Prolonged follow‐up on lenalidomide‐based treatment for mucosa‐associated lymphoid tissue lymphoma (MALT lymphoma)—Real‐world data from the Medical University of Vienna

Abstract Based on results of two pilot trials, lenalidomide (LEN) was found to be active and safe as monotherapy and showed an increased response rate of 80% in combination with rituximab (R) for patients with mucosa‐associated lymphoid tissue (MALT) lymphoma. While initial results were promising, there are currently no data on long‐term outcome, and larger international phase II/III trials on LEN for indolent lymphoma lack specific subgroup analyses. Thus, we have systematically analyzed 50 patients treated with LEN‐based therapy (LEN‐monotherapy n = 16, R‐LEN n = 34) at the Medical University of Vienna 2009 to 2019 and investigated long‐term outcome and relapse patterns. At a follow‐up of more than 5 years (median 68 months), 54% of patients are free of relapse, and estimated median progression‐free survival (PFS) was 72 months (95%CI 49‐96). There was no difference in PFS according to stage of disease, i.e. localized versus disseminated disease (P = .67) and previous systemic treatment (P = .16). Interestingly, but with the caveat of the limited number of patients included in this series, primary extragastric disease had a superior PFS compared with gastric lymphoma (P = .04) and also depth of response, i.e. complete or partial response versus stable disease was associated with significantly prolonged PFS (P = .01). We documented four patients (8%) with pronounced improvement of response during follow‐up including three patients initially rated as partial remission and finally achieving complete remission at 12 to 32 months. This highlights the potential of delayed responses to LEN treatment. Estimated overall survival at 5 years was excellent at 92%. These “real‐world” data confirm long‐term activity of LEN in MALT lymphoma.


| INTRODUCTION
Mucosa-associated lymphoid tissue lymphoma (MALT lymphoma) constitutes a distinct type of indolent lymphoma, histologically characterized by a marginal zone B-cell phenotype of CD20+ CD5− CD10− cyclinD1−, +/− light chain restriction, and variable presence of plasmacytic differentiation. 1 MALT lymphoma cells develop following chronic antigenic stimulation highlighted by the association with chronic infections such as Helicobacter pylori (HP) for gastric MALT lymphoma and autoimmune disorders, e.g. autoimmune thyroiditis (Hashimoto's disease) and Sjogren's syndrome for various localizations. [2][3][4][5] According to the common conception, both conditions result in a multistep process of accrual of (HP-antigen) specific T-cells and production of proinflammatory immune mediators triggering a clonal B-cell proliferation via nuclear transcription factor kappa B (NF-κB) pathway activation. This concept has been further underlined by successfully using HP-eradication for therapy of gastric MALT lymphoma, leading to 80% long-term remissions in gastric lymphoma following elimination of the bacteria, thus proving a striking dependency of MALT lymphoma cells on the tumor microenvironment. 6,7 Following these data, HP-eradication is the treatment standard for localized gastric MALT lymphoma, but there is still no clear explicit therapeutic algorithm for extragastric, disseminated, and HP-refractory disease. [8][9][10] Radiotherapy is widely used and may result in potential cure (or at least long-term remission) for patients with localized disease, 11,12 but also chemotherapy-based regimens such as chlorambucil or bendamustine +/− rituximab (R) are highly effective irrespective of stage. 13,14 Based on the pathogenesis, however, investigation of immunomodulatory therapies appears feasible in patients with MALT lymphoma.
As of 2019, a variety of chemotherapy-free and/or immunomodulatory treatment concepts have been evaluated for MALT lymphoma including anti-CD20-antibody monotherapy with rituximab (R) or ofatumumab, the proteasome inhibitor bortezomib, tyrosine kinase inhibitor ibrutinib, and the macrolide-antibiotics clarithromycin and azithromycin. [15][16][17][18][19] However, results reported so far were mostly phase II data with promising results in terms of response rates and toxicity profiles, but there is a lack of prolonged follow-up reports and the durability of responses beyond the defined treatment protocol. In addition, some agents were tested in and published from mixed collectives of marginal zone lymphoma (MZL) patients also including splenic and nodal MZL patients, what may further bias interpretation of results due to post-hoc analyses.
Starting in 2005 and acknowledging the importance of immunomodulatory drug development in this specific disease, our department has extensively evaluated the effect of IMiDs in MALT lymphoma, as these compounds were reported to be highly effective in multiple myeloma, a disease not dissimilar to MALT lymphoma considering the close relationship of both malignancies. 20,21 Whereas an initial pilot on eight patients treated with thalidomide failed and resulted in no response during the observation period, 22 prolonged follow-up outside the protocol showed delayed effects of therapy in some patients.
As opposed to this, treatment with the second generation drug lenalidomide (LEN) turned out as more promising with documented overall response rates (ORR) >60% for LEN-monotherapy and improved outcome of 80% ORR for combination treatment with R-LEN in the AGMT-MALT2 study, an Austrian multicenter trial (n = 46 patients). 23,24 Toxicity profiles were favorable for both treatment schedules with moderate skin adverse events being the main reported side effect. In addition to our data, there is also evidence from larger phase II and III studies including mixed collectives of indolent lymphoma that LEN is an active and safe drug in this disease, but results are once again inconsistent due to only small subgroups of MZL included, particularly in the relapsed/refractory setting. [25][26][27] To date, we have treated a total of 50 MALT lymphoma patients with LEN-based treatment at the Medical University of Vienna, a tertiary referral center for patients with extranodal lymphoma of MALT type. Considering above discussed caveats in the current trial landscape of MALT lymphoma, the objective of this article is to present here consistent "real-world" follow-up data on response, relapse patterns, and safety with a median follow-up of more than 5 years.

| Statistical analysis
Statistical analysis was performed using IBM statistics for Mac OS version 25.0 (IBM, Armonk, NY). Metric data were described using median and range or interquartile range (IQR), respectively. For categorical data, absolute frequencies and percentages are presented.
Associations of binary variables were calculated by use of Fisher's exact test. Overall survival (OS) and PFS estimations were plotted by Kaplan Meier method, and differences between groups were compared using log-rank test. P-values less than 0.05 were considered statistically significant (two-sided).

| RESULTS
We could identify a total of 50 patients who received LEN-based treatment for histologically verified MALT lymphoma at our institution. Median age at treatment start was 67 years (range; 33-85 years); 62% of patients were female and 38% male. At initial diagnosis, 32% of patients had primary gastric involvement, while the majority presented with primary extragastric MALT lymphoma (68%). The most common extragastric manifestation were the ocular adnexa (30%, 15/ 50), followed by MALT lymphoma of the lung (10%, 5/50) and parotid gland (8%, 4/50), and one patient each had primary of the breast, colon, skin, liver, and small intestine. Furthermore, five patients (10%) had multiple organ involvement at first diagnosis. In terms of Ann Arbor stage at LEN-treatment start, 66% were rated as localized disease (stage IE or IIE) and 34% had disseminated disease (stage IIIE or IV). A history of autoimmune disease was present in 24% of patients.
Risk stratification according to the MALT-IPI scoring system resulted in 26% low risk, 62% intermediate risk, and 12% high risk patients.
See Table 1 for more detailed patient's characteristics.  Initial ORR for the entire cohort was 72%, with 48% achieving a CR, 24% a PR and 22% SD as best outcome, while 6% (three patients) progressed during treatment. In the entire cohort, median time to documentation of best response was 5.1 months (IQR; 2.9-6.7), and remarkably four patients (8%) improved their outcome during prolonged follow-up and converted to a better classification of response after the last restaging within the study protocol, including three patients with delayed CR at 12 to 32 months after LEN-start and one converting from SD to PR after 11 months. Thus, the final outcome according to best response documented during follow-up was 74% ORR, 54% CRs, and 20% SDs. ORR and CR rates were higher for the combination group being 77% versus 69%, and 62% versus 38%; however, none of these differences reached statistical significance (P = .731 and P = .136, respectively). There was no difference of frequency in response in terms of primary localization (ORR extragastric 74% versus gastric 75%, P = .912) or disease dissemination status (ORR localized 76% versus disseminated 71%, P = .741).
To There was no difference in PFS in terms of dissemination, i.e. localized versus disseminated disease (P = .668), MALT-IPI scores (P = .186), or presence of an autoimmune disease (P = .279), but patients with primary extragastric MALT lymphoma at initial diagnosis had statistically a longer estimated PFS than patients with gastric origin (P = .039, Figure 4). This, however, needs to be seen within the context of the high rate of pretreated patients in the latter cohort due to previous HP-eradication (significantly more patients pretreated in the cohort of gastric MALT lymphoma, 88% versus 29%, P < .001), and in view of the limited number of cases included in this series. As expected, there was a trend toward worse PFS in patients who had received prior treatment but without reaching statistical significance (P = .083). Prior immuno-/chemotherapy did not significantly influence PFS (P = .155).
In line with the nature of the disease, OS was excellent with an

| DISCUSSION
Application of LEN has become a widely used approach in various lymphoid malignancies including follicular lymphoma in combination with rituximab, as well as in mantle cell lymphoma. 25,27,30 In this article, we present our long-term experience with patients suffering from F I G U R E 1 Kaplan-Meier curve for estimated progression-free survival in MALT lymphoma patients treated with lenalidomide-based therapy (n = 50). Legend. X-axis follow-up in months; y-axis cumulative progression-free survival MALT lymphoma undergoing a chemo-free immunomodulatory therapy based on the application of the IMiD LEN either as monotherapy (n = 16) or in combination with rituximab (n = 34). As already seen in other trials performed at our institution, the majority of patients had extragastric MALT lymphoma, with only 32% having gastric MALT lymphoma. However, this trend is not only seen at our institution, 31 but also in larger international studies. 32 Whether this reflects an increase in awareness and higher diagnostic yield in extranodal MALT lymphomas or a decline in the rate of gastric MALT lymphomas is an ongoing debate. As opposed to other studies on MZL, also patients with localized disease were treated within the context of the current analysis.
F I G U R E 2 Kaplan-Meier curve for estimated progression-free survival in MALT lymphoma patients with objective response versus stable disease following lenalidomide. Legend. X-axis follow-up in months; y-axis cumulative progressionfree survival F I G U R E 3 Kaplan-Meier curve for estimated progression-free survival in MALT lymphoma patients with complete remission versus partial remission following lenalidomide. Legend. X-axis follow-up in months; y-axis cumulative progressionfree survival F I G U R E 4 Kaplan-Meier curve for estimated progression-free survival in patients with primary gastric versus extragastric MALT lymphoma treated with lenalidomide Legend. X-axis follow-up in months; y-axis cumulative progression-free survival