Role Of Maintenance Therapy In Follicular Lymphoma

Introduction

Definition of follicular lymphoma

Follicular lymphoma (FL) is the most prevalent subtype of clinically indolent non-Hodgkin lymphoma (NHL) and the second most common kind of NHL, making up over 30% of all lymphomas. FL is a β-cell lymphoproliferative illness that grows slowly and has a years-to-life survival rate.¹

Description and classification

The World Health Organization( WHO) revised Euro- the American lymphoma( REAL) classification and the Ann Arbor Cotswolds staging system for follicular lymphoma NHL as well as the Follicular Lymphoma International Prognostic Index( FLIPI) score. 

The 2016 WHO classification of mature β- cell tumours includes the following subtypes of FL. 

1. In situ follicular neoplasia 
2. Duodenal- type FL 
3. Pediatric- type FL
4. generally verbose FL with 1p36 omission.²

 WHO REAL classification 

 FL is classified into the following 3 histologic grades 

•  Grade 1: 0- 5 centroblasts/high-power field( HPF) 
• Grade 2: 6- 15 centroblasts/ HPF 
• Grade 3: > 15 centroblasts/ HPF 

The WHO classification consolidates cases with many centroblasts as FL grade 1- 2(low-grade). FL grade 3 is divided into 3A and 3B( absence of centrocytes).²

Epidemiology

With an estimated incidence of 6 new cases per 100,000 people annually, FL is the second most frequent form of NHL in the US. Compared to Asians and African Americans, Caucasians have a greater rate of FL. FL is less common in the rest of the world but more common in the US and Europe. It is mostly a disease of elderly adults (median age 55 years) and is rarely diagnosed in youngsters under the age of 20. Pesticide and herbicide exposure has already been proven as a risk factor.¹

Overview of maintenance therapy 

Definition and purpose

Maintenance treatment is long-term treatment, often lasting several years. Sometimes it is given after the first treatment has cured your lymphoma (it has shrunk or disappeared completely). Maintenance treatment aims to control the lymphoma cells that remain in your body. This helps make your remission last as long as possible.³

Purpose of maintenance therapy

For patients with advanced FL who require treatment, the goal is to control disease and reduce lymphoma-related symptoms. Because of the high risk of relapse with current therapy, achieving a long-term disease-free period with current regimens is the main goal of treatment. Maintenance treatment with rituximab (Rituxan, Roche/Genentech/Biogen Idec) significantly improves outcomes in patients with FL who have not been treated and relapsed.⁸

General objectives in cancer treatment

In cancer treatment, maintenance therapy plays an important role in long-term disease treatment and management. The general goals/objectives of maintenance therapy in cancer treatment are:

1. Preventing/minimising disease progression
2. Preventing relapses
3. Improving quality of life
4. Maintaining remission
5. Enhancing long-term survival
6. Monitoring and adapting treatment

Current treatment paradigms for follicular lymphoma

Treatment options depend on tumour stage and tumour severity as assessed by the GELF criteria. Currently, FL is considered an indolent and often incurable disease, so the goal of treatment is to prolong patients' lives and achieve disease control to maintain a good quality of life. The patient must understand all the treatment steps to make a decision about the treatment and be comfortable and confident about this decision.⁴

Initial treatment approaches

The initial treatment strategies include:

Chemotherapy regimens

In symptomatic patients with previously untreated FL, combination chemotherapy regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), cyclophosphamide, vincristine, and prednisone (CVP) or conventionally such as fludarabine, mitoxantrone, and dexamethasone (FND) or fludarabine and mitoxantrone (FM).⁵ Chemotherapy alone is not indicated, as studies comparing chemotherapy (CHOP or CVP ) and chemotherapy with rituximab (rituximab and CHOP) [R-CHOP] or rituximab and CVP (R-CVP) have consistently shown that rituximab improves patient outcomes.^6,7

Targeted therapies (e.g., Rituximab)

Several medications are prescribed for follicular lymphoma. Many of these drugs have been studied in other haematological malignancies and have been adapted for use in FL.

Rituximab, a type I chimeric anti-CD20 monoclonal antibody, has long been a mainstay of therapy for B-cell lymphomas, and in FL, it is commonly used in front-line, subsequent-line, and maintenance therapies in combination with chemotherapy or as monotherapy.⁹ Efforts to enhance anti-CD20 activity have resulted in obinutuzumab, a type II glycoengineered anti-CD20 monoclonal antibody that has been shown in previous in vitro and in vivo studies to enhance B-cell depleting activity and increase antibody-dependent cellular phagocytosis when compared to rituximab.¹⁰ In rituximab-refractory FL patients, obinutuzumab with bendamustine is superior to obinutuzumab alone, suggesting that its enhanced anti-CD20 activity when compared to rituximab can be translated to meaningful clinical benefit even in patients who were pre-treated with rituximab. Furthermore, in the GALLIUM study, FL patients who received obinutuzumab with chemotherapy followed by obinutuzumab maintenance demonstrated improved PFS compared with those patients who received rituximab with chemotherapy followed by rituximab maintenance, suggesting that obinutuzumab may be more active in the front-line setting than rituximab.¹¹

Role of radiation therapy

Radiation therapy (RT) is a first-line treatment option for early-stage follicular lymphoma (FL) and a curative treatment option for advanced-stage FL. FL is a type of non-Hodgkin's lymphoma (NHL) that is highly sensitive to RT. RT can be curative for localized FL, with previous series showing a 10-year disease-free survival rate of 40-50%. RT can also provide long-term local control and clinical benefits for the FL stage. Indeed, studies have shown that patients with relapsed FL are highly responsive to RT.RT can be used for early-stage FL, and in combination with immunochemotherapy for advanced-stage FL. A CT scan can be used to guide RT therapy, with the beam delivered in different directions to target the lymphoma while avoiding normal structures.¹²

Side effects of RT can include:¹³

• Skin: Reddening, dryness, and itchiness that usually heals within a few weeks
• Abdomen or pelvis: Diarrhea, frequent bowel movements, or appetite loss 
• Chest: Lung damage, breathing problems, and increased risk of heart attack 
• Neck: Thyroid problems, fatigue, and weight gain 
• Brain: Headaches, memory loss, personality changes, and trouble concentrating

Evidence-based approaches to maintenance therapy

Rituximab maintenance⁹

The prognosis of patients with FL has significantly improved since the introduction of rituximab to first-line (1L) and salvage therapies. Advanced-stage FL is thought to be incurable in most patients due to inevitable relapses; however, strides have been made to extend the duration of remission without exposure to additional cytotoxic treatment. Previous research has shown that rituximab maintenance has a considerable clinical benefit in patients with recurrent illness after induction with chemotherapy with or without rituximab, or single-agent rituximab, and in patients receiving autologous stem-cell transplantation. Rituximab maintenance following either chemotherapy or single-agent rituximab has also been tested in patients with previously untreated FL, with promising outcomes. However, neither of these induction regimens is considered for patients with advanced-stage disease.

Clinical trial evidence (e.g., PRIMA trial)

The primary PRIMA research was the first phase III trial to assess the potential benefit of two years of rituximab maintenance in patients with high-tumor burden FL responding to 1L rituximab-containing immunochemotherapy. After a median follow-up of three years, rituximab maintenance significantly prolonged progression-free survival (PFS) compared with observation; the risk of disease progression was reduced by 45% (hazard ratio [HR], 0.55; 95% CI, 0.44 to 0.68; P,.001), and 3-year PFS rates were 74.9% and 57.6%, respectively. This PFS advantage occurred regardless of the induction regimen, responsiveness to induction treatment, or patient age. Rituximab maintenance significantly increased the time to the next anti-lymphoma treatment (TTNLT) and time to the next chemotherapy treatment (TTNCT) but did not improve overall survival (OS). 

An updated 6-year follow-up of the PRIMA trial corroborated its initial findings. Rituximab maintenance is now recommended for patients with FL who responded to first-line rituximab-based immunochemotherapy. This report presents the final PFS and OS results from the PRIMA study after 9 years of follow-up, along with a safety review.

Safety profile

Since random assignment, 285 patients (56.9%) in the rituximab maintenance arm and 194 patients (38.2%) in the observation arm had reported at least one adverse event (AE) (Data Supplement). Rituximab maintenance was associated with a higher rate of grade 3 to 4 AEs (24.4% v 16.9%) and serious AEs (21.2% v 13.4%) compared with observation; the higher rate of grade 3 to 4 AEs was driven mostly by higher rates of cytopenias (5.2% v 1.6%) and infections (4.4% v 1.0%). 

The most common grade 3 to 4 adverse events were benign, malignant, and undefined neoplasms (including cysts and polyps), with a comparable incidence in both research arms (about 4%). Eight patients (1.6%) of 501 and three patients (0.6%) of 508 randomly assigned to rituximab maintenance and observation experienced Grade 5 (fatal) adverse events (Data Supplement). Since random assignment, 88 patients (17.4%) died in the rituximab maintenance arm, compared to 84 (16.4%) in the observation arm (see Table 3). The leading causes of death were progressive illness (51.1% for rituximab maintenance, 47.6% for observation) and solid tumours (5.7% for rituximab maintenance and 20.2% for observation).

Novel agents and strategies

New monoclonal antibodies

The mainstay of treatment still relies on cytotoxic chemotherapy, often using alkylators and purine analogues. About a decade ago, the addition of the chimeric monoclonal antibody (mAb) rituximab improved response rates, duration of response, and overall survival, establishing immunotherapy as the standard of care. However, not all patients benefit from this approach. 20% of patients experienced disease progression within 2 years of diagnosis despite receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with are 5- 5-annual survival rate of 50%, compared to 5.90% per year. life for the remaining patients. This low-risk group represents the patients most likely to have FL.¹⁴

Examples of monoclonal antibodies:

Rituximab, Ofatumumab, Veltuzumab, Ocaratuzumab, Obinutuzumab, Blinatumumab, etc.

CAR-T cell therapy

Chimeric antigen receptor (CAR) T-cell therapy that targets B-cell antigens, such as CD19 or CD20, can be an effective treatment for patients with R/R follicular lymphoma, especially for those who recover quickly and prevent alkylating agents. appearing. CD20 monoclonal antibodies, which result in high rates of long-term responses in a large proportion of patients.¹⁵ Examples include Tisagenleucel, Axicabtagene Ciloleucxel.

Combination therapies

Some people with follicular lymphoma have relapses or complications after treatment. They may need several sets of treatments over time. This depends on tumour size, symptoms, age or general health.

1. Watchful watching
2. Chemotherapy: In Combination chemotherapy (chemo-immunotherapy), patients with FL can take different chemo drugs combined with steroid or monoclonal antibodies. This can kill or slow down the progress of lymphoma cells. Chemo combination therapies include CHOP and CVP.¹⁶

Other chemo combination therapies include-

• Rituximab and bendamustine
• Obinutuzumab with bendamustine
• Chlorambucil with rituximab¹⁶

Conclusion

Importance of maintenance therapy in follicular lymphoma management

Maintenance therapy plays a pivotal role in the management of follicular lymphoma, significantly impacting patient outcomes and quality of life. For individuals with this indolent form of non-Hodgkin lymphoma, maintenance therapy serves multiple crucial functions:

1. Prolonging Remission
2. Reducing Relapse Rates
3. Improving Survival
4. Enhancing Quality of Life
5. Tailoring Treatment

Balance between benefits and risks

Maintenance therapy offers significant advantages, including prolonged remission, reduced relapse rates, improved overall survival, and enhanced quality of life. By extending the period of disease control and managing residual cancer cells, it contributes to long-term stability and minimises the need for more intensive treatments.

However, the benefits must be weighed against potential risks. Maintenance therapy can be associated with adverse effects, including an increased risk of infections, immune system suppression, and other treatment-related complications. The choice of maintenance therapy must therefore be individualised, considering factors such as the patient’s overall health, disease characteristics, and treatment goals.