Long-term follow-up of azacitidine, venetoclax, and gilteritinib in patients with newly diagnosed FLT3-mutated Acute Myeloid Leukemia Free

Background: Patients (pts) with FLT3-mutated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy, especially those with FLT3-ITD mutations, have poor outcomes with azacitidine and venetoclax (VEN). The combination of azacitidine, VEN, and gilteritinib (GILT) has demonstrated promising results, with CR/CRi rate of 96%, flow measurable residual disease (MRD) negativity rate of 93%, and median overall survival (OS) not reached (NR) at a median follow-up of 19.3 months. Here we report long-term (>3-year) follow-up from a phase II trial of this triplet regimen in patients with newly diagnosed (ND) FLT3-mutated AML.

Methods: Adult pts with ND FLT3-mutated AML who were ineligible for intensive chemotherapy received azacitidine 75mg/m² on days 1-7, VEN 400mg on days 1-28, and GILT 80mg on days 1-28. On day 14, a bone marrow was performed and both VEN and GILT were held if bone marrow blasts <5% or if aplastic/insufficient. For cycle 2-24, pts received azacitidine on days 1-5, VEN 400mg on days 1-7, and continuous GILT. Starting in cycle 25, GILT 80mg daily was maintained as monotherapy. Astellas Pharma provided funding and GILT drug support for this study.

Results: Between October 2020 and December 2022, 30 pts with ND FLT3-mutated AML were enrolled. The median age was 71 years (range, 18-86 years) with 8 pts (30%) aged ≥75 years. 15 pts (50%) had an ECOG of 2. 22 pts (73%) had FLT3-ITD mutations and 8 (27%) had FLT3-TKD mutations. Mutations in RAS pathway (KRAS, NRAS, PTPN11, CBL1, NF1 and/or BRAF) were detectable in 7 pts (23%).

14 pts (47%) underwent allogeneic stem cell transplantation (SCT) in first remission at a median time of 4.8 months from treatment initiation (11 with FLT3-ITD; 3 with FLT3-TKD). 6 pts (43%) received post-transplant FLT3i maintenance (5 with GILT). Among pts who underwent SCT, 6 (43%) are alive in continuous CR, 5 (36%) died in CR, and 3 (21%) relapsed at 9.1, 9.9, and 20.7 months after SCT. Of the 16 pts (53%) who did not undergo SCT, 5 (31%) remain in continuous CR, 3 (19%) died in CR, and 8 (50%) relapsed after a median remission duration of 21.1 months (range, 2.9-38.4 months).

Among 11 pts who had relapsed, 8 had FLT3-ITD and 3 had FLT3-TKD mutations at study enrollment. At relapse, 6 of 9 pts (67%) tested by PCR no longer had detectable FLT3 mutations, and 6 of 8 pts (75%) who underwent cyto-molecular testing showed evidence of clonal evolution.

With a median follow-up of 41.5 months, the median relapse-free survival (RFS) was 23.4 months, with a 3-year RFS of 43%. The median OS was 29.7 months, and the 3-year OS was 46%.

Among pts with FLT3-ITD mutations, median RFS and OS were 17 and 21.8 months, and 3-year RFS and OS were 32% and 36%, respectively. For those with FLT3-TKD mutations, median RFS and OS were 38.5 months and NR, and the 3-year RFS and OS were both 75%. No survival difference was observed by age group. Pts <75 years had a 3-year RFS of 45% and OS of 50%, while those ≥75 years had 38% for both (RFS: p=0.54; OS: p=0.53). Pts with RAS pathway mutations trended toward worse outcomes compared with those without these mutations (3-year RFS: 29% vs. 48%, p=0.1; 3-year OS: 29% vs. 52%, p=0.2). In a landmark analysis, outcomes did not differ significantly based on SCT status. The 3-year RFS was 43% for pts who underwent SCT versus 54% for those who did not (p=0.75); the 3-year OS was 50% versus 54%, respectively (p=0.78).

No unexpected adverse events (AEs) were observed with longer follow-up. The most common grade ≥3 nonhematological AEs were infection (19 pts, 63%), febrile neutropenia (12 pts, 40%), and sepsis (5 pts, 17%). The median number of cycles received was 3 (range, 1-36). 10 (33%) and 7 (23%) pts received ≥6 and ≥12 cycles, respectively. 4 pts (13%) completed 24 cycles. Among 25 pts who received ≥2 cycles, 17 (68%) required dose reductions of at least one drug, including VEN in 12 pts (48%), azacitidine in 11 pts (44%), and GILT in 7 pts (28%). Among pts who received at least 6 cycles of therapy, the median duration of azacitidine, VEN, and GILT were 5 (range, 3-5), 7 (range, 3-7), and 28 days (range, 7-28), respectively.

Conclusion: Continued follow-up of pts with ND FLT3-mutated AML treated with azacitidine, VEN and GILT demonstrates durable responses and encouraging survival. Outcomes appear superior to standard azacitidine and venetoclax, and randomized studies are warranted.