Early Relapse in Follicular Lymphoma: Clinical Trial Data May Guide Management Decisions

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We and others are working on novel combinations specifically in patients failing chemoimmunotherapy and mostly in the relapsed setting. The good news for patients who relapse within 2 years is that help is on the way.
— Nathan H. Fowler, MD

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Approximately 20% of patients with follicular lymphoma will relapse within 2 years of diagnosis. Although the optimal management of these patients has not been established, clinicians may be guided by data from recent clinical trials, according to Nathan H. Fowler, MD, Associate Professor and Director of Clinical and Translational Research, Department of Lymphoma/Myeloma, at The University of Texas MD Anderson Cancer Center, Houston. Dr. Fowler described this early relapsing subset of patients and offered suggestions for management at the 2016 Pan Pacific Lymphoma Conference in Koloa, Hawaii.1

More than 95% of newly diagnosed patients with follicular lymphoma will respond to front-line chemoimmunotherapy. Their 5-year survival rates reach 70%, and median overall survival is approximately 14 years.

“In general, patients with follicular lymphoma live a long time; however, there’s a subset that does not. We know that given the same therapy, there are patients who can have dramatically different outcomes,” Dr. Fowler said, adding that early relapse can occur regardless of the induction regimen.

The National LymphoCare study identified 2,168 newly diagnosed patients with stage II, III, or IV follicular lymphoma.2 Of 588 patients who received first-line R-CHOP (rituximab [Rituxan]/cyclophosphamide/doxorubicin/vincristine/prednisone), 20% progressed within 2 years, and the 5-year overall survival of these “early progressors” was only 50%, compared with 90% for patients without early disease progression. Survival for patients who did not progress early actually mirrored that of the general population, an observation also made by other researchers.

“Median overall survival for all follicular lymphoma patients is over 14 years, so clearly this is a different subset of patients,” he reiterated. “Median overall survival is often less than 5 years if patients relapse early.”

Can Early Relapse Be Predicted?

Can poor-risk patients—those likely to progress early—be identified at baseline? To some degree, the answer is yes. Based on risk group as determined by the FLIPI (Follicular Lymphoma International Prognostic Index) score, 10-year survival after R-CHOP is 71% in low-risk patients but diminishes to 51% in intermediate-risk patients and to 36% in the poor-risk group.3

“You can predict groups that will do poorly, but if you look at individual patients, they are all over the board. Even some patients with high-risk disease will have remissions lasting a decade or longer,” noted Dr. Fowler.

Early Relapse in Follicular Lymphoma

Approximately 20% of patients with stage II, III, and IV follicular lymphoma will relapse within 2 years of front-line therapy. Their 5-year survival is about 50%.

There are no validated tests for predicting which patients will relapse, although patients who are PET-positive after induction are clearly at higher risk.

Management includes bendamustine or R-CHOP if they did not receive these regimens front line; combinations of bendamustine and rituximab or obinutuzumab; idelalisib; and lenalidomide plus a monoclonal antibody.

Stem cell transplant is a curative option in patients who can tolerate it.

Gene-expression profile may also predict survival, although this strategy lacks validation. According to risk profiles developed from a National Institutes of Health study 10 years ago, median survival ranges from approximately 4 years to 14 years depenting on a patient’s genetic risk.4 The study also found that the predictive genes resided in the tumor microenvironment, not in malignant clones.

“This key finding launched a number of studies that attempted to identify characteristics within lymph nodes, by immunohistochemistry, that can help us understand how patients will do after treatment. Unfortunately, most of the findings were contradictory, and few of the potentially predictive factors were further validated,” he said.

Therefore, according to Dr. Fowler, it is not possible to identify poor-prognosis patients by immunohistochemistry alone, but a recent model that pairs high-risk genes with FLIPI-related clinical factors may be more informative. The M7 FLIPI clinicogenetic risk model revealed a subset of patients remaining at particularly high risk after R-CHOP, whose median survival was only 3 years.5

Perhaps more useful for gauging prognosis after induction therapy is positron-emission tomography (PET) imaging. In a retrospective subset analysis of the PRIMA trial of upfront R-CHOP plus maintenance, PET-negative patients had a 42-month progression-free survival of 71%, vs 32% for PET-positive patients (P < .001).6 Similar findings were made in other studies.

Treating Early Relapses With Bendamustine

For patients relapsing within 2 years of induction therapy, Dr. Fowler offered some recommendations for management. The first step is to biopsy the tumor to rule out transformation. Treatment options for transformed patients include multiple chemotherapy regimens and, for some, stem cell transplant. For patients without transformation, treatment should be individualized and guided by clinical trial data, he added.

Bendamustine has been approved by the U.S. Food and Drug Administration (FDA) for relapsed disease and is a key option. “For patients who have had R-CHOP, bendamustine plus a monoclonal antibody—rituximab or obinutuzumab [Gazyva]—is what I recommend. If they have failed bendamustine within the first 2 years, I use R-CHOP,” he said.

In the LymphoCare study of patients relapsing after R-CHOP, salvage therapy with bendamustine led to a median progression-free survival of 8.26 months for nontransformed patients and 4.2 months for transformed patients. Both alkylator-refractory and fludarabine-refractory patients had response rates exceeding 60%.7

Bendamustine plus a second agent may be even better. The regimen of bendamustine plus rituximab and bortezomib (Velcade) yielded an overall response rate of 88%, a complete response rate of 53%, and median progression-free survival of 14.9 months in the phase II VERTICAL study, which was led by Dr. Fowler.8 Bendamustine plus obinutuzumab (followed by obinutuzumab maintenance) in the phase III GADOLIN study of rituximab-refractory patients was associated with a 2-year progression-free survival of 60%, vs < 40% for bendamustine monotherapy, and a 44% reduced risk of disease progression in patients refractory to both alkylating agents and rituximab.9

“For patients failing R-CHOP, I think bendamustine plus obinutuzumab is a reasonable strategy,” Dr. Fowler offered.

Idelalisib, Duvelisib, Ibrutinib, and Lenalidomide

For the challenging “double-refractory” subset, the selective PI3K inhibitor idelalisib (Zydelig) has also shown benefit. In a pivotal phase II study, 57% of patients responded to the single agent, and median progression-free survival was 11 months,10 which is similar to that seen with bendamustine, noted Dr. Fowler. “I think idelalisib is a very active drug in follicular lymphoma and is a very effective tool if toxicity is managed appropriately,” he added.

Its unique side effects include transaminitis (early on), colitis (delayed), and less commonly pneumonitis. Although some severe episodes and even deaths occurred soon after idelalisib’s approval, toxicities are generally manageable. To prevent reactivation of cytomegalovirus or infection with Pneumocystis carinii—which was observed in trials of idelalisib in combination with rituximab or bendamustine and led to an FDA alert11—patients should receive antibiotic prophylaxis and be monitored for cytomegalovirus, Dr. Fowler emphasized.

A similar PI3K inhibitor, duvelisib, achieved a 46% response rate in the phase II Dynamo study in double-refractory patients, according to a company press release stating the study met its primary endpoint.12 The phase II FRESCO study is now evaluating duvelisib plus rituximab vs R-CHOP in early relapsed disease.

Ibrutinib (Imbruvica) is also being evaluated in relapsed/refractory follicular lymphoma, and data will be presented at the 2016 American Society of Hematology (ASH) Annual Meeting, he added.

Lenalidomide (Revlimid) combinations may also be good options. Response rates of 61% have been seen when lenalidomide is paired with rituximab13 and 77% (including complete remissions in 70%) when given with obinutuzumab.14 These rates far exceed those achieved with lenalidomide as a single agent (21%), indicating lenalidomide may be resensitizing patients to rituximab, he said.

Stem Cell Transplant and Beyond

Finally, stem cell transplant offers an excellent chance for long-term survival for eligible patients. Long-term follow-up of autologous transplant studies shows a plateauing of the curve after 3 to 4 years and very few relapses after 8 years.15,16 Autologous transplant appears to “change the natural history” of 60% of patients, making it a “very nice option in patients who will tolerate it,” he commented.

Dr. Fowler and his colleagues are now performing “mini” allogeneic transplants in young, healthy patients, resulting in progression-free survival rates > 70% at 10 years or longer.17 Although this approach appears to offer the majority of patients a cure, he acknowledges the mortality risk is 15% in the first 20 months. “I think this is a potentially curative option, but only in patients who can tolerate it,” he cautioned.

Looking ahead, Dr. Fowler emphasized that current studies are evaluating immunomodulatory agents, small molecule inhibitors, and checkpoint inhibitors. “We and others are working on novel combinations specifically in patients failing chemoimmunotherapy and mostly in the refractory setting. Nearly all new trials are exploring novel biologic or targeted agents that won’t have the same resistance patterns and may be active in chemorefractory patients,” he explained. “The good news for patients who relapse within 2 years is that help is on the way.” ■

Disclosure: Dr. Fowler has served on the advisory board for and received research funding from Roche, Celgene, Infinity, and AbbVie.


1. Fowler NH: How to manage early relapsing/refractory follicular lymphoma. 2016 Pan Pacific Lymphoma Conference. Presented July 20, 2016.

2. 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.

3. Buske C, Hoster E, Dreyling M, et al: The Follicular Lymphoma International Prognostic Index (FLIPI) separates high-risk from intermediate- or low-risk patients with advanced-stage follicular lymphoma treated front-line with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with respect to treatment outcome. Blood 108:1504-1508, 2006.

4. Dave SS, Wright G, Tan B, et al: Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 351:2159-2169, 2004.

5. 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.

6. Trotman J, Fournier M, Lamy T, et al: Positron emission tomography-computed tomography (PET-CT) after induction therapy is highly predictive of patient outcome in follicular lymphoma: Analysis of PET-CT in a subset of PRIMA trial participants. J Clin Oncol 29:3194-3200, 2011.

7. Friedberg JW, Cohen P, Chen L, et al: Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin’s lymphoma: Results from a phase II multicenter, single-agent study. J Clin Oncol 26:204-210, 2008.

8. Fowler N, Kahl BS, Lee P, et al: Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: The phase II VERTICAL study. J Clin Oncol 29:3389-3395, 2011.

9. 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.

10. Gopal AK, Kahl BS, de Vos S, et al: PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 370:1008-1018, 2014.

11. FDA Alerts Healthcare Professionals About Clinical Trials with Zydelig (idelalisib) in Combination with other Cancer Medicines. Available at Accessed August 20, 2016.

12. Infinity Reports Topline Results From DYNAMO, A Phase 2 Monotherapy Study Of Investigational Molecule Duvelisib In Refractory Indolent Non-Hodgkin Lymphoma. Available at Accessed August 20, 2016.

13. 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.

14. Forbes SG, Samaniego F, Neelapu S, et al: Lenalidomide and obinutuzumab: Incidence and management of adverse events from a phase I/II study. 2016 Pan Pacific Lymphoma Conference. Poster.

15. Peters AC, Duan Q, Russell JA, et al: Durable event-free survival following autologous stem cell transplant for relapsed or refractory follicular lymphoma: Positive impact of recent rituximab exposure and low-risk Follicular Lymphoma International Prognostic Index score. Leuk Lymphoma 52:2124-2129, 2011.

16. Rohatiner AZ, Nadler L, Davies AJ, et al: Myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma at the time of second or subsequent remission: Long-term follow-up. J Clin Oncol 25:2554-2559, 2007.

17. Khouri IF, Saliba RM, Erwin WD, et al: Nonmyeloablative allogeneic transplantation with or without 90 yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results. Blood 119:6373-6378, 2012.