Quizartinib Effective in Patients With FLT3-ITD–Positive Relapsed, Refractory AML

In acute myeloid leukemia (AML), patients with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations are less responsive to salvage chemotherapy and have shorter survival following relapse compared with FLT3-ITD—negative patients. These poor outcomes also are associated with older AML patients, with most of them intolerant of chemotherapy. To better treat these patients, there is a demand for novel therapies outside of conventional chemotherapy.

Quizartinib is an oral, second-generation FLT3 inhibitor that has shown clinical activity in both FLT3-ITD—positive and –negative relapsed/refractory (RR) patients, and a phase 2 trial aimed to further validate the efficacy and safety of quizartinib in this patient population. The results of the study have been published in Lancet Oncology.

There were 333 patients who were divided into 2 cohorts. Cohort 1 patients were ≥60 years with RR AML within 1 year after first-line therapy, and cohort 2 were patients ≥18 years with RR AML following salvage chemotherapy or hematopoietic stem cell transplantation (HSCT). Patients in both cohorts were further categorized as FLT3-ITD—positive, designated as an allelic frequency ≥10%, or FLT3-ITD–negative. Patients took quizartinib daily until relapse, intolerance, or HSCT.

The trial ran for approximately 3 years, at which point all but 4 patients discontinued quizartinib. In cohort 1, 63 of 112 FLT3-ITD­—positive patients (56%) achieved composite complete remission (CCR), defined as either complete remission (CR), complete remission with incomplete platelet recovery, or complete remission with incomplete hematological response, with 3 patients (3%) achieving CR. Sixteen of 44 FLT3-ITD­­—negative patients (36%) achieved CCR, with 2 patients (5%) achieving CR. FLT3-ITD—­positive and FLT3-ITD—negative patients had a median duration of CCR of 12.1 weeks and 16.4 weeks, respectively.

In cohort 2, 62 FLT3-ITD—positive patients (46%) achieved a CCR, with 5 patients (4%) achieving CR. Twelve of 40 FLT3-ITD—negative patients (30%) achieved CCR, with 1 patient (3%) achieving CR. FLT3-ITD—positive patients had a median duration of CCR of 10.6 weeks in comparison to 7.0 weeks in FLT3-ITD—negative patients. Sixty-one of 176 (35%) patients were bridged to HSCT.

In both cohorts, a total of 125 of 333 (38%) patients died with 18 (5%) deaths attributed to an adverse event (AE). The most common AEs (>20% occurrence) were nausea, QT prolongation, and fatigue. Serious AEs leading to discontinuation of treatment in both cohorts were QT prolongation and infection.

Quizartinib was shown to have a superior CCR than salvage chemotherapy (response rate ~25%) in both FLT3-ITD—positive and –negative patients. The beneficial responses in elderly patients also demonstrated the potential usage of quizartinib in this population. Quizartinib was also able to reduce bone marrow blasts significantly enough for many patients to undergo HSCT, an important factor to improving survival. The high response rates in all patient groups demonstrated that quizartinib may be very promising in refractory/relapsed AML cases.

Reference

Cortes J, Perl AE, Döhner H, et al. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2018;19(7):889-903. doi:10.1016/s1470-2045(18)30240-7.