Pacritinib Suppresses Leukemic Outgrowth in FLT3-ITD-Driven Acute Myeloid Leukemia (AML)
Pacritinib suppresses leukemic outgrowth from stroma-adherent cells in FLT3-ITD–driven AML.
SAN FRANCISCO—The dual FLT3 and JAK2 inhibitor, pacritinib, suppresses leukemic outgrowth from stroma-adherent cells in FLT3-ITD–driven acute myeloid leukemia (AML), a study in primary AML samples (Abstract 270) reported at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition.
“Targeting the stroma-AML cell interaction is a new dimension in anti-leukemia therapy,” said Ceri Marrin, MBBCh, of the Department of Haematology, Institute of Cancer & Genetics at Cardiff University, in Cardiff, United Kingdom.
“We set up this study to determine if pacritinib as a single agent is sufficient to abrogate the stroma-mediated resistance of AML, and to investigate leukemic signaling in stroma-adherent AML cells,” she added, in describing the study's rationale.
The efficacy of pacritinib was assessed in 62 primary AML samples. After 48 hours of exposure to pacritinib in vitro, FLT3-ITD samples were significantly more sensitive that FLT3 wild type AML samples.
Although the leukemic outgrowth was suppressed in both medium-term (14 days) and long-term (5 weeks) assays, “short-term intracellular signaling profiles suggest that resistance pathways can remain active in some cases and may require AKT/ERK targeting for their eradication,” Dr. Marrin said. “Good synergy is seen with MEK inhibition, making this an attractive combination for clinical evaluation.”
Short-term drug response Cell Glo luminescent assays, which reflected results from intracellular signaling experiments, found significant synergy when pacritinib was combined with a MEK inhibitor (PD0325901), with accompanying down-regulation of ERK.
This potential to overcome environment-mediated resistance in AML has led to pacritinib being included in a UK National Cancer Research Institute phase 2 trial that is part of a larger ongoing study, AML 17. The study, initiated in January 2014, plans to enroll 80 adults with relapsed AML with mutations of the FLT3-ITD gene in England and Wales, Dr. Marrin said.
In the Medical Research Council AML 17 trial, pacritinib is currently offered as stand-alone therapy for patients with relapsed AML with FLT3-ITD mutant disease.Reference