Lenalidomide Plus Rituximab Safe and Effective as Initial Treatment for MCL

Jia Ruan, MD, PhD

Lenalidomide (Revlimid) plus rituximab (Rituxan) is a feasible combination that is also safe and active, as initial and maintenance therapy for patients with mantle cell lymphoma (MCL), said Jia Ruan, MD, PhD, during her presentation at the 2017 ASH Annual Meeting and Exposition held Dec. 9-12 in Atlanta.

Patients treated with the agents saw a high rate of complete responses (CR) and patients were able to achieve minimal residual disease (MRD) negativity with durable remissions beyond 4 years.

“Prior studies of initial treatment of MCL have focused on the use of chemotherapy, which is generally not curative,” said Ruan, of Weill Cornell Medicine and New York Presbyterian Hospital in New York, New York.

Ruan, as well as researchers from Moffit Cancer Center, Tampa, Florida; Abramson Cancer Center, Philadelphia; and the University of Chicago, previously reported early results of a multicenter phase II study of lenalidomide plus rituximab as initial treatment for MCL, which showed an overall response rate of 92%, with 64% of patients who achieved CRs.

In this study, the researchers examined these outcomes with 5-year follow-up, exploratory analysis of immunologic biomarkers, and MRD measurement.

Thirty-eight patients requiring therapy were enrolled at 4 centers from July 2011 to April 2014; however, 2 were unable to be evaluated since one withdrew consent and the other was intolerant of tumor flare. The majority of patients were men (71%), with a median age of 65 years, and had stage III-IV disease. Mantle Cell Lymphoma International Prognostic Index (MIPI) scores were evenly distributed between low-, intermediate-, and high-risk. Median follow-up was 58 months, ranging from 36-70 months.

Lenalidomide was administered at 20 mg daily on days 1-21 of a 28-day cycle for 12 cycles during induction, followed by dose reduction to 15 mg during maintenance. Standard dose rituximab was administered 4 times weekly during cycle 1, then once every other cycle. Treatment continued until progression, with an option to stop therapy after 3 years. In total, 38 patients were included in the induction phase, with 33 patients who remained on maintenance therapy.

The researchers found that 22 (61%) of the 36 patients evaluated remain in remission, including 13 patients (36%) beyond 5 years. Nineteen patients remain on treatment, with 3 discontinuing therapy after 3 years. Eleven patients had progression—3 with primary refractory disease and 8 following initial responses.

Six patients died, 3 from progression and 3 from unrelated comorbidities, said Ruan. Median progression-free survival (PFS) and duration of response have not been reached.

The 3- and 4-year PFS rates were 80.3% (95% CI, 63.0-90.1) and 70.6% (95% CI, 50.6- 82.6). The 3- and 4-year overall survival rates were 91.9% (95% CI, 76.9-97.3) and 83.0% (95% CI, 65.3-91.9).

Adverse events (AEs) during maintenance were asymptomatic grade 3-4 cytopenias including neutropenia (42%), thrombocytopenia (5%), and anemia (3%). Grade 1-2 AEs included upper respiratory infection (45%), urinary tract infection (21%), sinusitis (13%), and cellulitis (11%), which were managed in outpatient settings.

Five patients required brief hospitalization for intravenous antibiotics: 1 (3%) developed febrile neutropenia, 3 (8%) had pneumonia and 1 (3%) had recurrent UTI.

“The severity and frequency of those AEs seems to be reduced during maintenance,” said Ruan. “For example, constitutional symptoms or inflammatory symptoms, which are prevalent during early phase induction, generally improve.”

Secondary malignancies were seen in 6 patients, including 2 who developed squamous-cell carcinoma, 2 melanoma in situ, and 1 basal-cell carcinoma. Merkel-cell carcinoma developed in an 86-year-old man after 18 months of therapy, and a 68-year-old man was diagnosed with pancreatic cancer after 12 months of therapy.

The researchers also looked at MRD status. They identified 10 patients who were treated for at least 3 years and found that 8 of them had MRD-negative remission.

Researchers also obtained plasma samples at baseline, including C2D1 and C4D1 to measure cytokines (IFNγ, IL10, IL12p70, IL12, IL1β, IL2, IL4, IL6, IL8, TNFα) and chemokines (MCP1, MCP4, Eotaxin, IP10, MDC, Eotaxin3, TARC, MIP1α, MIP1β, IL8), using MesoScale Discovery V-plex assays.

Compared to baseline, cytokine levels at C2D1 and C4D1 showed Th1/Th2 modulation, with significant increase in IFNγ (P = .004 and P = .007) and IL4 (P = .004 and P = .017), as well as significant decrease in IL2 (P = .046 and P = 0.032), IL10 (P = .004 and P = .007) and TNFα (P < .0001 and P < .0001).

Chemokine levels showed uniform reduction in MCP1 (P < .0001 and P = .001), MDC (P < .0001 and P < .0001), MIP1α (P = .007 and P = .001) and MIP1β (P < .0001 and P < 0.0001), suggesting Th2 to Th1 switch.

Responses at month 3 correlated with C4D1 higher levels of IL10 (P = .04) and IL2 (P = .05), both anti-tumor cytokines, and lower levels of MDC (P = .04). An AE of rash was significantly associated with increased IL2 levels at C2D1 (P = .03) and C4D1 (P = .01).

“We hope that further evaluation of this active regimen can be conducted in a larger, randomized frontline study,” said Ruan.

Ruan J, Martin P, Christos P, et al. Initial treatment with lenalidomide plus rituximab for mantle cell lymphoma: 5-year follow-up and correlative analysis from a multi-center phase II study. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 154.