Benefit to Targeting Btk in Selected Patients With AML?

Ibrutinib may be an effective therapy for myeloid leukemias with G-CSFR mutations, according to researchers at the University of Cincinnati (UC) College of Medicine and Cincinnati Children’s Hospital Medical Center. They reported a murine study in Leukemia which indicates that ibrutinib may offer another treatment option in this disease setting. These new findings, they say, should make it easier to move ibrutinib quickly into clinical trials since the drug is already approved for treatment of other hematologic malignancies.

The US Food and Drug Administration (FDA) has approved ibrutinib for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), CLL/SLL with 17p deletion, Waldenström macroglobulinemia, marginal zone lymphoma, and mantle cell lymphoma.

Study coauthor Ken Greis, PhD, a professor in the Department of Cancer Biology and a member of the Cincinnati Cancer Center, Cincinnati, Ohio, said mutations in G-CSFR have a harmful effect on the production of neutrophils and are reported in several types of blood disorders, including severe congenital neutropenia (SCN), chronic neutrophilic leukemia (CNL), and acute myeloid leukemia (AML). However, he noted that the malignant signaling of mutated G-CSFR is not well understood, despite years of investigation.

For the current investigation, Greis and colleagues used an advanced mass spectrometry–based technology to create a comprehensive signaling network of the normal vs the mutated receptors, to understand how abnormal cellular signaling from the mutant receptors results in disease development. The researchers evaluated phosphorylation events (pTyr) in the normal vs mutant receptor cells.

Analysis of the pTyr activity revealed differential phosphorylation that included abnormal activation of Bruton tyrosine kinase (Btk), a regulatory protein associated with the maturation of antibody-producing B cells. The researchers validated their findings in murine models. They also found that retrovirally transduced human CD34+ umbilical cord blood cells expressing mutant receptors displayed enhanced sensitivity to ibrutinib. The researchers observed a synergistic effect with ibrutinib and ruxolitinib in murine and human primary cells.

Amanda Cashen, MD, Associate Professor of Medicine at Washington University School of Medicine in the Division of Leukemia and Stem Cell Transplantation, St. Louis, Missouri, said these new findings provide compelling preclinical evidence that myeloid leukemias with mutated G-CSFR have abnormal activation of Btk.  “Although Btk is only one of many kinases with abnormal activity in these leukemias, [the study results] show that inhibition of Btk with ibrutinib is sufficient to reduce proliferation of the leukemia cells. Translation of these findings to a clinical trial should be straightforward, since ibrutinib is a well-tolerated oral therapy that is commonly used to treat lymphoid malignancies,” Dr. Cashen told Cancer Network.

She said targeting proliferative signals through Btk could provide control of the white blood cell count and slow progression to AML. However, she cautioned that the question of whether ibrutinib could impact disease control in acute leukemias with mutated G-CSFR is unclear, since the mutational landscape of AML is often complex.