Lenalidomide/Rituximab Demonstrate PFS Benefits In Elderly Patients With Indolent Non-Hodgkin Lymphoma

Findings from a subgroup analysis of the phase III AUGMENT trial of patients aged 70 or older with indolent non-Hodgkin lymphoma showed a 34% reduction in the risk of disease progression or death with treatment of lenalidomide (Revlimid) and rituximab (R²) compared with rituximab plus placebo, according data presented at the 2019 American Society of Hematology (ASH) Annual Meeting and Exposition.¹

However, the PFS benefit was more pronounced in patients with follicular lymphoma and were ≥70 years old (HR, 0.49; 95% CI, 0.25-0.99; P = .043). Additionally, the safety profiles of the regimen were similar to that of the overall study population of patients with indolent NHL.

“These data show that R²maintained efficacy improvements versus rituximab/placebo in patients aged ≥70 years, despite higher unfit status and lower overall lenalidomide treatment and exposure compared with the overall population,” lead study author Martin Trněny, MD, professor of medical oncology, director of Stem Cell Transplantation Program and Lymphoma Program at General Hospital, Charles University Prague, said in a presentation during the meeting. “R²is an effective and available treatment option for patients with indolent NHL, including those with advanced age.”

In May 2019, the FDA approved the R²regimen for use in patients with previously treated follicular lymphoma and marginal zone lymphoma (MZL). The decision was primarily based on results of the phase III AUGMENT study, in which the combination reduced the risk of disease progression or death by 54% versus rituximab alone in patients with relapsed/refractory indolent non-Hodgkin lymphoma.²

“Because advanced age at diagnosis is a risk factor in patients with indolent non-Hodgkin lymphoma, we performed posthoc subgroup analyses by age from AUGMENT, and data here focused on patients aged more than 70 years,” Trněny explained as the rationale for the subgroup analyses.

The double-blind, phase III AUGMENT trial included 358 patients with relapsed/refractory follicular lymphoma or MZL in need of treatment. Across the study, 295 patients had follicular lymphoma and 63 patients had MZL. Patient had to have received ≥1 prior chemotherapy, immunotherapy, or chemoimmunotherapy regimen, and could not be rituximab refractory.

Patients were randomized to rituximab at 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1, and day 1 of cycles 2 through 5, plus either 20 mg of lenalidomide/daily on days 1 through 21 every 28 days for up to 12 cycles (n = 178) or placebo (n = 180). 

In the intent-to-treat population, patient characteristics at baseline were well balanced overall between the 2 arms. The median age was 63 years; over 70% of patients had advanced-stage disease at study entry. About 50% of patients had high tumor burden per the GELF criteria. Around 83% of patients in each arm had follicular lymphoma, with the remaining 17% having MZL; 34.5% of patients had a FLIPI score ≥3.

The posthoc analysis stratified patients who were ≥70 years (n = 91) and received R²(n = 47) or placebo (n = 44). Here, the median age was 75 years, and 55% of patients on R²had an ECOG performance status of 1 to 2 versus 36% of patients who received rituximab plus placebo. Additionally, about half of patients in each arm had a FLIPI score ≥3, and about three-fourths of patients had follicular lymphoma.

In the ITT population, 57% of patients on R²received 1 prior systemic regimen, 17% had received 2, and 25% had received ≥3. In the control arm, the corresponding rates were 54%, 23%, and 23%, respectively. Eighty-five percent of patients in the R²arm and 83% of patients in the placebo arm had prior rituximab. About 75% of patients in each arm had received a prior rituximab-containing chemotherapy regimen. Thirty-seven percent of patients in the R²arm and 42% of patients in the placebo arm had progressed within 2 years of their last regimen. 

In the ≥70-year subgroup, 53% of patients on R²received >1 prior systemic therapy compared with 39% for those who received rituximab 39%; furthermore, 36% and 14% of patients, respectively, relapsed ≤2 years following their initial diagnosis. Trněny explained these were notable differences between the 2 arms. However, 85.5% of patients received prior rituximab, and 66% received a prior rituximab-containing regimen. Fifteen percent of patients on R²were refractory to their last regimen versus 7% who were randomized to receive rituximab with placebo.

While the median number of treatment cycles was 12 for both the ≥70-year subgroup and the overall population, fewer patients aged ≥70 years completed 12 cycles of lenalidomide at 57% versus 71% in the total population. Additionally, more of the older patients started lenalidomide at the lower 10-mg dose (35%) versus 14% in the overall population due to low creatinine clearance. Moreover, the average daily lenalidomide dose was 14.4 mg daily compared with 17.0 mg daily, respectively, and the median relative dose intensity was 86% versus 95% for the ≥70-year subgroup and total population, respectively.

Notably, 70% of patients in the ≥70-year group required dose interruptions due to treatment-emergent adverse events (TEAEs) compared with 20% of these patients who were on rituximab/placebo. In the overall population, these rates were 66% and 29%, respectively. Dose reductions due to TEAEs with R²occurred in 35% of both the subgroup and the overall population; 20% of patients ≥70 years discontinued R²due to a TEAE compared with 9% of those in the total study group.

In the ITT population, the median PFS per independent central review (IRC) was 39.4 months (95% CI, 22.9—not evaluable) with R²versus 14.1 months (95% CI, 11.4-16.7)&nbsp;with rituximab alone (HR, 0.46; 95% CI, 0.34-0.62;&nbsp;P&nbsp;<.0001), at a median follow-up of 28.3 months. However, the PFS advantage was not consistent with the overall population was the subgroup of patients with MZL (HR, 1.00; 95% CI, 0.47-2.13). By investigator assessment, the median PFS was 25.3 months (95% CI, 21.2—not evaluable) versus 14.3 months (95% CI, 12.4-17.7), respectively (HR, 0.51; 95% CI, 0.38-0.69;&nbsp;P&nbsp;<.0001).

In all patients &ge;70 years, the median PFS was 24.9 months (95% CI, 16.4—not reached [NR]) and 14.3 months (95% CI, 11.3-27.7) for R²and rituximab/placebo, respectively (HR, 0.66; 95% CI, 0.37-1.18;&nbsp;P&nbsp;= .1576), which Trněny noted was not statistically significant.

However, when stratified by patients &ge;70 years with follicular lymphoma (n = 66), the PFS benefit by IRC was more pronounced, with a median PFS of 28.0 months (95% CI, 16.4—NR) for R²and 14.3 months (95% CI, 11.3-27.7) for rituximab/placebo (HR, 0.49; 95% CI, 0.25-0.99; P&nbsp;= .043).

&ldquo;When we analyzed the follicular lymphoma subset, you can see a significant improvement in with regard to PFS in terms of a risk reduction in death or progression of 51%,&rdquo; Trněny explained.

IRC-assessed response rates for the &ge;70-year subgroup were comparable with the total population. For patients &ge;70 years, the ORRs were 81% and 59% for R²and rituximab plus placebo, with complete response (CR) rates of 26% and 16%, respectively, with the rest comprised of partial responses. In the overall group, the ORRs were 78% and 53% for R²and rituximab/placebo; the CR rates were 34% and 18%, respectively.&nbsp;

The median OS was not reached in both arms for all patients &ge;70 years (HR, 0.79; 95% CI, 0.21-2.93) and for those in the follicular lymphoma subgroup &ge;70 years (HR, 0.24; 95% CI, 0.03-2.18). Overall survival (OS) data across the entire population showed that at a median follow-up of 28.3 months, the HR for OS was 0.61 (95% CI, 0.33-1.13).

The time to next lymphoma treatment for all patients &ge;70 years was also not reached in either arm and was not statistically significant (HR, 1.02; 95% CI, 0.50-2.09; P&nbsp;= .9586). It was also not reached for the &ge;70-year-old follicular lymphoma group (HR, 0.52; 95% CI, 0.20-1.31;&nbsp;P&nbsp;= .0156). In the entire study population, this was not reached with R2&nbsp;and was 32.2 months with rituximab/placebo (HR, 0.54; 95% CI, 0.38-0.78). &nbsp;

Previously reported safety for the overall population showed that the most common, all-grade, adverse events (AEs) occurring in patients with MZL/follicular lymphoma were neutropenia (58%), diarrhea (31%), constipation (26%), cough (24%), fatigue (22%), rash (22%), pyrexia (21%), leukopenia (20%), pruritus (20%), upper respiratory tract infections (18%), abdominal pain (18%), anemia (16%), headache (15%), and thrombocytopenia (15%).

For patients &ge;70 years, no significant differences in safety and serious AEs were reported compared with the ITT population. Most grade 3/4 TEAEs were hematologic, comprising neutropenia, leukopenia, and anemia. One patient on R²&ge;70 years old experienced febrile neutropenia, and 1 patient died on the rituximab/placebo arm due to pneumonia. Four secondary primary malignancies were observed in both arms, Trněny concluded.

References

1. Trněny M, Leonard JP, Zhang H, et al. Subgroup analyses of elderly patients aged &ge; 70 years in AUGMENT: a phase III randomized study of lenalidomide plus rituximab (R2) vs rituximab plus placebo (r-placebo) in patients with relapsed/refractory (r/r) indolent non-Hodgkin lymphoma (iNHL). Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 347. bit.ly/353kfmQ.
2. Leonard JP, Trněn&yacute; M, Izutsu K, et al. AUGMENT: a phase III randomized study of lenalidomide plus rituximab (R2) vs rituximab/placebo in patients with relapsed/refractory Indolent non-Hodgkin lymphoma. Presented at: 2018 ASH Annual Meeting; December 4-8, 2018; San Diego, CA. Abstract 445.