Contributor

Amir T. Fathi, MD
Medical Oncologist and Hematologist
Massachusetts General Hospital
Cancer Center
afathi@partners.org

Seth A. Wander, MD, PhD
Senior Resident in Medicine
Massachusetts General Hospital
Cancer Center
swander@partners.org

 

Using FLT3 Inhibitors to Treat Acute Myeloid Leukemia

Can FLT3 inhibitors yield a cure?

In a paper published in the April 2014 issue of Therapeutic Advances in Hematology, Amir T. Fathi, MD, medical oncologist and hematologist at the Massachusetts General Hospital Cancer Center, and his colleagues reviewed the results from preclinical studies and early clinical trials of first- and second-generation FLT3 inhibitors in acute myeloid leukemia (AML), which have been tested in combination with more traditional chemotherapy and hematopoietic stem cell transplants.

Dr. Fathi was joined by Seth A. Wander, MD, PhD, a senior resident in medicine at Mass General Cancer Center, and Mark J. Levis, MD, PhD, director of the leukemia program at Johns Hopkins’ Sidney Kimmel Comprehensive Cancer Center. Together, Dr. Fathi and his colleagues examined numerous studies published between 1994 and 2013.

One of the more prominent DNA mutations in AML (the most common form of acute leukemia in adults) affects the FLT3 enzyme, a tyrosine kinase receptor at the surface of bone marrow cells usually involved in cell cycling. The mutation results in unregulated activity of the FLT3 enzyme, which causes an uncontrollable replication of leukemic cells, and generally leads to an aggressive form of AML, with frequent relapses and poor prognosis. But Dr. Fathi and his colleagues across the country are studying drugs called FLT3 inhibitors that can effectively suppress the unregulated FLT3 activity in vitro and in vivo, with clinical response in some patients with advanced AML.1  

Binding of mutated FLT3 receptors by type

Aberrant FLT3 Signaling

FLT3 mutations come in two varieties. The more common is the ITD (internal tandem duplication) mutation, which consists of multiple repeats of DNA segments that are inappropriately inserted into the gene. A less common form is a tyrosine kinase domain (TKD) duplication, a point mutation. Both of them lead to abnormal unregulated activation of the FLT3 enzyme, which plays an established role in growth and differentiation of hematopoietic precursor cells. Normal FLT3 enzyme must bind to a FLT3 ligand to become activated, but the mutated FLT3 is less dependent on the ligand, and this can lead to an uncontrollable proliferation of cells.

Early FLT3 inhibitors, including sunitinib, midostaurin and lestaurtinib, were not initially designed to target FLT3. These drugs inhibit other key enzymes in cancer, but were later found to also inhibit FLT3. Sunitinib and lestaurtinib, as well as other early FLT3 inhibitors, ultimately were limited in their clinical impact, because of suboptimal pharmacokinetics and drug metabolism, non-sustained FLT3 inhibition or drug toxicity.2  These early suboptimal results from clinical trials nevertheless were not wholly discouraging. The studies offered molecular insights that allowed researchers to better understand FLT3 pathobiology and design FLT3 inhibitors that more narrowly targeted the FLT3 enzyme with greater potency and duration and lower toxicity. In addition, some older, less selective FLT3 inhibitors, such as midostaurin and sorafenib, are still under clinical study and may have a future role in AML.

A newer, more selective agent, quizartinib, was identified as particularly effective in patients with FLT3-ITD mutations. In one study of patients over 60 years of age with relapsed or refractory AML, those with the FLT3-ITD mutation demonstrated 54 percent composite complete remission following treatment, a very high rate of single-agent remission for the test group. A significant number of these patients were able to successfully receive hematopoietic stem cell transplants. Similarly, a second cohort, consisting of patients aged 18 or older who had relapsed or were refractory to second-line treatment or transplants, and had the FLT3-ITD mutation, demonstrated a 44 percent composite complete remission rate. A separate compound, PLX3397, has also been identified as a potent targeted inhibitor of FLT3-ITD mutant AML and is under study. 

FLT3 structure and function

Overcoming Resistance

Additional trials assessing the efficacy of quizartinib and other FLT3 inhibitors are ongoing, even as new evidence suggests that many patients develop resistance to FLT3 inhibitors over time. Some research suggests that resistance to quizartinib and other FLT3 inhibitors develops because of new TKD mutations acquired after treatment has begun. Resistance has also been associated with upregulation of parallel and downstream signal transduction pathways. Other mechanisms may be implicated as well, including the tumor microenvironment, which may provide important pro-growth and anti-apoptotic cell signaling. 

Some research indicates that combinatorial FLT3 inhibitor therapy may prevent the emergence of resistance. One highly potent FLT3 inhibitor, crenolanib, has been found to be effective in patients who have developed resistance to other FLT3 inhibitors. This is thought to be related to crenolanib being a type I tyrosine kinase inhibitor, and therefore can bind the active conformation of the TKD-altered FLT3 enzyme. Further study will be needed to determine whether this finding will be of clinical use. Individual pharmacokinetics, toxicities and drug interactions may be a significant challenge in combinatorial therapies. 

 

REFERENCES

(1) Wander, Seth A., Mark J. Levis and Amir T. Fathi, “The Evolving Role of FLT3 Inhibitors in Acute Myeloid Leukemia: Quizartinib and Beyond,”Therapeutic Advances in Hematology, vol. 5, no. 3 (2014): 65.

(2) Fathi, Amir, and Mark Levis, “FLT3 Inhibitors: A Story of the Old and the New,” Current Opinion in Hematology, vol. 18, no. 2 (2011): 71–76.

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