MCL Patients Progressing on Ibrutinib Respond Poorly to Salvage Therapy

Chan Yoon Cheah, MBBS, FRACP

Patients with mantle cell lymphoma (MCL) who develop ibrutinib (Imbruvica) resistance are unlikely to respond favorably to salvage chemotherapy, according to a study recently published in Annals of Oncology.

The retrospective study examined patients with MCL treated with ibrutinib at The University of Texas MD Anderson Cancer Center (MDACC) between 2011 and 2014. Among the 31 patients included in the study who experienced disease progression following ibrutinib and underwent salvage therapy, the overall response rate (ORR) and complete response rates (CRR) were 32% and 19%, respectively. The median duration of response was 5.8 months. The median overall survival was 8.4 months and elevated LDH at disease progression was adversely prognostic.

“Essentially, once ibrutinib stops working, only one-third of patients respond to their next line of treatment; those who do respond experience only brief remissions and have poor outcomes, irrespective of stem cell transplantation,” said Chan Yoon Cheah, MBBS, FRACP, one of the study authors and a clinical fellow and researcher at MDACC, in an interview with OncLive. “Considering recent molecular data suggesting subclonal heterogeneity in MCL, our findings suggest that ibrutinib exposure may have selected an aggressive chemorefractory clone which is difficult to treat.”

There were 78 patients with MCL treated with ibrutinib at MDACC between January 2011 and January 2014, 42 (54%) of whom had discontinued therapy. Patients were treated either with ibrutinib alone (n = 34, 81%), or rituximab and ibrutinib (n = 8, 19%). The median time from initial diagnosis of MCL to discontinuing ibrutinib was 3 years (range, 0.5-15.5).

Thirty-five patients (83%) were male the median age was 69 years. The median number of prior treatments was two (range, 1-8). Subsequent treatment after discontinuation of ibrutinib was determined by the treating clinicians and varied from patient to patient.

Of the 42 patients with MCL, 28 discontinued therapy due to disease progression on treatment, six due to toxicity, four due to elective stem cell transplant in remission, and four dropped out of the study for unrelated reasons. Thirty-one of these patients experienced disease progression and underwent salvage therapy.

The results from this study highlight the critical need to define mechanisms of resistance to ibrutinib, said Cheah. As more patients with MCL are treated with ibrutinib, the need for understanding this resistance will only continue to grow, he said.

“Ibrutinib has been a major breakthrough for patients with relapsed/refractory mantle cell lymphoma. Unfortunately, not all patients respond, and it seems that the drug stops working in some patients,” said Cheah. “This is a problem that we will be encountering increasingly frequently.”

The FDA approved ibrutinib for MCL in November 2013, based on the phase II PCYC-1104 trial, which found the therapy to be highly effective for patients with MCL as a single agent.

The study, lead by MDACC, found an ORR of 68%, including a CRR of 21%. The median duration of response was 17.8 months.

A second MDACC phase II study found that ibrutinib in combination with rituximab resulted in objective responses from 88% of evaluable patients, including complete responses in 18 (40%) patients. The trial also revealed a potential predictor of response, as all patients with lower levels (<50%) of the proliferation marker Ki-67 responded to the combination.

Ibrutinib is an irreversible small-molecule inhibitor of BTK activity. The agent works by blocking B-cell activation and signaling, which prevents the growth of malignant B cells that overexpress BTK.

In February 2014, the FDA also approved ibrutinib for the treatment of chronic lymphocytic leukemia (CLL) in patients who have received at least one previous therapy. In January 2015, the FDA expanded the approval to include patients with Waldenström’s macroglobulinemia (WM), a rare form of cancer that begins in the body’s immune system. The drug received a breakthrough therapy designation for this use.

Cheah CY, Chihara D, Romaguera JE, et al. Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to salvage chemotherapy and have poor outcomes. [published online February 23, 2015]. Ann Oncol. doi: 10.1093/annonc/mdv111