Rituximab-Lenalidomide Combo Superior to Rituximab Alone in Relapsed/Refractory Indolent NHL

For patients with relapsed/refractory indolent non-Hodgkin lymphoma (NHL), adding lenalidomide to rituximab treatment improved response rates and prolonged time to next treatment, compared with rituximab alone, according to findings from the phase III AUGMENT trial. John Leonard, MD, of the Meyer Cancer Center of Weill Cornell Medicine and New York Presbyterian Hospital, presented the results at the 2018 ASH Annual Meeting.

The trial met its primary endpoint for improvement in progression-free survival (PFS) with the lenalidomide and rituximab (R2) combination, which also was shown to have a manageable toxicity profile, Dr. Leonard reported. “Taken together, we believe R2 represents an important new treatment option for patients with relapsed/refractory indolent non- Hodgkin lymphoma,” he said.

The AUGMENT trial included 358 patients with marginal zone lymphoma (MZL) or grade 1 to 3a follicular lymphoma (FL) who had received at least one prior course of chemotherapy or immunotherapy, but whose disease was not refractory to rituximab. Refractoriness was defined as achieving less than a partial response to rituximab or rituximab-chemotherapy or disease progression within 6 months of last rituximab dose.

After stratification by prior rituximab treatment, time since last anti-lymphoma treatment, and histology (MZL or FL), patients were randomized to receive either R2 (n=178) or rituximab-placebo (n=180) for up to one year.

All patients received rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1, then on day 1 of cycles 2 through 5. Patients in the R2 group received lenalidomide 20 mg/m2 on days 1 through 21 of each 28-day cycle, while patients in the rituximab-placebo group received matched capsules on a similar schedule.

Follow-up continued for five years to evaluate overall survival (OS), development of second primary malignancies (SPMs), subsequent treatment, and histologic transformations.

Baseline characteristics were well balanced between the two arms, Dr. Leonard noted. Approximately 60 percent of patients in each group were ≥60 years of age and approximately 70 percent had advanced-stage disease. The majority in each group had FL (83% [n=147] in R2 and 82% [n=148] in rituximab-placebo).

The median number of prior anti-lymphoma treatments was one (range = 1-12), and the most common treatment was rituximab (85% and 83%). Also, about half the patients were enrolled within two years of their last anti-lymphoma therapy.

Over one year of treatment, 71 percent of patients completed R2 treatment, while 61 percent completed rituximab-placebo treatment. “This imbalance was due to the fact that more patients progressed in the placebo arm (30% vs. 12%),” Dr. Leonard reported, adding that “progression was the most common cause for discontinuation – not toxicity.”

Adverse events (AEs) were mostly grade 1 or 2 in each arm. The largest difference in AEs between each arm (≥10%) occurred with grade 3/4 toxicities, including higher rates of neutropenia, infections, cutaneous reactions, constipation, leukopenia, anemia, thrombocytopenia, and tumor flare in the R2 arm.

Histologic transformation was observed in two patients in the R2 group (1%) and 10 in the rituximab-placebo group (6%), and fewer patients in the R2 group developed an SPM (3% [n=6] and 6% [n=10]).

At a median follow-up of 28.3 months (range not reported), R2 was associated with a longer median PFS, assessed by independent review committee (IRC), than rituximab plus placebo: 39.4 months (range = 22.9 months to not estimable) versus 14.1 months (range = 11.4-16.7 months). This translated to an approximately 54-percent lower risk of death or disease progression with R2 (hazard ratio [HR] = 0.46; 95% CI 0.34- 0.62; p<0.0001).

All subgroup analysis favored the R2 arm for PFS, except in patients with MZL, the authors noted. Rates of two-year OS also appeared to be higher with R2 than rituximab-placebo (93% vs. 87%; p value not reported).

The overall response rate (ORR; a secondary endpoint) was 78 percent for R2 versus 53 percent for rituximab-placebo (p<0.0001). Again, the ORR benefit was seen in all subgroups regardless of prior rituximab therapy, age, race, time since last therapy or tumor burden. Median duration of response was longer in the R2 group, as well (36.6 months vs. 21.7 months; HR=0.53; 95% CI 0.36-0.79; p=0.0015).

When asked about where R2 fits in the landscape of relapsed FL, Dr. Leonard noted that, although there are several other agents approved for recurrent FL, including single-agent rituximab, “our data suggest that many patients could instead benefit from the combination of R2.” However, the trial was not designed to compare R2 with other regimens containing chemotherapy and other agents, and these decisions “depend on individual patient situations,” he added.

As a limitation of the study, Dr. Leonard noted that the trial population included a small number of patients with MZL, which may limit the results’ generalizability to patients with MZL.

The authors report relationships with Celgene, the manufacturer of lenalidomide, which sponsored the trial.


Leonard JP, Trněný 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. Abstract #445. Presented at the 2018 ASH Annual Meeting, December 2, 2018; San Diego, CA.