Addition of Lenalidomide to Rituximab Maintenance Improves PFS in Elderly Patients With MCL

The addition of lenalidomide (Revlimid) to rituximab (Rituxan; R2) maintenance treatment significantly improved progression-free survival (PFS) compared with rituximab alone following first-line chemoimmunotherapy in patients with mantle cell lymphoma (MCL), according to results from the MCL R2 Elderly Clinical Trial (EUDRACT: 2012-002542-20).¹

Results, which were presented during the 2021 ASH Annual Meeting, showed that at a median follow-up of 2.1 years, the 2-year PFS rate for those in the R2 arm was 76.6% (95% CI, 70.1%-81.9%) vs 60.8% (95% CI, 53.7%-67.2%) in the rituximab-alone arm (RR = 0.579; 95% CI, 0.429-0.781, P = .003).

At a median follow-up of 32.4 months, no difference in overall survival (OS) since induction randomization was observed between the arms. At a median follow-up of 25.2 months, no difference in OS since maintenance randomization was observed between the arms, either. The 2-year OS rate in the R2 arm was 87.3% (95% CI, 81.6%-91.4%) vs 85.8% (95% CI, 79.8%-90.0%) in the rituximab-only arm.

“Considering the primary end point, PFS, the R2 arm is better than the rituximab arm,” study author Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France, said in a presentation on the data. “However, there is no difference in OS between the 2 arms.”

Currently, no international standard-of-care treatment exists for elderly patients with MCL who are not eligible to receive high-dose therapy (HDT) with autologous stem cell transplantation (ASCT). Induction chemoimmunotherapy remains the backbone of treatment for this population. A prior MCL elderly study established the use of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) as induction treatment followed by maintenance treatment with rituximab.²

The R2 combination has been shown to have high efficacy and an acceptable toxicity profile in the treatment of patients MCL.³ However, the benefit of adding lenalidomide to rituximab in the maintenance treatment of these patients had not been investigated.

To be eligible for enrollment, patients needed to be at least 60 years of age and could not be eligible for HDT and ASCT. Patients were required to have MCL according to World Health Organization classification, with cyclin D1 overexpression or t(11;14)(q13;q32).

Other eligibility criteria included having previously untreated MCL, Ann Arbor stage II to IV disease, and an ECOG performance status of 0 to 2. Additional requirements to undergo randomization in the maintenance phase of the trial was to have achieved a complete response (CR), an unconfirmed complete response (uCR), or partial response (PR) following induction treatment.

Patients who had received less than 6 cycles of R-CHOP21, or less than 4 cycles of R-CHOP21 and R-HAD28, were excluded from undergoing randomization in the maintenance phase. Other exclusion criteria included having calculated creatinine clearance of less than 30 mL/min, an absolute neutrophil count of less than 1000 cells/mm³ (1.0 x 10⁹/L), or a platelet count of less than 50,000 cells/mm³ (50 x 10⁹/L).

A total of 620 eligible patients underwent randomization for induction treatment, where they received either 8 cycles of 3-weekly R-CHOP, or 6 cycles of alternating 3-weekly R-CHOP and 4-weekly R-HAD (rituximab, cytarabine, and dexamethasone). A total of 514 patients responded to induction treatment, with an overall response rate of 87% and a CR/uCR of 41%.

Patients who achieved a CR, uCR, or PR to induction treatment (n = 495) then underwent a second randomization between maintenance with rituximab every 2 months or R2, which was comprised of lenalidomide at 15 or 10 mg plus rituximab. Maintenance treatment was continued in both arms for 24 months.

The primary end point of the trial was PFS, and secondary end points focused on evaluating whether adding cytarabine into induction treatment would improve clinical outcome vs R-CHOP, and comparing OS from induction to randomization.

The median age of all 620 patients included in the induction intent-to-treat population at the time of inclusion was 71.0 years, and most patients were male (71.5%). Additionally, 90.3% of patients had Ann Arbor stage IV disease and 42.1% had a lactate dehydrogenase (LDH) level above the upper limit. Furthermore, most patients were classified as MIPI high risk at baseline (49.3%); 44.3% and 6.4% of patients, respectively, were determined to be intermediate risk and low risk.

Among the 447 patients who were randomized to receive maintenance treatment on the trial, the median age was 71.0 years, 70.5% were male, 89.5% had Ann arbor stage IV disease, 38.0% had a LDH greater than the upper limit, 46.0% had a complete response to induction treatment, and 99.5% experienced an overall response to treatment.

Of the patients who received R2 as maintenance treatment (n = 238), 140 experienced adverse effects involving blood and lymphatic system disorders. Additionally, 119 patients experienced neutropenia that was higher than grade 2 in severity, 7 had grade 2 or higher anemia, 26 had infections or infestations, and 32 had second primary malignancies (SPM).

Of the patients who received rituximab monotherapy as maintenance treatment (n = 250), 68 patients reported AEs that involved blood or lymphatic system disorders, 47 had grade 2 or higher neutropenia, 1 had grade 2 or higher anemia, 6 experienced infections or infestations, and 26 had SPM.

Notably, 1 death due to toxicity associated with study treatment was reported in the R2 group during the maintenance phase vs 0 with rituximab only.

Furthermore, 29 and 31 patients died due to their disease in the R2 and rituximab arms, respectively. One and 3 patients died of other causes in the R2 and rituximab arms, respectively.

References

1. Ribrag V, Safar V, Kluin-Nelemans HC, et al. Rituximab-lenalidomide (R2) maintenance is superior to rituximab maintenance after first line immunochemotherapy in mantle cell lymphoma: results of the MCL R2 elderly clinical trial. Presented at: 2021 ASH Annual Meeting; December 9-14, 2021; Atlanta, GA. Abstract 379.
2. Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle cell lymphoma (MCL): long-term follow-up of the randomized european MCL elderly trial. J Clin Oncol. 2020;38(3):248-256. doi:10.1200/JCO.19.01294
3. Ruan J, Martin P, Christos P, et al. Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma. Blood. 2018;132(19):2016-2025. doi:10.1182/blood-2018-07-859769