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New Inhibitor Drug Shows Promise

Published: 2017-06-23 |

Source: University of Pennsylvania

A new drug shows promise in its ability to target one of the most common and sinister mutations of acute myeloid leukemia (AML), according to researchers at the Perelman School of Medicine at the University of Pennsylvania and Penn's Abramson Cancer Center. The Fms-like tyrosine kinase 3 (FLT3) gene mutation is a known predictor of AML relapse and is associated with short survival. In a first-in-human study, researchers treated relapsed patients with gilteritinib, an FLT3 inhibitor, and found it was a well-tolerated drug that led to frequent and more-sustained-than-expected clinical responses, almost exclusive with this mutation. They published their findings today in The Lancet Oncology.

FLT3 is one of the most commonly mutated genes in AML patients. FLT3 mutations are found in about 30 percent of patients' leukemia cells. Clinically, these mutations are associated with aggressive disease that often leads to rapid relapse, after which the overall survival is an average of about four months with current therapies. To avoid relapse, oncologists often recommend the most aggressive chemotherapy approaches for patients with FLT3 internal tandem duplication (FLT3-ITD), including marrow transplantation. But even that cannot always stave off the disease.

The FLT3 gene is present in normal bone marrow cells and regulates the orderly growth of blood cells in response to daily demands. When the gene in mutated in a leukemia cell, however, the mutated cells grow in an uncontrolled manner unless the function of FLT3 is turned off.

"Other drugs have tried to target these mutations, and while the approach works very well in the laboratory, it has proven very challenging to develop FLT3 inhibitors in the clinic for several reasons," said Alexander Peri, MD, MS, an assistant professor of Hematology Oncology in Penn's Abramson Cancer Center and the study's lead author. "First, we've learned it takes unusually potent inhibition of the FLT3 target to generate clinical responses. Second, many of these drugs are not selective in their activity against FLT3. When they target, multiple kinases, it can lead to more side-effects. That limits whether you can treat a patient with enough drug to inhibit FLT3 at all. Finally, with some FLT3 inhibitors, the leukemia adapts quickly after response and cells can develop new mutations in FLT3 that don't respond to drugs at all. So, ideally, you want a very potent, very selective, and very smartly designed drugs. That's hard to do."

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