How I Treat in Brief: Early Relapsing Follicular Lymphoma

Carla Casulo, MD, and Paul M. Barr, MD, from the Wilmot Cancer Institute at the University of Rochester Medical Center in New York, reviewed the treatment options for patients with follicular lymphoma (FL) whose disease relapses within 24 months of treatment with chemoimmunotherapy, including investigational therapies. Below, we summarize their approach.

This material is repurposed from “How I treat early-relapsing follicular lymphoma” published in the January 30, 2019, edition of Blood.

  • One in 5 patients with FL will experience early disease recurrence after frontline chemoimmunotherapy – a robust marker of poor outcome in FL.
  • Strategies to identify predictors of early relapse, such as the m7-FLIPI and use of gene expression profiling, are ongoing, combining molecular and clinical biomarkers. Circulating tumor/cell-free DNA is another emerging method for predicting early relapse.
  • Because no treatment has been shown to be superior to another in this setting, clinical trial referral should be prioritized.
  • If a patient is not a candidate for a clinical trial, treatment options include chemotherapy (such as bendamustine or CHOP) and targeted therapies (such as immunomodulators, PI3K inhibitors, and anti-CD20 antibodies).
  • For transplant-eligible patients, consolidative transplant should be considered to induce prolonged remissions and improve prognosis.

Follicular lymphoma (FL) is the most frequently occurring indolent non-Hodgkin lymphoma. Although usually considered incurable, the development of anthracycline-containing chemotherapy and the anti-CD20 monoclonal antibody rituximab have improved outcomes for FL with each passing decade. However, most patients have a relapsing and remitting pattern of illness, requiring numerous treatments over the course of their lifetime.

Approximately 20% of patients with FL experience early disease recurrence, defined as progression of disease within 24 months of frontline chemoimmunotherapy initiation (POD24). Early relapse has been established as one of the best available predictors of poor survival, with an estimated 5-year overall survival (OS) rate of 50%, compared with 90% among those without POD24.

In this overview, Drs. Casulo and Barr discuss the prognostic impact of early relapse and share their approach to identifying and treating these patients.

Predicting Early Relapse

There is no standardized method to prospectively identify which patients with new FL will have future POD24. Although three-quarters of patients with POD24 have a high-risk pretreatment FL International Prognostic Index (FLIPI) score, a high-risk FLIPI score at the time of FL diagnosis can also be found in approximately 40% of patients without subsequent POD24.

Researchers have developed and are testing other predictive models adding clinical and genetic variables – including male sex, elevated baseline β2 microglobulin, poor performance status (PS), and molecular markers – to improve the accuracy of identifying future POD24.

Other novel models have incorporated relevant biologic factors into existing prognostic models, such as m7-FLIPI, which includes the mutational status of 7 frequently recurring genes in FL. Gene expression profiling before treatment also is being studied to establish which gene signatures are associated with patients who will experience treatment failure and poor progression-free survival.

In addition to these biomarkers, PET is under consideration for use alone and in combination with clinical and molecular markers (e.g., circulating tumor DNA) to identify the highest-risk patients, but further validation is required.

Currently, there are insufficient data to use the FLIPI, the m7-FLIPI, or other prognostic systems to predict for early progression. As such, outside of a clinical trial, FLIPI is recommended at the time of diagnosis for standard risk stratification, as well as clinical monitoring of all patients after completion of initial chemoimmunotherapy.

Treatment of Early Relapsing FL

The goal for any next therapy after early relapse after frontline chemoimmunotherapy involves overcoming chemotherapy resistance, targeting mechanisms of disease, and achieving durable disease control. Ideally, treatment will induce complete remission (CR), given the association with improved outcomes after chemoimmunotherapy and consolidative hematopoietic cell transplantation (HCT).

Clinical trial participation should be considered the primary treatment option for patients experiencing POD24, given the limited prospective evidence guiding treatment decisions for this population. A treatment algorithm is presented in the FIGURE.

Role of Biopsy

Patients with recurrent FL should undergo an excisional biopsy before initiating next therapy to rule out transformation to another histology or malignancy. If large-cell transformation or grade 3b FL is discovered on biopsy, however, patients should be treated with a regimen similar to that used in relapsed/refractory diffuse large B cell lymphoma rather than an FL regimen.


Bendamustine-based therapy has become a common induction strategy for patients with symptomatic advanced-stage FL, given its favorable safety profile and the suggestion of superior disease control. A similar proportion of patients experience early disease progression with bendamustine-based therapy compared with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), although this proportion is somewhat smaller when bendamustine-based therapy is combined with obinutuzumab.

There are few data on the use of bendamustine plus rituximab (BR) or rituximab plus CHOP (R-CHOP) as secondline therapy for patients with POD24, but a more aggressive chemotherapy-based sequence, such as R-CHOP followed by maintenance rituximab, may help overcome therapeutic resistance in this setting.

Hematopoietic Cell Transplantation

For fit patients younger than age 65 who do not have an appropriate clinical trial option, we consider aggressive treatment involving salvage chemoimmunotherapy and consolidative autologous HCT (AHCT) to induce prolonged remissions in FL.

Matched sibling donor (MSD) or unrelated donor (URD) allogeneic HCT (alloHCT) may be an option for those who have had a relapse after AHCT or who have extensive bone marrow involvement that precludes use of AHCT. Studies have shown that MSD and URD alloHCT are associated with lower relapse rates and similar OS to those undergoing AHCT, but with increased non-relapse mortality.

Given the consideration of clinical trials and HCT at this point in the treatment algorithm, this is often an appropriate time for referral of patients to large academic institutions.

Case 1: High Risk for Early Relapse?

A 48-year-old man presents for a second opinion after treatment of grade 3a FL. He had stage III disease at diagnosis with a bulky (12-cm) retroperitoneal mass. He received 6 cycles of R-CHOP, with CR by PET and marked reduction in the size of the lymph node mass. He tolerated therapy well and has been on rituximab maintenance for 1 year. Routine surveillance CT scans showed an increase in a large retroperitoneal lymph node mass, new pulmonary nodules, and bony lesions. He had a laparoscopic biopsy of the retroperitoneal mass, showing a mix of grade 2 to 3a FL. A CT-guided biopsy of a pulmonary nodule showed grade 2 FL. He has no other medical history, and PS is 0. The patient received BR for 6 cycles with PET CR and resolution of hypermetabolic pulmonary nodules and bony lesions.

Case 1 Commentary: Given promising survival outcomes in subsets of patients with POD24 who are young and have good PS and few comorbidities, consolidation with AHCT is the recommended course for this patient. The survival benefit with AHCT is greatest when transplantation is performed within the first year of therapy failure, so ideally the patient will undergo AHCT now. Based on his young age and short remission duration, human leukocyte antigen typing of his two siblings is recommended if he relapses after AHCT to allow the future possibility of MSD alloHCT if needed.

Targeted Therapies for Early Relapsing FL

Data from clinical trials suggest that targeted agents provide similar efficacy patients with FL and POD24, compared with unselected patients with relapsed disease. For patients without clinical trial options and who are not candidates for HCT, we recommend use of targeted therapeutics, with primary consideration of lenalidomide, obinutuzumab, or a PI3K inhibitor.


An alternative treatment strategy for early progressing FL uses agents with molecular targets distinct from those of traditional chemoimmunotherapy. Lenalidomide has significant activity in relapsed FL, with a documented overall response rate (ORR) of 55%. Research has shown that response rates are increased further when lenalidomide is combined with rituximab or obinutuzumab.

PI3K Inhibition

Phosphatidyl-inositol-3 kinase (PI3K) inhibition also has demonstrated significant activity in patients with relapsed FL. Idelalisib, copanlisib, and duvelisib have been approved for patients with relapsed or refractory FL who have received at least two prior systemic therapies, with ORRs of more than 50%.

The investigational PI3K delta (PI3Kd) inhibitor umbralisib has a distinct chemical structure that allows for once-daily dosing, and early-stage research suggests a similar pattern of response, with a potentially improved safety profile, compared with other PI3Kd inhibitors.

Anti-CD20 Inhibition

The anti-CD20 monoclonal antibody rituximab, either alone or in combination with chemotherapy regimens, is a standard firstline treatment for FL. Further study with anti-CD20 agents is being pursued, given nonoverlapping toxicity profiles and possible synergistic efficacy. Obinutuzumab, a glycol-engineered humanized type 2 anti-CD20 monoclonal antibody, is approved in combination with chemotherapy, followed by obinutuzumab alone, for the firstline treatment of patients with stage II bulky, stage III, or stage IV FL.

Case 2: A Clinical Trial Candidate?

A 71-year-old woman with obesity and asthma was diagnosed with grade 2 FL less than 1 year ago after noticing enlarging lymph nodes, fatigue, and night sweats. She had high tumor burden disease, with lymphadenopathy in the bilateral cervical chains, axillae, mediastinum, retroperitoneum, mesentery, and inguinal areas, ranging in size from 2 to 4 cm. She had bone marrow involvement, but no other areas of extranodal disease. FLIPI score was 4 (intermediate risk) and a PET scan revealed standardized uptake values up to 8. Treatment with rituximab and chemotherapy resulted in PET CR and resolution of her initial symptoms. She presents 8 months after completing therapy (14 months from diagnosis) with new enlarged axillary and inguinal lymphoma nodes and progressive fatigue. A CT scan demonstrates extensive lymphadenopathy above and below the diaphragm, measuring between 2.5 and 5 cm.

Case 2 Commentary: The patient had an excisional biopsy demonstrating recurrent grade 2 FL. Blood tests were normal. A PET scan did not reveal occult areas suggestive of transformation. Bone marrow biopsy showed no evidence of involvement. Aside from asthma and obesity, she had no other competing comorbid conditions. Eastern Cooperative Oncology Group PS was 0. The patient was enrolled in the SWOG1608 intergroup clinical trial for patients with FL and POD24. The trial is comparing CR rates of additional chemoimmunotherapy (obinutuzumab with CHOP or bendamustine) against obinutuzumab paired with either lenalidomide or umbralisib. The patient was randomly assigned to the umbralisib arm. She has completed 5 cycles of treatment with good tolerance. She is experiencing clinical response, with reduction in size of her lymphadenopathy.

Future Directions

Identification of novel therapies for the vulnerable group of patients with early relapsing FL has emerged as the highest priority in lymphoma clinical trial research by the National Cancer Institute. Because no treatment has been shown to be superior to another in this setting, clinical trial referral should be prioritized.

Ongoing research is attempting to identify which patients experiencing early therapy failure have the greatest risk of death, which factors predict response to treatment, and which pathways should be targeted therapeutically. There also is optimism regarding the study of biomarkers of FL disease resistance and transformation. We expect these new discoveries to pave a way for risk-adapted approaches that can be applied at the time of diagnosis, change the natural history of FL, and help patients live longer, healthier lives.