Over the past two decades, improved diagnostic accuracy and novel therapeutic approaches have resulted in profound improvements in overall survival in patients with follicular lymphoma (FL).
A 2013 study of patients diagnosed with FL demonstrated a median overall survival exceeding 18 years.1 That is nearly three times longer than that reported in a study of FL patients diagnosed between 1981 and 1990, where median overall survival with observation or immediate chlorambucil treatment was only 6.7 and 5.9 years, respectively; furthermore, only 34 percent of patients were alive at 10 years.2
Anti-CD20 monoclonal antibody therapy may be largely responsible for this improvement,3 but other new therapeutic approaches (including bendamustine,4,5 lenalidomide,6 and hematopoietic cell transplantation7) have also contributed to longer survival among FL patients. Whether or not any of these patients are definitively cured outside of the setting of allogeneic hematopoietic cell transplantation is not known, but as FL commonly presents in older patients, death from causes other than FL is becoming a more frequent occurrence.
Seeking a New Endpoint
Traditional endpoints for oncologic drug development have included complete and partial response rates and progression-free survival (PFS) – the latter of which has been viewed by the U.S. Food and Drug Administration as a surrogate for both clinical benefit and overall survival.8 In a disease like FL, however, where overall survival is now measured in decades rather than months or years, it is becoming increasingly challenging to demonstrate clinical benefit with novel therapeutic regimens when using PFS as an endpoint.
Indeed, an international collaborative group has recently suggested that complete response at 30 months is a good surrogate for PFS in FL, proposing this as a regulatory endpoint for new drug studies to improve feasibility and efficiency.9
Given the therapeutic progress in FL, we feel a new paradigm is needed for clinical research and an integration of exciting novel therapeutics in FL. PFS may no longer be a reasonable surrogate for clinical benefit in this disease, given that patients are frequently asymptomatic and are likely to have outstanding overall survival, with or without treatment.
Two recent randomized trials in low tumor-burden FL are instructive in this regard:10 Ardeshna et al. randomized asymptomatic patients to either observation or two years of rituximab therapy, and demonstrated (not surprisingly) improved PFS in patients receiving rituximab treatment.11 However, the three-year overall survival was 97 percent in both groups, and almost half of the patients assigned to initial observation had not required any treatment.
Kahl et al. randomized a similar patient population who responded to induction with single-agent rituximab to a prolonged maintenance strategy, or retreatment with rituximab upon progression.12 Although PFS was enhanced with continuous – and expensive – rituximab maintenance therapy, there was no significant difference between the two approaches in terms of the time to failure of rituximab treatment. As with the trial by Ardeshna et al., overall survival was outstanding in both arms, but a quality-of-life analysis suggested no improvements in anxiety and other measures for patients on continuous treatment, calling the true importance of "remission" in low-tumor burden FL into question.13
Rewriting the Disease's Natural History
Given these recent observations, it is clear that the vast majority of patients with FL have very prolonged overall survival and, given the asymptomatic and non-morbid nature of their disease, are at risk for overtreatment. However, certain subsets of patients remain resistant to standard therapies and suffer significant morbidity and mortality from this disease.
In an analysis from the National LymphoCare Study (NLCS), a longitudinal registry that enrolled more than 2,700 patients with FL between 2004 and 2007 and followed them for 10 years, the most common chemoimmunotherapy induction treatment was R-CHOP.14 Unfortunately, 20 percent of patients treated with R-CHOP either did not respond or experienced disease progression within two years; these patients had a markedly increased hazard ratio for death, and the median overall survival for this subgroup was only five years.15 After almost nine years of follow-up, two-thirds of the deaths among R-CHOP–treated patients in the NLCS occurred in these 20 percent of patients with early disease progression.
These results have been validated in an independent cohort from the Iowa–Mayo SPORE,15 who have preliminarily demonstrated that patients with FL without early PFS events have similar overall survival to age-matched controls.16 Taken together, these datasets indicate to us that the largest unmet clinical need in FL is the "high-risk" subset of patients who progress early, where it remains imperative to change the natural history of FL.
Presumably, these "high-risk" tumors have a unique biology which, to date, is not easily identified at diagnosis. Patients with high-risk disease by standard scores such as the Follicular Lymphoma-International Prognostic Index (FL-IPI) still may have prolonged overall survival with current therapeutic approaches.17,18
In the pre-rituximab therapeutic era, certain biomarkers were proposed (the presence of bcl-2 mutations and an "immune-response-2" gene expression profile) but have not been validated in the modern era.19,20
Vitamin D insufficiency has been validated as a predictor for inferior overall survival in patients with FL treated with R-CHOP,21 but whether this is indicative of tumor biology, or a surrogate for generalized illness, is not yet known. A recent effort to improve the clinical FL–IPI by adding gene mutation status (called "M7-FL–IPI") has improved the fidelity of high-risk FL–IPI to some degree and represents an important step in the right direction.22 However, more than 50 percent of patients with high-risk disease according to the M7 FL–IPI rating remain in remission two years after R-CHOP, suggesting this still may be an inadequate biomarker to truly determine the subset of patients with FL at highest risk for early death.
We feel that the most important advances in FL moving forward will come from understanding the underlying "high-risk" FL biology – including the events leading to histologic transformation, a frequent cause of morbidity and mortality – and applying precision medicine approaches to this biologically defined subset. Large phase III trials enrolling unselected patients with advanced-stage FL that incorporate prolonged maintenance approaches or continuous treatment with expensive medications and that use PFS should be avoided. Even in the relapsed setting, maintenance therapy has been shown to improve PFS over observation after bendamustine treatment, as seen in the recently reported GADOLIN trial, but this observations is unlikely to translate ultimately to clinical benefit for an unselected group of patients.23
Defining the Unmet Needs of Follicular Lymphoma Patients
For the majority of patients with FL who will die with rather than from their disease – and who have survival length similar to their counterparts without lymphoma – it is appropriate to consider rethinking our therapeutic goals. Such patients may receive numerous treatments over many years, all of which may be associated with acute, chronic, or long-term toxicities. If the patient's overall survival is not limited by the disease, then the objective of therapy should be to optimize his or her quality of life.
To that end, our field is in need of quality-of-life measurements that can sufficiently characterize aspects of disease, treatment-related side effects, and psychological and social factors (including financial effects of therapy) to serve as a primary endpoint for studies of novel approaches in lower-risk individuals. These tools will be essential for patients and for clinicians as they apply new agents and regimens to truly provide meaningful benefit beyond PFS.
To help the patients with greatest need (those who are most likely to die of FL), we propose to uniquely focus on the high-risk population in the U.S. National Clinical Trials Network.
First, we will study patients who experience relapse within two years of chemoimmunotherapy induction. In addition to exploring the role of novel therapeutic strategies (of which there are many candidates24) in a prospective clinical trial in this group of patients with known high mortality, we also plan to bank diagnostic tissue to extensively explore the biology of these tumors. With these enriched tumor banks for the high-risk population, we hope to establish and validate optimal biomarkers to identify these high-risk patients at diagnosis and utilize rational targeted therapeutic approaches in a precision way.
We ask pharmaceutical sponsors and international study groups to join us in this important focused approach. If we are able to substantially improve outcome in these 20 percent of FL patients, the majority of deaths in FL will be avoided; the other 80 percent of patients are doing extremely well with our current non-targeted therapeutic paradigm, and may even be considered for therapy de-escalation questions. Such a precision approach will substantially decrease costs of therapy, minimize morbidity, and truly provide clinical benefit for patients with FL – an added value currently missing from our empiric approaches to treatment.
- 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. 2013;122:981-7.
- Ardeshna KM, Smith P, Norton A, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet. 2003;362:516-22.
- Fisher RI, LeBlanc M, Press OW, et al. New treatment options have changed the survival of patients with follicular lymphoma. J Clin Oncol. 2005;23:8447-52.
- 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. 2008;26:204-10.
- Kahl BS, Bartlett NL, Leonard JP, et al. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a Multicenter Study. Cancer. 2010;116:106-14.
- Leonard J, Jung SH, Johnson J, et al. A randomized trial of lenalidomide alone vs. lenalidomide + rituximab in patients with recurrent follicular lymphoma: CALGB 50401 (Alliance). J Clin Oncol. 2015;33:3635-40.
- Evens AM, Vanderplas A, LaCasce AS, et al. Stem cell transplantation for follicular lymphoma relapsed/refractory after prior rituximab: a comprehensive analysis from the NCCN lymphoma outcomes project. Cancer. 2013;119:3662-71.
- McKee AE, Farrell AT, Pazdur R, et al. The role of the U.S. Food and Drug Administration review process: clinical trial endpoints in oncology. Oncologist. 2010;15 Suppl 1:13-8.
- Sargent DJ, Shi Q, De Bedout S, et al. Evaluation of complete response rate at 30 months (CR30) as a surrogate for progression-free survival (PFS) in first-line follicular lymphoma (FL) studies: Results from the prospectively specified Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) analysis with individual patient data (IPD) of 3,837 patients (pts). Abstract #8504. Presented at the 2015 American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, June 2, 2015.
- Friedberg JW. End of rituximab maintenance for low-tumor burden follicular lymphoma. J Clin Oncol. 2014;32:3093-5.
- Ardeshna KM, Qian W, Smith P, et al. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol. 2014;15:424-35.
- Kahl BS, Hong F, Williams ME, et al. Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: eastern cooperative oncology group protocol e4402. J Clin Oncol. 2014;32:3096-102.
- Wagner LI, Zhao F, Hong F, et al. Anxiety and health-related quality of life among patients with low-tumor burden non-Hodgkin lymphoma randomly assigned to two different rituximab dosing regimens: results from ECOG trial E4402 (RESORT). J Clin Oncol. 2015;33:740-8.
- Friedberg JW, Taylor MD, Cerhan JR, et al. Follicular lymphoma in the United States: first report of the national LymphoCare study. J Clin Oncol. 2009;27:1202-8.
- 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.
- Maurer MJ, Ghesquieres H, Ansell SM, et al Event-free survival at 12 months (EFS12) from diagnosis is a robust endpoint for disease-related survival in patients with follicular lymphoma in the immunochemotherapy era. Abstract #1664. Presented at the 2014 ASH Annual Meeting, San Francisco, California, December 6, 2014.
- Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood. 2004;104:1258-65.
- Nooka AK, Nabhan C, Zhou X, et al. Examination of the follicular lymphoma international prognostic index (FLIPI) in the National LymphoCare study (NLCS): a prospective US patient cohort treated predominantly in community practices. Ann Oncol. 2013;24:441-8.
- Correia C, Schneider PA, Dai H, et al. BCL2 mutations are associated with increased risk of transformation and shortened survival in follicular lymphoma. Blood. 2015;125:658-67.
- 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. 2004;351:2159-69.
- Kelly JL, Salles G, Goldman B, et al. Low serum vitamin D levels are associated with inferior survival in follicular lymphoma: a prospective evaluation in SWOG and LYSA studies. J Clin Oncol 2015;33:1482-90.
- Pastore A, Jurinovic V, Kridel R, et al. Integration of gene mutations improves risk prognostication in follicular lymphoma. Lancet Oncol. 2015;16:1111-22.
- Sehn LH, Chua N, Mayer J, et al. Primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma. Abstract #LBA8502. Presented at the 2015 American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, June 2, 2015.
- Jacobson CA, Freedman AS. Rethinking prognosis and therapy for follicular lymphoma. J Clin Oncol. 2015;33:2489-91.