Real-World Outcomes of Acute Myeloid Leukemia Patients Undergoing Treatment with Tyrosine Kinase Inhibitor (TKI) Therapy Targeting FLT3, IDH1, or IDH2

Background

Acute Myeloid Leukemia (AML) is the most common and fatal acute leukemia in adults. Tyrosine kinase inhibitors (TKIs) have shown promise for certain patients in randomized clinical trials. Real-world survival outcomes of patients with AML treated with TKIs have seldom been described.

Methods

This retrospective study included 482 patients with AML (excluding promyelocytic and mixed phenotype leukemia) who were ≥18 years at diagnosis and treated with a TKI targeting FLT3, IDH1, or IDH2 as monotherapy or with a hypomethylating agent (HMA) on or after January 1, 2015, in the nationwide Flatiron Health electronic health record-derived de-identified database. We used unadjusted Kaplan-Meier methods to estimate median real-world event-free survival (rwEFS) and overall survival (rwOS) from treatment initiation by line of therapy. We used a Cox regression model to assess factors associated with rwOS, modeling post-treatment stem cell transplant (SCT) as a time-varying covariate. We further excluded patients with possible TKI use as post-SCT maintenance therapy and evaluated rwEFS and rwOS on the remaining patients (n=284) by target genomic alteration, TKI vs. HMA combination therapy (TKI+HMA), and race/ethnicity.

Results

Among all patients, 52% were male, 70% were non-Hispanic white (NHW), 52% received therapy in a community setting, 31% had a previous hematologic malignancy, 18.4% received TKI+HMA, and 10% of patients received a SCT after initiating TKI targeted therapy . Per ELN 2017 risk stratification, 6% of patients were favorable, 52% intermediate, and 42% adverse.

TKIs were received in the first line (1L) setting for 14% (n=68) of patients and 86% (n=414) in second-line or beyond (2L+). Among 1L patients, the median age at TKI initiation was 77 years, 62% were NHW, 15% had commercial health insurance, and 50% had prior MDS and MPN. Patients who received a TKI at 2L+ did so at a median age of 68 years, 71% were NHW, 29% had commercial health insurance, and 28% had prior MDS or MPN. Patients treated at 1L and 2L+ had similar duration of TKIs (3.7 vs. 3.4 months), rwEFS (2.2 vs. 2.5 months), and rwOS (12.3 vs. 13.1 months). Among all patients, improved rwOS was associated with younger age (p=0.043), receiving a pre-TKI SCT (p<0.001), commercial insurance (vs. Medicaid; p=0.035), and favorable 2017 ELN risk classification (vs. adverse; p=0.032). Receiving a TKI in earlier lines was also associated with improved rwOS when compared to later lines (2L, 3L, 4L+), though only the 1L vs. 3L and 1L vs. 4L+ comparisons were statistically significant.

When restricting to patients who received TKI at 2L+ without prior SCT, rwEFS was 2.1, 1.6 and 1.4 months by target (FLT3, IDH1, and IDH2) respectively, and rwOS was 9.5, 15.4 and 8.7 months respectively, with no statistically significant differences. Patients who received TKI+HMA did not have statistically significant differences compared to monotherapies in rwEFS (2.1 vs 1.5 months) and rwOS (11.8 vs 9.7). There were also no statistically significant differences in rwEFS nor rwOS between NHW patients and patients of color (POCs; i.e., Hispanic/Latino or Black, Asian, or a non-Hispanic other race), though POCs were younger at diagnosis (median: 69 vs. 73 years). Of note, POCs were more likely to be in the lowest socioeconomic index quintile (29% vs 9.5%) as compared to NHW patients.

Conclusion

In this large, real-world cohort of patients with AML receiving FLT3- or IDH-targeted TKI therapy, clinical outcomes remained poor regardless of timing of TKI initiation, mutational target, presence or absence of HMA, and race/ethnicity. Factors such as favorable ELN classification, lower age, SCT usage, and commercial insurance were associated with improved prognosis and may warrant further investigation.