Initial Treatment with Lenalidomide Plus Rituximab for Mantle Cell Lymphoma: 5-Year Follow-up and Correlative Analysis from a Multi-Center Phase II Study

BACKGROUND: We previously reported early results of a multicenter phase 2 study of lenalidomide plus rituximab as initial treatment for MCL (NEJM 2015:373:1835), which was highly effective (ORR 92%, CR 64%) and well tolerated. Here we present outcomes with 5-year follow-up, as well as exploratory analysis of immunologic biomarkers and minimal residual disease measurement.

METHODS: The study includes both induction and maintenance. 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 weekly x 4 during cycle 1, then once every other cycle. Treatment was continuous until progression, with option to stop therapy after 3 years. Plasma samples were obtained at baseline, C2D1 and C4D1 to measure cytokines (IFN γ , IL10, IL12p70, IL12, IL1 β , IL2, IL4, IL6, IL8, TNF α) and chemokines (MCP1, MCP4, Eotaxin, IP10, MDC, Eotaxin3, TARC, MIP1 α , MIP1 β, IL8), using MesoScale Discovery V-plex assays. The cytokine/chemokine levels over time, and their associations with responses and treatment-emergent rash were analyzed with Wilcoxon signed-rank and rank-sum tests. MRD was assessed using ClonoSEQ^TM (Adaptive Biotechnologies, Seattle WA) on subjects with available paired pre-treatment tissue and post-induction PB samples.

RESULTS: 38 subjects requiring therapy were enrolled at 4 centers from 7/2011 to 4/2014. The median age was 65 and MIPI scores evenly distributed between low-, intermediate-, and high-risk. Median follow-up was 58 months with range of 36-70 months. Two patients were inevaluable - one withdrew consent, other was intolerant of tumor flare. Twenty-two (61%) of the evaluable 36 patients remain in remission, including 13 (36%) beyond 5 years. Nineteen patients remain on treatment and 3 opted to stop therapy after 3 years. Eleven patients had progression - 3 with primary refractory disease and 8 following initial responses (4 CRs with PFS of 18, 38, 39 and 49 months, 4 PRs with PFS at 14, 25, 28 and 43 months). Six evaluable patients died, 3 from progression, 3 from unrelated comorbidities. Median PFS and DOR have not been reached. The 3-yr and 4-yr PFS rates were estimated at 80.3% (95% CI = 63.0%, 90.1%) and 69.7% (95% CI = 50.6%, 82.6%), with 3-yr and 4-yr OS rates at 91.9% (95% CI = 76.9%, 97.3%) and 82.6% (95% CI = 65.3%, 91.9%). TEAEs during maintenance included asymptomatic grade 3-4 cytopenias (42% neutropenia, 5% thrombocytopenia, 3% anemia), and grade 1-2 infections (45% URI, 16% UTI, 13% sinusitis and 8% cellulitis), all managed in outpatient settings. Five patients required brief hospitalization for IV antibiotics: 1 (3%) developed neutropenic fever in setting of cholecystitis, 3 (8%) had pneumonia and 1 (3%) had recurrent UTI. Secondary malignancies included squamous-cell carcinoma in 2 subjects, basal-cell carcinoma in 1 subject, and melanoma in situ in 2 subjects. Merkel-cell carcinoma developed in an 86-year-old subject after 18 months of therapy, and pancreatic cancer was diagnosed in a 68-year-old patient after 12 months of therapy.

Compared to baseline, cytokine levels at C2D1 and C4D1 showed Th1/Th2 modulation, with significant increase in IFNγ (p=0.004 and p=0.007) and IL4 (p=0.004 and p=0.017), as well as significant decrease in IL2 (p=0.046 and p=0.032), IL10 (p=0.004 and p=0.007) and TNFα (p<0.0001 and p<0.0001). Chemokine levels showed uniform reduction in MCP1 (p<0.0001 and p=0.001), MDC (p<0.0001 and p<0.0001), MIP1α (p=0.007 and p=0.001) and MIP1β (p<0.0001 and p<0.0001), suggesting Th2 to Th1 switch. Responses at month 3 correlated with C4D1 higher levels of IL10 (p=0.04) and IL2 (p=0.05), both anti-tumor cytokines, and lower levels of MDC (p=0.04). TEAE of rash was significantly associated with increased IL2 levels at C2D1 (p=0.03) and C4D1 (p=0.01). One time MRD assay in 7 CR subjects with available samples who have completed at least 3-year study treatment showed MRD negativity in 6 out of 7 (86%) patients.

CONCLUSIONS: Lenalidomide and rituximab as initial treatment for MCL can achieve high rate of complete responses and MRD negativity with durable remissions beyond 4 years. The nature of toxicity was not significantly affected by continuous treatment, particularly in the context of close follow-up. Further evaluation of this active regimen in larger, randomized frontline trials is warranted (ClinicalTrials.gov - NCT01472562).