At the 65th ASH Annual Meeting in San Diego, California, Emanuele Zucca, MD, Università della Svizzera Italiana, Lugano, Switzerland, discussed the long-term results from an updated analysis of the SAKK 35/10 trial, which indicated that rituximab plus lenalidomide combination therapy demonstrated durable efficacy compared to rituximab alone among patients with follicular lymphoma (FL). 

This treatment combination had a significantly shorter schedule than the standard rituximab regimen, Zucca and coauthors noted, highlighting its potential as an alternative when treatment is needed, but durable immunosuppression is undesirable.

Transcript:

Hello to everybody. My name is Emanuele Zucca, and I am a consultant at Oncology Institute of Southern Switzerland in Bellinzona and working also at the Institute of Oncology Research in Bellinzona, Switzerland. As a former president of the Swiss Clinical Oncology Study Group, the SAKK, I was aware of a randomized study which was assessing a 6-month regimen of rituximab and lenalidomide in follicular lymphoma patients in need of first therapy. This study was conducted together with the Nordic Lymphoma Study Group, and this year at the American Society of Hematology Annual Meeting in San Diego, we presented updated results with a follow-up of nearly 10 years of this study. 

Nowadays with an expected median survival of about 20 years, long-term safety has become increasingly important for follicular lymphoma patients, leading to [the] explor[ation of] less toxic frontline regimens. In prioritize[ation] from this SAKK, the Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group, initial therapy with rituximab alone led to long-term remissions in a sizable subset of patients with overall survival, not inferior to those achieved by chemoimmunotherapy regimens. 

This has provided a rationale for developing chemotherapy-free frontline strategies. One of the most common combinations in this context is the combination of rituximab and lenalidomide. Lenalidomide is a modulating drug with a boosting effect on immune system cells, thereby it analyzes rituximab activity against the lymphoma B-cell in vivo. This agent has clinical efficacy and a favorable toxicity profile in lymphoma. 

Moreover, the very early clinical trials of rituximab plus lenalidomide, even more than 10 years ago, have shown very promising resolve with remission rates up to 90%. On this basis, we developed and conducted the SAKK 35/10 regimen comparing rituximab plus lenalidomide with rituximab alone in patients with advanced follicular lymphoma in need of therapy. Patients in both arms received rituximab at the standard dose on day 1 of weeks 1 to 4, repeated during weeks 12 to 15 in responding patients. 

Whilst, patients randomized to the combination arm had also lenalidomide 15 milligram daily, starting 2 weeks before the first rituximab dose and continuously administered until 2 weeks after the last rituximab dose, up to a total of 18 weeks of treatment. The primary endpoint was the overall remission rate, which was met and published previously in the Blood journal in 2019. 

This year at the annual meeting of the American Society of Hematology, we presented the long-term update of this trial. Patients treated in this trial were all in need of therapy, which means that they had symptomatic and progressive tumor lesions, B symptoms, cytopenias, bulk lesions, or at least 3 individual lymph nodes larger than 3 centimeters. Patients allocated to the combination arm after a median follow-up, which is now over 9.5 years, had significantly longer progression-free survival than those with the monotherapy arm, with a median survival of 9.3 versus 2.3 years. 

Overall survival was similar in both arms, about 78% at 10 years and not significantly different. Lymphoma was the most common cause of death, but only 1 treatment-related death was reported, this in the combination arm. The combination improved the quality of responses. The median duration of complete remission was around 3 years with rituximab a single agent, but it was not reached with the combination with another ratio of 0.4 and with over 60% of patients responding to frontline therapy still in first remission at 10 years after receiving this combination, while only less than 1/3 were still in first remission in the rituximab only arm. 

The median time to the next of trial lymphoma treatment was also not reached in the combination arm [and] was about 2 years in the monotherapy arm, again with another ratio of about 0.4. The  Kaplan-Meier curve showed that much more patients, 22% had an early progression in the monotherapy arm versus only 4% with the combination. The good outcome we [observed] at 10 years was not associated with unexpected toxicity. 

The overall safety in both arms was consistent with the first already published analysis. Toxicity was most common with the combination, but manageable without novel safety concerns emerging during the prolonged follow up. 

It should be noted that there was a higher rate of secondary malignancy in the combination arm. However, the causal relationship of this, which was commonly associated with aging in most cases was not fully clarified and may need a factor study to better assess it. 

We compare our 6-month duration regimen versus the standard R2 combination of rituxumab plus lenalidomide given for 120 weeks. We see that in spite of the longer combination resulting in some better responses and slightly longer 6-year progression-free survival, our longer follow-up is very promising, especially for survival because the short regimen is tolerated by more patients. 

Other trials, such as those reported by the MD Anderson group a couple of years ago with the long-term data of an initial phase 2 study of this combination, also suggest that a short regimen [provides] long-term benefit in responding patients. Therefore, we think that a short-duration combination of rituximab in lena[lidomide] can be or may be quite a valuable frontline option for follicular lymphoma patients. However, more data should be achieved on the optimal duration schedule of this combination before making it a defined standard treatment.

Source:

Zucca E, Schaer S, Vanazzi A, et al. Long-Term Efficacy of a 6-Month Regimen of Rituximab and Lenalidomide in Follicular Lymphoma Patients in Need of First Therapy: Updated Analysis of the SAKK 35/10 Randomized Trial. Presented at the 2023 ASH Annual Meeting: December 9-12, 2023. San Diego, CA. Abstract 295