TKIs May Be Option for Ph-Like ALL

Researchers may have found a new way to treat a common subtype of acute lymphoblastic leukemia (ALL) that was identified just 5 years ago.

Children and young adults with Philadelphia chromosome–like (Ph-like) ALL have genetic alterations that may be vulnerable to tyrosine kinase inhibitors (TKI), researchers reported in September at the American Association for Cancer Research conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

ALL is the most common childhood cancer. In 2009, scientists first identified Ph-like ALL, a precursor B-cell ALL subtype with a poor prognosis that has a gene expression profile similar to that of BCR–ABL1-positive ALL. Intensive chemotherapy is the current standard of care for patients with Ph-like ALL.

The new research, led by Kathryn Roberts, PhD, a postdoctoral research associate in the department of pathology at St. Jude Children's Research Hospital in Memphis, TN, is the first to describe the genomic landscape of Ph-like ALL.

Fusions involving the kinase genes ABL2 and CSF1R, Roberts's team found, can induce B-cell ALL in mice, and the TKI dasatinib (Sprycel; Bristol-Myers Squibb) inhibits the growth of cells expressing these fusions both in vitro and in vivo.

Each gene fusion triggers a distinct cell signaling pathway. For example, ABL2 fusions activate both CRKL and STAT pathways.

“These are new kinases that haven't been studied before in ALL,” Roberts says. “If we can target them with FDA-approved TKIs, we can hopefully improve the survival and outcomes of these patients.”

The findings are an extension of research that Roberts and her colleagues published in September (N Engl J Med 2014;371:1005–15). Among 1,725 patients ages 1 to 39 with precursor B-cell ALL, 264 (15.3%) had Ph-like ALL. The risk of Ph-like ALL increased with age, from 10% in standard-risk childhood ALL to 27% among young adults. Older patients also had a much higher risk for relapse and death within 5 years.

Next-generation sequencing on 154 patients with Ph-like ALL identified kinase-activating alterations in 91% of patients. Researchers found 35 distinct alterations of 13 kinase and cytokine receptor genes, with ABL1, CRLF2, JAK2, and EPOR among the most common.

Using the first mouse models of Ph-like ALL, researchers found that treating mice with dasatinib reduced the tumor burden of leukemia cells harboring ABL1, ABL2, or CSF1R fusions. In vitro analyses suggest that cells expressing EPOR and JAK2 rearrangements are sensitive to ruxolitinib (Jakafi; Incyte) and those with the ETV6–NTRK3 fusion are sensitive to crizotinib (Xalkori; Pfizer).

Researchers also treated 12 patients with Ph-like ALL with dasatinib, imatinib (Gleevec; Novartis), or ruxolitinib on a compassionate-use basis. Eleven continue to respond, with one in remission for nearly 3 years, Roberts says.

The Children's Oncology Group plans to launch a clinical trial in July 2015 to screen all B-cell ALL patients for Ph-like ALL. Those with Ph-like ALL who test positive for a kinase alteration will receive a TKI in combination with chemotherapy.

For now, Roberts says, some children receive TKIs off-label. “If a B-ALL patient comes through Children's Oncology Group with high-risk clinical features and an assay that indicates they have a kinase alteration, clinicians are advised to add a logical TKI to chemotherapy,” she says.

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