Lenalidomide Combo Shows Promise as Frontline Treatment in Follicular Lymphoma

Herve Tilly, MD

Herve Tilly, MD

The immunomodulating agent lenalidomide (Revlimid) induced a complete response (CR) in 74% of patients with high tumor burden follicular lymphoma when used in combination with rituximab and a 4-drug chemotherapy regimen, according to a study published inThe Lancet Haematology. Although this result failed to meet the primary endpoint for the phase II trial, the investigators commented that the rate of CRs was comparable with rates seen in large trials of similar patient populations.

When lenalidomide was added to the standard frontline immunochemotherapy regimen of rituximab (Rituxan) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), it showed promising efficacy and safety in several phase I and II studies in B-cell lymphomas prompting the phase II study in patients with untreated, high tumor burden follicular lymphoma.

“In line with previous trials, our study suggests that the combination of lenalidomide and R-CHOP [R2-CHOP] has an acceptable safety profile,” the trial investigators, led by Hervé Tilly, MD, wrote. “Our results suggest it could help improve response and progression-free survival [PFS].”

The phase II, single-arm, multicenter study examined treatment-naïve patients with CD20-positive follicular lymphoma with a median age of 57 years (range, 49-65). Participants were eligible if they had an Eastern Cooperative Oncology Group performance status of ≤2; a World Health Organization Classification of 1, 2, or 3a; a minimum life expectancy of >3 months; and at least 1 measure of high tumor burden, based upon the Groupe d’Etude des Lymphomes Folliculares criteria.

The total treatment schedule was 24 weeks comprised of six 3-week cycles of induction R2-CHOP followed by 2 infusions of rituximab at 3-week intervals. Patients received oral lenalidomide and intravenous rituximab on days 1 to 14; intravenous doxorubicin, cyclophosphamide, and vincristine on day 1; and oral prednisone on days 1 to 5 of each 3-week cycle. Additionally, pegfilgrastim was administered subcutaneously on day 4 of each cycle and a 100-mg aspirin was given daily during the induction cycle as prophylaxis for thrombosis.

The primary endpoint of the trial was the proportion of patients achieving a CR, which included those with unconfirmed CRs, according to the International Workshop to Standardize Response Criteria. Secondary endpoints included overall response rate, PFS, overall survival (OS), and safety.

Out of 80 patients enrolled, 68 (85%) completed all 6 cycles of R2-CHOP. Seventy-five patients (94%; 95% CI, 86%-98%) had an objective response, including 59 with CRs and 16 (20%) with partial responses (PRs).

The PFS rate at 3 years was 79% (95% CI, 68%-87%) and the OS rate was 95% (95% CI, 87%-98%). In an exploratory post-hoc analysis, the 3-year PFS rate was 86% (95% CI, 74%-93%) in patients who achieved a CR at the end of the induction phase and 69% (95% CI, 40%-86%) in those who achieved a PR.

Another analysis compared the 3-year PFS of patients in the low- and intermediate-risk group (96%; 95% CI, 77%-100%) with that of patients considered to be high-risk (70%; 95% CI, 55%-80%). Risk was assessed in accordance with the Follicular Lymphoma International Prognostic Index (FLIPI) with low- and intermediate risk patients having a FLIPI score of 0 to 2 and high-risk patients having a FLIPI score of 3 to 5.

There were 3 patients who converted to a CR during maintenance after initially achieving a PR in the induction phase. Sixty-nine percent of patients sustained a CR at 30 months from study entry.

The toxicity profile was similar to that observed from standard R-CHOP. Hematologic adverse events (AEs) were the most common, with grade 4 neutropenia occurring most frequently in 65% of patients. Other grade 4 hematologic AEs included leucopenia (27%), thrombocytopenia (13%), and febrile neutropenia (1%). Grade 1/2 anemia was also observed in 88% of patients. Ninety-two percent of patients received pegfilgrastim according to the protocol.

Most frequent nonhematologic grade 1/2 AEs included peripheral neuropathy (35%), transient rash (34%), liver function abnormalities (34%), and pulmonary events (13%). No grade 3/4 nonhematologic AEs occurred in >5% of the study population.

Four patients died during the study period, but no deaths were determined to be related to treatment with R2-CHOP.

“It would be of further interest to compare R2-CHOP and R-CHOP in a head-to-head trial, and to explore the possibility of lenalidomide and rituximab as maintenance treatment in patients who respond to R2-CHOP,” the investigators concluded.

Reference:

Tilly H, Morschhauser F, Casasnovas O, et al; Lymphoma Study Association. Lenalidomide in combination with R-CHOP (R2-CHOP) as first-line treatment of patients with high tumour burden follicular lymphoma: a single-arm, open-label, phase 2 study.Lancet Haematol.2018;5:e403-410. thelancet.com/journals/lanhae/article/PIIS2352-3026(18)30131-5/fulltext.