Venetoclax plus Ibrutinib in Mantle-Cell Lymphoma

Three clinical trials of ibrutinib in patients with relapsed and refractory mantle-cell lymphoma (MCL) have been conducted: SPARK, RAY, and PCYC-1104. In these studies, patients received ibrutinib orally once daily until their disease progressed or until toxicity became unacceptable. Patients who were benefiting from ibrutinib at the end of these studies could then enroll in a long-term extension study called CAN3001. Disease evaluations in CAN3001 were conducted using routine clinical practices, and patients could continue therapy with ibrutinib if they were benefiting clinically.

To assess the clinical benefits of treatment regimens that patients received prior to ibrutinib, researchers calculated the time to next therapy (TTNT). TTNT was defined as the date of the first dose of the prior regimen to the date of the first ibrutinib dose. This TTNT measure was used as a surrogate for progression-free survival (PFS). Patients were divided into 2 groups based on how long they had benefited from their prior therapy: “early” progressers had TTNT of less than 24 months, and “late” progressers had TTNT of 24 or more months.

A total of 99 patients with relapsed and refractory MCL received ibrutinib as second-line therapy. Of these, 43% had “early” disease progression and 57% had “late” progression on their initial treatment. In patients who progressed early, median PFS with ibrutinib was similar to their median TTNT on initial therapy: 14 months each. Median overall survival (OS) on ibrutinib was 24 months. In patients who progressed late on initial treatment, median PFS with ibrutinib was longer than their median TTNT on initial treatment: 58 versus 42 months. Median OS on ibrutinib cannot be calculated yet. There were no unexpected toxicities with ibrutinib.

Overall, median PFS for ibrutinib patients was 13 months, whereas median TTNT on their prior regimen had been 11 months. PFS with ibrutinib was longer than TTNT on the prior regimen for 50% of patients. For 27% of patients, PFS was 12 or more months longer than TTNT on the prior regimen. Disease-related factors that were common among patients who achieved 12 months’ longer PFS while taking ibrutinib were low-risk disease, no extranodal disease, no bulky disease, nonblastoid histology, and unmutated TP53.

As of April 2019, 37% patients with relapsed and refractory MCL who were participating in the long-term CAN3001 study were still taking ibrutinib. Therapy was given for 3 or more years in 22% of these patients. After 5 years of treatment with ibrutinib, 19% of patients were progression-free and 41% of patients were still alive.

Based on this pooled analysis of ibrutinib in relapsed and refractory MCL, which included follow-up for 7.5 years, researchers found that a significant percentage of patients experienced disease remissions that lasted for 5 years or more. Half of all patients treated with ibrutinib experienced more progression-free time than they had experienced on their initial treatment regimen for MCL.

Abstract 1538. ASH 2019.