Abstract: S135

Type: Oral Presentation

Session title: Developments in AML therapy

Background
The FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib (Gilt) improves survival compared with standard salvage chemotherapy in patients (pts) with FLT3-mutated (FLT3^mut+) acute myeloid leukemia (AML) who are relapsed/refractory (R/R) to standard chemotherapy. Interim analysis of an ongoing, multicenter, open-label, Phase 1b trial (NCT03625505) of Gilt + the B-cell lymphoma 2 (BCL‑2) inhibitor venetoclax (Ven) in pts with R/R FLT3^mut+ AML reported high rates of marrow blast elimination and a modified composite complete remission (mCRc) rate of 84% (Daver et al. ASH 2020; Abstract 333).

Aims
To provide updated results from a Phase 1b trial of Ven + Gilt in R/R FLT3^mut+ AML.

Methods
The study design has been described previously (Daver et al. ASH 2020; Abstract 333).In brief, pts with R/R AML FLT3^mut+ received dosages up to Ven 400 mg daily with Gilt (80 mg or 120 mg) daily in 28-day cycles, following Ven ramp-up. The primary endpoint was mCRc (complete response [CR] + CR with incomplete platelet recovery + CR with incomplete blood count recovery [CRi] + morphologic leukemia-free state) to align with the Phase 3 ADMIRAL trial CRc responses. Duration of response (DOR) of mCRc was a secondary endpoint; overall survival (OS) and changes in FLT3 allelic burden were exploratory. Safety evaluation included adverse event (AE) monitoring.

Results
At the data cutoff of November 30, 2020, 43 pts with FLT3^mut+ had been enrolled. Median age (range) was 63 years (23–85). FLT3 internal tandem duplications (ITD) were identified in 37 pts (86%) and 6 pts (14%) had only tyrosine kinase domain (TKD) mutations. Baseline cytogenetic risk was favorable in 2 pts (5%), intermediate in 23 pts (55%), poor in 13 pts (31%), and 5 pts (12%) had no mitoses/missing data. The median (range) prior lines of therapy was 2 (1–5), and 33 pts (77%) had 2 or more prior lines of therapy; 28 pts (65%) had received at least one prior FLT3 inhibitor and 3 pts (7%) received prior Ven. Fourteen pts (33%) had prior transplant. 

Grade 3/4 AEs were reported in 42 pts (98%). Grade ≥3 cytopenias occurred in 34 pts (79%) and were predominantly managed by Ven and/or Gilt dose interruptions and shorter Ven duration on subsequent cycles. The only grade 3/4 nonhematologic AE reported in >20% of pts was pneumonia (n=9; 21%). There was 1 instance of clinical tumor lysis syndrome. Serious AEs were reported in 32 pts (74%). Overall, 30- and 60-day mortality rates were 0% and 12%, respectively. AEs led to either Ven or Gilt interruptions in 24 pts (56%), reductions in 3 pts (7%), and discontinuations in 6 pts (14%).

mCRc was achieved by 86% of the FLT3^mut+ efficacy population (36/42) with a median time to first response of 1.0 month (range: 0.7–4.6), and by 86% of pts with prior FLT3 tyrosine kinase inhibitor (TKI) exposure (24/28). FLT3 molecular clearance (<10^-2) was observed in 69% of pts with mCRc who had PCR analyzed at baseline and at least one follow-up timepoint (18/26). DoR and OS are summarized in the Table.

Conclusion
These updated analyses show that Ven + Gilt achieved high rates of mCRc in pts with heavily pretreated and prior TKI-exposed R/R FLT3^mut+ AML with encouraging molecular clearance rates. Using similar response criteria to previously studied FLT3^mut+ populations, the high mCRc rate with Ven + Gilt reported here suggests strong antileukemic activity. Cytopenias were prominent but manageable. Updated follow-up and molecular data will be presented at the meeting.

Keyword(s): Acute myeloid leukemia, Clinical data, FLT3, Outcome