Diffuse large B-cell lymphoma is the most common lymphoid malignancy. It is a highly aggressive form of non-Hodgkin lymphoma that carries with it a poor prognosis. 

One of the major problems in treating patients with diffuse large B-cell lymphoma is that a large percentage of patients do not respond adequately to first-line therapy. At present, first-line therapy utilizes immunochemotherapy. Common drugs used at this stage of treatment include cyclophosphamide, vincristine, doxorubicin, prednisolone+rituximab (R-CHOP), and others. 

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Immunochemotherapy functions adequately in roughly 60% of patients diagnosed with diffuse large B-cell lymphoma. However, the remaining 40% of patients that do not respond to any of the commonly used immunotherapy drugs have limited therapeutic options. In addition, there has also been evidence that some first-line immunotherapy drugs did not live up to the hype they initially generated. 

Take, for example, R-CHOP (prednisolone+rituximab). When it was first introduced as a first-line immunotherapy combination for diffuse large B-cell lymphoma, there was much optimism among the medical community regarding its ability to improve clinical outcomes. However, clinical studies have since demonstrated that this combination of immunotherapy drugs failed to meet its primary endpoint. 

“First-line therapy for [diffuse large B-cell lymphoma] has remained unchanged for almost two decades,” Morin and colleagues wrote in the British Journal of Haematology. However, Morin et al offered this caveat: “Although the promise of molecularly targeted therapy in [diffuse large B-cell lymphoma] may be more elusive than we had hoped, one can also view this as an opportunity to re-assess the design of clinical trials to increase our chances of future improvements to clinical management.” 

Diffuse Large B-Cell Lymphoma Is an Umbrella Term 

Our understanding of diffuse large B-cell lymphoma increasingly points to it being an umbrella term for various pathologies of distinct molecular origins. 

“Over the last few decades, multidisciplinary efforts from pathologists, molecular scientists, and clinicians have identified unique [diffuse large B-cell lymphoma] subtypes by either cell of origin or molecular characteristics,” Susanibar-Adaniya and Barta wrote in the Annual Clinical Updates in Hematological Malignancies. 

The fact that the term “diffuse large B-cell lymphoma” behaves more like an umbrella term of distinct pathologies hampers the ability of medical researchers to search for a uniform cure that treats this disease as one might expect treating a disease with less heterogeneity. 

In addition, scientists are just beginning to distinguish the variety of entities present under the term “diffuse large B-cell lymphoma.” These efforts mean that we are far from being able to spell out the various subtypes of this disease in a clinically meaningful way. 

Morin and colleagues elucidated this problem in greater detail: “Since each entity may rely on distinct oncogenic pathways, it is reasonable to assume that novel therapies designed to inhibit specific oncogenic pathways may have activity only in certain subgroups and therefore may show little detectable activity if used in a blanket approach.” 

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However, we must be cautious in assuming that a full mapping of the various subtypes of diffuse large B-cell lymphoma can produce a therapeutic breakthrough. Tragic as it sounds, the molecular profiling of the subtypes of diffuse large B-cell lymphoma may yield little information regarding possible therapeutic strategies to treat the disease. Nevertheless, it may provide a framework in which future researchers can interpret results and design clinical strategies. 

Hope for the Future 

While progress with regards to leveraging knowledge regarding diffuse large B-cell lymphoma into actionable treatment remains disappointing, progress has still been made. 

“Molecularly and genetically agnostic immunotherapeutics have positively impacted outcomes in patients with relapsed disease,” Susanibar-Adaniya and Barta wrote. “The addition of immunotherapy to the arsenal treatment of [diffuse B-cell lymphoma] is poised to define a new standard of care in the upfront and relapsed setting.” 

Given the stalled progress in creating new therapeutics for diffuse B-cell lymphoma, a few options can be considered. The first is to continue studying the various subtypes of diffuse B-cell lymphoma until a breakthrough discovery is obtained. Another strategy is to study if these various subtypes of the disease can yield predictive biomarkers that can help future researchers better choose participants in their clinical trials and design their trials in a smarter fashion. 

The difficulty with rare diseases is that the pool of potential participants is small, and funding tends to be limited. Hence, medical researchers have the arduous task of preparing well thought-out study designs in order to gain both regulatory and financial approval. 

These efforts are hampered in diseases of which we know little; they are also hampered because they affect such a small segment of the population, meaning that investment returns are likely to be less attractive. 

However, the beauty of rare disease research is that discoveries made in a particular clinical trial can then be built on in subsequent trials, and at some point, our body of knowledge regarding the disease is no longer scarce. Momentum picks up, and it is usually then that breakthrough discoveries are made. Medical researchers must remain honest about what they do know and what they don’t and cast their vision to the future in which the present mysteries regarding a rare disease are solved in earnest. 


Susanibar-Adaniya S, Barta SK. 2021 Update on diffuse large B cell lymphoma: a review of current data and potential applications on risk stratification and managementAm J Hematol. Published online March 4, 2021. doi:10.1002/ajh.26151

Morin RD, Arthur SE, Hodson DJ. Molecular profiling in diffuse large B-cell lymphoma: why so
many types of subtypes?
 Br J Haematol. Published online August 31, 2021. doi:10.1111/bjh.17811