ALK INHIBITORS MAY BE ACTIVE IN SOME LEUKEMIAS

Drugs targeting mutations in the anaplastic lymphoma kinase gene (ALK) are already useful in lung cancer, but they may also find a use in the treatment of leukemias.

ALK mutations were found in two patients with leukemia, and laboratory experiments suggested that leukemias with these mutations may be treatable with ALK inhibitors, according to a study published online June 1 in Cancer Research.

"Our findings suggest that broader use of ALK inhibitors should be considered, specifically for patients with ALK-mutant hematologic malignancies, and that drugs targeting ALK could be applied on the basis of genetic features of patients' tumor cells," commented lead author Jeffrey Tyner, PhD, an assistant professor at Oregon Health Science University, in Portland.

"[These findings] could change practice for certain patients," he added.

Two drugs targeting ALK are already on the market, crizotinib (Xalkori, Pfizer Inc) and ceritinib (Zykadia, Novartis Pharmaceuticals Corporation); both are indicated for use in patients with non–small cell lung cancer whose tumors have tested positive for ALK.

Study Details

Dr Tyner and colleagues performed deep sequencing of 1862 kinase and kinase-associated genes from blood and bone marrow samples of 185 patients (96 with acute myelogenous leukemia [AML], 51 with acute lymphoid leukemia, and 38 with myeloproliferative neoplasms). The analyses identified two patients who were heterozygous for ALK point mutations. One was a pediatric patient with B-cell lymphoblastic leukemia, and the other was an adult with AML.

Next, the researchers tested whether these mutations were oncogenic by introducing them into laboratory-grown leukemia cells that required the growth factor cytokine IL3 for growth. The experiments showed that cells with these mutations acquired the ability to grow even without IL3, suggesting that these mutations could spur abnormal cell growth.

Finally, the researchers examined whether ALK inhibitors could inhibit cells that have ALK mutations. Laboratory studies found that both mutations conferred sensitivity to ALK kinase inhibitors, including the FDA-approved drugs crizotinib and ceritinib and four other ALK inhibitors currently in development.

Because the study used ALK inhibitors that are not currently approved for blood cancers, use of ALK inhibitors in leukemia patients would be considered off-label use. A prospective clinical trial would be ideal for assessing the use of these drugs in patients with leukemia that harbor these mutations, according to Dr Tyner, but finding enough participants for such a trial would be "challenging."

In the absence of clinical trial data, Dr Tyner suggested: "[T]reating physicians will need to use their professional discretion to determine whether off-label use is a viable option for any patients they treat who present with ALK-mutant hematologic malignancies."

Very Preliminary Evidence

The findings are "interesting, but [provide] very preliminary evidence that targeting ALK in the rare cases of leukemia that harbor these mutations may be a therapeutic strategy," Wendy Stock, MD, told Medscape Medical News. Dr Stock, who was not involved in the study, is a professor of medicine and director of the leukemia program at the University of Chicago.

"More information about the role of ALK mutations in the multistep development of leukemia is required to determine whether ALK inhibition will actually inhibit leukemia growth in vivo and in primary leukemia cells from patients," Dr Stock added.

More studies are also needed to evaluate whether these ALK mutations drive the development of leukemia, Dr Stock continued. In addition, more preclinical studies in animal models are needed to assess the efficacy of ALK inhibitors such crizotinib in leukemias with ALK mutations.

"Given the rarity of these mutations, this specific finding, even if effective, is not likely to impact clinical treatment significantly," she concluded.

"Nevertheless, it demonstrates that careful genomic evaluation of leukemias in the era of personalized medicine yields interesting new findings that could be very relevant for treatment of an individual patient. That is the promise and the hope for the future."

The authors report no relevant financial relationships.

Cancer Res. Published online June 1, 2015. Abstract