Final Results of a Phase I/II Trial of the Combination Bendamustine and Rituximab With Temsirolimus (BeRT) in Relapsed Mantle Cell Lymphoma and Follicular Lymphoma

Abstract

In this phase I/II study, we explored the combination of Temsirolimus with Bendamustine and Rituximab (BeRT) in patients with relapsed or refractory (r/r) follicular lymphoma (FL) or mantle cell lymphoma (MCL). Patients with 1 to 3 previous therapies received Bendamustine (90 mg/m2, day 1 + 2) and Rituximab (375 mg/m2, day 1) with Temsirolimus in doses from 25 to 75 mg in phase I and 50 mg Temsirolimus in phase II, added on day 1, 8, 15 of a 28 days cycle. The primary endpoint of the phase II was ORR at the end of treatment. Overall, 39 (29 MCL, 10 FL) patients were included. Median age was 71 years and median pretreatment number was 2. Grade 3/4 non-hematologic adverse events were rare and included hyperglycemia in 3 patients (7%) and angioedema in 2 patients (5%). Infectious complications grade 3/4 were observed in 9 patients (23%). Hematologic grade 3/4 events included leukopenia in 22 (56%), neutropenia in 18 (46%), lymphopenia in 16 (41%) and thrombocytopenia in 14 patients (36%). An objective response (best response) was observed in 33/39 patients (89%; 24 MCL (89%) and 9 FL (90%)), including 14 CR (38%; 12 MCL (36%) and 2 FL (20%)). Median PFS is 1.5y for MCL and 1.82 years for FL, and median OS has not been reached for either entity. This data demonstrates promising efficacy of Temsirolimus in r/r MCL and FL with acceptable toxicity. The BeRT regimen may be used as a treatment option for both entities.

Mantle cell lymphoma – advances in molecular biology, prognostication and treatment approaches

“…Several targeted therapy approaches have been investigated in different studies as single agents or in combination with immunochemotherapies or other targeted therapies (Table III). 29,31,32,[88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104] Targeting the BCR pathway with the BTK inhibitor ibrutinib resulted in remarkable response rates leading to its approval in relapsed MCL. In a large international phase II study, response rates of 68% were achieved with ibrutinib in patients with relapsed disease.…”

“…91 Convincing response rates have also been observed in combination with BR. 92 Immunotherapies. Immunotherapy approaches have already been integrated in treatment algorithms of MCL.…”

Follicular Lymphoma Microenvironment: An Intricate Network Ready for Therapeutic Intervention

“…In recent years, several phase I and II clinical trials have been engaged to evaluate the use of temsirolimus or everolimus as single agents [ 56 ] and in combination with other drugs. Among these combinations, we highlight temsirolimus with bendamustine and rituximab, achieving an ORR of 90% [ 57 ] and with the proteasome inhibitor, bortezomib, resulting in an ORR of 56% [ 58 ] ( Table 1 ).…”

Combined treatment with crizotinib and temsirolimus is an effective strategy in mantle cell lymphoma and can overcome acquired resistance to temsirolimus

“…13 Despite favorable initial response rates, early relapses and disease progression limit the clinical value of temsirolimus as a single agent. 14 Resistance to targeted therapies occurs often and remains a general problem in targeted cancer treatment. Acquired resistance is based on therapy-induced clonal evolution of pre-existing resistant variants in the original cancer cells or by acquisition of new mutations or adaptations.…”

“…Based on these findings, temsirolimus, a rapamycin derivate targeting mTOR, was approved in 2009 for the treatment of relapsed and refractory (r/r) MCL after failure of first line therapy 13 . Despite favorable initial response rates, early relapses and disease progression limit the clinical value of temsirolimus as a single agent 14 . Resistance to targeted therapies occurs often and remains a general problem in targeted cancer treatment.…”