Interim Analysis Of An Ongoing PHASE II Trial Assessing Safety and Efficacy Of Lenalidomide Maintenance In Patients With Chemosensitive Relapse Of Diffuse Large B-CELL Lymphoma (DLBCL)

Patients (pts) with relapsed DLBCL who can not be managed with consolidative autologous or allogeneic transplantation exhibit a poor prognosis. Despite a high response rate to induction chemo(immuno)therapy, these pts invariably experience early relapse and die of lymphoma progression. Single-drug maintenance may be a good alternative to intensified consolidation to prolong response duration in these pts. Lenalidomide is an oral immunomodulator, active against DLBCL, which can be taken for several years with an excellent safety profile. Accordingly, we designed a multicenter phase II trial addressing safety and efficacy of lenalidomide maintenance in pts with chemosensitive relapse of DLBCL who are not suitable for intensified consolidation or experienced a failure after autologous transplant (NCT00799513). Herein, we report the interim analysis on the first 17 enrolled pts.

Selection criteria were: 1) adult HIV-negative pts; 2) histologically-proven de novo or transformed DLBCL; 3) relapsed disease responsive (partial or complete response) to conventional salvage therapy; 4) ECOG PS ≤3; 5) time to progression from the previous line ≥3 months. Pts with CNS involvement, HBV-DNA or HCV-RNA positivity or active infections were excluded. After confirmation of objective response to salvage therapy, pts were registered and treated with lenalidomide 25 mg/day once daily for 21 days out of 28, for two years or until lymphoma failure or unacceptable toxicity. Primary endpoint was the 1-year PFS. With the null hypothesis (P0) of 1-year PFS of 30%, this study will consider a satisfactory efficacy of lenalidomide a P1 corresponding to a 1-yr PFS of 50%, 47 pts will be needed (α: 0,05; β: 80%).

17 pts were enrolled (median age 73, range 52-86; M:F ratio: 1.1). Eleven pts had a de novo DLBCL, 6 had a transformed DLBCL. Fifteen pts were enrolled after the first relapse, two pts after the 3^rd and 4^th relapse. All pts experienced a relapse after anthracycline- and rituximab-based chemotherapy, with a median time to progression after the previous line of 16 months (range 6-88). Only one patient was previously managed with autologous transplant. Most pts had unfavourable features: IPI ≥2 in 15 cases, advanced stage in 14, extranodal disease in 13, high LDH in 7. Two pts had bone marrow infiltration; one had HCV and HBc seropositivity. Salvage chemotherapy consisted of high-dose-cytarabine-based combinations in 12 pts, high-dose-ifosfamide-based regimens in 3 and anthracycline-based regimens in 2; all pts received rituximab as part of salvage therapy. Response to salvage therapy was complete in 12 pts and partial in 5.

Three pts completed the planned maintenance, treatment is ongoing in 4; 3 pts interrupted maintenance due to lymphoma relapse, treatment was interrupted due to toxicity in 7 pts (diarrhoea in 3, rash in 2, prolonged neutropenia, anorexia) after 3, 10, 14, 6, 8, 12, and 1 course, respectively. Eight pts needed a transient dose reduction to 10 or 15 mg/d due to rash (n=5), neutropenia (n=2) and neuropathy. There were 4 SAEs (febrile neutropenia and diarrhoea) in 3 pts. Grade 3-4 haematological toxicity consisted of neutropenia in 7 pts and thrombocytopenia in 2. Grade 3-4 non-haematological toxicity consisted of diarrhoea in 3 pts and rash in 5.

Four of the 5 pts in partial response after induction chemoimmunotherapy achieved a complete remission during maintenance. At the last delivered lenalidomide course, 14 (82%; 95%CI: 64-100%) pts were in complete remission, and 3 pts experienced progressive disease, with a median response duration of 26+ months. At a median follow-up of 23 months, 12 (71%) pts remained in complete remission, two responders experienced relapse (27 & 34 months). The 1-year (primary endpoint) PFS was 79% for the whole series. Pts who received at least six lenalidomide courses had a 2-year PFS of 90%. Dose reductions were non influential on PFS (1-year: 75% vs. 83%). All pts are alive (NED in 14).

Lenalidomide maintenance is feasible and well tolerated in pts with relapsed DLBCL. As expected, diarrhoea and rash remain frequent dose-limiting side effects in this elderly population. With obvious limitations, this interim analysis shows encouraging PFS figures, with long-lasting remission in most pts who received at least six lenalidomide courses. Accrual completion is warranted.

No relevant conflicts of interest to declare.