Initial induction therapy with the immunomodulatory agent lenalidomide plus the anti-CD20 monoclonal antibody rituximab led to prolonged, durable responses with a manageable safety profile in patients with previously untreated mantle cell lymphoma.
Initial induction therapy with the immunomodulatory agent lenalidomide (Revlimid) plus the anti-CD20 monoclonal antibody rituximab (Rituxan) led to prolonged, durable responses with a manageable safety profile in patients with previously untreated mantle cell lymphoma (MCL), according to findings from the 9-year follow-up of a phase 2 trial (NCT01472562) published in Blood Advances.1
At a median follow-up of 103 months, findings from the final analysis of the study demonstrated that response-evaluable patients who received the combination of lenalidomide and rituximab (n = 36) achieved a median progression-free survival (PFS) of 9 years with 17 ongoing responses, including responses extending beyond 6 (n = 17), 7 (n = 15), 8 (n = 11), and 9 years (n = 6). The estimated 7- and 9-year PFS rates were 61% (95% CI, 41.8%-75.2%) and 51% (95% CI, 31.5%-68.0%), respectively. Additionally, the estimated 7- and 9-year overall survival (OS) rates were 76% (95% CI, 58.7%-86.7%) and 66% (95% CI, 47.3%-79.2%), respectively.
“The lenalidomide/rituximab study is the first chemotherapy-free frontline treatment for MCL, and our report provides the long-term data using a chemotherapy-free approach in MCL,” lead study author Samuel Yamshon, MD, and colleagues wrote. “The efficacy of first-line lenalidomide/rituximab, as evidenced by high response rates and durable remissions as well as long-term safety with the convenience of an outpatient treatment regimen support the broad-based applicability of this regimen as a novel approach to previously untreated MCL.”
Yamshon is an assistant professor of medicine at Weill Cornell Medicine/New York Presbyterian Hospital in New York, New York.
Lenalidomide was granted approval by the FDA for the treatment of patients with relapsed/refractory MCL after 2 prior therapies, including bortezomib (Velcade), in June 2013.2 Then in May 2019, the FDA approved lenalidomide plus rituximab for patients with previously treated follicular lymphoma and previously treated marginal zone lymphoma.3
The multicenter, open-label phase 2 trial enrolled a total of 38 patients with measurable, histologically confirmed, untreated MCL. Patients were required have a low- to intermediate-risk MCL International Prognostic Index (MIPI) score, or a high-risk MIPI score with contraindications to chemotherapy; an ECOG performance status of 2 or less; and a minimum creatine clearance of 30 mL/min. Those with central nervous system lymphoma; known HIV infection; active hepatitis B or C; or invasive malignant tumors within 5 years preceding treatment initiation were excluded from the study.1
The single-arm trial included induction and maintenance phases. Following enrollment, patients received lenalidomide at 20 mg daily for the first 21 days of each 28-day cycle for 12 cycles during the induction phase, with dose escalation to 25 mg daily after the first cycle as tolerated, and at a dose of 15 mg daily during the maintenance phase, plus rituximab at 375 mg/m2 weekly during cycle 1 and then administered once every eight weeks, including during maintenance. Treatment continued until disease progression, unacceptable adverse effects (AEs), or patient withdrawal. Patients were permitted to cease treatment after 3 years if they experienced clinical regression by CT scan.
The primary end point was objective response rate (ORR). Secondary end points included PFS, OS, and safety.1
At baseline, the median age was 65 years (range, 42-86), and all patients had Ann Arbor stage III or IV disease. Most patients were male (71%), had an ECOG performance status of 0 or 1 (97%), had bone marrow involvement (89%), and had a Ki-67 index of less than 30% (68%). MIPI score was evenly distributed at less than 5.7 (34%), 5.7 to less than 6.2 (34%), and at least 6.2 (32%).1,4
The previously reported ORR was 92%, including a complete response (CR) rate of 64%.4 Additional findings from the final analysis revealed that although MIPI scores were not associated with response or PFS, high-risk MIPI scores were associated with diminished OS (P = .03). Investigators noted that a Ki-67 index exceeding 30% did not impact PFS or OS.1
Thirty-three patients completed the induction phase and started maintenance therapy. Fifteen total patients experienced progressive disease, including 3 during the induction phase and 12 during maintenance after an initial response. Among patients who progressed during maintenance, 6 had initial CRs, and 6 had initial partial responses.1
In terms of safety, during the induction phase, common any-grade AEs included fatigue (76%), neutropenia (68%), rash (68%), and fever (58%). Grade 3 or greater AEs included neutropenia (42%), rash (29%), thrombocytopenia (11%), and fatigue (11%).1
In the maintenance phase, the most common any-grade AEs were neutropenia (68%), upper respiratory hyperglycemia (58%), and diarrhea (55%). Grade 3 or higher AEs included neutropenia (42%), pneumonia (8%), thrombocytopenia (5%), and febrile neutropenia (5%).1
Overall, 8 patients developed secondary primary malignancies. Invasive systemic malignancies were reported in 2 patients, consisting of 1 with Merkel cell carcinoma and 1 with pancreatic cancer. Both patients died as a result of their secondary malignancies.1
To date, 12 evaluable patients died, with deaths attributed to lymphoma progression (n = 7) and non-lymphoma causes (n = 5), including heart failure, West Nile virus infection, pancreatic cancer, and COVID-19 pneumonia. As of June 2022, among the 17 patients still in remission, 7 remained on study treatment, including 5 on rituximab maintenance, 1 on lenalidomide, and 1 on lenalidomide plus rituximab. Ten patients discontinued study treatment.1
“At the time that the lenalidomide/rituximab study was designed, there were no data available on the optimal duration of maintenance therapy with the frontline chemotherapy-free approach,” investigators wrote in conclusion. “Our data have indicated that in 17 long-term responders, 10 subjects were able to discontinue study treatment and enjoy ongoing remissions. Future studies are needed to examine the feasibility of limited-duration maintenance therapy tailored to disease risks and response qualities to minimize treatment-related toxicities while maintaining efficacy.”