Jonathan W. Friedberg, MD, MMSc
We have seen remarkable progress in the outcomes of patients with advanced-stage follicular lymphoma over the past 2 decades.1 Recent manuscripts and presentations describing long-term follow-up of randomized trials comparing various chemotherapy platforms (all combined with anti-CD20 antibodies) suggest that nearly half of patients with advanced-stage follicular lymphoma may remain disease-free 10 years after initial treatment.2-4 Indeed, the expected median overall survival of patients diagnosed with advanced-stage disease is now well over 2 decades.5 Rituximab (Rituxan) maintenance, and substituting obinutuzumab (Gazyva) for rituximab with chemotherapy combinations, may further improve progression-free survival, without demonstrating an impact on overall survival or histologic transformation.6,7
Based upon these data, there are now several excellent options for the initial treatment of advanced-stage, high tumor burden follicular lymphoma.
The combination of bendamustine and rituximab is commonly used,8 and it is my first choice for most patients requiring therapy.
RELEVANCE Trial Details
In September of this year, Morschhauser and colleagues published the results of the RELEVANCE trial9—reviewed in this issue of The ASCO Post—which compared rituximab/chemotherapy with rituximab/lenalidomide (Revlimid) in patients with previously untreated follicular lymphoma meeting GELF (Groupe d’Etude des Lymphomes Folliculaires) criteria10 for treatment. For patients randomized to receive rituximab/chemotherapy, treatment options included R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), R-CVP (rituximab, cyclophosphamide, vincristine, prednisone), and rituximab/bendamustine; the choice of chemotherapy regimen was made by the investigator for each patient prior to randomization. Maintenance rituximab was administered to all patients for 2 years.
Patients randomized to rituximab/lenalidomide were treated with 20 mg of lenalidomide daily for 3 weeks out of 4; dosing was then adjusted based upon response and tolerance, for a total of 18 months of treatment. Rituximab was administered in a similar fashion to the chemotherapy arms. The trial was designed as a superiority study, with 90% power to demonstrate a 12% difference in complete response rate at the end of treatment and 80% power to show a 23% lower risk of disease progression with rituximab/lenalidomide, corresponding to a hazard ratio of 0.77.
More than 1,000 patients were enrolled on the study. The majority of patients (72%) randomized to rituximab/chemotherapy received R-CHOP; 23% received rituximab/bendamustine. Although the toxicity differed between the two regimens, roughly 30% of patients in both arms did not complete therapy, and the overall rate of grade 3 and 4 events was similar in the two groups overall.
With a median follow-up of just over 3 years, the complete response rate (55% for rituximab/lenalidomide, 58% for rituximab/chemotherapy) and progression-free survival (hazard ratio = 1.10) were also similar between the arms. Subgroup analyses were unable to identify a group that benefited from rituximab/lenalidomide, but there appeared to be improved outcomes for the small number of patients with favorable early-stage disease treated with rituximab/chemotherapy. Two-year progression-free survival, a key prognostic factor in follicular lymphoma,11 was also equivalent between the two arms. Importantly, the outcomes of both arms were consistent with previously published trials in this disease.
New Treatment Option for Most Patients?
Based upon these results, should rituximab/lenalidomide be a new treatment option for previously untreated patients with follicular lymphoma? I think the answer is a qualified ‘yes’: it is an option, but one that I’m unlikely to currently recommend for use in most patients. To me, since overall toxicity and withdrawals were similar between the two arms, there was no substantial benefit demonstrated with the “chemo-free” approach.
Eighteen months of rituximab/lenalidomide is a prolonged duration of therapy, which increases both the physical and financial costs of treatment. With early follow-up, the progression-free survival curves are overlapping, suggesting short-term equivalent outcomes. Since rituximab/lenalidomide was administered for 18 months, the time off of lenalidomide for many patients was limited at the current analysis, with the relatively short median follow-up of 3 years. Since we know that outcomes with rituximab/chemotherapy may be durable for at least 10 years, it will be important to follow patients on the RELEVANCE trial to ensure the progression-free survival curve of the rituximab/lenalidomide group does not separate from the rituximab/chemotherapy group.
To me, since overall toxicity and withdrawals were similar between the two arms, there was no substantial benefit demonstrated with the ‘chemo-free’ approach.— Jonathan W. Friedberg, MD, MMSc
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Despite these limitations, the RELEVANCE trial clearly demonstrates the substantial activity of the rituximab/lenalidomide combination in follicular lymphoma and makes this an appealing second-line option after induction chemoimmunotherapy. Smaller studies in relapsed disease emphasize the importance of rituximab combined with lenalidomide compared with lenalidomide alone.12
The recently published GALEN trial determined the recommended phase II dose to be 20 mg of lenalidomide when combined with obinutuzumab in the relapsed setting, and 63% of patients in the phase I trial responded to the combination.13 The lenalidomide/obinutuzumab combination is currently being studied in the U.S. National Clinical Trials Group study S1608 (ClinicalTrials.gov identifier NCT03269669), which is targeting patients with follicular lymphoma who relapse within 2 years of induction chemoimmunotherapy. This approach is in keeping with a recent clinical trials planning meeting, which concluded the greatest unmet need in follicular lymphoma is the early-relapse patient population.14
More Data Needed to Predict Those Who May Benefit
Morschhauser and colleagues are to be congratulated on the rigor of the RELEVANCE trial, accomplishing a 1,000+ patient study in previously untreated follicular lymphoma. Ideally, subsets of patients may ultimately be identified who particularly benefit from one induction strategy over another or possibly the combination of chemotherapy, rituximab, and lenalidomide.15 As previously mentioned, there were no clinical factors identified in the trial that could predict such a subset of patients. Whether novel biologic subsets defined by gene-expression profiles published by the LYSA group16 and others17 may assist in this
Until we have longer follow-up or can identify subsets of patients who particularly benefit from rituximab/lenalidomide, I will continue to use rituximab/chemotherapy as my standard induction approach.— Jonathan W. Friedberg, MD, MMSc
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regard remains to be seen. Ideally, quality of life and patient preferences should play a major role in the decision of upfront therapy; these measures unfortunately were not included in the RELEVANCE publication.
Until we have longer follow-up or can identify subsets of patients who particularly benefit from rituximab/lenalidomide, I will continue to use rituximab/chemotherapy as my standard induction approach. However, based in part on the results of the RELEVANCE trial, I now strongly consider lenalidomide combinations in first relapse of follicular lymphoma. ■
Dr. Friedberg is Samuel Durand Professor of Medicine and Oncology at the University of Rochester, New York, and Director of the Wilmot Cancer Institute, Rochester, New York.
DISCLOSURE: Dr. Friedberg is a consultant/advisor to Bayer, has received (institution) research funding from Seattle Genetics and Kite Pharma, and has received travel/accommodations/expenses from Roche.
1. Friedberg JW: Progress in advanced-stage follicular lymphoma. J Clin Oncol 36:2363-2365, 2018.
2. Luminari S, Ferrari A, Manni M, et al: Long-term results of the FOLL05 Trial comparing R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage symptomatic follicular lymphoma. J Clin Oncol 36:689-696, 2018.
3. Rummel MJ, Maschmeyer G, Ganser A, et al: Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment in patients with indolent lymphomas: Nine-year updated results from the StiL NHL1 study. 2017 ASCO Annual Meeting. Abstract 7501. Presented June 3, 2017.
4. Shadman M, Li H, Rimsza L, et al: Continued excellent outcomes in previously untreated patients with follicular lymphoma after treatment with CHOP plus rituximab or CHOP plus (131)I-tositumomab: Long-term follow-up of phase III randomized study SWOG-S0016. J Clin Oncol 36:697-703, 2018.
5. Tan D, Horning SJ, Hoppe RT, et al: Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: The Stanford University experience. Blood 122:981-987, 2013.
6. Marcus R, Davies A, Ando K, et al: Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 377:1331-1344, 2017.
7. Salles GA, Seymour JF, Feugier P, et al: Long term follow-up of the PRIMA study: Half of patients receiving rituximab maintenance remain progression free at 10 years. 2017 ASH Annual Meeting. Abstract 486.
9. Morschhauser F, Fowler NH, Feugier P, et al: Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med 379:934-947, 2018.
10. 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. J Clin Oncol 15:1110-1117, 1997.
11. Casulo C, Byrtek M, Dawson KL, et al: Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: An analysis from the National LymphoCare Study. J Clin Oncol 33:2516-2522, 2015.
12. Leonard JP, Jung SH, Johnson J, et al: Randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma: CALGB 50401 (Alliance). J Clin Oncol 33:3635-3640, 2015.
13. Morschhauser F, Salles G, Le Gouill S, et al: An open-label, phase Ib study of obinutuzumab plus lenalidomide in relapsed/refractory follicular B-cell lymphoma. Blood. August 1, 2018 (early release online).
14. Maddocks K, Barr PM, Cheson BD, et al: Recommendations for clinical trial development in follicular lymphoma. J Natl Cancer Inst 109:djw255, 2017.
15. Tilly H, Morschhauser F, Casasnovas O, et al: Lenalidomide in combination with R-CHOP (R2-CHOP) as first-line treatment of patients with high tumour burden follicular lymphoma: A single-arm, open-label, phase 2 study. Lancet Haematol 5:e403-e410, 2018.
16. Huet S, Tesson B, Jais JP, et al: A gene-expression profiling score for prediction of outcome in patients with follicular lymphoma: A retrospective training and validation analysis in three international cohorts. Lancet Oncol 19:549-561, 2018.
17. Pastore A, Jurinovic V, Kridel R, et al: Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: A retrospective analysis of a prospective clinical trial and validation in a population-based registry. Lancet Oncol 16:1111-1122, 2015.
In the phase III RELEVANCE trial reported in The New England Journal of Medicine by Franck Morschhauser, MD, PhD, of The University of Lille, Centre Hospitalier Universitaire Lille, France, and colleagues, no difference in the complete response rate or interim progression-free survival was found...