Lenalidomide/Rituximab Induction as Effective as Rituximab Plus Chemo in Follicular Lymphoma Subset

Lenalidomide in combination with rituximab (Rituxan, R2) induction has the ability to achieve high rates of complete molecular response (CMR), similar to rituximab plus chemotherapy, when used as frontline therapy in patients with follicular lymphoma (FL), according to results from the phase 3 RELEVANCE trial (NCT01650701).

Lenalidomide in combination with rituximab (Rituxan, R2) induction has the ability to achieve high rates of complete molecular response (CMR), similar to rituximab plus chemotherapy, when used as frontline therapy in patients with follicular lymphoma (FL), according to results from the phase 3 RELEVANCE trial (NCT01650701).

The goal of the study was to address minimal residual disease (MRD)-positivity following treatment for FL leading to recurrent relapses in patients. RELEVANCE included an MRD analysis to test the possibility of using a chemotherapy-free regimen compared with using rituximab plus chemotherapy. The coprimary end points were the rate of complete responses (CRs) and progression-free survival (PFS). The key secondary end points included safety, time to treatment failure, event-free survival, overall survival (OS), objective response rate, and health-related quality of life.

Of the 1040 patients enrolled in the study, 581 patients received study treatment. A total of 226 patients received the R2 regimen and 214 patients received rituximab plus chemotherapy. Patients with BCL2-JH rearrangements were considered to be eligible for the MRD study, and this analysis included 222 patients.

Clinical characteristics for the overall population screened at baseline showed a median age of 60 years (range, 30-89). Most patients (54%) were males. In terms of ECOG performance status, 67% of patients had a score of 0, 37% had a score of 1, 2% had a score of 2, and the ECOG score was not evaluated in 0.5% of the population. Most patients with Ann Arbor stage III-IV (96%) and the remaining 4% were stage I-II. Follicular Lymphoma International Prognostic Index (FLIPI) scores were in the 3 to 5 range for 50% of patients, but 41% had a score of 2, 9% had a score of 3 to 5, and 28% had a score of 2, 26% had a score of 0-1, and 2% of patients were missing data.

Beta-2-microglobulin was tested at baseline and showed < 3 mg/L in 62% of patients. Most patients (71%) did not have elevated lactate dehydrogenase.

In terms of BM involvement, 62% of patients tested positive, 34% tested negative, and 2% were unspecified. The BM test was not conducted in the remaining 3% of patients.

Ann Arbor stage III-IV disease was more frequent in patients who had MRD data (96%) compared with those who did not (90%; P =.004). Patients with MRD data were also more likely to have a FLIP score > 1, specifically 91% in the R2 arm had a FLIP score > 1 compared with only 83% in the rituximab plus chemotherapy arm (P =.002). Bone marrow involvement also had observed more frequently in patients with MRD data available (62%) versus those without (48%; P =.003). The trends among patients with MRD data remained when comparisons were applied to the full study population.

To assess molecular response, peripheral blood and bone marrow samples were extracted 220 and 139 patients who had BCL2-JH rearrangements, respectively. At the time of diagnosis, 97% of the peripheral blood samples were detectable for molecular response, as were 98%o of the bone marrow samples. The median tumor/total cell ratio was 5.8 x 10-3 for peripheral blood and 2.1 x 10-2 for bone marrow.

Samples were analyzed again at week 24, for peripheral blood alone in 74 patients, for bone marrow alone in 3 patients, and both peripheral blood and bone marrow were tested for 130 patients. The CMR results showed molecular responses in only 2.5% of the peripheral blood samples. In the bone marrow samples, on the other hand, residual disease was observed in 22.5% of patients. In the peripheral blood and/or bone marrow group, 32 out of 207 patients did not have a molecular response.

There was further analysis according to baseline characteristics, which were compared to patients with and without CMR. The analysis found that 66% of FLIPI scores of 3 to 5 compared with 40% CMR (P =.011) and molecular quantitative values at the time of diagnosis were significantly associated with MRD-positivity. This finding was 10-fold higher in patients who were MRD-positive at week 24. Specifically, the MRD was 0.056 in peripheral blood samples and 0.16 in bone marrow samples. In comparison, patients who were MRD-negative at week 24, had an MRD of 0.0056 in the peripheral blood at week 24 and an MRD of 0.016 in the bone marrow. The p values were .03 and .02, respectively.

PFS outcomes were significantly impacted by the detection of molecular disease in the peripheral blood or bone marrow at week 24 (P =.0063). The 3-year PFS observed was 84% among patients who had a CMR compared with 55% in patients with detectable MRD (Hazard ratio [HR], 2.6; 95% CI, 1.27-5.13; P =.015). The study authors led by Marie-Helene Delfau-Larue, MD, PhD, note that MRD positivity and its negative prognostic value related to bone marrow results were only significant (P =.011) with a 3-year PFS of 55% among patients with a CMR and 54% among patients with detectable MRD.

Eleven (34%) of the patients, for whom residual molecular disease was detected in the peripheral blood or bone marrow, were considered to be complete responders or unconfirmed complete responders at week 24. Contrarily, 61 (35%) of the 175 patients who were in CMR using bone marrow and/or peripheral blood were had clinical CRs or unconfirmed CRs (CRu). Thirty-nine patient responses were later reduced to partial responses after CT scan measurements. A Cox multivariable analysis demonstrated that MRD-positivity in the peripheral and bone marrow significantly shortened PFS (HR, 2.6; 95% CI, 1.3-5.2; P =.0076). When the clinical response was adjusted for patients who had no CR or Cru, the HR was 1.8 (95% CI, 0.9-3.6; P =.09).

Overall, 90% of patients in the rituximab plus chemotherapy arm had a CMR at week 24 to treatment versus 77% in the R2 arm (P =.022). Both arms had similar PFS; however, a prognostic value analysis showed that persistence of molecular response at week 24 correlated with inferior PFS, regardless of the treatment arm.

A statistical significance was shown with MRD-positivity and -negativity in the rituximab plus chemotherapy arms (HR, 3.3; 95% CI, 1.2-9.2; P =.02), but this was not observed in the R2 arm (HR, 2; 95% CI, 0.6-6.8; =.27). When bone marrow results were considered, Delfau-Larue et al noted that similar results were observed.

Delfau-Larue et al concluded based on these results that MRD status distinguished by quantitative BCL2-JH polymerase chain reaction can be used to evaluate the effectiveness of therapy in a subset of patients.


Delfau-Larue MH, Boulland ML, Beldi-Ferchiou A, et al. Lenalidomide/rituximab induces high molecular response in untreated follicular lymphoma: LYSA ancillary RELEVANCE study. Blood Adv. 2020. 4 (14): 3217–3223. doi: 10.1182/bloodadvances.2020001955