Lenalidomide/Rituxumab Combo Maintains Durable Responses at 5 Years in MCL

Patients with mantle cell lymphoma who were treated with the combination of lenalidomide (Revlimid) and rituximab (Rituxan) continued to have durable responses and manageable side effects at 5 years of follow-up.

Jia Ruan, MD, PhD

Patients with mantle cell lymphoma (MCL) who were treated with the combination of lenalidomide (Revlimid) and rituximab (Rituxan) continued to have durable responses and manageable side effects at 5 years of follow-up.

In these updated results, recently published inBlood, the estimated overall survival (OS) at 64 months of follow-up was 77.4% (95% CI, 59.4-88.1). The estimated 5-year progression-free survival (PFS) was 63.9% (95% CI, 44.8-77.9). The median PFS and duration of response have not been reached.1

There were 23 complete responses (CR) and 10 partial responses (PR) in 33 evaluable patients. As of February 2018, 21 (58%) patients remain in durable remission beyond 3 years, including 5 who stopped treatment after 3 years. Response has lasted more than 6 years in 6 patients and more than 5 years in 10. Sixteen patients remain on study treatment, including 7 on the lenalidomide/rituximab (R2) doublet, 7 on rituximab alone, and 2 on lenalidomide alone.

“Our long-term data provide proof of concept that an outpatient-based induction and maintenance strategy free of conventional chemotherapy is effective, safe, and feasible as first-line therapy for MCL,” first author Jia Ruan, MD, PhD, and colleagues wrote. “The efficacy and survival outcome observed in our study compared favorably to those reported with lenalidomide either as single agent or in combination with rituximab in relapsed and refractory setting, lending support for prioritizing novel agents such as lenalidomide early in the treatment sequence, to compare to conventional chemotherapy-based approach.”

Ruan, an associate professor of Clinical Medicine in the division of Hematology and Medical Oncology at Weill Cornell Medicine, previously presented data from this phase II study at the 2017 ASH Annual meeting. The overall response rate was 92%. 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 OS rates were 91.9% (95% CI, 76.9-97.3) and 83.0% (95% CI, 65.3-91.9).2

A total of 38 patients enrolled at 4 centers from July 2011 to April 2014. Eligible patients had histologically confirmed untreated mantle cell lymphoma with measurable disease; low to intermediate mantle cell lymphoma international prognostic index (MIPI) or high MIPI with contraindications to chemotherapy; Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2; and creatinine clearance ≥30 mL/min.

Most patients were men (71%) and all had stage III-IV disease. The median age was 65 years (range, 42-86). Mantle Cell Lymphoma International Prognostic Index (MIPI) scores were evenly distributed between low-, intermediate-, and high-risk patients.

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.

Investigators identified tumor clonotypes in 10 of 11 patients with available diagnostic tissue who were in remission during maintenance. They analyzed 1-time minimal residual disease (MRD) levels in peripheral blood samples collected at a median follow-up of 46 months (range, 42-62).

Three of 10 remained on R2maintenance at the time of peripheral blood sampling while 5 were on rituximab maintenance alone. Two patients had discontinued all treatment, 1 for 3 months and the other for 10 months. Of the 9 patients evaluated for MRD who had CR, 8 had levels below the detection threshold of 10-6, including the 2 off therapy.

Investigators found no new safety signals from the 2017 results, and toxicity was generally mild. A total of 12 patients had progression; 9 during maintenance therapy following initial response and 3 during induction for primary refractory disease. Four patients who had progression initially had CR and 5 had PR. Three evaluable patients died from lymphoma progression and 3 died from unrelated comorbidities.

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 (UTI; 21%), sinusitis (13%), and cellulitis (11%), which were managed in outpatient settings.

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

References:

  1. Ruan J, Martin P, Christos P, et al. Five-year follow-up of lenalidomide plus rituximab as initial treatment for mantle cell lymphoma [published online September 4, 2018].Blood. doi: 10.1182/blood-2018-07-859769.
  2. 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.

“Primary hematologic toxicity was asymptomatic myelosuppression, which was managed with dose modifications,” Ruan et al wrote. “Neutropenic fever was rare, and there were no treatment-induced toxic deaths. Non-hematologic adverse effects included an inflammatory syndrome with cutaneous rash and tumor flares at the initiation of induction therapy, which resolved with supportive care.”