Elias Jabbour, MD
mutations are well established as a prognostic marker in patients with acute myeloid leukemia (AML), efforts to target the aberration therapeutically were underway for more than 15 years before yielding success. That happened in April, when the FDA approved midostaurin (Rydapt), the first new therapy for AML in about 40 years.
Midostaurin is approved for the treatment of adult patients with newly diagnosed FLT3
-positive AML in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. The drug has also been approved for patients with advanced systemic mastocytosis (SM), including aggressive systemic mastocytosis (ASM), SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia.
AML is a genetically complex disease that researchers are still seeking to elucidate. Researchers believe that AML is driven by somatic alterations in a “2 hit” process: a proliferative mutation in a class I gene such as FLT3
and an aberration in a class II gene that prevents cells from maturing.1FLT3
mutations are among the epigenetic drivers of AML in normal karyotypes (Figure
Investigators have found somatic mutations in FLT3
genes in several spots, notably in 27% to 34% of samples in the internal tandem duplication (ITD) domain in various studies.1
The presence of an FLT3
-ITD mutation confers a poor risk for patients with AML, with worse outcomes in diseasefree and overall survival.3
In recently updated joint guidelines, the College of American Pathologists and the American Society of Hematology strongly recommend testing all pediatric and adult patients with suspected or confirmed AML for FLT3
Midostaurin was approved along with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, to test for FLT3
mutations in DNA extracted from mononuclear cells obtained from peripheral blood or bone marrow aspirates.
Although it was approved for patients with FLT3
mutations, midostaurin is a small molecule that inhibits multiple receptor tyrosine kinases; in vitro biochemical and cellular assays also have suggested that it can inhibit wild-type FLT3
In reference to aberrant FLT3
activity, the drug inhibits FLT3 receptor signaling and cell proliferation, and induces apoptosis in leukemic cells expressing ITD and tyrosine kinase domain mutant FLT3 receptors.4
The midostaurin approval has generated much excitement in the field. Several other FLT3 inhibitors have entered the later-stages of clinical development (Table
) and the prospects for more targeted agents are building.
“Use of next-generation sequencing technology has generated a plethora of novel insights into the genetics of AML, providing important information about dysregulated signaling involved in leukemic transformation and leading to new therapeutic targets,” said Elias Jabbour, MD, an associate professor at The University of Texas MD Anderson Cancer Center in Houston, during a recent OncLive®
“After a dearth of new therapies available for acute myeloid leukemia over the last few decades, we are transitioning into a new era with several promising strategies in latestage development.”
aStudy is ongoing but not recruiting participants. AML indicates acute myeloid leukemia; FLT, FMS-like tyrosine kinase 3; ITD, internal tandem duplication.
Table. Selected Later-Stage Clinical Trials of FLT3 Inhibitors in AML
Pivotal Midostaurin Findings
The midostaurin approval is based on the phase III RATIFY trial in AML and 2 single-arm, open-label studies of patients with SM. In RATIFY, the addition of midostaurin to standard chemotherapy reduced the risk of death by 23% compared with chemotherapy alone in patients with FLT3-mutant AML. After censoring for patients who received stem cell transplants, the overall survival (OS) benefit with midostaurin remained steady at 25%.
In the phase II trial considered for the SM approvals, among patients receiving 6 cycles of midostaurin, the rates of confirmed complete remission (CR) plus incomplete remission (ICR) by modified Valent criteria were 38% for ASM and 16% for SM-AHN. One patient with mast cell leukemia had a CR.