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Combination Immunotherapy With Lenalidomide Plus Rituximab in Indolent NHL: Time to Replace Rituximab Monotherapy?


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With increasing knowledge on the key role of the tumor microenvironment in lymphomagenesis, treatments for indolent B-cell lymphoma, especially follicular lymphoma, are mechanistically moving toward a more immunomodulatory approach. Chemotherapy-free regimens are an attractive alternative to conventional, cytotoxic immunochemotherapy regimens.

Lenalidomide is an immunomodulatory agent with multiple mechanisms of action that are not fully characterized; however, recently identified pathways support a substantial biologic effect by reactivating and heightening immune system responses to


R2 [lenalidomide plus rituximab] represents an important new treatment option in patients with previously treated follicular lymphoma.
— Franck Morschhauser, MD, PhD

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malignant cells.1 Preclinical and ex vivo studies have shown that lenalidomide synergizes with anti-CD20 antibodies (eg, rituximab, obinutuzumab) to enhance the function of T and NK cells, increase antibody-dependent cellular cytotoxicity, and repair defective synapse formation in B-cell lymphoma cells.1,2 These complementary mechanisms lead to restoration of the immune system, enabling a battle against tumor cells without permanently damaging the healthy microenvironment or causing long-term immune suppression. It is hypothesized that the complementary mechanisms between lenalidomide and anti-CD20 agents allow opportunities for better outcomes with subsequent lines of therapy as well, which is important because relapse is expected in indolent B-cell lymphoma.

Results From the AUGMENT Trial

Results from the phase III, multicenter, randomized AUGMENT trial—reviewed in this issue of The ASCO Post—lend credence to the use of lenalidomide plus rituximab (R2) especially in patients with relapsed or refractory follicular lymphoma grades 1 to 3a, which accounted for 82% of the study population.3 This study compared outcomes with R2 vs rituximab (with placebo [R/placebo]) administered over 1 year.

The primary endpoint of progression-free survival was significantly superior in all patients receiving R2, including all prespecified subgroups and along with improvements in other secondary/exploratory efficacy endpoints (eg, response rates, overall survival, time to next treatment). The exception to this outcome was in patients with marginal zone lymphoma, although it is difficult to draw strong conclusions in this small subgroup because these patients made up only 18% of the overall patient population.

Additionally, the safety profile was similar to past experiences with the combination and either single agent, and without an increase in second primary malignancies. Although there was a higher incidence of adverse events with the R2 arm, it did not prevent patients from receiving therapy, as indicated by a higher percentage of patients completing therapy with R2 than R/placebo (71% vs 61%). The most common toxicities with R2 were predictable and manageable with physicians becoming increasingly familiar with this regimen.

LENALIDOMIDE PLUS RITUXIMAB

For more on the AUGMENT trial of lenalidomide plus rituximab in relapsed or refractory indolent lymphoma, see an interview with John P. Leonard, MD, on The ASCO Post Newsreels at www.ascopost.com/videos.

The AUGMENT trial showed an unexpected overall survival benefit in patients with follicular lymphoma, with fewer than half the number of patient deaths in the R2 arm (n = 11) than in the R/placebo arm (n = 24). Although the study was not powered to detect statistical differences, and overall survival data are immature requiring longer follow-up, the estimated 2-year overall survival rates were impressive at a reported 95% for R2 and 86% for R/placebo.

The AUGMENT trial had a few limitations, mainly selection of patients with more favorable prognostic features since they could not be refractory to rituximab, and 57% of patients had received only a single prior therapy. However, 73% had stage III/IV disease, and 51% had a high tumor burden according to the Groupe d’Etude des Lymphomas Folliculaires (GELF) criteria,4,5 reinforcing the need to effectively manage their disease with an active treatment regimen.

Another well-acknowledged study limitation was the difference in median progression-free survival for the R2 treatment assessed by independent review committee (39.4 months) and investigators (25.4 months). However, the hazard ratios were similar for each comparison with R/placebo, and the main message is the consistent durability of disease control compared with R/placebo (median progression-free survival = 14.1 months).

Experience With Lenalidomide Plus Anti-CD20 Antibodies

Results from the AUGMENT trial follow a recent report from the RELEVANCE trial, which evaluated R2 in the front-line setting in patients with advanced follicular lymphoma and compared it with rituximab combined with different chemotherapy combinations (R-chemotherapy: R-CHOP [rituximab plub cyclophosphamide/doxorubicin/vincristine/prednisone], R-B [rituximab plus bendamustine], or R-CVP [rituximab plus cyclophosphamide/vincristine/prednisolone]).6 Although R2 did not show superiority over R-chemotherapy in the RELEVANCE trial, efficacy outcomes were similar between the arms. These findings support R2 as an active treatment option in the front-line setting in patients who may be unable or unwilling to receive

The collective study experience reinforces that lenalidomide/anti-CD20 regimens show consistent safety profiles in multiple settings and provide an active therapy….
— Franck Morschhauser, MD, PhD

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chemotherapy. Promising activity has also been reported from the GALEN phase Ib/II study of obinutuzumab,7,8 with accompanying supportive evidence from ex vivo studies to corroborate the complementary mechanisms of action.2

Altogether, the immunotherapy regimen of lenalidomide plus an anti-CD20 antibody (rituximab or obinutuzumab) has now been studied in multiple phase II and III studies, both in the front-line6,9 and relapsed or refractory7,8,10 setting in indolent B-cell lymphoma. The collective study experience reinforces that lenalidomide/anti-CD20 regimens show consistent safety profiles and provide an active therapy, even in patients with bulky disease or high-risk Follicular Lymphoma International Prognostic Index at primary diagnosis, those with multiple prior lines of therapy, those deemed refractory to rituximab, and patients with relapse or disease progression within 2 years of initial -treatment.6-8,10,11

Closing Thoughts

As Leonard and colleagues have proven in their AUGMENT trial and as noted in their publication, the magnitude of efficacy differences between R2 and R/placebo arms was clinically meaningful, with R2 presenting a good benefit:risk profile.3 Coupled with the acceptance and integration of R2 as a valuable clinical treatment option by a panel of lymphoma experts, these results support the replacement of rituximab monotherapy with R2 as standard of care in relapsed or refractory indolent non-Hodgkin lymphoma. Additionally, R2 represents an important new treatment option in patients with previously treated follicular lymphoma. It is encouraging to see the progression-free and overall survival advantages for R2 with a convenient and straightforward 1-year treatment duration in the AUGMENT study. It will be of interest to follow how survival data mature with longer follow-up in AUGMENT compared with the MAGNIFY, GALEN, and even RELEVANCE trials—all of which had maintenance treatment with a longer exposure to lenalidomide and an anti-CD20. Overall, the AUGMENT trial and complementary molecular analyses pave the way for continued evaluation of immunotherapy approaches with lenalidomide combined with anti-CD20 antibodies as a backbone in patients with B-cell follicular lymphoma. 

Dr. Morschhauser is Professor of Hematology at the University of Lille, Centre Hospitalier Régional Universitaire de Lille in Lille, France.

DISCLOSURE: Dr. Morschhauser has received honoraria from Celgen, Roche, BMS, Giliad, Epizyme, and Bayer; is a consultant/advisor for Celgene, Roche, BMS, Gilead, and Epizyme; and has received lecture fees from Janssen and Novartis.

REFERENCES

1. Chiu H, Trisal P, Bjorklund C, et al: Combination lenalidomide-rituximab immunotherapy activates anti-tumour immunity and induces tumour cell death by complementary mechanisms of action in follicular lymphoma. Br J Haematol 185:240-253, 2019.

2. Vo DN, Alexia C, Allende-Vega N, et al: NK cell activation and recovery of NK cell subsets in lymphoma patients after obinutuzumab and lenalidomide treatment. Oncoimmunology 7:e1409322, 2017.

3. Leonard JP, Trneny M, Izutsu K, et al: AUGMENT: A phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol. March 21, 2019 (early release online).

4. Brice P, Bastion Y, Lepage E, et al: Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: A randomized study from the Groupe d’Etude des Lymphomes Folliculaires. Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 15:1110-1117, 1997.

5. Salles G, Seymour JF, Offner F, et al: Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): A phase 3, randomised controlled trial. Lancet 377:42-51, 2011.

6. Morschhauser F, Fowler NH, Feugier P, et al: Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med 379:934-947, 2018.

7. Morschhauser F, Le Gouill S, Feugier P, et al: A phase II LYSA study of obinutuzumab combined with lenalidomide for relapsed or refractory follicular B-cell lymphoma. Hematol Oncol 35:52-53, 2017. Abstract 37.

8. Morschhauser F, Salles G, Le Gouill S, et al: An open-label phase 1b study of obinutuzumab plus lenalidomide in relapsed/refractory follicular B-cell lymphoma. Blood 132:1486-1494, 2018.

9. Fowler NH, Davis RE, Rawal S, et al: Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: An open-label, phase 2 trial. Lancet Oncol 15:1311-1318, 2014.

10. Rummel MJ, Andorsky DJ, Coleman M, et al: Response rate to lenalidomide plus rituximab (R2) is independent of rituximab-refractory status: Initial interim analysis of MAGNIFY phase IIIb study of R2 followed by maintenance in R/R indolent NHL. 2018 European Hematology Association Congress. Abstract PF439. Presented June 15, 2018.

11. Tuscano JM, Dutia M, Chee K, et al: Lenalidomide plus rituximab can produce durable clinical responses in patients with relapsed or refractory, indolent non-Hodgkin lymphoma. Br J Haematol 165:375-381, 2014.


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