Bortezomib is approved by the U.S. Food and Drug Administration (FDA) for relapsed or refractory MCL based on the phase II PINNACLE trial, in which bortezomib induced an overall response rate of 33% (CR in 8%), with a median duration of response of 9 months and median time to progression of 6 months [31
]. Long-term follow-up confirmed these effects [32
]. Bortezomib combined with rituximab has shown activity in heavily pre-treated patients with relapsed/refractory disease.
The immunomodulating agent, lenalidomide, has shown efficacy in relapsed or refractory aggressive non-Hodgkin lymphoma, with subset analysis of MCL patients showing an ORR of 35% and CR rate of 12% at a median follow-up of 12 months in a phase II trial [33
]. In this study the duration of response was 16 months, and the median PFS was approximately 9 months.
Another recent phase II study of patients with rituximab-resistant B-cell lymphomas [34
] treated 43 patients with lenalidomide 10 mg by mouth daily for 8 weeks followed by 4 weekly doses of rituximab 375 mg/m2
intravenously. Six out of the eleven patients with MCL showed a clinical response (3 CR, 1 Cru, 2 PR); the addition of rituximab did not change the ORR, although two PR improved to CR [4
The small-molecule Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib, has shown promising activity in several B-cell malignancies. Subgroup analysis of phase I data in 9 patients with relapsed and/or refractory MCL showed response in 7 patients, including a CR in 3 patients, with no dose-limiting toxicities and no significant myelosuppression even with the full dose of 560 mg daily [35
]. A multicenter phase II trial of 111 patients who had been previously treated with bortezomib and/or rituximab-containing regimens, 72% of whom had advanced disease and 42% of whom had high-risk MIPI scores, showed an ORR of 68% with CR rate of 21% after 15 months of ibrutinib [36
]. The median duration of response was 17.5 months, median PFS was 14 months, and estimated OS rate at 18 months was 58%. The response rates appeared to increase with longer duration of therapy. In November 2013, the FDA approved ibrutinib to treat MCL on the basis of an “unprecedented” response. The most common adverse event rated grade ≥3 were neutropenia (16%), thrombocytopenia (11%), anemia (10%), pneumonia (6%), diarrhea (6%), fatigue (5%) and dyspnea (5%). The use of ibrutinib causes a transient lymphocytosis that resolves after an average of 8 weeks, and caused grade ≥3 bleeding events in 5% of patients [37
]. Thus, ibrutinib is emerging as a potential preferred salvage option due to ease of daily oral dosing and favorable side effect profile.
Although ibrutinib can extend the lives of heavily treated, relapsed, or refractory patients with mantle cell lymphoma (MCL), many become resistant to the drug. Analysis of longitudinal functional genomics in MCL [38
] showed that 30% of the patients who developed resistance to ibrutinib expressed high levels of activated phosphatidylinositol-3 kinase (PI3K-AKT) and cyclin-dependent kinase 4 (CDK4). (PI3K-AKT proteins promote survival; CDK4 drives MCL cells through the cell cycle.) These two mechanisms appeared to override ibrutinib’s inhibitory action in resistant cells. An experimental selective CDK4/CDK6 inhibitor, palbociclib, has demonstrated cytotoxicity against the mutated BTKC481S protein.
Stepwise treatment with palbociclib followed by ibrutinib, or palbociclib followed by the PI3K pathway inhibitor, idelalisib, which is FDA-approved to treat CLL, might treat MCL patients who initially do not respond to ibrutinib. Or, the drugs given together might prevent resistance.
A 48-week study using idelalasib [39
] evaluated 39 patients with relapsed or refractory mantle cell lymphoma patients who had received a median of four prior therapies. Overall, nine (18%) patients discontinued therapy due to adverse effects including diarrhea, transaminase elevations, pneumonia, and acute renal failure. Thirty-three (84.6%) patients had some reduction in lymph node size, with CR in two (5%) patients, PR in 14 (35%) patients, and stable disease in nineteen (47.5%) patients.
Table 4 provides a summary of the novel agents used in MCL.