations were associated with primary and secondary resistance to the triplet. Accrual continues, and updated clinical, NGS, and mass cytometry (CyTOF) data will be presented. Clinical trial information: NCT03661307.
Subgroups | n/N (%) |
---|---|
Prior GILT | 12/16 (75) |
No Prior GILT | 6/7 (85) |
Prior HMA + VEN | 8/11 (72) |
No Prior HMA + VEN | 10/12 (83) |
DNMT3A + | 8/12 (66) |
DNMT3A - | 10/10 (100) |
NPM1 + | 7/9 (77) |
NPM1 - | 11/13 (84) |
RAS/MAPK* + | 2/5 (40) |
RAS/MAPK* - | 16/17 (94) |
*RAS/PTPN11/CBL/NF1/BRAF.
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Abstract Disclosures
2021 ASCO Annual Meeting
First Author: Musa Yilmaz
2023 ASCO Annual Meeting
First Author: Graeme Murray
2024 ASCO Annual Meeting
First Author: Chengyuan Gu
2022 ASCO Annual Meeting
First Author: Ian Michael Bouligny