Lenalidomide Plus Rituximab Elicits Prolonged Responses in 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.”

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. FDA approves revlimid (lenalidomide) for the treatment of patients with relapsed or refractory mantle cell lymphoma. News release. Celgene Corporation. June 5, 2013. Accessed November 17, 2023. https://www.drugs.com/newdrugs/fda-approves-revlimid-lenalidomide-patients-relapsed-refractory-mantle-cell-lymphoma-3806.html
3. FDA approves lenalidomide for follicular and marginal zone lymphoma. News release. FDA. May 28, 2019. Accessed November 17, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lenalidomide-follicular-and-marginal-zone-lymphoma
4. Ruan J, Martin P, Shah B, et al. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015;373(19):1835-1844. doi:10.1056/NEJMoa1505237