A phase 2 study of rituximab plus lenalidomide for mucosa-associated lymphoid tissue lymphoma

To the editor:

Chemotherapy-containing regimens are effective for the treatment of advanced mucosa-associated lymphoid tissue (MALT) lymphoma, and recent data on R-chlorambucil and R-bendamustine may potentially have set new treatment standards for progressive disease.^1-4  However, because of the indolent course of MALT lymphoma investigating the use of immunomodulatory, chemotherapy-free strategies appear reasonable. The ability of lenalidomide (LEN) ± rituximab (R) to induce objective responses in different hematologic malignancies has repeatedly been shown in the past several years with overall response rates (ORR) up to 80% to 90% for indolent B-cell lymphomas.^5-9  A pilot trial on LEN monotherapy for MALT lymphoma patients at our institution resulted in an ORR of 61% with no unexpected toxicities, but the complete remission (CR) rate of 33% appeared lower than with other evaluated regimens.¹⁰  Thus, in analogy to the data referred to previously and because of the activity of R—both as monotherapy as well as in combination with cytostatic agents in MALT lymphoma—we have conducted a multicenter trial to assess the activity and feasibility of R-LEN in MALT lymphoma.

The primary endpoint of the Arbeitsgemeinschaft Medikamentöse Tumortherapie (AGMT) MALT-2 trial was to evaluate the clinical potential of R-LEN to induce objective/histological responses with safety being the secondary endpoint. The protocol was approved by the local ethical committees of the participating institutions and had been registered at www.clinicaltrials.gov as #NCT01611259. Patients with gastric and extragastric disease were eligible, but in case of gastric MALT lymphoma, only patients judged Helicobacter pylori (HP)-negative or refractory to HP eradication by a minimum of 12 months after successful elimination of HP could be included. Further key inclusion criteria were appropriate blood counts (absolute neutrophil count ≥1000/µL, platelet count ≥60 × 10⁹/L), an Eastern Cooperative Oncology Group (ECOG) performance status of <3 and adequate renal, cardiac, and liver function.

Treatment consisted of LEN (Revlimid, Celgene Cooperation) 20 mg orally on days 1 through 21 followed by a 7-day rest (28-day cycle) and R (MabThera, Roche Ltd., Switzerland) 375 mg/m² IV on day 1 of each cycle. Radiological response criteria were defined as CR, partial remission (PR), stable disease (SD), and progressive disease (PD). In gastric MALT lymphoma, response was based on Groupe d' Etude des Lymphomes de l' Adulte histological response criteria.¹¹  Restaging was performed after 3 courses; in case of SD or better, patients were scheduled for another 3 cycles. Patients with CR after 6 cycles stopped treatment, whereas patients with PR/SD received another 2 cycles for a maximum of 8. Before initiation of a new cycle, absolute neutrophil count had to be ≥1000/µL and platelet count ≥50 × 10⁹/L.

A total of 50 patients were enrolled in this trial, but 4 patients were excluded, resulting in 46 evaluable patients according to protocol, including 2 patients withdrawing informed consent before the first dose of treatment for personal reasons and 2 patients who stopped treatment because of adverse events (AEs) with unclear relationship to the study medication early during the first cycle. Forty-eight patients received at least 1 dose of R-LEN and were included in the toxicity analysis. Fourteen patients (30%) had primary gastric and 70% (32/46) extragastric MALT lymphoma; 39% (18/46) presented with disseminated disease (Ann Arbor IIIE-IV). Roughly one-quarter of patients (11/46; 24%) had received prior systemic treatment(ie, chemo-/immunotherapy). For further details, see Table 1.

R-LEN showed an ORR of 80% (37/46; 95% confidence interval [CI], 69-92) with a median time to best response of 3.6 months (interquartile ratio, 2.8-5.8). A total of 25/46 (54%; 95% CI, 40-69) achieved CR, 12/46 (26%; 95% CI, 13-39) PR, and 8/46 (17%; 95%CI 6% to 28%) had SD. One patient with gastric MALT lymphoma showed PD at first restaging and was successfully salvaged with R-bendamustine (ongoing remission for 18+ months). The mean number of cycles was 6 (95% CI, 5.5-6.5), with 54% (25/46) receiving 6, 28% (13/46) receiving 8, and 17% (8/46) receiving 5 or fewer cycles. Remarkably, 2 patients given only 1 cycle because of AEs showed durable PR now ongoing for 15+ and 20+ months. Eleven patients (11/46; 24%) converted to a better response between the first and second restagings, and an additional 3 (3/46; 7%) further improved from cycle 6 to 8. Two patients with initial SD and PR as best response had PD at final restaging after cycle 8.

Univariate analysis (Fisher exact test) revealed no significant differences for response according to gender, localization, dissemination status, and prior treatment. There was a trend toward a worse response in patients with elevated lactate dehydrogenase (LDH) at baseline (P = .079) and none of the patients with elevated LDH achieved CR. After a median follow-up of 27.0 months (range, 13.2-36.3), 3 patients have relapsed (5.0-8.8 months after response), suggesting durable responses in the majority of cases (91% progression-free survival at 27 months).

Tolerability in terms of nonhematologic AEs was good with no toxicity grade 4 reported. A total of 38% (18/48) of patients experienced mild infusion reactions following R. Common adverse reactions to LEN consisted of mild musculoskeletal pain in 42% (grade 1/2 = 18/48, 3 = 2/48), mild fatigue in 33% (1/2 = 16/48), cough/respiratory infections in 33% (1/2 = 13/48, 3 = 3/48), diarrhea in 23% (1/2 = 10/48, 3 = 1/48), and mild vertigo in 23% (1/2 = 9/48, 3 = 2/48). LEN-associated exanthema occurred in 46% of patients, but was usually mild (1/2 = 19/48, 3 = 3/48). Hematologic AEs were rare with a rate of grade 3/4 neutropenia below 20% (18.8%; 9/48). See Table 2 for hematologic AEs.

To the best of our knowledge, this is the first study to explicitly address the activity of R- LEN in MALT lymphoma. Although a large, pivotal, phase 2 trial on indolent lymphoma had included 27 patients with marginal zone lymphoma, no subgroup analysis for extranodal origin was performed.⁹  The response rate achieved with an identical regimen used also for this study was 89%, with a reported median progression-free survival of 54 months (95% CI, 51-not available). In our trial, an ORR of 80%, a CRR of 54%, and a disease control rate of 97% were obtained, suggesting R-LEN may be superior to LEN monotherapy.¹⁰  Although the collective consisted of both gastric and extragastric patients with varying pretreatment status, the current trial still allows some hypothesis generation for R-LEN in MALT lymphoma. A total of 24% of our patients were pretreated with (immuno-)chemotherapy, including 9 (20%) with R-containing regimens and 9 (20%) with more than 1 prior treatment line. R-LEN was equally effective for pretreated vs nontreated patients in terms of response. This is particularly interesting because both large recent trials on systemic treatment of MALT lymphoma—the randomized International Extranodal Lymphoma Study Group-19 study on chlorambucil ± R and the R-bendamustine trial of the Grupo Español de Linfomas/Trasplante de Médula Ósea group—had excluded patients with prior systemic treatment.^2,3  Consequently, R-LEN appears to be an attractive and reasonable treatment approach in this specific setting.

Time to response with R-LEN (3.6; interquartile ratio, 2.8-5.8 months) and the total duration of treatment were longer than published for R-bendamustine.³  This might be based on the immunomodulatory effects of LEN influencing the tumor microenvironment in contrast to direct effects of cytostatic agents.^12-15  In addition, late remissions appear to be a common phenomenon in patients treated with immunomodulatory drugs for MALT lymphoma and long-term effects of R-LEN might still be underestimated in the current analysis.¹⁶ 

In conclusion, the data generated in the AGMT MALT-2 trial suggest R-LEN to be feasible, safe, and active for treating patients with MALT lymphoma irrespective of primary localization and pretreatment.