FLT3 Inhibitor Treatment in FLT3-Mutated AML Is Associated with Development of Secondary FLT3-TKD Mutations

The two most frequent mutations in the FMS-like tyrosine kinase 3 (FLT3) receptor are internal tandem duplication (ITD) of the juxtamembrane region and mutations involving the D835/I836 residues of the tyrosine kinase domain (TKD). They are present in approximately 30% and 7% of AML cases respectively, and have been associated with higher relapse rate and worse overall survival. ITD and TKD mutations produce constitutive activation of the FLT3 receptor; however they appear to have different downstream effectors and different clinical significance. Currently, several FLT3 kinase inhibitors are in development and although some have shown promising clinical activity, responses tend to be transient and insufficient to induce a durable response. Sensitivity of different mutants to diverse FLT3 inhibitors is variable (Zhang et al. JNCI 2008; 100: 184). Aim: To determine the change in mutation status of patients with FLT3 ITD treated with FLT3 inhibitors. Methods: We analyzed 67 patients with FLT3 mutation positive AML, treated in our institution in clinical trials with different FLT3 inhibitors from October 2002 to July 2011 and in whom we obtained mutational assessment before and after treatment. Results: At baseline 58 (87%) patients had an ITD mutation, 5 (7%) had a D835/I836 mutation and 4 (6%) had combined ITD and codon D835/I836 mutations. Thirty three patients were male, median age was 55 years (range 18–87), and the median number of prior leukemia treatments was 2 (range 1–6). Karyotype was diploid in 36%, miscellaneous in 17%, complex in 14%, not done in 23%, and insufficient in 9% of patients. Concomitant NPM1, RAS, and CEBPA mutations were observed in 21%, 13%, and 4% of the patients, respectively. Patients remained on therapy for a median time of 50 days (range 18–561) before progression, 45 (67%) did not achieve response, 13 (19%) cleared their bone marrow blasts, 6 (9%) achieved a partial response, 4 (6%) a complete response and 1 (1%) patient died during treatment. None of the patients with D835/I836 or ITD+D835/I836 achieved a response. Treatment was always discontinued due to progressive disease, except in 9 (13%) patients, 6 who cleared bone marrow blasts and proceeded to hematopoietic stem cell transplantation and 3 who discontinued due to toxicity. One of them was in complete response but progressed within 4 months, and 2 who cleared their bone marrow blasts and were also bridged with other treatments to transplant. All patients in this cohort had assessment of their FLT3 mutation status at the time FLT3 inhibitor was discontinued, 14 (21%) patients progressed from a single ITD mutation to have combined ITD+D835/I836 mutations, 7 (10%) patients (6 ITD and 1 D835/I836) were negative for FLT3 mutation, and 46 (69%) patients had unchanged mutation status. At the time of this analysis, 10 patients were alive, 1 was lost to follow and 56 had died. The median survival in the entire group from the time of FLT3 inhibitor start was 5.3 months, and from time of treatment discontinuation 3.2 months. In those patients in whom the FLT3 mutation became negative the median survival was 7 months, in those with unchanged mutation 4.5 months, and in those with ITD-D835/I836 mutations the median survival was 6.1 months. Further therapy with another FLT3 inhibitor was attempted in 6 out of 14 patients with ITD-D835/I836 mutations, 5 failed to respond and 1 had a transient decrease in bone marrow blasts and peripheral white blood cell count (2 months) with a combination of a FLT3 inhibitor and a hypomethylating agent. Conclusion: There is evidence that a secondary TKD mutations arise after the use of FLT3 inhibitors in patients with single FLT3-ITD mutated AML, a phenomenon that is associated with a poor prognosis.

Ravandi:Bayer: Research Funding; Onyx: Research Funding. Cortes:Ambit: Research Funding; Novartis: Research Funding.