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Relapsed and Refractory Follicular Lymphoma
Introduction
Follicular lymphoma is an incurable B-cell neoplasm characterized by substantial biochemical and clinical heterogeneity. As the most prevalent indolent lymphoma and the second most common non-Hodgkin lymphoma (NHL), it has a relapsing and remitting course with the potential to progress to aggressive disease. About 20% of the patients with follicular lymphoma develop disease progression within the first 2 years of chemotherapy, with an overall 5-year survival rate of 50%. The duration of remission appears to have prognostic significance, as those who relapse within 24 months of chemotherapy or 12 months of rituximab are reported to have a poor prognosis.[1][2] While anti-CD20-based chemoimmunotherapy remains an essential standard of treatment, more biologically active agents are increasingly used. This review explores diagnostic and therapeutic strategies for relapsed/refractory follicular lymphoma.
Etiology
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Etiology
Follicular lymphoma is believed to originate from germinal center B-cells, including both centrocytes and centroblasts.[3] Although the pathophysiology of follicular lymphoma is not well understood, follicular lymphoma is defined by the translocation t(14;18), which occurs in 90% of the cases. This translocation results in the juxtaposition of the B-cell leukemia/lymphoma 2 (BCL2) gene with regulatory elements of the immunoglobulin heavy chain gene (IGH) as a consequence of aberrant V(D)J recombination. This leads to an increase in Bcl-2 protein expression and cell survival.[4] Early gene mutations encoding chromatin-modifying proteins have been a significant discovery in recent years.[5][6] These 'epimutations' are a second distinguishing characteristic of follicular lymphoma. These include N-methyltransferase 2D (KMT2D), histone acetylases, CREBBP, enhancer of zeste homologue 2 (EZH2), and E1A binding protein P300 (EP300).[5][7][8][9] These mutations accelerate the proliferation of the germinal center, inhibit cellular differentiation, and restrict immunological invasion. These mutations, together with the BCL2 translocation, are early events happening in a common progenitor cell.
Epidemiology
Follicular lymphoma affects individuals of all races and geographic regions. Follicular lymphoma accounts for roughly 35 percent of NHLs in the United States, with an estimated incidence of 3.18 cases per 100,000 individuals. In contrast, the estimated incidence in Europe is 2.18 cases per 100,000 people per year.[10] The incidence in White people is more than twice as high as in Black population and Asian groups.[11][12][13] Follicular lymphoma seems less prevalent in Central and South America, contributing to around 20% of NHL.[14] There is no significant gender variation. The median age at diagnosis is 65 years.[14][15] Incidence rises with age; middle-aged and elderly patients are most often affected. Follicular lymphoma seldom occurs in adolescents or children.[16][17][18]
Histopathology
The nodular development pattern of follicular lymphoma, which mirrors the typical germinal centers of secondary lymphoid follicles and obliterates the typical lymphoid architecture, is 1 of the most conspicuous morphologic characteristics of follicular lymphoma. In contrast to normal reactive follicles, the nodules in follicular lymphoma are often densely packed and of varying size and form. The neoplastic follicles may be present throughout the tumor tissue or just in a section, with a diffuse component comprising the remainder of the tumor. Centrocytes are small cleaved follicular cells with elongated or cleaved nuclei, inconspicuous nucleoli, and scant pale cytoplasm. Centroblasts are noncleaved follicular center cells with round or oval nuclei, vesicular chromatin, often multiple peripheral nucleoli, and a narrow rim of basophilic cytoplasm. Centrocytes typically predominate in follicular lymphoma, and centroblasts are usually in the minority. WHO classifies follicular lymphoma into grades 1,2 and 3a/3b based on the cell counting method of centroblasts.[19]
Malignant follicles include T-cells and densely structured networks of follicular dendritic cells, similar to those in normal germinal centers. The polarization of normal reactive germinal centers into dark zones rich in centroblasts and light zones rich in centrocytes is absent in neoplastic follicles. Interfollicular spaces in follicular lymphomas may house normal T-cells and a varied percentage of malignant cells. Neoplastic follicles generally have a smaller Ki-67+ proportion (a sign of proliferation) than reactive follicles. The number of mitotic figures and cells that are positive for the Ki-67 marker rises with increasing grade. The immunophenotype of follicular lymphoma is confirmed by flow cytometry or immunohistochemistry. The tumor cells have surface immunoglobulin expression, with 50-60% of cells expressing IgM. Either kappa or lambda light chains are present. Cells are positive for B-cell antigens, including CD19, CD20, CD79a, and CD10. No expression of CD5, CD43, and CD11c is noted.[20][21] CD23 expression is variable. Cells are also positive for Bcl-2 protein expression.[22][23]
History and Physical
Most patients with follicular lymphoma present with painless peripheral lymphadenopathy. The adenopathy commonly waxes and wanes spontaneously but does not altogether disappear.[24] Some patients present with relatively asymptomatic large abdominal masses, with or without evidence of gastrointestinal or urinary tract obstruction. Follicular lymphoma evaluation can show the involvement of the spleen, liver, or bone marrow.[25] Only about 20 percent of patients have B symptoms (fevers, night sweats, or unintentional weight loss).[24] Patients are evaluated at regular intervals after completion of the initial therapy to monitor for treatment complications and progression. Patients are assessed with detailed history and physical examination, complete blood count, comprehensive metabolic panel, and lactate dehydrogenase. On physical examination, a rapid rise in the size and number of lymph nodes, or the development of B symptoms such as night sweats, fevers, weight loss, and fatigue, generally indicate relapsed disease.
Evaluation
Imaging with positron emission tomography/computed tomography (PET/CT) scans can provide information about the disease's new baseline, the anatomic regions involved, and their metabolic activity. Biopsy should target the lymph node with the highest metabolic activity. Bone marrow biopsy is reserved for individuals with unexplained cytopenias. Follicular lymphoma may evolve into a more aggressive and higher grade of lymphoma, such as diffuse large B-cell lymphoma. Hence, a biopsy is essential to diagnose this transformation at relapse.
Treatment / Management
Early relapse: Early treatment failure is defined as the progression of follicular lymphoma within 24 months (POD24) of the initiation of immunochemotherapy with R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab), BR (bendamustine plus rituximab), R-CVP (cyclophosphamide, vincristine, and prednisone) or within 12 months (POD12) of single-agent rituximab treatment. Asymptomatic relapsed follicular lymphoma cases do not need immediate treatment and should be monitored regularly for symptom development.
The prognostic value of POD24 was validated in a pooled analysis of 13 international clinical trials that included >5000 patients treated initially with chemotherapy (49 percent), chemoimmunotherapy (46 percent), or rituximab alone (5 percent). A 24-month landmark analysis was used to report subsequent overall survival (OS) according to disease status 24 months after initial treatment. After adjustment for gender and stratification per performance status and follicular lymphoma international prognostic index (FLIPI), POD24 was associated with worse subsequent OS (estimated 5-year OS 71 versus 94 percent; HR 3.03, 95% CI 2.65-3.47). This prognostic impact was seen in all treatment groups.[26] In early relapse cases, a biopsy is needed to confirm relapse and exclude aggressive histology or transformation. (A1)
Immunotherapy or chemoimmunotherapy alone is not likely to result in long-term survival for patients who experience early treatment failure. Patients who have a complete response to chemoimmunotherapy [bendamustine plus obinutuzumab (BG) or obinutuzumab plus CHOP (G-CHOP)] may benefit from autologous hematopoietic stem cell transplantation (HSCT) as it improves survival. Individuals who have not achieved a complete response may be good candidates for chimeric antigen receptor T-cell (CAR-T) treatment or 1 of the novel agents discussed below. For patients who are not HSCT candidates, using novel agents such as lenalidomide, copanlisib, and tazemetostat is recommended. Several retrospective analyses suggest autologous HSCT improves survival when compared with chemoimmunotherapy alone.[27][28][29] High-dose chemotherapies with autologous HSCT (hematologic rescue) and nonmyeloablative or reduced-intensity allogeneic HSCT have been used to treat follicular lymphoma. (A1)
CAR-T therapy is an option for patients with multiply relapsed follicular lymphomas. CAR-T cells are created from the patient's T-lymphocytes that have been genetically modified (transfected) with a gene encoding a CAR to direct the T-cells against the lymphoma cells. The T-cells are genetically changed ex vivo, multiplied in a production facility, and then reinfused into the patient as a form of treatment. Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-directed CAR-T therapies that are approved by the Food and Drug Administration (FDA).[30][31]
- Axi-cel – Among the 86 patients with follicular lymphoma treated with axi-cel in ZUMA-5, the overall response rate (ORR) was 94% (79% complete remission [CR], 15% partial remission [PR]) with a median time to first response of 1 month. Response rates were similar in patients with and without high-risk features, including early treatment failure. The estimated progression-free survival (PFS) at 18 months was 73% (95% CI 64-80 percent), and the estimated OS at 18 months was 92% (95% CI 85-95 percent). Cytokine release syndrome (CRS) of any grade was reported in 78 percent (6 percent ≥grade 3). Management included tocilizumab (50 percent), corticosteroids (18 percent), and vasopressors (5 percent).[30]
- Tisa-cel – Among the 90 patients with follicular lymphoma treated with tisa-cel, the ORR was 86 percent (69 percent CR, 17 percent PR) with a median time to first response of 2.9 months. The median duration of response was not reached, with a median follow-up of 9.1 months. The estimated PFS at 12 months was 71 percent (95% CI 58-80 percent). CRS of any grade was reported in 53 percent, all less than grade 3.[31]
CAR-T therapy is associated with significant side effects, such as catastrophic neurologic events and CRS, a severe systemic reaction (e.g., high fever, flu-like symptoms, hypotension, mental state abnormalities) due to the activation and proliferation of CAR-T cells.
Late relapse: Relapses that occur more than 24 months or 12 months after the first chemoimmunotherapy or single-agent rituximab, respectively, are associated with a clinically indolent course, needing intermittent treatment across the course of the disease over decades and survival rates that are comparable to those seen in the general population.[1] The current conventional treatment often leads to full or partial remissions, but it is not curative. Treatment goals include symptom relief, restoration of normal cell counts, and enhancement of quality of life. Similar to early relapse, asymptomatic late-relapsed cases usually do not need immediate treatment and are usually monitored for symptom development. For symptomatic late relapsed cases, options include anti-CD20 monoclonal antibodies, chemoimmunotherapy, or novel agents.
Treatment choice is based on several factors, including the patient's response to prior therapy, the existence or absence of certain mutations, the patient's performance status, and the presence of comorbidities that may influence the patient's tolerance to systemic therapy. Rituximab monotherapy is recommended for patients with comorbidities that deem them poor candidates for chemotherapy and those with advanced tumor burden and good past treatment response to single-agent rituximab owing to its low toxicity profile. The dosing schedule of the rituximab can be either IV 375 mg/m per week for 4 doses[32] or IV 375 mg/m per week for 4 weeks, followed by additional doses administered every 2 months for 2 years as maintenance.[33] When compared with ofatumumab, rituximab was at least as effective in terms of overall response rate (ORR, 66 versus 50 percent) and PFS (median 21 versus 16 months) in randomized phase III trial of patients with rituximab-sensitive indolent NHL (predominant follicular lymphoma) relapsed greater than 6 months after single agent rituximab or a rituximab-containing regimen.[34] Patients who received extended rituximab regimen after nonprogression on the initial 4 weekly regimens had superior event-free survival but a similar OS.[35](A1)
Chemoimmunotherapy options include anti-CD20 monoclonal antibodies (rituximab or obinutuzumab) with CHOP, bendamustine, or lenalidomide. Combining bendamustine with obinutuzumab or rituximab is preferred for patients previously receiving CVP or CHOP. Bendamustine can be used again in patients who had prolonged remission with the same treatment. In the GADOLIN trial, 6 cycles of bendamustine plus obinutuzumab followed by maintenance obinutuzumab versus 6 cycles of bendamustine alone showed superior PFS and OS.[36] CHOP with either rituximab or obinutuzumab is preferred in patients who received bendamustine-based therapy. Maintenance with anti-CD20 monoclonal antibody improves PFS but no OS. If offered, it is usually given every 2 months for 2 years. If the lymphoma relapses while on maintenance therapy, then continued maintenance with anti-CD20 is not advisable. However, patients on rituximab maintenance might be eligible for obinutuzumab maintenance. A meta-analysis of 9 trials including 2586 adult patients with follicular lymphoma reported that patients who received maintenance rituximab demonstrated superior rates of OS for patients with the relapsed disease (HR 0.72, 95% CI 0.57-0.91) but not for those with previously untreated follicular lymphoma (HR 0.86, 95% CI 0.60-1.25) or if the patients were eligible for rituximab retreatment at disease progression (HR 0.86, 95% CI 0.49-1.49).[37](A1)
First-relapse patients with EZH2 mutations and second-relapse patients without EZH2 mutations are both eligible for tazemetostat. About 20% of follicular lymphoma cases are associated with EZH2 mutations, and such patients have a better prognosis and a better response to therapy overall. Tazemetostat is approved as a single agent for treating patients with relapsed or refractory EZH2 mutation-positive follicular lymphoma who have received at least 2 prior systemic therapies. Tazemetostat is also approved for patients with relapsed or refractory follicular lymphoma with no satisfactory alternative treatment options and no EZH2 mutations. Approval was based on phase 1/2 trial - among patients with EZH2 mutated follicular lymphoma, ORR was 69% with 13% CR and 56% PR, and median PFS was 14 months. Among patients with EZH2 wild-type follicular lymphoma, ORR was 35%, 4% CR, and median PFS was 11 months. The most common side effects of tazemetostat include infections, fatigue, muscle pain, nausea, and abdominal pain.[38]. Lenalidomide with rituximab or obinutuzumab are other alternatives. AUGMENT trial evaluated the addition of lenalidomide to rituximab, resulting in improved PFS (39 months versus 14 months); OS data was immature. Patients on lenalidomide plus rituximab had higher rates of infections, cutaneous reactions, and cytopenia.[39]
After 2 prior systemic therapies, the phosphoinositide 3'-kinase (PI3K) inhibitor copanlisib is approved by the FDA for use in relapsed or refractory follicular lymphoma. CHRONOS-3 trial randomly assigned 458 patients with relapsed clinically indolent non-Hodgkin lymphoma (275 with follicular lymphoma) in a 2:1 ratio to receive copanlisib plus rituximab versus placebo plus rituximab.[40] After a median follow-up of 19 months, copanlisib plus rituximab improved PFS (median 22 versus 14 months, HR 0.52, 95% CI 0.39-0.69). The addition of copanlisib increased serious treatment-emergent adverse events (47 versus 18 percent) with higher rates of grade 3/4 hyperglycemia and hypertension. High-dose chemotherapy with autologous HSCT, CAR-T, or other experimental treatments is recommended in patients with multiple relapses.(A1)
Differential Diagnosis
Differential diagnosis for relapsed and refractory follicular lymphoma include the following:
- Autoimmune disorders
- Chronic infections
- Reactive follicular hyperplasia
- Chronic lymphocytic leukemia/small lymphocytic lymphoma
- Diffuse large B-cell lymphoma
- Acute lymphoblastic lymphoma
- Marginal zone lymphoma
- Mucosa-associated lymphoid tissue (MALT) lymphoma
- Mantle cell lymphoma
- Lymphoplasmacytic lymphoma
Radiation Oncology
Radiation therapy can palliate symptoms in patients with localized symptoms associated with the follicular lymphoma affecting a single site. However, radiation has no role in the definitive management of relapsed follicular lymphoma.
Prognosis
The clinical course of follicular lymphoma is variable. Some patients can have waxing and waning disease for years without needing treatment. Others with more disseminated disease and rapid tumor growth require therapy due to organ dysfunction. At the time of initial diagnosis, there are 2 widely used prognostic indices for follicular lymphoma: the follicular lymphoma international prognostic index (FLIPI) and the PRIMA prognostic index (PRIMA-PI).[41][42] FLIPI is based on 5 adverse prognostic factors (age >60 yrs, stage III or IV disease, Hemoglobin levels of <12 g/dL, number of involved nodal areas >4, and serum LDH greater than the upper limit of normal). PRIMA-PI score uses beta-2 microglobulin and bone marrow involvement to identify prognostic subgroups. Approximately 20 percent of patients have an aggressive disease course with short remission durations, frequent relapses, and shortened OS.
At the time of relapse, the best predictor of tumor aggressiveness is the duration of remission following initial treatment. Early treatment failure is defined as patients with follicular lymphoma progressing within 24 months (POD24) of initial immunochemotherapy or within 12 months of single-agent rituximab. In addition, a small group of follicular lymphoma patients undergo histologic transformation to more aggressive lymphomas. Patients with histologic transformation generally have a worse prognosis and require more aggressive therapy.
Complications
As mentioned above, about 20% of patients with follicular lymphoma have an aggressive course of disease with shorter remissions, frequent relapses, and reduced overall survival.
Deterrence and Patient Education
Patients should be educated on the clinical course of relapsing and remitting follicular lymphomas and the available treatment options. Despite the slow-growing nature of follicular lymphoma, it is unknown whether current treatments can cure most cases. Patients should be informed of the potential complications, side effects, and toxicity of chemotherapy, immunotherapy, and stem cell transplantation, as well as the fact that most patients require several of these treatments over the course of follicular lymphoma management. Medication adherence and clinic follow-ups should be emphasized, as patients require close monitoring for potential treatment complications, response assessments, and recurrence evaluation.
Enhancing Healthcare Team Outcomes
Follicular lymphoma is an indolent lymphoma with chronic and variable clinical course. Its optimal management requires an interprofessional approach involving a team of medical oncologists or hematologists, stem cell transplant physicians, radiation oncologists, primary care physicians, a palliative care team, psychiatrists, psychologists, infectious disease physicians, pharmacists, registered dieticians, social workers, and case managers. Interpersonal communication and updates regarding treatment plans can significantly alleviate patients' and patients' families' concerns and bring all care team members together. Because cancer diagnosis and recurrence frequently cause psychological distress, prompt identification and referral to a psychiatrist or psychologist can improve overall treatment adherence and outcomes. This interprofessional team approach yields optimal patient results.
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