Optimizing therapy in relapsed CLL: ibrutinib and beyond

Ibrutinib plus CAR-T cells

In a pilot trial funded by Novartis, investigators led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor–T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy.

Trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.

At 3 months, eight (89%) of nine evaluable patients had no evidence of disease in bone marrow, reported Dr. Gill, who disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for acute myeloid leukemia, among other disclosures. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes.

Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.

Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.

“We don’t know what will happen if the patients stop ibrutinib at some point, which is a question for the future,” commented Dr. Brown, the discussant.

“CAR-T cell therapy in CLL has historically had lower response rates than in ALL, but preclinical and early clinical data support ongoing investigation of combination therapy with ibrutinib as it appears that ibrutinib may enhance the production and engraftment of the T cells,” she noted. “Ultimately, of course, the role of CAR-T cell therapy in CLL will require a very clear, well-defined safety [protocol] if it is being used in comparison to some of the oral drugs that we can maintain many of the patients on for a long time.”