Combined therapy in MCL: less may be more?

In this issue of Blood, Albertsson-Lindblad et al report on the efficacy of a bendamustine (B)/lenalidomide (LEN)/rituximab (R) combination in first-line therapy of mantle cell lymphoma (MCL). Essentially, this combination achieved high response rates (complete response, 64%; molecular remission, 36%) and a prolonged median progression-free survival (PFS) of 42 months, but rate of infections (42%) and secondary malignancies (16%) were significant.¹  So how should we evaluate these results in light of other trials?

Based on 2 phase 3 studies on both sides of the Atlantic, bendamustine-rituximab (B-R) became the standard approach in elderly MCL patients achieving long-term remissions at least comparable to conventional rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) but being better tolerated^2,3  (see table,^1-6 ). However, further analysis revealed an unexpected increased rate of atypical infections based on reduced CD4 counts for a prolonged period. Accordingly, with regard to anti-infectious comedication, some authors have suggested the use of antimicrobial prophylaxis (review in Dreyling and Subklewe⁷ ). Although there was also concern of a potential increased rate of secondary malignancies, randomized trials did not confirm an increased risk. In multiple myeloma, a similar concern of an increased rate of secondary malignancies in LEN-treated patients was shown to be most likely due to alkylating agents given with LEN.⁸  Excellent results have been published for a LEN-R combination in a small oligocentric first-line trial⁵  (see table). Most frequent adverse events were grade 3/4 neutropenias, but overall the regimen was tolerated better than conventional chemotherapy.

Based on the favorable tolerability and the benefit of maintenance therapy in MCL, these 2 approaches have been combined in patients who do not tolerate high-dose cytarabine-containing regimens.⁹  As initial phase 1 trials suggested increased myelotoxicity, subsequent guidelines recommended dose reductions of the B-LEN combinations.⁸  Currently, 2 phase 2 studies have been reported in MCL. The Italian study group explored this combination in relapsed disease. Tolerability with a reduced bendamustine dose (70 mg/m²) was reasonable, and a response rate of 79% with a median PFS of 20 months has been observed.⁴  In the study reported in this issue, the LEN dose had to be held during cycle 1 and given at a reduced dose (10 mg) afterward due to rash and infectious complications; with such a modified scheme, grade 3/4 infections were still observed in 42% of patients, mostly during induction. In comparison with the different first-line strategies, it appears that the combined BR-LEN regimen seems to be superior to the immunochemotherapy regimen^2,3  but showed no benefit in comparison with the R-LEN approach of the New York group⁵  (see table). However, MCL is an especially heterogeneous disease, and such comparisons are hampered by that heterogeneity.¹⁰ 

We have to address the same dilemma as in multiple myeloma: is it worthwhile to move on to triple or quadruple regimens or might it be beneficial to spare various options for sequential strategies? Surveying local MCL patients, a median of >3 therapeutic regimens have been given, and the armamentarium of targeted approaches is likely to extend during the new few years. Especially for the BR-LEN combination, we have to carefully balance the observed side effects to the high efficacy of this regimen. Thus, we may have to challenge the dogma of such mixed approaches, as the “nonchemotherapy” component may add significant toxicity. On the other hand, we have to realize that chemotherapy-based strategies achieve long-term remissions in first-line therapy of MCL. However, today we already have a spectrum of targeted drugs registered in the United States or Europe (bortezomib, ibrutinib, temsirolimus, LEN), and promising additional approaches (including dual phosphatidylinositol 3-kinase, BCL-2, or cdk inhibitors) are in early clinical evaluation. In this regard, the high response rates, especially of the Bruton tyrosine kinase inhibitor ibrutinib, may challenge the future predominance of chemotherapy-based regimens.¹⁰  If current clinical studies confirm recent preclinical data regarding the high efficacy of complementary ibrutinib combinations, we will finally have the opportunity to challenge chemotherapy-based approaches even in first-line therapy of MCL, a disease which used to have a dismal outcome only 2 decades ago. In this way, the study of Albertsson-Lindblad et al represents an important milestone to reconsider our clinical standards.