Novel Treatment Approaches in Early Relapse of Follicular Lymphoma

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“Patients with follicular lymphoma who relapse early after treatment are a minority of patients, fortunately, but they are clearly patients with a different disease,” according to Jonathon B. Cohen, MD, of Emory University School of Medicine. At Emory’s 2018 Debates and Didactics in Hematology and Oncology conference on Sea Island, Georgia, Dr. Cohen described his approach to managing this challenging subset of patients.1

Most newly diagnosed patients with follicular lymphoma will have a reasonably long-life expectancy. Even patients in the intermediate-risk category have a 10-year overall survival rate exceeding 50%.2 High-risk patients certainly exist, but they account for less than one-third of the follicular lymphoma population, he pointed out.

Patients with follicular lymphoma who relapse early after treatment are a minority of patients, fortunately, but they are clearly patients with a different disease.
— Jonathon B. Cohen, MD

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The message from the German StiL study was that regardless of which induction regimen is given, the median progression-free survival is quite good.3 Even 6 cycles of chemotherapy (bendamustine/rituximab [Rituxan]) without maintenance rituximab was associated with prolonged remission (41 months) in that trial. Subsequent to the StiL trial, the MAINTAIN study evaluated the benefit of maintenance rituximab, showing improved outcomes with both 2 and 4 years of maintenance after first-line bendamustine/rituximab4; after 3 years of observation, the median progression-free and overall survival times had not been reached. Similarly, the BRIGHT trial validated the benefit of maintenance rituximab after bendamustine/rituximab.5 Finally, a relatively recent retrospective review of rituximab maintenance following bendamustine/rituximab found such benefits accrued in partial responders, although maintenance proved of little value for complete responders.6

“These trials are retrospective studies of patients who were treated according to their physician’s discretion, but they still suggest there are many patients with follicular lymphoma who will stay in remission for many years,” he said.

Poor Outcomes After Early Relapse

“There is one study, however, that changed how I think about follicular lymphoma and how I manage patients in the relapsed setting,” he said, referring to the National LymphoCare Study, which followed 2,655 patients diagnosed between 2004 and 2007. Using those data, Casulo et al evaluated the impact of early progression of disease after rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP). They showed that patients whose disease did not progress within 2 years of treatment had an overall survival comparable to that of the age-matched control population.7 “In general, these are not the patients I worry much about,” he commented. “They are typically not the patients who need novel therapies.”

In contrast, the patients in the study who developed early progression of disease had “a very different disease trajectory,” with a median overall survival of only about 5 years. Based on retrospective evaluations from a number of studies, about 20% of patients fall into this subset, although they tend to receive treatment that is comparable to that of their late-relapsing peers.8

“These patients have much worse results, despite similar management, so they are clearly a different group of patients than our typical patients with relapsed follicular lymphoma,” Dr. Cohen concluded.

Treatment Options for Early Relapse

Dr. Cohen’s first step in managing a patient with early relapse is to confirm the diagnosis and to exclude transformation (for which treatment may be different). When patients experience disease progression after treatment with something other than front-line induction therapy, Dr. Cohen approaches them as treatment-naive and offers bendamustine/rituximab, lenalidomide/rituximab (R2), or R-CHOP, frequently followed by maintenance therapy. However, the majority of those with early relapse have received chemoimmunotherapy, and alternative approaches are needed for them. Clinical trial enrollment is often the preferred option, but there are several other potentially effective treatments.

For patients with early-progressing follicular lymphoma who are young and fit, transplant is a reasonable consideration.
— Jonathon B. Cohen, MD

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One option is autologous stem cell transplant (ASCT). The National LymphoCare Study and the Center for International Blood and Marrow Transplant Research evaluated the role of early ASCT, comparing survival among patients who received ASCT within 1 year of treatment failure and those who did not.9 Overall survival at 2 years was 84% in the early-ASCT group vs 76% in the no-ASCT group; at 5 years, it was 73% and 60%, respectively. The German Low-Grade Lymphoma Study group also evaluated ASCT vs no-ASCT in patients treated in the prerituximab era and found improved outcomes with transplant.10

“To me, the real question is, does the patient with early-relapsed disease need a transplant or not? Although we typically think of transplant more for patients with aggressive disease, I think the data show that for patients with early-progressing follicular lymphoma who are young and fit, transplant is a reasonable consideration,” he maintained.

Is allogeneic transplant also a good option? A recent study by Smith et al found 5-year survival to be similar between the autologous transplant group (70%) and patients whose stem cells came from a matched sibling donor (73%); survival was inferior (49%) with stem cells from a matched unrelated donor.11 The nonrelapse mortality rate was lowest for the autologous transplant group, highest for the matched unrelated donor group, and intermediate for the matched sibling group. “In general, if you’re looking at where a patient will be in 5 years, there’s not a clear difference between autologous and allogeneic transplant,” he concluded.

“Autologous transplant is appropriate therapy off-protocol for transplant candidates with early progression of disease. I would not just give another cycle of chemotherapy and stop. This means that if a patient received bendamustine/rituximab before, I would not just give R-CHOP and stop, nor would I do the opposite. I also think there is a limited role for allogeneic transplant, although it’s something we consider for very young patients and for those who may have relapsed more than once,” he said.

He added that the transplant candidate pool has been growing. “We’ve liberalized our criteria for transplant in the past several years, and many patients whose disease progresses early—even in their 60s and early 70s—can be considered for transplant.”

Options Other Than Transplant

For patients who are not candidates for transplant (or opt against it), there are other effective treatments. One is the monoclonal antibody obinutuzumab (Gazyva), which has shown modest benefits over rituximab. In the GADOLIN trial of rituximab-refractory, mostly high-risk patients, obinutuzumab plus bendamustine followed by obinutuzumab maintenance was associated with a median progression-free survival of 29.2 months, vs 14.0 months with bendamustine alone (P < .0001).12 Although the better comparison may have been to rituximab, he said, the study suggests, especially in the early-relapse setting, “it’s appropriate to consider changing the antibody.”

The patients who fall into the early-relapsing category really need something different, and this trial [SWOG 1608 trial] is a step toward identifying optimal therapy.
— Jonathon B. Cohen, MD

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Lenalidomide (Revlimid) is also an option. In the MAGNIFY study, patients with non-Hodgkin lymphoma received induction with R2 and then were randomly assigned to receive maintenance with the same combination (in lower doses) or rituximab alone.13 In the subset of early-relapse patients, the overall response rate was 48% (vs 64% for the entire follicular lymphoma cohort). The median duration of response was not reached, and the 1-year progression-free survival rate was 45%. “If a patient with early relapse receives R2 and achieves a response, the patient is likely to remain in remission for an appreciable period” with this approach, he concluded.

Another choice would be the phosphoinositide 3-kinase (PI3K) inhibitor idelalisib (Zydelig), which is approved in the treatment of relapsed follicular lymphoma. In a subgroup analysis of a single-agent phase II study of mostly treatment-refractory, high-risk patients, the median progression-free survival was 11 months, vs 5 months for the prior regimen.14 Because of the known toxicities associated with idelalisib, “it is not for everyone,” he added. “However, if the patient is not a transplant candidate and a clinical trial is not an option, I would favor a drug like this, as opposed to giving another course of chemotherapy.”

SWOG 1608 in Follicular Lymphoma

  • A next-generation PI3K inhibitor, umbralisib (TGR-1202) is being evaluated in the ongoing SWOG 1608 trial.
  • Patients with early-progressing or refractory follicular lymphoma will be randomly assigned to one of three arms.
  • The three arms are: CHOP plus obinutuzumab, lenalidomide plus obinutuzumab, and umbralisib plus obinutuzumab. 

The next-generation PI3K inhibitor umbralisib (TGR-1202) is being evaluated in the phase II SWOG 1608 trial. Patients with early-progressing (within 2 years of bendamustine- or R-CHOP–based therapy) or refractory follicular lymphoma will be randomized to one of three arms: CHOP plus obinutuzumab, lenalidomide plus obinutuzumab, or umbralisib plus obinutuzumab. “This is a very important study,” commented Dr. Cohen. “The patients who fall into the early-relapsing category really need something different, and this trial is a step toward identifying optimal therapy.” ■

DISCLOSURE: Dr. Cohen is a consultant/advisor to Seattle Genetics, Pharmacyclics, Celgene, Millennium, Novartis, Infinity Pharmaceuticals, and AbbVie. He also has received research funding from Janssen, Novartis, Bristol-Myers Squibb, and Takeda.


1. Cohen J: My approach to patients with follicular lymphoma who relapse early. 2018 Debates and Didactics in Oncology and Hematology conference. Invited lecture. Presented July 26, 2018.

2. Solal-Céligny P, Roy P, Colombat P, et al: Follicular lymphoma international prognostic index. Blood 104:1258-1265, 2004.

3. Rummel MJ, Niederle N, Maschmeyer G, et al: Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: An open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 381:1203-1210, 2013.

4. Rummel MJ, Buske C, Hertenstein B, et al: Four versus two years of rituximab maintenance following bendamustine plus rituximab: Initial results of a prospective, randomized multicenter phase 3 study in first-line follicular lymphoma (the StiL NHL7-2008 MAINTAIN study). 2017 ASH Annual Meeting. Abstract 483.

5. Kahl BS, Burke JM, van der Jagt R, et al: Assessment of maintenance rituximab after first-line bendamustine-rituximab in patients with follicular lymphoma: An analysis from the BRIGHT trial. 2017 ASH Annual Meeting. Abstract 484.

6. Hill BT, Nastoupil L, Winter AM, et al: Maintenance rituximab or observation after frontline treatment with bendamustine-rituximab for follicular lymphoma: A real world analysis across 13 US cancer centers. 2017 ASH Annual Meeting. Abstract 2779.

7. 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.

8. Link BK, Day BM, Zhou X, et al: Second-line and subsequent therapy and outcomes for follicular lymphoma in the United States: Data from the observational National LymphoCare Study. Br J Haematol. April 2, 2018 (early release online).

9. Casulo C, Friedberg JW, Ahn KW, et al: Autologous transplantation in follicular lymphoma with early therapy failure: A National LymphoCare Study and Center for International Blood and Marrow Transplant Research analysis. Biol Blood Marrow Transplant 24:1163-1171, 2018.

10. Jurinovic V, Metzner B, Pfreundschuh M, et al: Autologous stem cell transplantation for patients with early progression of follicular lymphoma: A follow-up study of 2 randomized trials from the German Low Grade Lymphoma Study Group. Biol Blood Marrow Transplant 24:1172-1179, 2018.

11. Smith SM, Godfrey J, Ahn KW, et al: Autologous transplantation versus allogeneic transplantation in patients with follicular lymphoma experiencing early treatment failure. Cancer 124:2541-2551, 2018.

12. Sehn LH, Chua N, Mayer J, et al: Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): A randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol 17:1081-1093, 2016

13. Andorsky DJ, Yacoub A, Melear JM, et al: Phase IIIb randomized study of lenalidomide plus rituximab (R2) followed by maintenance in relapsed/refractory NHL: Analysis of patients with double-refractory or early relapsed follicular lymphoma. 2017 ASCO Annual Meeting. Abstract 7502. Presented June 3, 2017.

14. Salles G, Schuster SJ, de Vos S, et al: Efficacy and safety of idelalisib in patients with relapsed, rituximab- and alkylating agent-refractory follicular lymphoma: A subgroup analysis of a phase 2 study. Haematologica 102:e156-e159, 2017.