• What are the therapeutic options for relapsed MCL?
TREATMENT OF RELAPSED MCL
Single-Agent and Combination Chemotherapy
Whenever possible, and since there is no standard, patients with relapsed MCL should be offered a clinical trial. Outside of a clinical study, many of the treatment regimens used at diagnosis can also be applied in the relapsed setting. In relapsed MCL, Rummel et al showed that BR for 4 cycles resulted in an ORR of 90%, with a CR of 60%. The median PFS was 24 months.41 Bortezomib, an inhibitor of the proteasome-ubiquitin pathway, leads to apoptosis and cell cycle arrest in MCL.42 Multiple studies have evaluated bortezomib both as a single agent and in combination for patients with relapsed MCL. In 2006, bortezomib became the first agent approved by the FDA in relapsed or refractory MCL, based on the phase 2 PINNACLE study. This prospective multicenter study involving 155 patients demonstrated an ORR of 33%, CR rate of 8%, and median treatment duration of 9 months. The median time to progression was 6 months.43 Subsequently, bortezomib-containing combinations evolved. In a multicenter study of relapsed and refractory indolent NHL and MCL, Friedberg and colleagues evaluated bortezomib in combination with BR.44 In the MCL cohort, the ORR was 71%. These promising results led to the study of this combination in the frontline setting. The ongoing ECOG 1411 study is using BR for the frontline treatment of MCL with or without bortezomib as induction. This study also includes rituximab maintenance, and randomizes patients to undergo maintenance with or without the immunomodulator lenalidomide. Bortezomib has been associated with herpes simplex and herpes zoster reactivation. Neuropathy has also been observed with bortezomib, which can be attenuated by administering it subcutaneously.
Lenalidomide is an immunomodulatory agent derived from thalidomide. It has significant activity and is a mainstay of treatment in multiple myeloma. Lenalidomide acts by enhancing cellular immunity, has antiproliferative effects, and inhibits T-cell function leading to growth inhibitory effects in the tumor microenvironment.45 In MCL, lenalidomide has demonstrated clinical activity both as a single agent and in combination, as well as in preclinical studies establishing its pro-apoptotic effects.46 The pivotal EMERGE study evaluated monotherapy with lenalidomide in heavily pretreated relapsed and refractory MCL. This multicenter international study of 134 patents reported an ORR of 28% with a 7.5% CR rate and median PFS of 4 months. All patients had relapsed or progressed following bortezomib. This led to the approval of lenalidomide by the FDA in 2013 for the treatment of patients with MCL whose disease relapsed or progressed following 2 prior therapies, one of which included bortezomib.47 Lenalidomide has been associated with neutropenia, secondary cancers, and deep venous thrombosis.
In combination with other agents in the relapsed setting, lenalidomide shows broader activity. A phase 1/2 study by Wang and colleagues demonstrated an ORR of 57%; the median response duration was 19 months when lenalidomide was combined with rituximab for relapsed/refractory MCL.48
Novel Therapies
More recently, novel treatment approaches have been tested in MCL based on an increased understanding of aberrant signaling pathways in this disease (Table 3). Constitutive activation of B-cell receptor signaling is critical for the survival and proliferation of lymphomas, and has led to the development of targeted agents inhibiting B-cell receptor–associated protein kinases. Bruton’s tyrosine kinase (BTK) is one essential component of the B-cell receptor.49 In particular, proteins upstream of the BTK pathway have been implicated in growth and proliferation of MCL, suggesting that inhibition of BTK may impede lymphomagenesis.50 Ibrutinib is an oral inhibitor of BTK, and demonstrates activity in multiple lymphoma subtypes. In a phase 1 study of ibrutinib in relapsed and refractory hematologic malignancies, an ORR of 60% was observed in 50 evaluable patients, with 16% CR. Median PFS was 13 months. Among these, 7 of 9 patients with MCL responded, including 3 CRs.51 Given these promising results, a phase 2 multicenter study evaluating ibrutinib in relapsed and refractory MCL was completed.52 At a dose of 560 mg daily, the response rate was 68%, with CR of 21%. The most common observed treatment-related side effects included diarrhea, fatigue, and nausea. Neutropenia and thrombocytopenia were also observed. Of importance, 5% of patients had grade 3 or higher bleeding events, including subdural hematoma, gastrointestinal bleeding, and hematuria. The estimated OS rate was 58% at 18 months. On the basis of this study, the FDA approved ibrutinib for relapsed and refractory MCL in November 2013.
