The clinical impact of co-occurrence of FLT3-TKD and NPM1 mutations in AML patients

This month, in Blood Advances, Prajwal Boddu and colleagues from The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas, reported results of their retrospective study which aimed to validate the prognostic impact of the co-occurrence of Fms Like Tyrosine Kinase 3  (FLT3)-Tyrosine Kinase Domain (TKD) and Nucleophosmin (NPM1) mutations on the outcomes of patients with Acute Myeloid Leukemia (AML).

In total, 1,319 newly diagnosed AML patients, who were treated at the MDACC from January 2009–January 2017, were evaluated. Of these 1,319 patients, 18 patients were FLT3-TKD⁺ mutated only, 21 patients were FLT3-TKD⁺NPM1⁺ mutated, 117 patients were NPM1 mutated only, and 107 were FLT3-Internal Tandem Duplication (ITD)⁺ NPM1⁺.

The key results of the study were:

• Median Relapse Free Survival (RFS) in patients that were FLT3-TKD⁺NPM1⁺ and NPM1⁺ mutated; Not Reached (NR) vs 18.3 months, P = 0.02
• Median Overall Survival (OS) in patients that were FLT3-TKD⁺NPM1⁺and NPM1⁺ mutated; NR vs 33.7 months, P = 0.29
• FLT3-TKD⁺ NPM1⁺ status was an independent prognostic factor for RFS

In summary, “FLT3-TKD⁺NPM1⁺ mutation status is associated with superior RFS compared to NPM1+ alone”.

Boddu et al. concluded by proposing that the “mechanistic links between FLT3-TKD and NPM1” should be investigated in “future molecular and murine model studies” in order to understand the “paradoxical cooperative effect” further.

Abstract

Although FLT3 internal tandem duplication (ITD) mutations in acute myeloid leukemia (AML) confer an adverse prognosis, co-occurrence with a nucleophosphomin (NPM1) mutation partially improves response and survival outcomes. In contrast, simultaneous NPM1 and FLT3 tyrosine kinase domain (TKD) mutations were reported to improve response over that of an isolated NPM1 mutation in one as yet unverified report. To validate this, we explored the impact of the co-occurrence of FLT3-TKD and NPM1 mutations on clinical outcomes. Study populations included 21 patients (8%) with FLT3-TKD+NPM1+ mutated, 18 patients (7%) with FLT3-TKD-only–mutated, 117 patients (44%) with NPM1-only–mutated, and 107 patients (41%) with FLT3-ITD+NPM1–mutated AML. Compared with NPM1+-only–mutated AML, FLT3-TKD/NPM1 double mutation status was associated with a significantly superior relapse-free survival (median, not reached vs 18.3 months; P = .03) and a trend toward improved overall survival (OS). The presence of FLT3-TKD/NPM1 double mutation status was an independent positive predictor in multivariable analysis. Allogeneic stem cell transplant did not improve outcomes in the FLT3-TKD/NPM1 cohort. Consistent with historical data, the co-mutation status defined a highly favorable prognostic group characterized by high response rates and prolonged disease-free and OS. These study findings substantiate previous data describing this intriguing paradoxical cooperative effect. Our results emphasize the need for elucidating the mechanistic links between FLT3-TKD and NPM1 in future molecular and murine model studies.