SAN DIEGO—Indolent non-Hodgkin lymphoma (iNHL) is a group of hematologic malignancies that typically exhibit slow disease progression, making up approximately 40 percent of all U.S.-based NHL cases. Among the diseases included in iNHL are chronic lymphocytic leukemia (CLL) and small cell lymphocytic lymphoma (SLL), cutaneous T-cell lymphoma (CTCL—including mycosis fungoides and Sézary syndrome), follicular lymphoma (FL), lymphoplasmacytic lymphoma and Waldenström macroglobulinemia, marginal zone lymphoma (MZL), and mucosa-associated lymphoid tissue lymphoma.
“Relapsed/refractory iNHL tends to recur over time and the disease tends to become more resistant to treatment with subsequent treatment courses,” noted John Leonard, MD, from the Meyer Cancer Center, Weill Cornell Medicine. “Therefore, patients need more effective treatment options; having alternatives and options that can improve efficacy is needed, particularly if such can be provided without major worsening of toxicity/side effects.”
To address this need for alternative therapeutic options, AUGMENT (NCT01938001), a phase III, randomized, double-blind, international clinical study was undertaken to evaluate the efficacy and safety of the investigational combination of rituximab plus lenalidomide (R2) versus rituximab plus placebo in patients with relapsed or refractory iNHL.
Findings were recently presented at the 2018 ASH Annual Meeting (Abstract 445).
Regarding the study's aims, Leonard, who is AUGMENT lead investigator, stated, “The primary purpose of the study was to evaluate whether the addition of lenalidomide to rituximab (vs. placebo + rituximab) improved efficacy as measured by progression-free survival (as well as other parameters), and to characterize the safety profile of the combination.”
ASH 2018 Abstract 445
Participation in this study was limited to patients with grade 1-3a follicular lymphoma or mantle zone lymphoma who were previously treated with one or more prior systemic therapy with documented relapsed or refractory disease but not refractory to rituximab.
Patient stratification was accomplished using a number of factors, including prior rituximab treatment (yes vs. no), time since last antilymphoma therapy (2 years or less vs. more than 2 years), and histology (FL vs. MZL). Randomization was done in a 1:1 manner to R2 or control for up to 1 year.
When asked about the study's objectives, Leonard replied, “The primary endpoint was progression-free survival (PFS) (comparison between the two arms) as assessed by an independent review committee. Secondary endpoints included overall survival (OS), overall response rate (ORR), complete response rate, efficacy in a number of pre-specified subgroups, and toxicity assessments/comparisons between arms.”
A total of 358 R/R iNHL patients were enrolled in this study; of these, 295 had follicular lymphoma while 63 had marginal zone lymphoma.
The R2 arm showed a highly statistically significant improvement in the primary endpoint of independent committee-assessed PFS relative to the rituximab-placebo arm. “The primary endpoint was met—PFS with the R2 combination was 39.4 months versus 14.1 months in the placebo + rituximab group,” Leonard said.
A positive trend for improvement was also observed for OS in the R2 arm (16 deaths) when compared to the rituximab-placebo arm (26 deaths). The 2-year OS rates for the R2 and rituximab-placebo patients were 93 percent and 87 percent, respectively.
The ORR for the R2 and rituximab-placebo arms were 78 percent and 53 percent, respectively. The median duration of response was significantly improved for R2 (37 months) versus rituximab-placebo (22 months) arms.
Frequently observed AEs noted in the R2 arm included neutropenia (58%), diarrhea (31%), constipation (26%), cough (23%), and fatigue (23%). Additionally, no unexpected safety findings were observed in this trial.
When assessing the implications of the study results, Leonard noted, “This trial offers a new option for patients with R/R iNHL, particularly in those who would otherwise be considering single agent rituximab. The improved efficacy, in the context of the safety profile, suggests clinically meaningful benefits for patients.
“Additionally, a survival advantage was noted in the FL subgroup, suggesting that these patients may live longer if treated with R2 versus rituximab alone,” he continued.
“The AUGMENT data, with R2 more than doubling progression-free survival over rituximab monotherapy, represents an important potential new treatment option for patients with R/R follicular or marginal zone lymphoma.
“Efficacy was greater with the R2 regimen versus rituximab (+ placebo) as assessed by progression-free survival, overall response rate, complete response rate, and time to next treatment. Efficacy favored the R2 combination in the majority of prespecified subgroups; however, that combination was also associated with greater frequency of cytopenias, infections, rash, tumor flare and constipation,” he elaborated.
“Interestingly, numbers of patients with second primary malignancies and histologic transformation were lower with R2.
“I believe that, for many patients in this disease setting who would otherwise be treated with rituximab alone or in some cases chemotherapy plus rituximab, the R2 regimen may be an additional option that could be employed in some cases,” Leonard noted regarding the therapeutic potential of the investigational regimen.
When queried as to future studies for the R2 combination, Leonard replied, “Lenalidomide and rituximab (or other anti-CD20 antibodies) will continue to be evaluated in a number of lymphoma subtypes and in combination with other novel agents.”
Richard Simoneaux is a contributing writer.
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