Chemotherapy-Free Treatment of Follicular Lymphoma: We Have the Ingredients, Now for Some Recipes

October 15, 2015

The treatment of patients with follicular lymphoma is undergoing a substantial shift due to rapid development of highly effective agents targeting lymphoma-specific biologic processes and the tumor microenvironment.

The treatment of patients with follicular lymphoma is undergoing a substantial shift due to rapid development of highly effective agents targeting lymphoma-specific biologic processes and the tumor microenvironment. This is particularly good news for patients and clinicians alike, since these drugs typically have favorable toxicity profiles relative to conventional cytotoxic chemotherapy, and in many instances have demonstrated substantial anti-lymphoma activity in heavily pretreated patients. The resulting US Food and Drug Administration (FDA) approvals of many of these drugs as single agents in specific indications have provided excellent therapeutic options for patients with relapsed or refractory follicular lymphoma.

In this issue of ONCOLOGY, Dr. Ujjani provides a comprehensive overview of the various agents in clinical development for treatment of B-cell lymphomas.[1] These agents include new monoclonal antibodies, antibody-drug conjugates, immunomodulatory drugs, agents targeting the B-cell receptor pathway, BH3 mimetics, checkpoint inhibitors, and chimeric antigen receptor (CAR)-modified T cells. Within each of these classes are several candidate therapeutic agents. Thus, with this ever-expanding repertoire it is becoming clear that many of the ingredients for the 21st century version of “CHOP” (cyclophosphamide, doxorubicin, vincristine, and prednisone) probably already exist, but the formulation of these into rationally designed biologic combinations is the key issue facing investigators. Since the approval of rituximab, monoclonal antibodies have been successfully combined with a variety of chemotherapies[2,3] and biologic agents,[4,5] as Dr. Ujjani describes in her article. In addition, Dr. Ujjani discusses experience with the next-generation monoclonal antibodies directed against B-cell surface antigens CD20, CD19, CD22, and CD79b. Importantly, however, while Sehn et al recently demonstrated that single-agent treatment with the next-generation anti-CD20 antibody obinutuzumab trended towards a higher objective response rate (ORR) than rituximab among patients with relapsed or refractory follicular lymphoma,[6] progression-free survival (PFS) was not significantly different between the two arms-a reminder that newer is not necessarily better.

Results of the phase III GALLIUM study of chemotherapy with either obinutuzumab or rituximab induction, followed by the same antibody as maintenance in treatment-naive indolent non-Hodgkin lymphoma are anticipated, although the different dosing schedules between the two monoclonal antibodies leaves the question of their relative equimolar potency open for debate. Nonetheless, a substantial PFS advantage in favor of obinutuzumab could result in this agent replacing rituximab as the monoclonal antibody of choice to be given with chemotherapy in front-line treatment of follicular lymphoma. Small-molecule inhibitors of key components of the B-cell receptor pathway-such as idelalisib, which inhibits the p110δ catalytic unit of phosphatidylinositol 3-kinase (PI3K),[7] and ibrutinib, which irreversibly binds to Bruton tyrosine kinase (BTK) to block downstream signaling[8]-have recently resulted in their FDA approval for specific disease indications. Although their toxicity profiles are more favorable than those of conventional cytotoxic agents, these agents are not entirely without risk: Idelalisib can cause transaminitis, colitis, and pulmonary toxicity,[9] while ibrutinib can provoke atrial fibrillation[10] and increase the risk of bleeding.[11] Unique toxicities may be dramatically and unpredictably potentiated when such agents are combined,[12] highlighting the need for caution in the design and conduct of these studies.

We are becoming increasingly aware that follicular lymphoma, like most cancers, is a heterogeneous disease. Casulo et al recently reported that patients who experience disease progression within 2 years of R-CHOP (rituximab with CHOP) therapy have a markedly increased risk of death.[13] It seems likely that many such patients bear mutations of genes responsible for DNA repair, such as TP53, or of epigenetic modifiers, which govern a range of cellular processes including proliferation, response to DNA damage, and apoptosis.[14] Pastore et al recently studied recurrent somatic mutations in a large number of patients with follicular lymphoma and found that genes such as EP300, FOXO1, CREBBP, and CARD11 were associated with shorter failure-free survival times, while mutations in MEF2B, ARID1A, and EZH2 were associated with longer treatment failure–free survival.[15] Although our understanding of the clinical implications of these data is rapidly expanding, the increasing availability of technologies such as next-generation sequencing is likely to facilitate the design and conduct of studies specifically targeting deregulated pathways in specific patients-so-called “precision medicine.”[16] Furthermore, the vast number of potential drug combinations makes rational selection of agents critical. Although there are many ways to approach this problem, methods such as in vitro drug screening often do not take into account the importance of the tumor microenvironment. This is particularly relevant in follicular lymphoma, since tumor cells appear to depend heavily on the microenvironment for survival and proliferation.[17] It may prove successful to select combinations of agents that target different steps of the cancer immunity cycle (eg, use of checkpoint inhibitors that enhance T-cell killing of lymphoma cells, paired with drugs that enhance cancer antigen release or presentation, are associated with priming and activation of T cells, or promote T-cell infiltration into tumors).[18] There are many ways to make a cake, as the saying goes; the task for us now is to develop “recipes” with the right “ingredients,” as nicely summarized by Dr. Ujjani. With time and new understanding, we hope our efforts will bring patients with follicular lymphoma closer to a cure.

Financial Disclosure:Dr. Fowler receives research funding from Celgene, Gilead, Janssen, and Roche, and he serves on the scientific advisory boards of Celgene, Janssen, and Roche. Dr. Cheah has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.


1. Ujjani C. Targeted approaches in the management of follicular lymphoma. Oncology (Williston Park). 2015;29:760-8.

2. 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. 2013;381:1203-10.

3. Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014;123:2944-52.

4. 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. 2014;15:1311-8.

5. Leonard JP, Jung S-H, 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. 2015 Aug 24. [Epub ahead of print]

6. Sehn LH, Goy A, Offner FC, et al. Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: final analysis of the GAUSS study. J Clin Oncol. 2015 Aug 17. [Epub ahead of print]

7. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370:1008-18.

8. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369:507-16.

9. Coutré SE, Barrientos JC, Brown JR, et al. Management of adverse events associated with idelalisib treatment: expert panel opinion. Leuk Lymphoma. 2015 May 19:1-8. [Epub ahead of print]

10. McMullen JR, Boey EJ, Ooi JY, et al. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 2014;124:3829-30.

11. Kamel S, Horton L, Ysebaert L, et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation. Leukemia. 2015;29:783-7.

12. Cheah CY, Nastoupil LJ, Neelapu SS, et al. Lenalidomide, idelalisib, and rituximab are unacceptably toxic in patients with relapsed/refractory indolent lymphoma. Blood. 2015;125:3357-9.

13. 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. 2015;33:2516-22.

14. Loeffler M, Kreuz M, Haake A, et al. Genomic and epigenomic co-evolution in follicular lymphomas. Leukemia. 2015;29:456-63.

15. 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. 2015 Aug 6. [Epub ahead of print]

16. Intlekofer AM, Younes A. Precision therapy for lymphoma--current state and future directions. Nat Rev Clin Oncol. 2014;11:585-96.

17. Scott DW, Gascoyne RD. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer. 2014;14:517-34.

18. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1-10.