The novel FLT3 inhibitor gilteritinib prolonged survival in patients with FLT3-mutated relapsed or refractory acute myeloid leukemia (AML) across all mutation cohorts, including NPM1, DNMT3A, DNMT3A/NPM1, and WT1, with the greatest benefit seen in patients with NPM1 and DNMT3A co-mutations, according to new research. These findings demonstrate the clinical benefit of gilteritinib in these patients regardless of mutation status.
In the phase III ADMIRAL study, Perl et al previously demonstrated that treatment with gilteritinib led to superior response and overall survival compared with salvage chemotherapy in patients with FLT3-mutated relapsed or refractory AML.1 The investigators subsequently analyzed the impact of baseline co-mutations and FLT3/ITD allelic ratio on response and overall survival.
Mark J. Levis, MD, PhD
Prapti A. Patel, MD
The results were originally presented at the 2019 ASCO Annual Meeting by Mark J. Levis, MD, PhD, Program Leader of the Hematologic Malignancies and Bone Marrow Transplant Program at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, and colleagues.2 The study was later discussed at the Best of ASCO Austin by Prapti A. Patel, MD, of The University of Texas Southwestern Medical Center in Dallas, along with other top selected abstracts in leukemia, myelodysplastic syndrome, and allotransplantation.3
FLT3 Mutation in AML
FLT3 is a ligand-activated transmembrane tyrosine kinase receptor found on normal hematopoietic progenitor cells. The FLT3 ligand will bind to the FLT3 receptor with subsequent downstream signal activation, which promotes cell survival, proliferation, and differentiation.
FLT3 is the most common AML mutation, seen in about 30% of cases, and there are two main types of FLT3 mutations: internal tandem duplication (ITD) and tyrosine kinase domain (TKD). FLT3 can also have a number of other co-occurring mutations, mostly seen within NPM1, WT1, and DNMT3A.
“In terms of prognosis, the ITD mutation has an inferior overall survival when compared with TKD mutations,” said Dr. Patel. “Gilteritinib can bind to both the activation loop and the ATP-binding pocket, so it will target both the FLT3 TKD and the FLT3 ITD mutations.”
Do Co-mutations or Allelic Burden of FLT3 Affect Outcomes?
In the ADMIRAL trial, 371 patients with relapsed or refractory AML with TKD or ITD mutations were randomly assigned 2:1 to receive either single-agent gilteritinib at 120 mg/d (n = 247) or salvage chemotherapy (n = 124). According to Dr. Patel, key findings of the trial included a “sizable” response rate with gilteritinib at 34%, compared with 15.3% with chemotherapy (P = .0001). Overall survival was 9.3 months in the gilteritinib arm and 5.6 months with chemotherapy.
“This abstract asked the question, do co-mutations or allelic burden of FLT3 affect the response and outcomes to gilteritinib therapy?” said Dr. Patel.
Next-generation sequencing revealed that more than 90% of the patients enrolled on the ADMIRAL trial had a FLT3/ITD mutation, and four major co-mutation cohorts were identified: NPM1 (47.9%), DNMT3A (31.9%), NPM1/DNMT3A (23.8%), and WT1 (18.0%).
They also analyzed FLT3/ITD allelic ratios (calculated by the number of mutant alleles divided by the number of wild-type alleles) and found a median FLT3/ITD allelic ratio of 0.77. Patients with an allelic ratio of at least 0.77 were classified as having a high allelic burden, and those with a ratio of up to 0.77 were classified as having a low allelic burden.
Better Responses Across All Subgroups
Across the entire population enrolled in the ADMIRAL trial, response rates were more than double for the gilteritinib arm. Relative to other co-mutated cohorts, the greatest survival benefit was seen in patients with NPM1/DNMT3A co-mutations, a group with a historically poor prognosis. According to Dr. Patel, this begs the question: “Can gilteritinib be moved to the front-line setting for this population?”
We see that across the board, regardless of co-mutation status, patients treated with gilteritinib did better.— Prapti A. Patel, MD
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The rates of complete remission or complete remission with partial hematologic recovery of peripheral blood cell counts were 40.0% vs 9.7% with gilteritinib and chemotherapy, respectively, in patients with NPM1/DNMT3A co-mutations and 35.6% and 5.0% in patients with WT1 co-mutations.
“We see that across the board, regardless of co-mutation status, patients treated with gilteritinib fared better than patients treated with chemotherapy,” said Dr. Patel. “And in the patients with NPM1/DNMT3A and those with WT1, the delta in complete remission rates of gilteritinib vs chemotherapy was much greater. This makes us think that maybe these particular populations are more sensitive to gilteritinib compared with others.” She also noted a plateau in the survival curve for patients with NPM1/DNMT3A, indicating the presence of some long-term survivors in this population.
The investigators also analyzed the impact of co-mutated NPM1 vs nonmutated NPM1 on overall survival. “We see that patients who have co-occurring FLT3 and NPM1 mutations did particularly poorly with chemotherapy alone,” noted Dr. Patel. “But when this population is treated with gilteritinib, their survival curve pulls away, and they do slightly better compared with chemotherapy alone.”
Better Survival in Patients With a High Allelic Ratio
“We already know that a high allelic ratio, which is reflective of a high tumor burden, portends a poor prognosis,” Dr. Patel explained. “And within this higher tumor burden, there’s going to be subpopulations of cells that have resistance mutations, rendering them more resistant to targeted therapy.”
Gilteritinib in AML: Co-mutation Cohorts
- Gilteritinib is effective across all co-mutation cohorts of FLT3-mutated relapsed or refractory acute myeloid leukemia (AML), including NPM1, DNMT3A, and WT1, with the greatest benefit seen in patients with NPM1/DNMT3A co-mutations.
- In patients with a high FLT3/ITD allelic ratio, overall survival was significantly longer with gilteritinib than with salvage chemotherapy.
- Although survival was improved with gilteritinib, improvements were modest, highlighting the need for better therapies in this patient population.
The researchers looked at the 335 patients with FLT3/ITD mutations and found that gilteritinib conferred longer overall survival than salvage chemotherapy in those with a high or low FLT3/ITD allelic ratio. However, in patients with a high FLT3/ITD allelic ratio, overall survival was significantly longer in patients treated with gilteritinib than in those treated with salvage chemotherapy, which was not the case in the group with a low allelic burden. Median overall survival was 7.1 months with gilteritinib and 4.3 months with salvage chemotherapy in patients with a high allelic ratio (hazard ratio = 0.5; P < .0001), compared with 10.6 months and 6.9 months, respectively, in patients with a low allelic ratio (hazard ratio = 0.8; P = .2719).
“We know that gilteritinib is effective in all mutation cohorts,” said Dr. Patel. “But we should also note that the survival is better only by a few months, which indicates that better therapies with long-term efficacy are still needed.” ■
DISCLOSURE: Dr. Levis has served as a consultant or advisor to Agios, Amgen, Astellas Pharma, Astex Pharmaceuticals, Daiichi Sankyo, Fujifilm, Karyopharm Therapeutics, Menarini, and Novartis; and has received institutional research funding from Astellas Pharma, Fujifilm, and Novartis. Dr. Patel has received honoraria from Dava Pharmaceuticals and France Foundation, has served as a consultant or advisor to Celgene, and has served on a speakers bureau for Celgene.
REFERENCES
1. Perl AE, et al: Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated relapsed/refractory acute myeloid leukemia: Results from the phase III ADMIRAL trial. 2019 American Association for Cancer Research Annual Meeting. Abstract CT184. Presented April 2, 2019.
2. Levis MJ, et al: Effect of gilteritinib on survival in patients with FLT3-mutated relapsed/refractory AML who have common AML co-mutations or a high FLT3-ITD allelic ratio. 2019 ASCO Annual Meeting. Abstract 7000. Presented June 1, 2019.
