Lenalidomide/Rituximab Maintains Durable Responses at 9 Years in MCL

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The combination of lenalidomide (Revlimid) plus rituximab (Rituxan) continues to show prolonged and durable responses along with manageable safety when given as initial induction therapy to patients with mantle cell lymphoma (MCL), according to long-term data from a multicenter, phase 2 study (NCT01472562).¹

According to 9-year follow-up results of the study, lenalidomide plus rituximab as induction and maintenance until progression, with optional discontinuation after 3 years showed the progression-free survival (PFS) rate to be 51% (95% CI, 31.5-68.0) and the overall survival (OS) rate to be 66% (95% CI, 47.3-79.2), respectively.

For safety, hematologic adverse events (AEs) observed during maintenance were asymptomatic grade 3 or 4 cytopenia, including neutropenia (42%), thrombocytopenia (5%), and anemia (3%). Mostly grade 1 to 2 infections including upper respiratory infections (50%), urinary tract infections (21%), sinusitis (16%), cellulitis (16%), and pneumonia (13%) were managed in the outpatient setting. Five percent of these infections required hospitalization.

"The lenalidomide and rituximab regimen is the first treatment of its kind free of conventional chemotherapy for patients with mantle cell lymphoma, heralding a new era of targeted therapy in first-line setting," Samuel Yamshon, MD, assistant professor of medicine, Bone Marrow Transplant and Cellular Therapy Program, Lymphoma Program at Weill Cornell Medicine, told Targeted Oncology^TM. "We've learned that the biologic combination is highly effective when given as induction and maintenance. With the extended 9-year follow up, we've also demonstrated that remissions are durable with over half of the study patients free of disease progression 9 years out, which is remarkable."

Currently, chemoimmunotherapy is the current standard of care for initial treatment of MCL. However, new data suggests that a chemotherapy-free approach may have potential in this patient population. This idea was further studied in a phase 2 trial.

Enrollment in the study was open to patients with measurable, histologically confirmed, untreated MCL who had a low- to intermediate-risk MCL International Prognostic Index (MIPI) score or high-risk MIPI score with contraindications to chemotherapy, an ECOG performance status score ≤ 2, and creatinine clearance ≥ 30 mL/min.²

During the induction phase, patients were treated with lenalidomide 20 mg daily for the first 21 days of a 28-day cycle for 12 cycles, with dose escalation to 25 mg daily after the first cycle as tolerated. For the maintenance phase, the dose of lenalidomide was reduced to 15 mg daily. Patients with creatinine clearance between 30 and 60 mL/min had their dose of lenalidomide adjusted to 10 mg daily for induction and 5 mg daily for maintenance. Further, rituximab was given to patients at a dose of 375 mg/m2 weekly during the 4 weeks of cycle 1, then once every other cycle, including during maintenance.

Patients continued to receive treatment until progression of disease, development of unacceptable AEs, or voluntary withdrawal from study. Further, patients were able to stop treatment after 3 years if they were in clinical remission based on computed tomography.

Between July 2011 and April 20124, 38 patients with untreated MCL requiring therapy were enrolled at 4 centers. The median age among patients was 65 years (range, 42-86 years). Patients mostly had advanced stage disease, and MIPI scores were evenly distributed between low-, intermediate-, and high-risk. A total of 87% of patients had evaluable Ki67 markers, 21% had Ki67 of >30%, and none had pleomorphic or blastoid histology.¹

Among the 36 patients evaluable for response, 33 completed the induction phase of therapy and started maintenance therapy with lenalidomide and rituximab. Fifteen patients had progression of disease, including 3 during induction therapy with primary refractory disease, and 12 during maintenance after initial response. Six of the patients who progressed during maintenance had initial complete responses (CRs) with PFS of 18, 38, 39, 49, 72, and 85 months, respectively, and another 6 patients had initial partial responses with progression at 14, 25, 28, 43, 44, and 92 months, respectively.

Previous data from the trial revealed that the overall response rate was 92% among the evaluable patients included in the study, and 64% achieved a CRcomplete response (CR). With a median follow-up of 103 months, 17 of 36 evaluable patients (47%) are still in remission.

During maintenance, 12 patients in CR discontinued study treatment and durable remissions were maintained in 10 patients. Though MIPI scores did not correlate with either response or PFS, high-risk MIPI scores were associated with a less favorable OS (P =.03). Further, Ki67 > 30% did not have an impact on either PFS or OS, which was consistent with prior data.

Grade 1 and 2 neuropathy was developed by more patients during maintenance therapy (29%) vs during induction therapy (8%), and 21% of patients developed secondary malignancies, including invasive malignancies (5%). Moreover, 2 patients discontinued treatment permanently due to immunosuppression concerns during the COVID-19 pandemic.

"According to the senior author of the study, Jia Ruan, MD, the lenalidomide and rituximab regimen is listed in the National Comprehensive Cancer Network MCL practice guideline as an initial treatment option for patients ineligible for intensive regimens. The combination is given as a convenient outpatient regimen available in the community, with lenalidomide administered daily every 3 weeks out of a 4-week treatment cycle, and rituximab administered weekly for 4 weeks during cycle 1, and then once every other cycle. Patients take thromboprophylaxis such as aspirin. The most common [adverse] effects include asymptomatic cytopenia and some GI symptoms, which can be managed by dose adjustment of lenalidomide," added Yamshon.

REFERENCES:

1. Yamshon S, Chen GZ, Gribbin C, et al. Nine-year follow-up of lenalidomide plus rituximab as initial treatment for mantle cell lymphoma. Blood Adv. 2023;7(21):6579-6588. doi:10.1182/bloodadvances.2023010606

2. Lenalidomide plus rituxan for untreated mantle cell lymphoma. ClinicalTrials.gov. Updated September 7, 2023. Accessed November 16, 2023. https://tinyurl.com/38a8s8kx