Diffuse large B-cell lymphoma (DLBCL) is a fast-growing blood cancer that can sometimes return even after successful treatment. Understanding recurrent DLBCL, including its risk factors, symptoms, and available treatment options, helps patients and families navigate what comes next when the cancer reappears.

Understanding Recurrent Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma, a blood cancer that develops when B cells—a type of white blood cell that normally helps fight infection—change into fast-growing cancer cells. Although DLBCL is aggressive, initial treatment often eliminates signs and symptoms of the disease, allowing many people to enter remission, which means there are no detectable cancer cells in the body.^[1]

When DLBCL comes back after a period of remission, doctors call this “relapsed” disease. The term “refractory” describes cancer that does not respond to treatment or when the response does not last very long. Together, these situations are often referred to as relapsed or refractory DLBCL, or R/R DLBCL for short.^[2]

The possibility of recurrence can create anxiety for patients who have already completed treatment. However, knowing what to expect and understanding the treatment options available can provide some measure of comfort and preparation for the journey ahead.

How Common Is DLBCL Relapse?

Around 40% of patients with diffuse large B-cell lymphoma experience either refractory disease or relapse after their first line of treatment. This means that between 15 and 20 percent of patients have refractory disease, while 20 to 30 percent experience relapse.^[5]

The standard first treatment for DLBCL is a combination of medicines called R-CHOP, which stands for rituximab, cyclophosphamide, doxorubicin (also known as hydroxydaunorubicin), vincristine (formerly sold as Oncovin), and prednisone. This treatment combines chemotherapy—powerful drugs that kill cancer cells—with immunotherapy, which helps the immune system fight the cancer. About 75 percent of people achieve complete remission after R-CHOP treatment.^[4]

It is estimated that about one-third of people who achieve complete response after initial treatment with R-CHOP will relapse within two years of treatment. The chances of DLBCL returning become lower the longer a person stays in remission.^[4]

Another 20 percent of people achieve only partial response to treatment, meaning some lymphoma cells remain. In these cases, DLBCL may become resistant to R-CHOP treatment. This form is known as primary refractory diffuse large B-cell lymphoma.^[4]

Causes and Risk Factors for Recurrence

DLBCL happens when B cells undergo changes, called mutations, during a person’s lifetime. These are acquired genetic changes, not ones people are born with. When the cancer returns after treatment, it means that some cancer cells survived the initial treatment and began growing again, or that new cancer cells developed.^[1]

Several factors influence the risk of DLBCL relapse. The initial response to treatment plays a major role. People who achieve complete remission have better outcomes than those who achieve only partial remission. The length of time a person stays in remission also matters, with longer remission periods associated with lower relapse risk.^[4]

Research shows that sex may also play a role in relapse rates. Males are more likely to develop DLBCL compared to females and are associated with worse overall survival and a poorer outlook. This means that fewer males than females are alive within a certain amount of time after receiving a DLBCL diagnosis.^[4]

Some people experience further cycles of treatment, improvement, and relapse. After achieving a second remission, there is still a chance that DLBCL may return again.^[4]

Symptoms of Recurrent DLBCL

Most people experience telltale symptoms during a DLBCL relapse. Research has found that 67 percent of participants were experiencing symptoms when they were diagnosed with a relapse. Most relapse symptoms are similar to the ones people experienced before their initial diagnosis, if they had any. Some are general symptoms that may be associated with other conditions or illnesses.^[18]

The most common symptom of recurrent DLBCL is swollen or enlarged lymph nodes. These appear as lumps underneath the skin, often in the neck, armpits, or groin. The lumps usually do not go away and seem to be getting larger. They are often painless, but can sometimes be tender or uncomfortable.^[1][18]

Swelling can also occur in lymph nodes deeper within the body, not just underneath the skin. When this happens in lymph nodes in the abdomen, it can cause pain, typically in the lower right side, though the pain can spread to other areas. This abdominal pain may be accompanied by nausea, vomiting, diarrhea, or fever.^[18]

About 30 percent of people with DLBCL have what doctors call “B symptoms.” These include a fever above 103 degrees Fahrenheit (39.5 degrees Celsius) that lasts longer than two days or comes and goes, unexplained weight loss involving more than 10 percent of body weight over six months, and heavy night sweats so intense that they drench the sheets.^[1]

Having these symptoms does not necessarily mean DLBCL has returned. Swollen lymph nodes can occur with common infections like colds or other upper respiratory illnesses. Abdominal pain can be caused by stomach viruses, constipation, or other intestinal issues. However, any symptoms that last for several weeks should prompt a visit to a healthcare provider.^[1][18]

Diagnosis and Testing for Recurrence

Before starting a second line of treatment, doctors recommend repeating the tumor biopsy—a procedure where a small sample of tissue is removed and examined under a microscope. This is important because imaging tests like PET scans (positron emission tomography) may give false-positive results in patients who did not achieve complete metabolic remission after the first line of treatment. If performing a biopsy is not possible, doctors may repeat the PET scan at 6 to 12 weeks to confirm results.^[5]

A repeat biopsy also helps exclude other diseases that can look similar on scans, such as tuberculosis, sarcoidosis, fungal infection, or carcinoma. It can also identify whether there have been any changes in the characteristics of the cancer cells since the initial diagnosis.^[5]

Treatment Options for Relapsed or Refractory DLBCL

Until relatively recently, the outlook for patients with relapsed or refractory DLBCL was very poor and treatment options were very limited. In recent years, several novel therapies have been approved that provide more effective options than conventional chemotherapy and that have manageable side effect profiles.^[5]

Stem Cell Transplantation

High-dose chemotherapy followed by stem cell transplantation can be used to treat patients with DLBCL whose disease is refractory or relapsed following initial chemotherapy. A stem cell transplant involves collecting healthy stem cells, giving high doses of chemotherapy to destroy cancer cells, then returning the stem cells to the body to help rebuild the blood and immune system.^[2]

The majority of patients undergoing stem cell transplantation will have an autologous transplant, meaning the patient receives his or her own stem cells, collected prior to the procedure. Occasionally, a patient will undergo an allogeneic transplant, where the patient receives stem cells from a donor.^[2]

Second-Line Chemotherapy Regimens

For those with relapsed or refractory DLBCL, several combination chemotherapy regimens are available as second-line treatments. These include:^[2]

• Ifosfamide, carboplatin, and etoposide (ICE)
• Dexamethasone, cisplatin, and cytarabine (DHAP)
• Gemcitabine-based therapy
• Bendamustine (Treanda) plus rituximab (Rituxan)
• Lenalidomide (Revlimid) plus rituximab (Rituxan)

Newer Targeted Therapies

Several newer medications have been approved for relapsed or refractory DLBCL. These include:^[2]

• Polatuzumab vedotin-piiq (Polivy)
• Selinexor (Xpovio)
• Tafasitamab-cxix (Monjuvi)
• Epcoritamab-bysp (Epkinly)
• Glofitamab-gxbm (Columvi)

The combinations of polatuzumab vedotin with bendamustine and rituximab, and tafasitamab with lenalidomide, are approved options for patients who are not candidates for transplant and have manageable toxicity profiles.^[5]

CAR T-Cell Therapy

For some patients with relapsed or refractory DLBCL, a form of immunotherapy called chimeric antigen receptor (CAR) T-cell therapy may be a possible treatment option. CAR T-cell therapy has become the new standard treatment for patients with refractory or early relapsed DLBCL, based on the positive results of clinical trials.^[5]

This treatment involves collecting a patient’s own T cells (another type of white blood cell), modifying them in a laboratory to recognize and attack cancer cells, then infusing them back into the patient’s body. The approved CAR T-cell therapies for relapsed or refractory DLBCL include:^[2]

• Axicabtagene ciloleucel (Yescarta)
• Lisocabtagene maraleucel (liso-cel, Breyanzi)
• Tisagenlecleucel (Kymriah)

Treatment for Specific Subtypes

For patients who have a subset of DLBCL called primary mediastinal large B-cell lymphoma (PMBCL), which starts in the center of the chest, pembrolizumab (Keytruda) may be included as a second-line treatment option.^[2]

Outcomes and Prognosis

Before the development of newer therapies, the outlook for patients with relapsed or refractory DLBCL was quite poor. A landmark study called SCHOLAR-1 established a benchmark by reporting outcomes for 636 patients with refractory DLBCL. In this study, refractory disease was defined as stable or progressive disease as the best response to first- or later-line therapy, or relapse within 12 months after autologous stem cell transplantation.^[12]

The SCHOLAR-1 study found an objective response rate of 26 percent, with only 7 percent achieving complete remission to treatment for relapsed or refractory disease. The median overall survival was 6.3 months, and the 2-year survival rate was only 20 percent.^[12]

However, these findings represent outcomes before the widespread availability of newer treatments like CAR T-cell therapy and novel targeted agents. With these newer options, outcomes have improved for many patients with relapsed or refractory DLBCL. The specific outlook depends on multiple factors, including the type and timing of relapse, previous treatments received, and the patient’s overall health.^[5]

Living with Recurrent DLBCL

Facing a DLBCL relapse can be emotionally overwhelming. Patients often experience fear, anxiety, and uncertainty about the future. The emotional toll can be significant, affecting not just the patient but also family members and caregivers who may feel helpless because they want to fix the situation but cannot.^[13]

Some patients develop post-traumatic stress disorder (PTSD) following relapse, particularly after multiple relapses. Psychiatric support and therapy can help patients learn how to cope and not be overwhelmed by difficult emotions. Many patients find they come out of the experience stronger than before.^[13]

Seeking support beyond medical appointments is important. Resources such as support groups, online forums, and patient advocacy organizations can provide valuable information and connect patients with others who understand what they are going through. Many patients wish they had found these resources sooner in their journey.^[13]

Patients should not be afraid to ask their doctors questions and should advocate for themselves throughout the treatment process. Trusting the healthcare team while also speaking up about concerns and preferences is an important part of navigating recurrent DLBCL. Despite the challenges, many patients maintain hope, focusing on the fact that DLBCL remains treatable even when it returns, and that there are always next steps available.^[13]

The Importance of Follow-Up Care

When there is no sign of lymphoma left after treatment, patients usually have follow-up appointments for 2 to 3 years. During these visits, doctors monitor for any signs of recurrence and manage any ongoing side effects from treatment. Regular monitoring helps catch any potential relapse early, when additional treatment may be most effective.^[10]

Patients should report any new or concerning symptoms to their healthcare provider promptly, even between scheduled appointments. Being vigilant about changes in the body while trying not to let anxiety take over is a balancing act that many survivors navigate with the help of their care team and support network.

Research and Future Directions

Medical researchers continue to study different treatments for DLBCL that comes back. Ongoing clinical trials are testing new therapies and treatment combinations to improve outcomes for patients with relapsed or refractory disease. Research brings the hope of even better treatment options in the future.^[1][10]

Physicians are encouraged to propose clinical trials to their patients whenever possible, as participation in well-conducted clinical trials helps advance medical knowledge and may provide access to promising new treatments before they become widely available.