Recent developments in marginal zone lymphoma

While immunochemotherapy using the anti-CD20 antibody rituximab (R) plus either bendamustine [10] or—according to the only randomized phase III trial IELSG19 [11] in extranodal marginal zone lymphoma—chlorambucil has been widely advocated and used, indirect comparisons and analyses have questioned the use of classic chemotherapy and shifted the focus toward more targeted therapies. Especially the results of the IELSG19 trial, which have shown a significantly prolonged progression-free survival (PFS) for the combination of R plus chlorambucil over either R‑mono or chlorambucil mono—but no difference between the latter two and, more importantly, no overall survival (OS) benefit for one of the three arms—have not resulted in unequivocal acceptance of R‑chlorambucil as standard treatment [11]. In addition, a retrospective analysis of 159 patients performed at our institution [12], while suggesting a somewhat higher response rate (90% vs. 68%), has not shown a benefit in terms of complete remission (CR) rate and PFS for chemotherapy-containing regimens over immunotherapeutic approaches for gastric, non-gastric, localized, or disseminated extranodal marginal zone lymphoma.

One of the earliest substance classes studied in more detail has been ImIDS, with lenalidomide being the most commonly reported agent with promising results both as single agent as well as in combination with R. Especially the latter has shown good activity in a cohort of “pure” extranodal marginal zone lymphoma patients resulting in an overall response rate of 80% with 54% CRs [13]. However, one of the dilemmas of treating and studying marginal zone lymphomas is exemplifies by the fact, that—in spite of promising initial data—the combination of lenalidomide and rituximab (or “R²”) has been approved by the US Food and Drug Administration (FDA), but not the European Medicines Agency (EMA). The pivotal trial for studying the R2 regimen in “indolent” lymphomas was the AUGMENT trial [14], which included both a cohort of follicular lymphomas and tested rituximab plus placebo versus rituximab plus lenalidomide. While the results showed a statistically significant advantage for the R² combination in terms of PFS, a subgroup analysis in the marginal lymphoma cohort, which comprised only 63 patients and included extranodal, splenic, and nodal marginal zone lymphoma patients showed a (disappointing) median PFS for R + placebo of 25.2 versus 20.2 months in the R² cohort. A closer analysis showed that apart from mixing the prognostically different histologies, the marginal zone lymphoma patients had not been stratified according to prognostic parameters, resulting in an imbalance with a relevant disadvantage in the experimental arm probably explaining the outcome of the study.

Recently, however, the chemo-free combination of the macrolide antibiotic clarithromycin and lenalidomide has also been tested in the IELSG40/CLEO phase II study [15]. The rationale behind this study was the well-established role of both agents in extranodal marginal zone lymphoma as well as the fact that clarithromycin is able to overcome resistance to lenalidomide in multiple myeloma. However, the CLEO study was terminated early after including 43 patients, as the overall response rate fell short of the pre-defined response rate for activity at an ORR of 44% (14% CR, 30% PR) in the intent-to-treat (ITT) cohort. However, in patients completing therapy, an ORR of 67% was documented (29% CR, 38% PR), and the median PFS in the ITT cohort was 40 months, with a 71% remission rate at 24 months which appeared comparable to, e.g., results obtained in the AUGMENT trial. In view of this, the use of clarithromycin beyond its established role as monotherapy in extranodal marginal zone lymphoma as a potential combination partner should be further explored.