Rituximab-CHOP21 Plus Lenalidomide (LR-CHOP21) Is Effective and Feasible in Elderly Untreated Diffuse Large B-Cell Lymphoma (DLBCL): Results of Phase II REAL07 Study of the Fondazione Italiana Linfomi (FIL)

R-CHOP21 is the standard treatment for untreated elderly DLBCL, however up to 40% of patients fail. There is a need to improve the efficacy of R-CHOP21; an option may be the addition of novel drugs in first line induction therapy. Lenalidomide has a complex mechanism of action as immunemodulation, antiangiogenesis, restoration of immunesynapses and direct antitumor effects. Lenalidomide monotherapy exhibits significant activity in patients with relapsed aggressive B-cell NHL and has in vitro synergy with rituximab and cytotoxic therapy. This rationale prompted FIL to conduct a prospective multicenter dose finding phase I-II trial aimed at evaluating toxicity and activity of lenalidomide plus R-CHOP21 (LR-CHOP21) in elderly untreated DLBCL (NCT00907348). In the dose-finding phase I study, 21 patients were enrolled, and 15 mg lenalidomide from day 1 to day 14 was identified as the maximum tolerated dose (MTD) in combination with R-CHOP21 (Vitolo, Ann Oncol 2011;22(4):331a). Patients and Methods. Based on the phase I results, 15 mg of lenalidomide in combination to R-CHOP21 was tested in a phase II study. Phase II was designed according to Simon's two stage design; primary endpoint was an improvement of overall response rate (ORR) of 15% in LR-CHOP21 compared to 70% of standard R-CHOP21 and the study would be considered of interest if at least 16/23 in step 1 and 39/49 in step 2 responses occurred. Response was evaluated according to 2007 Cheson criteria. PET scan was mandatory at the end of the treatment; patients in partial remission (PR) who underwent radiotherapy were considered as failure in progression free survival (PFS) analysis. Inclusion criteria were: age 60–80 FIT at the comprehensive geriatric assessment; untreated CD20+ DLBCL; Ann Arbor stage II/III/IV; IPI at LI/IH/H risk. Treatment plan was: R-CHOP21 plus 15 mg lenalidomide from day 1 to 14 for 6 courses. Mandatory supportive care included: GCSF or PegGCSF, cotrimoxazole as Pneumocystis Jiroveci prophylaxis and low molecular weight heparin or low dose aspirin as deep venous thrombosis prophylaxis. Results. From April 2010 to May 2011, 49 patients were enrolled in the phase II study including 9 patients treated at the MTD during phase I. Clinical characteristics were: median age 69 years (range 61–80); stage III/IV 43 (88%), performance status >1 31 (63%), IPI IH/H 30 (61%). The step-1 of the trial showed an ORR of 22/23. At the end of 6 LR-CHOP21, ORR was 45/49 (92%). Complete remissions (CR) were 42 (86%) and PR 3 (6%); 3 patients (6%) did not respond and one (2%) died for violent death. At a median follow-up of 18 months, overall survival (OS) was 94% (95% CI: 82–98) and PFS was 75% (95% CI: 57–86). (Figure 1). Of the 294 planned courses of LR-CHOP21, 277 (94%) were administered, of which 221 (75%) with lenalidomide as planned, 40 (14%) with dose and/or day reduction and 16 (5%) without lenalidomide. Median dose of lenalidomide delivered in 49 patients was 1185 mg (IQR 900–1260), i.e. 94% of the planned dose (1260 mg). The most frequent cause of lenalidomide reduction or withdrawal was neutropenia. At least 90% of the planned dose of doxorubicine, cyclophosphamide and vincristine were administered, in: 91%, 95% and 83% of the R-CHOP21 courses, respectively. Median interval time between R-CHOP21 courses was 21 days (range 19–48). Hematological toxicity was mild: grade III/IV thrombocytopenia occurred in 13% of courses, anemia in 5% and neutropenia in 33%, with only 4% of febrile neutropenia. No grade IV extra-hematological toxicities were observed. Grade III non-hematological toxicities were reported in 7 patients: cardiologic, gastroenteric and renal in one patient respectively, grade III neurological toxicities, sensory and motorial neuropathy in two, thromboembolic event in one not receiving anti-thrombotic prophylaxis, and skin rash in one. No toxic deaths occurred during treatment. One patient died three months off therapy while in CR, due to aeromonas hydrophila sepsis and multi-organ failure. Conclusions. The addition of 15 mg lenalidomide on days 1–14 to R-CHOP21 is safe, feasible and effective in elderly untreated DLBCL. The primary objective of the phase II study was met, with 92% of ORR of which 86% CR and promising PFS rates. The addition of lenalidomide did not impair the administration of R-CHOP21. Based on these data, the efficacy of LR-CHOP21 needs to be investigated in a large phase III randomized trial in elderly DLBCL.

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Off Label Use: Trial partially supported by a research grant by Celgene. Lenalidomide was provided free by Celgene. The use of Lenalidomide is off-label in untreated DLBCL. Dreyling:Roche: Membership on an entity's Board of Directors or advisory committees. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees.