New Therapeutic Targets for Patients with Leukemia

In a recent study published in Cancer Research, investigators were able to identify mutations in the anaplastic lymphoma kinase (ALK) genes in a small subset of patients with leukemia for the first time – suggesting that patients harboring these mutations may benefit from treatment with ALK inhibitors such as crizotinib and ceritinib.

“This study illustrates a new oncogenic driver – point mutations of ALK – that occurs in a rare subset of patients with hematologic malignancies,” corresponding author Jeffrey Tyner, PhD, from the Knight Cancer Institute at Oregon Health & Science University in Portland, told ASH Clinical News. “While genetic lesions involving ALK have been seen recurrently in a number of different types of solid tumors, to my knowledge, ALK mutations have not previously been implicated as a major contributor to leukemia.”

Led by Julia E. Maxson, PhD, a postdoctoral fellow in the Clinical Research Division at Fred Hutchinson Cancer Research Center in Seattle, Washington, Dr. Tyner and investigators performed genome sequencing of 1,862 kinase and kinase-associated genes in 185 tumor samples from 96 patients with acute myeloid leukemia (AML), 51 patients with acute lymphocytic leukemia (ALL), and 38 patients with myeloproliferative neoplasms.

Of the tumors studied, two samples – one from a pediatric patient with B-cell ALL and another from an adult patient with AML – each had one ALK mutation.

The researchers then introduced the two mutations into laboratory-grown leukemia cells that normally depend on an external growth factor for survival. They found that the mutations allowed the cells to grow, despite the absence of an external growth factor, thus indicating that these mutations were capable of driving abnormal cell growth.

Additional laboratory studies indicated that leukemia cells harboring either of the two established mutations could be inhibited by several ALK inhibitors, including crizotinib and ceritinib, both of which are approved by the U.S. Food and Drug Administration for the treatment of ALK-positive metastatic non-small cell lung cancer.

“Genome sequencing is revealing a vast mutational landscape in leukemia, offering new opportunities for treatment with targeted therapy,” the authors concluded. “We propose that tumors harboring ALK mutations may be therapeutically tractable for personalized treatment of certain aggressive leukemias with ALK inhibitors.”

“The ALK-targeted drugs used in our study are not currently approved for hematologic malignancies, so use of ALK inhibitors for leukemia patients would currently be considered off-label use of the drugs,” Dr. Tyner added. “Ideally, a clinical trial would be run to prospectively evaluate these drugs for leukemia patients with tumors exhibiting ALK mutations. Comprehensive genomic testing will be important to inform the broadest possible use of targeted therapies.”

It is not yet known whether ALK inhibitors will have the same effect on ALK-positive leukemia cells in clinical practice, nor whether the unselected prevalence of such lesions would be similarly low in clinical practice.


Reference

Maxson JE, Davare MA, Luty SB, et al. Therapeutically targetable ALK mutations in leukemia. Cancer Res. 2015;75:2146-50.

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