HOUSTON, May 15 — An antiviral drug that targets a growth-promoting oncogene led to stable disease or better response in all but two patients with relapsed or refractory acute myeloid leukemia in a small Canadian study.

• Explain to patients that a drug that blocks the activity of a cancer gene showed clinical activity in patients with a subtype of acute myelogenous leukemia.
• Note that the study involved only 11 patients.
• The drug is not approved for treatment of leukemia.

Of 11 evaluable patients, three had major responses, two had blast responses, and four had stable disease when treated with ribavirin, Katherine L.B. Borden, Ph.D., of the University of Montreal, and colleagues reported online in Blood.

Lack of effect on the eIF4E oncogene protein activity correlated with disease progression.

“Ribavirin-induced relocalization of nuclear eIF4E to the cytoplasm and reduction of eIF4E levels were associated with clinical response,” the authors said. “Lack of response or relapse coincided with continued or renewed nuclear localization of eIF4E.

“This first clinical study to target eIF4E in human malignancy demonstrates clinical activity and associated molecular responses in leukemic blasts.”

The translation initiation factor eIF4E is elevated in about 30% of cancers, including the M4/M5 subtype of AML.

The factor’s oncogenic potential arises from its ability to bind the 7-methyl guanosine cap (m⁷G cap) on messenger RNA, selectively enhancing eIF4E-dependent nuclear mRNA export and translation, the authors explained.

Ribavirin mimics the m⁷G cap, providing a rationale for using the antiviral agent to target eIF4E. To explore the rationale, investigators treated 11 patients with M4/M5 AML. Patients received ribavirin daily for as many as six 28-day cycles.

Assessment of response by the Cheson criteria occurred after 30 days.

One patient had a complete response and two had partial responses. The complete response and one partial response were associated with a marked decline in bone marrow blasts and restoration of normal hematopoiesis.

One patient with a blast response had decline from 60% blasts to 0% in peripheral blood and 95% to 29% in bone marrow, which persisted for 50 days. The second blast response was associated with a 66% decrease in blast count, lasting for 35 days. One patient with stable disease for 56 days had a 48% decline in blast count.

All of the patients had elevated levels of eIF4E prior to treatment with ribavirin. After treatment, 10 of the 11 patients had declines in eIF4E RNA levels that ranged from two- to 10-fold.

Neither cytogenetics nor mutations in FLT3 or NPM predicted response.

Besides demonstrating ribavirin’s ability to target eIF4E, the results suggested that nuclear localization of eIF4E and its mRNA export function contribute to the oncogene’s transformation capacity, the authors said.

There was no significant treatment-related toxicity.

Because multiple proteins modulate eIF4E relocalization, future studies should focus on elucidating more information about the relocalization process, they added.

The study was funded by the Leukemia and Lymphoma Society. Dr. Borden holds an equity position in Translational Therapeutics.

Primary source: Blood

Source reference:

Assouline S et al. “Molecular targeting of the oncogene eIF4E in AML: a proof-of-principle clinical trial with ribavirin” Blood 2009; DOI: 10.1182/blood-2009-02-205153.

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