MD Anderson Fellow Dives Deep into the Unknowns of FLT3-TKD-Mutated AML

Dr. Arora is a rising physician-scientist currently in his second year of a Hematology-Oncology fellowship at the University of Texas MD Anderson Cancer Center. His work has a strong focus on acute leukemias and myeloproliferative neoplasms (MPNs), particularly acute myeloid leukemia (AML).

Originally from Mumbai, Dr. Arora earned his medical degree from GS Medical College & KEM Hospital, where he also completed a year-long clinical internship. He then moved to the United States to pursue residency training in internal medicine at The University of Alabama at Birmingham, sharpening both his clinical acumen and his drive to pursue research.

Dr. Arora is now honing his expertise with an eye toward becoming a clinical investigator and leading early-phase clinical trials.

Among clinicians who treat patients with FLT3 tyrosine kinase domain (TKD)-mutated acute myeloid leukemia (AML), the use of FLT3 inhibitors and venetoclax has been increasing; however, the impact of using these therapies represents an unanswered question in AML.

“FLT3-TKD mutations occur in 7%-10% of newly-diagnosed AML, but their characteristics and outcomes are not well described in the literature. In addition, how the incorporation of venetoclax and targeted FLT3 inhibitor therapy would impact outcomes in FLT3-TKD-mutated AML is unknown. Our research is aimed to address these points and utilized one of the largest retrospective cohorts of frontline FLT3-TKD-mutated AML,” Sankalp Arora, MBBS, clinical fellow, The University of Texas MD Anderson Cancer Center, told Blood Cancers Today.

During The HemOnc Pulse Live! in Austin, Texas, Dr. Arora gave a live Emerging Experts presentation centered around unanswered questions and shared data from a retrospective study. Dr. Arora and colleagues set out to better understand the use of FLT3 inhibitors or venetoclax as frontline treatment by comparing outcomes with the use of intensive chemotherapy.

The analysis set included 124 patients of which 44% had a NPM1 co-mutation. These patients were divided into three cohorts: the full cohort (n = 54), NPM1 mutant (n = 24), and NPM1 wild-type (wt; n = 30).

With intensive chemotherapy only, findings showed that responses varied based on the existence of NPM1 mutations and NPM1wt mutations. The trend continued when investigators observed patients who also received venetoclax and/or FLT3 inhibitors.

Introducing Venetoclax and FLT3 Inhibition

When venetoclax was added to intensive chemotherapy, the CR rate among 17 patients was 88%, and the CRi rate was 6%. In 10 patients who received intensive chemotherapy in combination with FLT3 inhibition, the CR rate was 70% with no CRis. In the 27 patients who received intensive chemotherapy alone, the CR rate was 63%, and the CRi rate was 15%.

At a median follow-up of 43 months in the full cohort, the median overall survival (OS) was not reached, and the 3-year overall survival rate was 56%. The media event-free survival (EFS) was also not reached, and the 3-year EFS rate was 53%.

“The most surprising finding was the very poor outcomes noted in patients with FLT3-TKD AML without co-mutated NPM1 who received low-intensity therapy. The median OS for this population was only 6 months. This may be due to enrichment of adverse risk karyotype/mutations in this patient population,” Dr. Arora explained.

Among patients with NPM1-mutated disease, the median OS was not reached, and the 3-year OS rate was 74%. In the NPM1wt group, the median OS was 13.8 months, and the 3-year OS rate was 40%. In terms of EFS, the median was not reached in the NPM1-mutant group, and the 3-year EFS rate was 65%. In the NPM1wt group, the median EFS was 12.5 months, and at 3 years, the EFS rate was 42%.

The Role of Transplant

Outcomes appeared to be slightly better for patients who also underwent allogeneic stem cell transplant (alloSCT) compared with those who did not, based on the landmark analysis. While median OS was not reached for those with FLT3-TKD– mutant, NPM1-mutant AML, the 3-year OS rate in patients who underwent alloSCT was 77% versus 70% in patients who did not undergo alloSCT.

In the FLT3-TKD– mutant, NPM1wt group, the median OS was not reached in patients who underwent alloSCT, and the 3-year OS was 88%. For those who did not undergo alloSCT, the median OS was 20.2 months, and the 3-year OS rate was 30%.

“The key message is that NPM1 mutations commonly co-occur in FLT3 TKD-mutated AML and seem to influence outcomes in this population, including the role of alloSCT.  Patients with FLT3-TKD AML who also have the NPM1 mutation have improved response rates and survival outcomes with therapy compared to those without NPM1 mutation,” Dr. Arora said.

“AlloSCT in first CR was not associated with an overall survival benefit in FLT3-TKD AML patients with NPM1 co-mutation, but it was found to increase overall survival in patients without co-mutated NPM1. Therefore, assessing NPM1 mutation status is crucial in FLT3-TKD-mutated AML,” he said.

Reference

Arora, Sankalp. Blood Cancers Today Presents: Emerging Experts.
Presented at The HemOnc Pulse Live! May 2-3, 2025; Austin TX.