Letters to Blood To the editor: A phase 2 study of rituximab plus lenalidomide for mucosa-associated lymphoid tissue lymphoma Barbara Kiesewetter, 1 Ella Willenbacher, 2 Wolfgang Willenbacher, 2 Alexander Egle, 3,4 Peter Neumeister, 5 Daniela Voskova, 6 Marius Erik Mayerhoefer, 7 Ingrid Simonitsch-Klupp, 8 Thomas Melchardt, 3,4 Richard Greil, 3,4 and Markus Raderer, 1 for the AGMT Investigators 1 Clinical Division of Oncology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria; 2 Department of Internal Medicine V, Hematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria; 3 IIIrd Medical Department with Hematology, Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, Austria; 4 Salzburg Cancer Research Institute, Salzburg, Austria; 5 Clinical Division of Hematology, Department of Medicine, Medical University of Graz, Graz, Austria; 6 Center for Hematology and Medical Oncology, Department of Internal Medicine III, Allgemeines Krankenhaus Linz, Linz, Austria; and 7 Department of Radiology and 8 Department of Clinical Pathology, Medical University Vienna, Vienna, Austria 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) 6 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 Medikament¨ ose 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/mL, platelet count $60 3 10 9 /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/m 2 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/mL and platelet count $50 3 10 9 /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 inter- val [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 181 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 151 and 201 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, dissemina- tion status, and prior treatment. There was a trend toward a worse response in patients with elevated lactate dehydrogenase (LDH) at baseline (P 5 .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 BLOOD, 19 JANUARY 2017 x VOLUME 129, NUMBER 3 383 Downloaded from http://ashpublications.org/blood/article-pdf/129/3/383/1401069/blood720599.pdf by guest on 21 June 2022