A new study using CML in blast crisis cells has identified existing anticancer agents that may provide benefit to patients with this difficult-to-treat disease.
A new study using chronic myeloid leukemia in blast crisis (CML BC) cells has identified existing anticancer agents that may provide benefit to patients with this difficult-to-treat disease. Tyrosine kinase inhibitors (TKIs) focused on BCR-ABL1 showed promise, as did vascular endothelial growth factor receptor (VEGFR) inhibitors and other agents.
TKI therapy has led to dramatic improvements in outcome for chronic phase CML patients. “Despite the treatment breakthroughs in chronic phase CML, advanced phase and blast crisis remain a therapeutic challenge,” wrote study authors led by Kimmo Porkka, MD, PhD, of the University of Helsinki in Finland. CML BC patients tend to respond less favorably to TKI therapy, and when those agents fail there are few other options. “None of the current treatment options are significantly effective in CML BC.”
In this study, researchers used high-throughput drug sensitivity and resistance testing of primary patient samples to identify agents that might help with CML BC patients. Results were published online ahead of print in Blood Cancer Journal.
The study included three distinct CML cell lines representing blast phase disease, as well as mononuclear cells from three CML BC patients and nine healthy donors. The analysis included 295 anticancer agents, with closer testing done on the 30 most promising candidate drugs.
The CML BC cell lines showed the most sensitivity to BCR-ABL1 inhibitors including nilotinib and ponatinib. The other major drug class showing responses was VEGFR inhibitors, such as tivozanib, axitinib, and nintedanib. One of the three cell lines was highly sensitive to BCL2 inhibitors including venetoclax and navitoclax. The nicotinamide phosphoribosyltransferase (NAMPT) inhibitor also showed high activity across all cell lines.
In the patient samples, all showed some sensitivity to BCR-ABL1 inhibitors; only ponatinib was effective in all of the patient samples. A group of three MEK inhibitors-refametinib, trametinib, and TAK-733-were among the most selective drugs in all three of the primary CML BC cases, and VEGFR inhibitors also were effective at inhibiting cell growth.
“New promising candidate compound classes such as VEGFR, NAMPT, and MEK inhibitors were identified for CML BC,” the authors concluded. “These drugs were highly sensitive in most samples (including TKI resistant patient samples), warranting their further evaluation as combination regimens and paving the way for proof-of-concept clinical studies.”