Data from the SPARK Study: Mutational Analysis of Patients with Primary Resistance to Ibrutinib in Relapsed/Refractory Mantle-Cell Lymphoma

Conference Correspondent - ASH 2014 - Castleman's Disease


Ibrutinib, a first-in-class, once-daily, oral covalent inhibitor of Bruton’s tyrosine kinase (BTK) is highly effective in patients with relapsed or refractory mantle-cell lymphoma (MCL), resulting in an overall response rate (ORR) of 68% (Wang ML, et al. N Engl J Med. 2013;369:507-516). However, some patients with MCL do not respond to ibrutinib, so Balabsubramanian and colleagues analyzed potential mechanisms associated with primary resistance to ibrutinib therapy in patients with MCL (Balabsubramanian S, et al. ASH 2014, Abstract 78).

In this phase 2, international, multicenter, single-arm study, patients with MCL received oral ibrutinib 560 mg daily until progressive disease or unacceptable toxicity. Patients who had progressive disease at the first disease evaluation were considered to have primary resistant disease. DNA was extracted from baseline/pretreatment tumor samples, and enriched libraries were constructed with probe sets specific for the coding region of 97 genes possibly involved in the response to and resistance to ibrutinib. Of the 120 patients enrolled in the study, 25 (22.7%) had Independent Review Committee–confirmed disease progression.

Sequence data could be collected from 23 of the 25 patients, with an average of 9 million reads. After data filtering, 27 genes were found with nonsynonymous variants in at least 2 or more patients. The majority of these variants were previously unreported in the Short Genetic Variations database or the Catalogue of Somatic Mutations in Cancer. No mutations previously described in patients with chronic lymphocytic leukemia (CLL) and acquired resistance to ibrutinib (BTK C481S, PLCg2 R665W) were seen in these patients, although 1 patient had a different mutation in PLCg2. Genes previously implicated in diffuse large B-cell lymphoma (DLBCL) pathogenesis (MLL2 and CREBBP) were also found to be mutated in these patients. In addition, mutations in PIM1 and ERBB4 kinase genes were more frequent in patients with progressive disease than in patients who were nonresistant to therapy. Interestingly, several of the mutations that were detected affect (NF)-?B signaling inhibition, which is thought to contribute to ibrutinib’s mechanism of action.

These studies have revealed a number of known and novel mutations, including genes involved in NF-?B signaling, which are associated with primary resistance to ibrutinib in MCL. Among others, the mutational status of PIM1 kinase and ERBB4 kinase genes may be of interest with respect to primary resistance to ibrutinib in patients with MCL.