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.
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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.
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