Outcomes of Salvage Treatment in Patients with Acute Myeloid Leukemia (AML) with FLT3 Mutations.

Constitutive activation of fms-like tyrosine kinase-3 (FLT3) because of mutations in the juxta-membrane or tyrosine kinase domains leads to cell proliferation and enhanced survival. FLT3 mutations occur in roughly 30% of adults with cytogenetically normal acute myeloid leukemia (AML) and are associated with a shorter remission duration and reduced survival. Multiple agents targeting FLT3 signaling are in clinical trials (front-line or salvage) and it is important to establish baseline expectations to evaluate the impact of such agents on disease outcomes. Objective: To evaluate responses to salvage therapies in patients with AML and FLT3 mutations. Patients and Methods: We reviewed medical records of 121 patients with newly diagnosed AML with FLT3-ITD (n=82; 68 %) or FLT3-D835 (n=28; 23%), or both mutations (n=11; 9%), who had received induction therapy between January 2003 and July 2007 at MD Anderson Cancer Center. Results: The median age of all patients was 59 years (range, 17 to 84). After frontline induction therapy, 69 patients (57%) achieved complete remission (CR) or CR with incomplete platelet recovery (CRp), 8 (7%) achieved partial remission and 44 (36%) had resistant disease. The rate of CR/CRp was 66% among patients receiving cytarabine-based induction versus 32% among patients receiving non-cytarabine-based induction (P=0.002). A total of 62 patients with relapsed or refractory AML received first salvage treatment, CR/CRp was achieved in 17 (27%) patients, 10 of whom received cytarabine-based chemotherapies, 3 received stem cell transplant (SCT), 2 received 5-azacitidine and 2 received clofarabine-based treatment; 2 had a partial response and 43 had resistant disease. Of these 17 patients, 6 had no prior exposure to high-dose cytarabine (HDAC) based induction. A total of 40 patients who relapsed or failed after first salvage therapy received second salvage treatment. Ten (25%) patients achieved CR/CRp; 4 of them received cytarabine-based chemotherapy, 5 received SCT, 1 received clofarabine-based treatment; 2 had partial remission (5%) and 28 failed to achieve response (70%). The median duration of first CR (CR1D) was 7.9 months. Patients with SCT in CR1/CRp1 (n= 14) had significantly better CR1D (median> 60 months) compared with patients without SCT (median 6.6 months; p=0.0015). The CR1D of patients with FLT3-ITD was much shorter when compared to patients with FLT3-D835 (p=0.0019). The median CR/CRp duration after salvage 1 and salvage 2 was 5.5 months and 5.1 months, respectively. The median overall survival (OS) was 10.6 months. Patients who had SCT in CR1 appeared to have better OS as compared with patients without SCT (median > 60 months vs 15 months; p=0.03). There was no significant difference in OS between patients with FLT3-ITD and patients with FLT3-D835 (p=0.07). The median OS for patients who received salvage 1 and salvage 2 was 12 months and 13 months, respectively.

Salvage outcomes are dismal in patients with AML and FLT3 mutations. SCT in CR1, HDAC-based salvage may be adequate for patients fit to receive this kind of therapy. Therapies targeting FLT3 in combination, alone or in combination with chemotherapy or other agents targeting resistance pathways need to be evaluated in front-line and relapsed setting and comparison with historical expectations should help in identification of active agents.

No relevant conflicts of interest to declare.