Temsirolimus in Combination with Bendamustine and Rituximab (BeRT) for the Treatment of Relapsed Mantle Cell and Follicular Lymphoma: Final Phase I/II Results
Authors: Hess Georg , Karola Wagner , LaRosee Paul , Keller Ulrich , Atta Johannes , Witzens-Harig Mathias , Crombé Anne , Medler Christoph , Borchmann Peter , Bitz Ulrich , Lerchenmüller Christian , Theobald Matthias , Dreyling Martin H. 
Published: October 2019

Abstract
Background: mTOR inhibition has been shown to be effective in various subtypes of malignant lymphomas (Smith et al, JCO 2010). Furthermore, in relapsed MCL a phase III trial demonstrated superiority of Temsirolimus to chemotherapy. Although novel treatment options as Ibrutinib have changed the treatment landscape for MCL, no curative potential could be shown for this approach and novel concepts continue to be needed. Several trials provided promising results when Temsirolimus is combined with agents like Rituximab (Ansell et al, Lancet Oncology 2011) or chemoimmunotherapy, as shown in part I (phase I) of the reported trial (Hess, Leukemia, 2015). We now report the final analysis of phase I and II results.
Methods: This is a multicenter, national, prospective trial. Inclusion criteria: Patients were eligible with histologically proven FL or MCL, 1-3 prior treatment lines, no curative option available, no refractoriness to Bendamustine, measurable disease, ECOG < 3, sufficient bone marrow reserve, no severe concomitant diseases and given informed consent. Treatment consisted of Bendamustine 90mg/m² day 1-2, Rituximab 375mg/m² day 1 and Temsirolimus 50 mg day 2, 8, 15 of a 28d cycle. A total of 4 cycles was planned with interim staging after 2 cycles.
Results: Overall, 39 patients (pts) have been included (15 pts phase I, 24pts phase II): median age was 71 years, with 29 MCL and 10 FL, and a median number of 2 pretreatments (1-3). Overall the treatment was well tolerated, and toxicity was predominantly hematologic. In 133 evaluable cycles of chemotherapy the following hematologic grade 3 / 4 toxicities were noted: leukopenia (17pts, 45%), lymphopenia (14 pts, 37%), neutropenia (12 pts, 32%), and thrombocytopenia (10 pts, 27%). Non-hematologic grade 3 / 4 side effects observed in at least two patients were angioedema, hyperglycaemia and stomatitis. AE's of special interest: pulmonary: rate of cough (4; 10%) and pneumonitis (1; 3%); gastrointestinal: diarrhea (11; 28%), nausea (19, 49%); general: fatigue (18; 46%), mucositis (17, 44%); bleeding: epistaxis (5; 13%), which all were predominantly grade 1 or 2. Response: currently, best responses were 13 CR (38%), 18 PR (53%) and 3 SD (9%) in 34 patients evaluable so far. Updated results will be presented at the meeting. Overall responses were 92% in MCL (11 CR, 11 PR, 2 SD) and 90% in FL (2 CR, 7 PR, 1 SD). After a median follow up of 24 months (mean: 26 months) median PFS is 22 months for the entire cohort, with 33 months for MCL and 22 months in FL. Median OS has not been reached for FL and is 3,55 years (95% CI: 2,7-4,4) for MCL.
Summary: The BeRT-combination of 50mg Temsirolimus (day 1,8,15) in combination with Bendamustine and Rituximab is a safe and feasible regimen with substantial activity. As mTOR inhibitors display a noticeable side effect profile especially with long term use, combination with chemoimmunotherapy demonstrates a clinically meaningful balance between efficacy and tolerability, thereby widening the therapeutic portfolio.

Disclosures
Hess: Roche: Honoraria; Roche, CTI, Pfizer, Celgene: Research Funding; Janssen: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Pfizer: Honoraria. LaRosee:Pfizer: Honoraria. Keller:Spectrum Pharmaceutical: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Witzens-Harig:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.