Gilteritinib Drug: New Inhibitor Offers Hope in Relapsed Leukemia

Highlights

• Leukemia is a cancer of the blood cells or the bone marrow
• Scientists have found a new drug to show promise in targeting the mutations of acute myeloid leukemia
• Gilteritinib drug is a Fms-like tyrosine kinase 3 (FLT3) inhibitor drug that targets the mutations of acute myeloid leukemia

A new drug has been found to show promise in targeting the mutations of acute myeloid leukemia (AML), finds a new study at the Perelman School of Medicine at the University of Pennsylvania and Penn’s Abramson Cancer Center. Acute myeloid leukemia is a type of cancer characterized by abnormal white blood cells in the bone marrow. The Fms-like tyrosine kinase 3 (FLT3) gene mutation is a predictor of AML relapse and is associated with short survival.

The research team treated relapsed patients with gilteritinib, FLT3 inhibitor drug. It is found to be a well-tolerated drug and could lead to a frequent and more-sustained-than-expected clinical responses specifically in patients with FLT3 mutations.

The findings were published in the journal The Lancet Oncology.

Alexander Perl, MD, MS, an assistant professor of Hematology Oncology in Penn’s Abramson Cancer Center, said, "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."

"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 the drugs at all. So ideally, you want a very potent, very selective, and very smartly designed drug. That's hard to do."

Clinical Trials
The research team evaluated the drug gilteritinib drug which is known as ASP2215. This could increase the dose in patients whose AML had relapsed or has no longer been responding to chemotherapy.

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The dose levels at 80mg and above were focused, this can be linked with more potent inhibition of the FLT3 mutation and higher response rates.

The research team found that these doses were associated with longer survival. Out of the 252 patients, around 67 were taking 120mg dose and around 100 people were on a 200mg dose.

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The FLT3 mutations were seen among 191 patients who participated in the trial. Around 49% of the patients with FLT3 mutations showed a response. And only 12% of these patients didn’t have the mutation that is responded to the drug.

Perl said, "The fact that the response rate tracked with the degree of FLT3 inhibition and was so much lower among patients who did not have an FLT3 mutation gives us confidence that this drug is hitting its target."

How Does the Drug Act?
In the leukemia cells, the FLT3 gene could mutate again to a form called D835 mutation that can be resistant to several FLT3 inhibitor treatments.

In the laboratory models of leukemia, gilterinitib drug can remain active against D835 mutations. The response rate could also be similar in patients were gilteritinib, the FLT3 inhibitor and to those who were previously treated with other FLT3 inhibitors.

The common side effects of the drug include:

• Diarrhea in 41 patients
• Fatigue in 37 patients
• Abnormal liver enzyme tests in 33 patients

They could be generally mild in severity and the discontinuation of gilteritinib as side effects are uncommon.

Perl said, "These look like data you want to see for a drug to eventually become a standard therapy."

FLT3 Gene
The Fms-like tyrosine kinase 3 (FLT3) gene is one of the commonly mutated genes in Acute myeloid leukemia. The mutations are present in about 30% of the patient’s leukemia cells and could be associated with aggressive disease that can lead to rapid relapse.

The overall survival is an average of four months with current therapies. In order to avoid relapse, the oncologists may recommend therapies for patients with FLT3 internal tandem duplication (FLT3-ITD) this may include marrow transplantation. However, they cannot always stave off the disease.

The FLT3 gene is present in the normal bone marrow cells and regulates the growth of blood cells. However, when the gene is mutated in a leukemia cell, it may grow in an uncontrolled manner, until the function of FLT3 gene is turned off.

Finally, a new multicenter trial that compares the gilteritinib drug to standard chemotherapy in patients with FLT3 mutations who relapsed or has not been able to respond to initial therapy.

The studies are underway that drugs can be given in combination with chemotherapy and also adjunct to bone marrow transplantation in preventing relapse.

References

1. Alexander E Perl, Jessica K Altman, Jorge Cortes, Catherine Smith, Mark Litzow, Maria R Baer, David Claxton, Harry P Erba, Stan Gill, Stuart Goldberg, Joseph G Jurcic, Richard A Larson, Chaofeng Liu, Ellen Ritchie, Gary Schiller, Alexander I Spira, Stephen A Strickland, Raoul Tibes, Celalettin Ustun, Eunice S Wang, Robert Stuart, Christoph Röllig, Andreas Neubauer, Giovanni Martinelli, Erkut Bahceci, Mark Levis. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1–2 study. The Lancet Oncology, 2017; DOI: 10.1016/S1470-2045(17)30416-3

Source-Medindia