Introduction
Marginal zone lymphoma is among the more common types of B‑cell lymphoma, with three different major subtypes being encountered in clinical practice. As opposed to follicular lymphoma, the most recent World Health Organization (WHO) classification has not resulted in major changes. The classification includes extranodal marginal zone B‑cell lymphoma (or MALT-lymphoma) as the most common subtype at roughly 8% of all newly diagnosed lymphomas, nodal marginal zone lymphoma, and the relatively rare and extremely benign pediatric marginal zone lymphoma along with the newly termed “primary cutaneous marginal zone lymphoma” (formerly included in the extranodal marginal zone lymphoma of mucosa-associated tissue type). In addition, splenic marginal zone lymphoma has formally been moved to the “splenic B‑cell lymphomas” [1].
While marginal zone lymphoma has been recognized as a distinct entity to a certain extent in recent years, the histological subtypes have been given little consideration and are mostly lumped together in clinical trials. In addition, histology-specific randomized trials are still mostly missing, due to the rarity of especially nodal, but to some extent also splenic marginal zone lymphoma [2].
Anzeige
However, there have been interesting, potentially clinically relevant results in marginal zone lymphoma as assessed in a talk given at the annual meeting of the Austrian Society for Hematology and Oncology (ÖGHO) in 2024. This article aims to briefly summarize some of the results that could influence clinical practice.
PET imaging in marginal zone lymphoma: beyond 18F-FDG-PET/CT
The use of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) for staging and response assessment has widely been implemented in the management of most lymphoma subtypes in clinical routine. However, marginal zone lymphoma is somewhat an exception, as current guidelines do not unequivocally recommend its use apart from nodal marginal zone lymphoma [3, 4]. Both splenic as well as extranodal marginal zone lymphoma are characterized by a relatively low 18F-FDG avidity, which has been reported at 67% and 54%, respectively, defining them as among the lymphoma entities with the lowest diagnostic reliability for imaging with 18F-FDG-PET/CT [5]. In view of this, the search for alternative tracers for imaging of marginal zone lymphoma has been on the agenda in recent years.
Initial in vitro data have demonstrated a high expression of the adhesion molecule CXCR4, a chemokine receptor in 93% of patients with MALT-lymphoma irrespective of origin [6], which was later expanded to other lymphomas including mantle cell lymphoma and CLL. The possibility of radiolabeling a CXCR4-seeking tracer with 68Ga has led to clinical studies using 68Ga-Pentixafor-PET-CT or magnetic resonance imaging (MRI) for imaging of (mostly extranodal) marginal zone lymphoma [6]. A high diagnostic accuracy in the range of 95% was found in various pilot series [6‐8], and comparison with 18F‑FDG-PET-CT performed within 14 days in 21 patients showed 95% accuracy again for the experimental tracer versus 42% for the latter tracer. In all of the series, a high sensitivity in the gastrointestinal tract was reported, resulting in a pilot study to compare 68Ga-Pentixafor-PET-MRI with histological assessment of gastric biopsies in patients following Helicobacter pylori eradication [9], which is still the gold standard for response assessment in gastric extranodal marginal zone lymphoma [3, 4]. A total of 26 patients underwent control biopsies as specified in the guidelines along with pre- and post-eradication PET/MRIs. A high diagnostic yield for the noninvasive imaging modality was demonstrated, resulting in a specificity of 100% and a sensitivity of 95%, rendering 68Ga-Pentixafor imaging a promising potential noninvasive tool for assessment of response to H. pylori eradication in gastric extranodal marginal zone lymphoma.
Treatment of marginal zone lymphoma
Revisiting the role of lenalidomide?
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.
Anzeige
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.
BTK inhibitors in marginal zone lymphoma
The advent of BTK inhibitors has radically changed the approach to various B‑cell lymphomas including CLL and has especially improved prognosis for mantle cell lymphoma. In view of the indolent nature of the majority of marginal zone lymphomas, however, only a small number of patients require more aggressive therapy.
Initial data with ibrutinib were published in 2017, including a total of 63 patients (32 extranodal, 17 nodal, and 14 splenic), showing an overall response rate of 53% (with 3% CR) and a 62% PFS rate at 18 months, with failures involving the initial site in all cases [16]. In addition to the toxicity profile of ibrutinib, the optimal response required a longer duration of therapy with 10% CR and 48% PR at 42 months as opposed to 5% CR and 43% PR at 12 months [17]. While the FDA has granted approval due to an “unmet medical need,” ibrutinib is not licensed for use in marginal zone lymphoma in Europe.
More recent data with the next-generation BTK inhibitor zanubrutinib have been published in the MAGNOLIA trial including a total of 68 anti-CD20 pretreated patients (26 extranodal, 26 nodal, 12 splenic, and 4 “unknown”), again showing a relatively imbalance toward the rare but more aggressive nodal variant requiring therapy [18]. An overall response rate of 65% was achieved, with 26% CR and 42% PR, which was seen after a median time of 3 months on therapy as opposed to ibrutinib, with extranodal and nodal subtypes responding in 77% and 73% of cases, while splenic marginal zone lymphoma had a lower response rate at 64%. In view of these results and the minimal toxicity, zanubrutinib is now approved for application in patients following anti-CD20 antibodies requiring therapy.
Summary
As opposed to other lymphoma subtypes, 18F-FDG-PET-CT is not recommended for staging and follow-up of especially splenic and extranodal marginal zone lymphoma due to the low sensitivity. Novel chemokine-receptor-seeking tracers (68Ga-Pentixafor) have shown promising results, suggesting a potential role also in the noninvasive follow-up of gastric marginal zone lymphoma after H. pylori eradication.
In terms of treatment, lenalidomide has not been approved in combination with rituximab in spite of promising results in marginal zone lymphoma-“only” trials, but has shown some promising results combined with clarithromycin in certain patients with extranodal marginal zone lymphoma. The second-generation BTK inhibitor zanubrutinib has now been approved for patients requiring therapy after anti-CD20 antibodies.
Conflict of interest
M. Raderer and B. Kiesewetter declare that they have no competing interests.
Anzeige
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
