B-cell lymphoma refractory is a challenging medical situation where a type of cancer called diffuse large B-cell lymphoma does not respond to initial treatment or returns after a period of improvement, requiring different approaches to manage the disease and support patients through difficult treatment decisions.
Understanding Relapsed and Refractory B-Cell Lymphoma
When someone receives treatment for diffuse large B-cell lymphoma (DLBCL), which is a form of cancer affecting the immune system’s B-cells, doctors hope the disease will go into remission, meaning the cancer is reduced or disappears. Unfortunately, this does not happen for everyone. Some patients face what doctors call relapsed or refractory disease, terms that describe two different but equally challenging situations.[1]
The term “relapsed” refers to disease that reappears or grows again after a period of remission. Imagine the cancer as a fire that seemed extinguished, only to reignite weeks, months, or even years later. The term “refractory” is used to describe when the lymphoma does not respond to treatment, meaning that the cancer cells continue to grow even during therapy, or when the response to treatment does not last very long.[1] In these cases, it is as though the cancer has built up resistance to the medications, refusing to retreat despite the treatment efforts.
How Common Is This Condition?
Overall, around 40% of patients with diffuse large B-cell lymphoma have refractory disease or experience relapse after the first line of treatment. More specifically, approximately 15 to 20% of patients have refractory disease, while 20 to 30% experience relapse after their initial treatment.[2] This means that a significant portion of people who receive treatment for this aggressive form of lymphoma will face the challenge of disease that either does not respond as hoped or returns after an initial period of control.
Diffuse large B-cell lymphoma is the most common aggressive non-Hodgkin lymphoma, a broader category of cancers that affect the lymphatic system. While frontline treatments can cure 60 to 70% of patients, the remaining patients face considerably more difficult circumstances.[8] The numbers show that this is not a rare occurrence, affecting thousands of people who must navigate complex treatment decisions and uncertain outcomes.
What Causes Refractory or Relapsed Disease?
Understanding why some patients develop refractory or relapsed disease is complex. The causes are not always clear, but they relate to the biological characteristics of the cancer cells themselves and how they interact with treatments. Some lymphoma cells may have genetic or molecular features that make them naturally resistant to certain chemotherapy drugs. These cells survive treatment and continue to multiply, leading to refractory disease.
In cases of relapse, small numbers of cancer cells may remain in the body after treatment, even when tests suggest the disease is gone. These remaining cells, sometimes called minimal residual disease, can grow back over time, causing the lymphoma to return. The aggressive nature of diffuse large B-cell lymphoma means these cells can multiply quickly once they begin growing again.[8]
The timing of disease return also matters significantly. Patients who experience early relapse, particularly within 12 months of their initial treatment, often have disease that is more resistant to standard therapies. This suggests that the underlying biology of their lymphoma is more aggressive or fundamentally different from cases that remain in remission longer.[8]
Who Is at Higher Risk?
While any patient with diffuse large B-cell lymphoma can develop refractory or relapsed disease, certain factors may increase the likelihood. The aggressive nature of this type of lymphoma means that the disease itself carries inherent risks, but individual patient characteristics and disease features can influence outcomes.
Patients with higher scores on prognostic indices at the time of relapse tend to face more difficult circumstances. The secondary International Prognostic Index takes into account various factors including age, overall health status, levels of certain blood markers, and extent of disease spread. These biological factors can help doctors understand how the disease might behave and what treatment approaches might be most appropriate.[11]
Before 2017, the prognosis for patients with relapsed disease was particularly challenging. Historical data showed that over 80% of patients failed to respond sufficiently to second-line chemotherapy or were ineligible to receive transplantation procedures, leaving only about 20% of patients with the possibility of cure through transplant.[8] The Scholar-1 study, which looked at 636 patients with refractory DLBCL, reported a median overall survival of only 6.3 months for patients who were refractory to their last line of therapy, with a two-year overall survival rate of just 20%.[8]
Recognizing Symptoms
The symptoms of relapsed or refractory B-cell lymphoma may differ from those experienced during the initial diagnosis. Patients might notice swollen lymph nodes returning in the neck, underarms, or groin, or they may feel swelling in different parts of the body than before. These swollen areas are where lymphoma cells have accumulated and begun growing again.[10]
Weight loss without trying to lose weight is another significant symptom. When the body is fighting cancer, it uses considerable energy, and the disease itself can interfere with normal metabolism and appetite. This can lead to unintended and sometimes dramatic weight loss that concerns both patients and their families.[10]
Fevers and night sweats are common symptoms that can be particularly distressing. Night sweats from lymphoma are not ordinary perspiration but can be severe enough to soak through nightclothes and bedding. These symptoms occur because the immune system is responding to the cancer, and certain substances released by lymphoma cells can affect the body’s temperature regulation.[10]
Fatigue or weakness that persists even when not exerting oneself much is another hallmark symptom. This is not the ordinary tiredness from a busy day, but a profound exhaustion that does not improve with rest. The cancer affects the body’s ability to produce normal blood cells, and the disease process itself demands significant energy from the body.[10]
Some patients experience itching, particularly in areas where lymph nodes are swollen. This can be an uncomfortable and persistent symptom that affects quality of life.[10]
Treatment Approaches Available
Treatment for relapsed or refractory B-cell lymphoma has evolved significantly in recent years, offering more options than were available in the past. The choice of treatment depends on many factors, including when the disease returned, previous treatments received, overall health status, and whether the patient is eligible for certain intensive procedures.
High-dose chemotherapy followed by stem cell transplantation remains an important option for eligible patients whose disease is refractory or relapsed following initial chemotherapy. The majority of patients undergoing stem cell transplantation will have an autologous transplant, where the patient receives their own stem cells that were collected before the procedure. Occasionally, a patient will undergo an allogeneic transplant, receiving stem cells from a donor.[1]
Several combination chemotherapy regimens are available for relapsed or refractory patients. These second-line regimens include combinations such as ifosfamide, carboplatin, and etoposide (ICE), or dexamethasone, cisplatin, and cytarabine (DHAP). Other options include gemcitabine-based therapy, bendamustine plus rituximab, and lenalidomide plus rituximab.[1]
Newer targeted therapies have been approved in recent years that provide more effective options than conventional chemotherapy. These include polatuzumab vedotin-piiq (Polivy), selinexor (Xpovio), tafasitamab-cxix (Monjuvi), epcoritamab-bysp (Epkinly), and glofitamab-gxbm (Columvi). These medications work differently than traditional chemotherapy, targeting specific features of lymphoma cells.[1]
The combinations of polatuzumab vedotin with bendamustine and rituximab, as well as tafasitamab with lenalidomide, have been approved as options for patients who are not candidates for transplant. These combination therapies have shown manageable toxicity profiles while providing meaningful responses for some patients.[2]
CAR T-Cell Therapy: A Newer Approach
For some relapsed or refractory patients, a form of immunotherapy called chimeric antigen receptor (CAR) T-cell therapy may be a possible treatment option. This represents one of the most significant advances in treating this condition in recent years.[1]
CAR T-cell therapy has become the new standard treatment for patients with refractory or early relapsed DLBCL, based on positive results from major clinical trials. The approved CAR T-cell therapies include axicabtagene ciloleucel (Yescarta), lisocabtagene maraleucel (liso-cel, Breyanzi), and tisagenlecleucel (Kymriah).[1]
This therapy works by engineering a patient’s own T-cells, a type of immune cell, to recognize and attack lymphoma cells. The process involves collecting T-cells from the patient’s blood, modifying them in a laboratory to express special receptors that target cancer cells, and then infusing these modified cells back into the patient. Once inside the body, these engineered cells multiply and seek out lymphoma cells to destroy them.[10]
In 2017, the first CAR T-cell therapy with axicabtagene ciloleucel for DLBCL patients demonstrated an overall response rate of 82% and complete response rate of 58%, with a five-year overall survival of 42.6%. This confirmed the curative potential of this cellular therapy for patients who had already failed multiple lines of treatment.[8]
By 2021, CAR T-cell therapy with either axicabtagene ciloleucel or lisocabtagene maraleucel were approved for patients with primary refractory disease or disease relapsing within 12 months as an alternative and preferred second-line treatment option instead of autologous stem cell transplant.[8]
Special Considerations for Specific Subtypes
For patients who have a subset of DLBCL called primary mediastinal large B-cell lymphoma (PMBCL), there are additional treatment options available. These patients may be treated with pembrolizumab (Keytruda), which works differently than traditional chemotherapy by helping the immune system recognize and attack cancer cells.[1]
The treatment landscape has become more complex with multiple therapies targeting similar pathways or using similar mechanisms. This means doctors must carefully consider the timing of relapse, eligibility for intensive treatments, mechanism of action of different drugs, and potential side effects when selecting the best approach for each individual patient.[5]
Diagnostic Tests and Monitoring
Diagnosing relapsed or refractory B-cell lymphoma often begins with a physical examination that checks for swollen lymph nodes in the neck, underarms, and groin, as well as checking for an enlarged spleen or liver. Beyond the physical exam, several tests help doctors understand the extent and characteristics of the disease.[3]
Blood tests can sometimes show whether lymphoma cells are present and may test for viruses including Epstein-Barr virus, HIV, hepatitis B, and hepatitis C. Blood tests also measure levels of lactate dehydrogenase (LDH), which is often higher in people with lymphoma.[3]
Imaging tests create pictures of the body and can show the location and extent of diffuse large B-cell lymphoma. Tests might include MRI, CT, and positron emission tomography (PET) scans. These imaging studies help doctors see where cancer is present and how it is responding to treatment.[3]
A lymph node biopsy or biopsy of other tissue is essential to look for cancer cells. This procedure involves removing all or part of a lymph node or taking samples from other parts of the body depending on symptoms and imaging test results. In the laboratory, specialized tests examine whether lymphoma cells are present and what their characteristics are.[3]
Bone marrow aspiration and biopsy are procedures to collect cells from the bone marrow for testing. Bone marrow is the soft matter inside bones where blood cells are made. These samples are typically taken from the hip bone and sent to a laboratory for detailed analysis.[3]
How the Disease Affects the Body
Diffuse large B-cell lymphoma affects the body’s lymphatic system, which is a crucial part of the immune system that helps fight infections and diseases. The lymphatic system includes lymph nodes, the spleen, bone marrow, and other organs. When B-cells, a type of white blood cell that normally helps fight infection, become cancerous, they multiply uncontrollably and accumulate in lymph nodes and other tissues.
These cancer cells crowd out normal, healthy cells and interfere with the body’s ability to function properly. As lymphoma cells accumulate in lymph nodes, they cause swelling and can compress nearby structures, potentially blocking blood vessels or airways depending on their location. The spleen may become enlarged as it fills with lymphoma cells, and this can cause discomfort in the upper left side of the abdomen.
When lymphoma affects the bone marrow, it can interfere with the production of normal blood cells. This can lead to anemia from too few red blood cells, increased risk of infections from too few normal white blood cells, and bleeding or bruising problems from too few platelets. The disease also affects metabolism and energy use throughout the body, contributing to the fatigue and weight loss that many patients experience.
The immune system itself becomes compromised because the cancerous B-cells cannot perform their normal function of producing antibodies to fight infections. This leaves patients more vulnerable to bacterial, viral, and fungal infections, which can become serious complications during and after treatment.
