Management of relapsed or refractory follicular lymphoma in adults

BR: bendamustine plus rituximab; CAR-T: chimeric antigen receptor T cell; CR: complete remission; CVP: cyclophosphamide, vincristine, and prednisone; FL: follicular lymphoma; HCT: hematopoietic cell transplantation; R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone;

* Clinicians should have a low threshold to biopsy at the time of disease progression to confirm relapse and evaluate for histologic transformation. Signs or symptoms that suggest histologic transformation include:

• Rapid progression of lymphadenopathy
• Infiltration of uncommon extranodal sites (excluding the bone marrow)
• Development of systemic symptoms (eg, fever, weight loss, night sweats)
• Elevated serum lactate dehydrogenase
• Hypercalcemia

Imaging with a combined positron emission tomography/computed tomography (PET/CT) scan can be used to target biopsy at a lymph node with the highest activity on PET.

¶ The management of histologic transformation is based on patient characteristics and disease biology. This is discussed separately.

Δ Patients with asymptomatic recurrent FL do not necessarily require immediate treatment, but they should be followed closely for the development of symptomatic disease. Watchful waiting is unlikely to impact overall survival in this setting.

◊ Patients with early treatment failure are unlikely to achieve long-term survival with immunotherapy or chemoimmunotherapy alone. Low quality evidence suggests that autologous HCT may prolong survival in such patients who achieve a complete response. Those unable to achieve a complete response may be candidates for CAR-T therapy. We favor novel agents (eg, lenalidomide, tazemetostat) for patients who are not candidates for HCT.

§ For patients without early treatment failure, the choice of therapy depends on the response to prior therapy, mutation status, and the patient's physical status/comorbidities that may impact their ability to tolerate systemic chemotherapy. Obinutuzumab plus either chemotherapy or lenalidomide is preferred for first relapse in fit patients with highly symptomatic disease. In contrast, single agent rituximab is preferred for patients with comorbid conditions that make them poor candidates for chemotherapy and for those with a low tumor burden, good prior response to single agent rituximab, and/or disease progressing slowly over years. We offer tazemetostat to patients with EZH2 mutation in first relapse and to patients without EZH2 mutation in subsequent relapse. Patients with multiply relapsed disease may be candidates for novel agents, high dose chemotherapy with autologous HCT, CAR-T, and/or trials of investigational therapies.

¥ We offer chemoimmunotherapy to patients with early treatment failure who are candidates for autologous HCT. We typically prefer bendamustine plus obinutuzumab for patients who have prior exposure to an anthracycline, whereas CHOP plus obinutuzumab is offered to patents who are anthracycline naive.

‡ Patients with early treatment failure after single agent rituximab who achieve a complete response with chemoimmunotherapy may reasonably defer high dose chemotherapy until subsequent relapse.