Lenalidomide In Combination With R-ESHAP (LR-ESHAP) In Patients With Relapsed Or Refractory Diffuse Large B-Cell Lymphoma Candidates To Autologous Stem-Cell Transplantation: A Phase 1b Study From Spanish Group Geltamo

Diffuse large B-cell lymphoma (DLBCL) patients with relapsed or refractory disease after rituximab-containing first-line therapy have a poor outcome with the current salvage regimens. Consequently, new drugs designed to increase the response rate of salvage regimens should be explored (Gisselbrecht et al, J Clin Oncol 2010, 28: 4184-90). We conducted a phase Ib trial (3+3 design) to establish the safety, tolerability and determination of the maximum-tolerated dose (MTD) of lenalidomide in combination with R-ESHAP (LR-ESHAP) in patients with relapsed or refractory DLBCL. Efficacy data were also collected as secondary objective.

Eligible patients must be refractory to, or have relapsed following, first-line treatment with rituximab in combination with an anthracycline-containing regimen, and be eligible for autologous stem-cell transplantation (ASCT). Subjects received three cycles of lenalidomide (5, 10 or 15 mg) given on days 1 to 14 of every 21-day cycle, in combination with R-ESHAP salvage chemotherapy at standard doses (rituximab 375 mg/m² day 1, etoposide 40 mg/m² days 1-4, cisplatine 25 mg/m² days 1-4; citarabine 2000 mg/m² day 5, and methilprednisolone 500 mg days 1-5). Responding patients received BEAM followed by ASCT.

During the escalating phase, 3 patients had dose-limiting toxicity in the 15 mg cohort: 1 grade 3 angioedema, and 2 mobilization failures. The MTD was therefore established at 10 mg of lenalidomide and this cohort was expanded to further explore the safety and efficacy of LR-ESHAP. A total of 20 patients (3, 13, and 4 in the 5, 10, and 15 mg lenalidomide cohorts, respectively) were enrolled (18 with DLBCL-NOS, and 2 with Burkitt-like lymphoma): 60% male, median age 58 (23–70) years. First-line treatment consisted of R-CHOP or similar in 18 patients and Burkitt’s lymphoma protocols in 2. Disease status at LR-ESHAP was: primary refractory disease in 13 patients (partial response [PR], n=7; and<PR, n=6), and relapsed disease in 7 (3 early and 4 late relapses). IPI was 0-1 in 35%, 2-3 in 40%, and 4-5 in 25%. To date, 16 serious adverse events (SAEs) have been reported, including 5 episodes of febrile neutropenia, 2 pneumonia, 2 sepsis, 1 ionic imbalance, 1 renal toxicity, 1 facial angioedema, 2 thrombosis, and 1 hepatic toxicity, all of them recovered, and there were no treatment-related deaths. Seventeen patients (85%) completed the planned three cycles of treatment (3 without lenalidomide in the third cycle due to significant toxicity) and 1 patient two cycles (due to persistent neutropenia and thrombocytopenia after the second cycle). Two patients discontinued treatment during the first cycle (1 due to angioedema and 1 due to hepatic toxicity). Of the 18 patients with at least one post-baseline tumor assessment, the overall response rate to LR-ESHAP was 77.8% (44.4% complete remission). All 18 patients were successfully mobilized after one (13 patients) or two (5 patients) mobilization procedures, and 14 (70% of the overall series) underwent ASCT according to protocol. Reasons for not performing the transplant were: early progression of lymphoma (n=4), clinical trial discontinuation due to toxicity (n=2). At the time of this analysis, 8 patients had disease progression and 5 patients have died (all of them from lymphoma). With a median follow-up of 7.4 (2.9 to 27.6) months, the estimated 1-year progression-free survival and overall survival were 52% and 72%, respectively.

LR-ESHAP shows an acceptable safety profile and encouraging activity in rituximab-pretreated relapsed or refractory DLBCL patients. Further investigation with this regimen is warranted.

No relevant conflicts of interest to declare.