Long-Term Data Support Rituximab Maintenance After R-CHOP in Older Patients With MCL

Older patients with mantle cell lymphoma (MCL) were more likely to have a maintained response with induction rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) followed by rituximab maintenance when compared against R-CHOP and interferon-alpha (IFN) maintenance. Treatment with rituximab beyond 2 years was also found to be effective and safe, according to an update from the randomized, open-label phase III European MCL Elderly trial.

“In this mature update of the European MCL Network trial for older patients, we confirm the initial results as far as progression-free survival (PFS)  and overall survival (OS) are concerned after R-CHOP induction followed by long-term rituximab maintenance,” Hanneke C. Kluin-Nelemans, MD, PhD, of the University Medical Center Groningen, University of Groningen, Groningen, the Netherlands, and colleagues wrote in their explanation of the data.

Overall, 560 patients were included in the first induction randomization—which administered either R-CHOP or rituximab, fludarabine, and cyclophosphamide (R-FC) to patients in a 1:1 ratio—and 316 responders were then randomized to maintenance treatment of either IFN or rituximab. Median follow-up for survival was 7.6 years.

The open-label, randomized phase III clinical trial (NCT00209209) stratified patients according to their national study group, age, and International Prognostic Index risk profile in both randomizations. In the second randomization, patients were additionally stratified by induction regimen and quality of response.

The induction regimens included either 6 cycles of R-FC every 4 weeks or 8 cycles of R-CHOP every 3 weeks. Fludarabine, cyclophosphamide, or doxorubicin were adapted if insufficient recovery occurred after a 1-week delay. Hematopoietic growth factors were also optional.

The objective response rate (ORR) in patients who received R-CHOP maintenance was 84% versus 78% with R-FC. The ORRs were slightly different between the 2 arms, partially due to more partial responses (PR) in the R-CHOP arm and more patients in the R-FC arm with refractory disease. Complete response (CR) rates were not significantly different between either arm in the induction portion of the study.

The median OS in patients treated with R-CHOP was 6.4 years versus 3.9 years with R-FC (P= .0054). However, the failure-free survival (FFS) overlapped, with medians of 2.2 months versus 2.4 months with R-FC and R-CHOP, respectively. The cumulative incidence of death without treatment failure was significantly higher after R-FC at 5 years (19%) versus R-CHOP (9%; P= .0043). More relapses were observed with R-CHOP versus R-FC (P= .054).

According to the results for the maintenance therapy portion of the trial, the median follow-up was 8 years in the 316 patients treated. Median PFS was 5.2 years for rituximab versus 2.0 years for IFN (P= .0109). The median OS was 9.8 years versus 6.4 years for rituximab and IFN, respectively, (P= .009). Patients who were responsive to R-CHOP received the most benefit from rituximab, with a median PFS of 5.4 years versus 1.9 years with IFN (P= .001), and the median OS was also improved at 9.8 years versus 7.1 years, respectively (P= .0026).

With longer follow-up, patients who were responsive to R-FC had a significantly better PFS with rituximab as compared with IFN maintenance, with a median PFS of 5.0 years versus 2.6 years, respectively (P= .0315). Additional analysis showed that rituximab maintenance had a strong effect in delaying progression in the R-FC group, but the cumulative incidence of death in remission remained high, 22% at 5 years. This occurred mainly due to infections or secondary tumors.

In the rituximab-maintenance arm, 58% of patients remained on treatment 2 years after the end of R-CHOP treatment, with 32% still on after 5 years. The median duration of rituximab maintenance after R-CHOP was 2.2 years. Rituximab maintenance was ongoing in 40% of patients at 2 years following the end of R-FC treatment and 20% at 5 years, with a median duration of 1.9 years. Additionally, rituximab discontinuation was most frequently due to toxicity, secondary malignancies, or physician or patient decisions as opposed to treatment failure.

An exploratory analysis was conducted to determine whether the continuation of rituximab after R-CHOP induction for more than 2 or 3 years was effective. The analysis looked at PFS for only patients in remission at 2 and 3 years from the end of R-CHOP induction. At 2 years, 11 patients out of 61 stopped rituximab, and at 3 years, 18 out of 53 patients stopped treatment. This discontinuation was most frequently due to physician decision, not toxicity. Investigators also noted that the PFS was significantly better in patients who continued rituximab treatment for longer than 2 years.

Maintenance regimens of either IFN at 3 million units subcutaneously 3 times per week or rituximab at 375 mg/m²every 2 months were offered to all patients with a CR or PR with leukocytes >3 × 109/L and platelets >100 × 109/L. Maintenance was initiated within 1 month after the second randomization to continue until disease progression.

“In conclusion, the excellent results of R-CHOP followed by rituximab maintenance for older patients with MCL persisted in a mature follow-up. Prolongation of rituximab maintenance beyond 2 or 3 years is effective and safe,” Kluin-Nelemans et al. wrote.

Reference:

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 [published December 5, 2019].J Clinl Oncol. doi: 10.1200/JCO.19.01294