Composite complete remission (CRc) rates decreased substantially with each sequential exposure of patients with FLT3-mutated acute myeloid leukemia (AML) to FLT3 inhibitor therapy following development of relapsed/refractory disease, according to results of a retrospective analysis published in the Journal of Hematology & Oncology.
Mutations in FLT3, particularly those associated with internal tandem duplication of the gene, are common drivers in the setting of AML. Moreover, AML characterized by this type of FLT3 mutation has been associated with a poor prognosis. Nevertheless, the integration of small-molecule FLT3 inhibitors into the treatment paradigm of patients with FLT3-mutated AML has improved the clinical outcomes of these patients.
The first-generation FLT3 inhibitors, sorafenib and midostaurin, lack specificity for FLT3, but the associated survival benefit of midostaurin in the setting of FLT3-mutated AML has led to its incorporation into frontline induction therapy as a standard approach for patients with previously untreated FLT3-mutated disease.
The second-generation FLT3 inhibitors, gilteritinib, quizartinib, and crenolanib, are more potent and specific for FLT3-mutated AML. In studies of these agents as salvage therapy for relapsed/refractory disease, most of the patients had not been previously exposed to FLT3-targeted therapy.
However, few contemporary real-world patients with relapsed/refractory FLT3-mutated disease are FLT3 inhibitor-naive, given the common practice of adding FLT3 inhibitor therapy to the frontline induction regimen.
“Establishing appropriate benchmarks for second and third FLT3 [inhibitor] exposure based on the current treatment paradigm will allow us to critically analyze emerging data from ongoing trials, thereby avoiding false-negative adjudications on trials or discarding drugs/combinations that may in fact be showing encouraging activity when correctly analyzed using contemporary benchmarks,” the study authors noted.
This study included 2 cohorts of patients with FLT3-mutated AML treated with at least 1 line of FLT3 inhibitor-based therapy, including single-agent FLT3 inhibitor therapy and FLT3 inhibitor therapy in combination with intensive or nonintensive chemotherapy, at the University of Texas MD Anderson Cancer Center, Houston, between November 2006 and December 2019.
Patients in cohort 1 (56 individuals) were first exposed to a FLT3 inhibitor in the frontline setting whereas patients in cohort 2 (183 individuals) were initially exposed to a FLT3 inhibitor in the setting of relapsed/refractory disease.
A key study finding was that the CRc rate, defined as the sum of complete remission, complete remission with incomplete hematological recovery, and complete remission with incomplete platelet recovery, in cohort 1 decreased from 77% for frontline treatment to 31% and then 25% with each subsequent exposure to a FLT3 inhibitor.
Similarly, in cohort 2 involving patients with relapsed/refractory disease, the CRc rates were 45%, 21%, 12%, and 0% with first-, second-, third- and fourth-line exposure to an FLT3 inhibitor in this setting.
Of note, these CRc rates were considerably lower than those reported in phase 2/3 trials of the second-generation FLT3 inhibitors, gilteritinib and quizartinib, conducted in patients with relapsed/refractory FLT3-mutated AML.
“Although lower, the CRc rates with sequential use of second-generation FLT3 [inhibitors] are still clinically meaningful and appeared to be higher with combinatorial approaches. These findings have direct practical implications for treating leukemia physicians,” the study authors maintained.
In their concluding remarks, the study authors noted that a number of ongoing clinical trials are investigating FLT3 inhibitor therapy in combination with induction chemotherapy, as well as hypomethylating agents and the BCL2 inhibitor, venetoclax, in the setting of FLT3-mutated AML, and they encouraged enrollment of patients with relapsed/refractory disease following prior treatment with a FLT3 inhibitor in these studies.
Yilmaz M, Alfayez M, DiNardo CD, et al. Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML. J Hematol Oncol. 2020;13:132. doi:10.1186/s13045-020-00964-5