Lymphomas: Moving to a Future of Personalised Medicine - Dr.Liri Seraj

“When my haematologist explained that my lymphoma had its own genetic fingerprint, everything shifted. It was no longer a generic diagnosis, it was mine, and for the first time the treatment plan started to make sense.”

“After my lymphoma returned twice, I thought I had run out of options. Hearing about CAR T-cell therapy felt like being handed a door I did not know existed.”

For decades, lymphoma treatment followed a relatively straightforward path: diagnose the type, assign a standard chemotherapy regimen, and hope for the best. The backbone of treatment for the most common aggressive lymphoma, diffuse large B-cell lymphoma (DLBCL), has been the R-CHOP regimen, which combines rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone. This regimen cures roughly fifty to sixty percent of patients. For those who do not respond or who relapse, options were historically limited and outcomes were often poor.

That era is ending. We are witnessing a fundamental transformation in how we think about, classify, and treat lymphomas. The shift is moving us away from a one-size-fits-all approach toward treatment that is increasingly tailored to each patient’s unique disease biology.

In this article, I will walk you through the key pillars of this personalised medicine revolution and what they mean for patients.

What you will find in this article

Understanding your lymphoma at the molecular level
CAR T-cell therapy: your own immune system, supercharged
Bispecific antibodies: a bridge therapy revolution
Liquid biopsy and ctDNA: monitoring through a blood test
Targeted protein degradation: a new mechanism on the horizon
AI and computational models: predicting your outcome
The challenges ahead
A message of hope

Understanding Your Lymphoma at the Molecular Level

Traditionally, lymphomas were classified mainly by how cells looked under a microscope and by a handful of protein markers on the cell surface. While this remains important, we now know that even within a single lymphoma subtype, there is enormous molecular diversity.

Take DLBCL as an example. Thanks to advanced genomic technologies such as next-generation sequencing (NGS), we can now identify distinct molecular subtypes based on the specific genetic mutations driving each patient’s lymphoma. Subtypes such as MCD (characterised by MYD88 and CD79B mutations), EZB (driven by EZH2 mutations and BCL2 translocations), BN2, N1, ST2, and A53 each behave differently and may respond differently to specific treatments [1, 2].

What this means for you: Your lymphoma is not identical to someone else’s, even if it carries the same name. Understanding the molecular fingerprint of your disease helps your medical team choose the most effective therapy and avoid treatments that are unlikely to work.

CAR T-Cell Therapy: Your Own Immune System, Supercharged

One of the most exciting breakthroughs in lymphoma treatment has been chimeric antigen receptor (CAR) T-cell therapy. This is a form of personalised immunotherapy in which a patient’s own immune cells (T-cells) are collected, genetically reprogrammed in a laboratory to recognise and attack lymphoma cells, and then infused back into the patient.

Several CAR T-cell products are now approved and in routine clinical use for various types of B-cell lymphomas, including products targeting the CD19 protein found on lymphoma cells. Long-term follow-up data now show that these therapies can produce durable, multi-year remissions, and potentially cures, even in patients whose lymphoma had resisted multiple prior treatments.

The field is also advancing rapidly. A next-generation “armoured” CAR T-cell product called huCART19-IL18, engineered to secrete interleukin 18 (a molecule that boosts the immune response), recently demonstrated an objective response rate of 81 percent, with 52 percent of patients achieving a complete response at three months. Importantly, this result was observed in heavily pretreated patients whose lymphoma had already progressed after earlier CAR T-cell therapy [3]. Manufacturing innovations have also shortened the production time for these engineered cells from over a week to as little as three days, getting treatment to patients faster.

Meanwhile, new bicistronic CAR T-cell therapies, which are designed to target two different proteins simultaneously such as CD19 and CD20 or CD19 and CD22, are showing encouraging early results. These dual-targeting approaches may improve efficacy and reduce the chance that lymphoma cells can escape treatment by losing a single marker.

What this means for you: If your lymphoma relapses or does not respond to initial treatment, CAR T-cell therapy may offer a powerful option. And if a first CAR T attempt does not work, newer generations of this technology are expanding the possibilities.

Bispecific Antibodies: A Bridge Therapy Revolution

Bispecific antibodies represent another major class of personalised therapy. These laboratory-made molecules are designed to simultaneously grab onto two different targets: typically CD20 on lymphoma cells and CD3 on the patient’s own T-cells. By physically bringing the T-cell and the lymphoma cell together, bispecific antibodies activate the immune system to destroy the cancer. The mechanism somewhat mimics that of CAR T-cells, but without requiring the complex manufacturing process.

Several bispecific antibodies are now approved for relapsed or refractory DLBCL. Epcoritamab and glofitamab received accelerated FDA approval in 2023 [4, 5], and odronextamab received European Commission approval in 2024. They are being explored in earlier treatment lines and in combination with chemotherapy and other targeted agents.

One of the key advantages of bispecific antibodies is their rapid availability. Unlike CAR T-cell therapy, which requires weeks of manufacturing, bispecific antibodies are “off-the-shelf” treatments that can be started quickly. This matters especially for patients whose disease is progressing rapidly.

What this means for you: Bispecific antibodies are expanding the treatment toolbox significantly, especially for patients who cannot access CAR T-cell therapy due to logistics, medical fitness, or other reasons. They also offer an important option for patients whose lymphoma progresses after CAR T.

Liquid Biopsy and ctDNA: Monitoring Through a Blood Test

Personalised medicine is not just about choosing the right treatment. It is also about monitoring how well that treatment is working in real time. This is where circulating tumour DNA, known as ctDNA or “liquid biopsy,” is transforming lymphoma care.

When lymphoma cells die, they release fragments of their DNA into the bloodstream. Using highly sensitive techniques, we can now detect and measure these tiny fragments from a simple blood draw. This allows us to:

Track treatment response in real time, often detecting whether therapy is working weeks before changes become visible on PET-CT scans
Identify patients at high risk of relapse early, when intervention may be most effective
Monitor for minimal residual disease (MRD), meaning the small number of cancer cells that may remain after treatment and that can eventually lead to relapse

Landmark studies have shown that ctDNA dynamics in DLBCL can predict treatment outcomes as early as three weeks into therapy, well before imaging confirmation [6]. In January 2025, the National Comprehensive Cancer Network (NCCN) formally incorporated ctDNA MRD testing into its B-cell lymphoma guidelines, the first such inclusion for lymphoma [7]. Clinical trials are increasingly using ctDNA dynamics to adapt treatment in real time. Patients who achieve rapid ctDNA clearance may be candidates for treatment de-escalation, avoiding unnecessary toxicity, while those with persistent ctDNA may benefit from early intensification with additional agents such as bispecific antibodies.

What this means for you: Your doctor may increasingly be able to fine-tune your treatment based on blood tests that detect your lymphoma’s molecular signature, potentially sparing you unnecessary therapy or adding targeted treatment before a relapse becomes clinically apparent.

Targeted Protein Degradation: A New Mechanism on the Horizon

Beyond CAR T-cells and bispecific antibodies, novel therapeutic mechanisms are emerging. One fascinating area is targeted protein degradation, which uses therapies designed to selectively destroy specific proteins inside lymphoma cells rather than simply blocking them.

Agents such as golcadomide, a first-in-class oral CELMoD™ agent, and BCL6 ligand-directed degraders are showing promising early results. In the phase 1b CC-220-DLBCL-001 trial, golcadomide combined with R-CHOP in previously untreated aggressive B-cell lymphoma achieved an end-of-treatment complete metabolic response rate of 88 percent and MRD negativity in 90 percent of evaluable patients at the 0.4 mg dose, including in high-risk disease [8]. These results are now being tested in the phase 3 GOLSEEK-1 trial.

Next-generation BCL2 inhibitors such as sonrotoclax, which preclinical data suggest is approximately 14 times more potent and 6 times more selective for BCL2 than its predecessor venetoclax [9], are also showing encouraging activity in mantle cell lymphoma. The agent was granted FDA priority review in late 2025.

What this means for you: The pipeline of novel lymphoma treatments continues to expand, with new mechanisms of action that may overcome resistance to existing therapies.

AI and Computational Models: Predicting Your Outcome

Artificial intelligence and computational modelling are increasingly being applied to lymphoma care. Researchers have developed personalised computer simulations that use a patient’s genomic sequencing data to predict how their specific cancer cells will behave and respond to treatment.

Deep learning and machine learning models are helping improve diagnostic accuracy, genetic profiling, and risk stratification in lymphoma, outperforming some traditional approaches. AI-driven tools can help quantify the impact of specific mutations on cancer cell behaviour, potentially guiding treatment decisions at the individual level.

What this means for you: While still largely in the research phase, AI-powered tools may soon help your doctor predict more accurately which treatment will work best for your specific lymphoma.

The Challenges Ahead

Despite this remarkable progress, important challenges remain.

Access and equity: Many of these advanced therapies, particularly CAR T-cell therapy, are expensive and available only at specialised centres in high-income countries. Bridging this gap is essential so that patients everywhere can benefit from personalised medicine.
Resistance: Lymphoma cells are resourceful. Some patients still relapse after CAR T-cell therapy or bispecific antibodies, and understanding and overcoming resistance mechanisms remains a major research priority.
Safety monitoring: As we use increasingly powerful immune-based therapies, managing side effects such as cytokine release syndrome and neurotoxicity, and monitoring for rare but serious complications, requires experienced multidisciplinary teams.
Integrating complexity: Molecular subtypes, ctDNA monitoring, imaging, and clinical factors all need to be integrated into coherent treatment algorithms. This requires ongoing clinical trials and collaborative effort across institutions and countries.

A Message of Hope

If you or someone you love is living with lymphoma, the message is clear: we are in a period of unprecedented progress. The landscape of lymphoma treatment is being reshaped by technologies that would have seemed like science fiction just a decade ago. From reprogramming your own immune cells to fight cancer, to detecting disease recurrence through a blood test before it shows on a scan, to matching your therapy to the exact molecular drivers of your lymphoma, personalised medicine is not a distant promise. It is arriving now.

Your lymphoma story is unique. And increasingly, your treatment can be too.

Want to learn more? Stay tuned to hemalily.com for more patient-friendly articles on blood disorders. If you have questions about your specific situation, always discuss them with your haematologist.

Disclaimer

This article is for general educational purposes only and is not intended as medical advice. It does not replace consultation with a qualified healthcare professional. Treatment decisions depend on many individual factors, including your specific lymphoma subtype, overall health, prior therapies, and personal preferences. Always discuss your care with your treating haematologist or oncologist. Information about specific therapies, regulatory approvals, and clinical trials reflects the best available evidence at the time of writing and may change as new data emerge.

References

Schmitz R, Wright GW, Huang DW, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. New England Journal of Medicine. 2018;378(15):1396-1407. doi:10.1056/NEJMoa1801445
Wright GW, Huang DW, Phelan JD, et al. A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications. Cancer Cell. 2020;37(4):551-568.e14. doi:10.1016/j.ccell.2020.03.015
Svoboda J, Landsburg DJ, Gerson J, et al. Enhanced CAR T-cell therapy for lymphoma after previous failure. New England Journal of Medicine. 2025. doi:10.1056/NEJMoa2408771
Thieblemont C, Phillips T, Ghesquieres H, et al. Epcoritamab, a novel, subcutaneous CD3xCD20 bispecific T-cell-engaging antibody, in relapsed or refractory large B-cell lymphoma: dose expansion in a phase I/II trial. Journal of Clinical Oncology. 2023;41(12):2238-2247. doi:10.1200/JCO.22.01725
U.S. Food and Drug Administration. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory diffuse large B-cell lymphoma and high-grade B-cell lymphoma. May 19, 2023. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases
Kurtz DM, Scherer F, Jin MC, et al. Circulating tumor DNA measurements as early outcome predictors in diffuse large B-cell lymphoma. Journal of Clinical Oncology. 2018;36(28):2845-2853. doi:10.1200/JCO.2018.78.5246
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: B-cell lymphomas. Version 1.2025. Updated December 2024. Available at: https://www.nccn.org
Nowakowski GS, Amzallag A, Hoffmann M, et al. Golcadomide plus R-CHOP in previously untreated aggressive B-cell lymphoma: 24-month efficacy results. Blood. 2025;146(Supplement 1):476. ASH Annual Meeting 2025.
Hu N, Guo Y, Xue H, et al. Sonrotoclax overcomes BCL2 G101V mutation-induced venetoclax resistance in preclinical models of hematologic malignancy. Blood. 2024. doi:10.1182/blood.2023021641