Relapse on ibrutinib linked to genetic changes in BTK and PLCG2

This study examined the association between specific genetic changes (mutations) and disease relapse with ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL). Researchers reported that the mutations BTK and PLCG2 appear early and could be used as a predictor for future relapse on ibrutinib.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is used as first-line therapy for CLL as well as salvage therapy after other lines of treatment have failed. Ibrutinib blocks BTK signals that keep CLL cells alive. Ibrutinib produces long-lasting remission (no sign of the disease) in the majority of patients. However, some patients relapse or even transform to a more aggressive form of CLL. Previous studies have shown that relapse on ibrutinib can be the result of specific genetic changes (mutations). These include mutations in the BTK gene or in the protein known as PLCG2. A better understanding of these mutations is needed to help improve outcomes for patients at risk of relapsing on ibrutinib.

308 CLL patients treated with ibrutinib were included in this study. Patients had an average of 3 prior therapies and most had high-risk disease. Analysis for BTK and PLCG2 was performed in those patients who experienced relapse during ibrutinib therapy.

After an average follow-up of 3.4 years, 44% patients remained on ibrutinib-based therapy. 51% of patients discontinued ibrutinib. Of these, 52.5% discontinued due to progression or transformation of the disease. 24% discontinued due to side effects. Transformation tended to occur within the first 2 years of therapy. Disease progression rates were 0.7% at 1 year and 19.1% at 4 years.

Risk factors for progression included high number of abnormalities in chromosomes (structures at the nucleus of living cells that carry genetic information), the presence of the mutation deletion(17)(p13.1), and age less than 65 years. For patients with all 3 risk factors, the risk of progression at 4 years was 44%.

85% of patients who experienced relapse were positive for the mutations in BTK or in PLCG2. On average, these mutations were detected 9.3 months before relapse.

A separate group of 112 CLL patients were monitored for relapse during ibrutinib therapy. At the time of the study, 8 patients had relapsed. All 8 patients were positive for the BTK mutation before relapse. The mutation was detected in a further 8 patients who had not yet shown signs of relapse.

This study concluded that relapse of CLL after ibrutinib is often associated with early mutations in BTK and PLCG2.

Larger studies are needed to confirm these results.