Everolimus in combination with rituximab induces complete responses in heavily pretreated diffuse large B-cell lymphoma

Abstract

Diffuse large B-cell lymphoma is an aggressive non-Hodgkin's lymphoma without a standard therapy for patients who relapse after or are not eligible for salvage autologous stem cell transplantation. In vitro analysis of lymphoma cell lines has shown that everolimus can inhibit cell cycle progression in vitro and inhibitors of the mammalian target of rapamycin have already demonstrated single-agent activity in relapsed non-Hodgkin's lymphomas including diffuse large B-cell lymphoma, validating mammalian target of rapamycin as a viable therapeutic target. We performed an open label phase II study of everolimus, an inhibitor of mammalian target of rapamycin, in combination with rituximab to examine efficacy and tolerability in patients with relapsed/refractory diffuse large B-cell lymphoma. Eligible patients were treated with everolimus 10 mg by mouth once daily on days 1-28 of a 28-day cycle with rituximab administered weekly during cycle one and then on day one of subsequent cycles. Patients were treated for a total of 12 cycles or until disease progression. The primary end-point was objective response rate, with secondary end-points being toxicity, progression-free survival, duration of response, and overall survival. Twenty-six patients (24 evaluable) were enrolled and had an overall response rate of 38% [90% CI (21%-56%)] with three complete responses and six partial responses among these 24 patients. The median duration of response among responders was 8.1 months. At a median follow-up of 12 months, the overall survival rate was 37% [90% CI (20%-54%)]. The most common grade 3 to 4 toxicities were neutropenia, anemia, and thrombocytopenia. In conclusion, everolimus in combination with rituximab is well tolerated and demonstrates activity in relapsed diffuse large B-cell lymphoma. Further studies of this combination are warranted.

Trial registration: ClinicalTrials.gov NCT00869999.

Figures

Figure 1.

Kaplan-Meier curve of the duration of response for the nine responding patients.

Figure 2.

Progression-free (A) and overall survival (B) for the 24 evaluable patients.

Figure 3.

Outomes of the nine responders. Dark bars denote response duration on therapy to day 0, the first day off treatment. Clear bars then demonstrate progression-free survival after treatment. The three patients with ongoing remissions at last follow up are indicated with a ((x025B8)) symbol. The three patients with a compete response to everolimus are indicated with a (+) symbol. One patient received an allogeneic stem cell transplant, indicated by a (*) symbol, prior to starting everolimus and also received one donor lymphocyte infusion (#) during everolimus treatment and two additional donor lymphocyte infusions after completing everolimus.