Single-Agent and Associated Therapies with Monoclonal Antibodies: What About Follicular Lymphoma?
Simple Summary
Abstract
1. Introduction
1.1. General Background
1.2. A Bit of History About Monoclonal Antibodies
1.2.1. The First Monoclonal Antibody: Rituximab
1.2.2. The First Antibody–Drug Conjugate: Gemtuzumab Ozogamicin
1.2.3. The First Bispecific Antibody: Blinatumomab
2. Follicular Lymphoma
2.1. From Diagnosis to Risk Stratification
2.2. Treatment of Follicular Lymphoma
2.3. Focus on Approved mAbs
2.3.1. Rituximab
2.3.2. Obinutuzumab
2.3.3. Mosunetuzumab
2.4. Ongoing Clinical Trials
3. Challenges and Future Directions
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Index | Year | Parameters | Risk Groups | Outcomes | References |
---|---|---|---|---|---|
FLIPI | 2004 | Age > 60 years Stage III/IV Hemoglobin < 12 g/dL >4 nodal areas Elevated LDH levels | Low (0–1), Intermediate (2), High (3–5) | 10-year Overall Survival (OS): Low 70%, Intermediate 50%, High 35% | [50,51,52] |
FLIPI-2 | 2009 | Age > 60 β2-microglobulin > normal Longest node > 6 cm Bone marrow involvement Hemoglobin < 12 g/dL | Low (0–1), Intermediate (2), High (3–5) | 5-year Progression-Free Survival (PFS): Low 79%, Intermediate 51%, High 19% | [50,51,52] |
m7-FLIPI | 2015 | FLIPI ECOG Performance Status Mutation status of 7 genes: EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11 | Low vs. high Risk | 5-year PFS: Low Risk ~77%, High Risk ~30% | [50,51,52] |
Therapy Class | Mechanism of Action | Advantages | Common Toxicities | References |
---|---|---|---|---|
Monoclonal Antibodies | Bind to CD20 on B cells and induce immune-mediated cytotoxicity | -Established efficacy -Well-tolerated -Synergistic with chemotherapy | -Infusion-related reactions -Risk of infections -Neutropenia | [2] |
Bispecific Antibodies | Bind both CD20 on B cells and CD3 on T cells and redirect T-cell cytotoxicity against lymphoma cells | -Off-the-shelf -Effective against R/R FL -No need for patient-specific manufacturing | -CRS -ICANS -Infections | [3,4] |
Antibody–Drug Conjugates | The antibody binds the target and, after internalization, there is the release of the cytotoxic payload and cell death | -Targeted delivery of chemotherapy -Reduced systemic toxicity -Activity in resistant cases | -Peripheral neuropathy -Myelosuppression -Diarrhea | [11] |
Feature | Rituximab | Obinutuzumab | Mosunetuzumab |
---|---|---|---|
Type | Chimeric anti-CD20 IgG1 (Type I) | Humanized anti-CD20 IgG1 (Type II) | Bispecific anti-CD20/CD3 IgG1 |
Mechanism of Action | ADCC, CDC, direct apoptosis | Enhanced ADCC, direct cell death, reduced CDC | T-cell redirection, independent of CDC/MHC |
Structure | Chimeric (murine/human) | Glycoengineered humanized antibody | Full-length humanized bispecific antibody |
Clinical Indication | First-line and relapsed/refractory FL | First-line and relapsed/refractory FL | Relapsed/refractory FL after ≥2 prior therapies |
Efficacy | Improved PFS and OS with chemoimmunotherapy | Superior PFS vs. rituximab (GALLIUM trial) | High ORR and CR in heavily pretreated patients (GO29781 study) |
Main Toxicities | Infusion reactions, infections, rare PML | Higher infusion reactions, neutropenia, infections | Cytokine release syndrome (mild/moderate), neutropenia |
Administration | Intravenous or subcutaneous | Intravenous | Step-up intravenous dosing (outpatient feasible) |
References | [95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115] | [116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132] | [88,133,134,135,136,137,138,139] |
Drug | Study Title | Object of the Study | Main Outcomes | Reference |
Glofitamab | Phase I/II NP30179 trial | heavily pretreated R/R FL patients | ORR of 81% and CR rate of 70% | [141] |
Epcoritamab | Phase II EPCORE NHL-1 | patients with advanced FL | ORR of 82.0% and CR rate of 62.5% | [142] |
Odronextamab | Phase II ELM-2 trial | heavily pretreated FL patients | ORR of 82% and a CR of 75% | [143] |
Tafasitamab | Phase III in MIND trial | residual malignant B cells in FL | A significant improvement in PFS compared to R2 alone, successfully meeting its primary endpoint while maintaining a favorable safety profile with no novel toxicity signals | [144,145] |
Loncastuximab and rituximab | Phase II LOTIS-5 trial | heavily pretreated FL patients | ORR of 97% and a CR rate of 77% in high-risk R/R FL patients, with a 12-month PFS rate of 95% | [146] |
Trial | Patient Population | Design | Key Outcomes | Limitations | References |
---|---|---|---|---|---|
GALLIUM | Previously untreated FL (Grade 1–3a) | Phase III, randomized obinutuzumab + chemotherapy vs. rituximab + chemotherapy → anti-CD20 maintenance therapy | The obinutuzumab arm exhibited an improved PFS at 7 years (63.4% vs. 55.7%). No OS difference. | Higher toxicity (e.g., neutropenia and infections) No OS benefit | [122] |
GADOLIN | Rituximab-refractory indolent NHL (incl. FL) | Phase III, randomized obinutuzumab + bendamustine vs. bendamustine alone | Median PFS: 29.2 vs. 13.7 months. OS benefit observed. | Rituximab-refractory population only Potential selection bias | [125] |
ZUMA-5 | R/R FL and MZL after ≥ 2 prior lines | Phase II, single-arm Axi-cel CAR-T cell therapy | ORR of 92% and CR of 76% in patients with FL. Durable remissions with 2-year PFS of ~60%. | Single-arm, no comparator toxicity: CRS and ICANS | [92] |
RELEVANCE | Treatment-naïve FL | Phase III, randomized R2 (rituximab + lenalidomide) vs. chemoimmunotherapy | Similar PFS and OS. Non-inferior but not superior. | Did not meet superiority The long-term safety of R2 is still under study | [4] |
ELARA | R/R FL after ≥ 2 prior therapies | Phase II, single-arm tisagenlecleucel (CAR T) | ORR of 91%, CR of 75%, 1-year PFS ~70% | No control arm CAR T toxicities require monitoring | [4] |
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Cancemi, G.; Campo, C.; Caserta, S.; Rizzotti, I.; Mannina, D. Single-Agent and Associated Therapies with Monoclonal Antibodies: What About Follicular Lymphoma? Cancers 2025, 17, 1602. https://doi.org/10.3390/cancers17101602
Cancemi G, Campo C, Caserta S, Rizzotti I, Mannina D. Single-Agent and Associated Therapies with Monoclonal Antibodies: What About Follicular Lymphoma? Cancers. 2025; 17(10):1602. https://doi.org/10.3390/cancers17101602
Chicago/Turabian StyleCancemi, Gabriella, Chiara Campo, Santino Caserta, Iolanda Rizzotti, and Donato Mannina. 2025. "Single-Agent and Associated Therapies with Monoclonal Antibodies: What About Follicular Lymphoma?" Cancers 17, no. 10: 1602. https://doi.org/10.3390/cancers17101602
APA StyleCancemi, G., Campo, C., Caserta, S., Rizzotti, I., & Mannina, D. (2025). Single-Agent and Associated Therapies with Monoclonal Antibodies: What About Follicular Lymphoma? Cancers, 17(10), 1602. https://doi.org/10.3390/cancers17101602