Hodgkin’s disease, also known as Hodgkin lymphoma, can sometimes return after a person has completed treatment and entered remission. When this happens, it is called recurrent or relapsed Hodgkin’s disease, and it presents unique challenges for patients who thought their cancer journey was over.

Recurrent Hodgkin’s disease means that cancer cells have grown back or appeared again in the body after a period when the disease was undetectable. This is different from having cancer that never fully responded to initial treatment, which is called refractory disease. Understanding the difference between these two situations is important because they may be treated somewhat differently, even though both require renewed medical attention and careful planning between patients and their healthcare teams.^[1]

What Does Recurrent Hodgkin’s Disease Mean?

The term relapsed refers to when Hodgkin lymphoma reappears or begins growing again after a period of remission. Remission is the medical term for when tests and examinations show no evidence of disease in the body. When someone is told they are in remission, it means that doctors cannot detect cancer cells through available testing methods, even though this does not always mean the disease is permanently gone.^[1]

For people with classical Hodgkin lymphoma, the most common type of this cancer, relapses typically happen within the first three years after the original diagnosis and treatment. However, it is important to know that some relapses can occur much later than this timeframe, even years or decades after initial treatment ended. This pattern means that people who have had Hodgkin lymphoma need to remain vigilant about follow-up care even when they feel completely healthy.^[1]

The good news is that when Hodgkin lymphoma returns, secondary therapies are often successful in achieving another remission. In fact, these second-line treatments may even cure the disease permanently in many cases. This offers real hope to patients facing the difficult news that their cancer has come back.^[1]

How Common Is Recurrent Hodgkin’s Disease?

Hodgkin lymphoma itself is not extremely common. Estimates suggest that over nine thousand new cases are diagnosed in the United States each year. The disease shows a particular pattern in who it affects, with the highest number of cases occurring in people between the ages of fifteen and thirty-four years. There is also a second, smaller peak in cases among people older than sixty years of age. This bimodal distribution means that Hodgkin lymphoma can affect both young adults in the prime of their lives and older adults.^[5]

Despite generally favorable outcomes for most patients with Hodgkin lymphoma, approximately one-quarter to one-third of patients will either not respond completely to their first treatment or will experience a relapse after initially successful therapy. Among these patients who relapse or have refractory disease, only about fifty percent will be effectively cured with standard second-line therapies. This statistic highlights the ongoing challenge that recurrent disease poses to both patients and medical professionals.^[5]

The outlook is particularly difficult for certain groups of patients. Those with chemotherapy refractory disease, meaning their cancer does not respond even temporarily to treatment, face especially poor odds. Similarly, patients who relapse after already undergoing high-dose chemotherapy followed by an autologous stem cell transplant (a procedure where a patient’s own stem cells are used to rebuild their bone marrow) also have more limited treatment options available to them.^[5]

Causes and Risk Factors for Relapse

Several factors have been identified that may increase the likelihood of Hodgkin lymphoma returning after treatment. Understanding these risk factors can help doctors and patients work together to create appropriate monitoring and treatment plans. A remission duration of less than one year is considered a significant negative prognostic factor. This means that if the disease returns within twelve months of achieving remission, the outlook tends to be more challenging than if it returns after a longer disease-free period.^[5]

Advanced stage disease at the time of relapse also presents greater difficulties. When Hodgkin lymphoma returns and has already spread to multiple areas of the body, treatment becomes more complex. Similarly, extranodal disease at relapse, meaning the cancer has spread beyond the lymph nodes to other organs or tissues, is associated with poorer outcomes. The presence of B symptoms at the time of relapse is another concerning sign. B symptoms include unexplained fever, drenching night sweats, and unintentional weight loss, all of which indicate more aggressive disease activity.^[5]

Recent advances in imaging technology have improved doctors’ ability to predict outcomes for patients with relapsed disease. For patients experiencing their first relapse and preparing to undergo autologous stem cell transplantation, having a negative positron emission tomography (PET) scan that suggests complete remission has been identified as an important positive prognostic indicator. This imaging technique can show whether cancer cells are still metabolically active in the body, even when other tests might miss small amounts of remaining disease.^[5]

Symptoms of Recurrent Hodgkin’s Disease

The symptoms of recurrent Hodgkin lymphoma can be similar to those experienced during the initial diagnosis, though they may appear in different locations or with different intensity. One of the most common signs is the development of swollen lymph nodes. These are small, bean-shaped structures that are part of the body’s immune system and can be found throughout the body, particularly in the neck, armpits, and groin. When Hodgkin lymphoma returns, these nodes may become enlarged and can sometimes be felt under the skin as painless lumps.^[2]

Systemic symptoms, also known as B symptoms, are particularly important warning signs that the disease may have returned. These include fever without an obvious cause such as an infection, night sweats so severe that they drench clothing and bedding, and significant weight loss that occurs without intentional dieting or changes in eating habits. Additionally, people with recurrent Hodgkin lymphoma often experience profound fatigue that does not improve with rest and interferes with daily activities.^[2]

Because these symptoms can also be caused by many other conditions that are not cancer, including common infections, it is crucial for anyone who has been treated for Hodgkin lymphoma to report new or persistent symptoms to their healthcare provider. Early detection of relapse often leads to better treatment outcomes, so maintaining open communication with medical professionals is essential for all Hodgkin lymphoma survivors.^[2]

Diagnosis of Recurrent Hodgkin’s Disease

When doctors suspect that Hodgkin lymphoma has returned, they use a variety of tests to confirm the diagnosis and understand the extent of the disease. Blood tests are typically among the first investigations performed. These tests measure the levels of different types of blood cells, as lymphoma can cause abnormally low blood counts. Blood tests can also reveal other abnormalities that may indicate the presence of Hodgkin lymphoma, such as elevated markers of inflammation or other changes in blood chemistry.^[4]

Imaging studies play a crucial role in detecting recurrent disease. CT scans (computed tomography scans) create detailed cross-sectional images of the body and can show enlarged lymph nodes or masses that may represent returning cancer. Ultrasounds, which use sound waves to create images, may also be employed to examine specific areas of concern. PET scans are particularly valuable because they can detect metabolically active cancer cells by tracking how different tissues in the body use glucose, a type of sugar. Cancer cells typically consume more glucose than normal cells, making them visible on PET imaging.^[4]

The definitive way to confirm that Hodgkin lymphoma has returned is through a biopsy. This procedure involves removing a small sample of tissue from a lymph node or other affected area so that it can be examined under a microscope by a pathologist. The pathologist looks for characteristic cells called Reed-Sternberg cells, which are abnormally large cells that are hallmarks of classical Hodgkin lymphoma. Biopsy results not only confirm whether the disease has relapsed but also help doctors determine the exact type and characteristics of the lymphoma, which guides treatment decisions.^[4]

Test results from all of these diagnostic procedures work together to help doctors create a complete picture of the relapsed disease. They can determine what stage the lymphoma is in, meaning how far it has spread through the body, and identify the best treatment approach for that particular patient’s situation. Staging is important because it influences both treatment choices and expected outcomes.^[4]

Treatment Options for Recurrent Hodgkin’s Disease

The approach to treating recurrent Hodgkin lymphoma depends on multiple factors. These include when the relapse occurred relative to the initial treatment, the patient’s age and overall health status, how extensively the disease has spread through the body, and what treatments were used during the first course of therapy. For most patients, the current standard approach involves combination therapy followed by autologous stem cell transplantation. Radiation therapy directed at specific involved sites may also be incorporated into the treatment plan.^[1]

Second-line chemotherapy is the backbone of treatment for most people with relapsed Hodgkin lymphoma. This chemotherapy typically uses different drugs than those employed in the initial treatment. The goal is to use medications that the cancer cells have not been exposed to before, reducing the chance that the disease has already developed resistance to the drugs. There are numerous chemotherapy regimen options available for recurrent disease, each with its own combination of medications.^[4]

Some commonly used chemotherapy combinations include ICE, which stands for ifosfamide, carboplatin, and etoposide. Another option is gemcitabine-containing regimens, such as GVD, which combines gemcitabine, vinorelbine, and pegylated liposomal doxorubicin. DHAP is another frequently used combination that includes dexamethasone, cisplatin, and cytarabine. ESHAP combines etoposide, methylprednisolone, cisplatin, and cytarabine. IGEV uses ifosfamide, gemcitabine, and vinorelbine together.^[1]

Beyond traditional chemotherapy, newer types of medications have shown promise in treating recurrent Hodgkin lymphoma. Targeted therapy drugs work by attacking specific molecules on or inside cancer cells. Brentuximab vedotin, marketed as Adcetris, is one such targeted therapy that has been approved for use in relapsed Hodgkin lymphoma. Bendamustine, known as Treanda, is another medication that may be used. Immunotherapy drugs, which help the body’s own immune system recognize and fight cancer cells, have also become important treatment options. Nivolumab (Opdivo) and pembrolizumab (Keytruda) are two immunotherapy drugs used in this setting.^[1]

Stem Cell Transplantation

For many patients with relapsed or refractory Hodgkin lymphoma, stem cell transplantation represents the primary treatment approach, particularly when the disease did not completely disappear after initial chemotherapy or radiation therapy, or when it returns soon after completing the original treatment. A stem cell transplant is a complex procedure that begins with high-dose chemotherapy designed to destroy all cells in the bone marrow, including both healthy cells and cancer cells.^[8]

The purpose of the very high doses of chemotherapy is to kill as many lymphoma cells as possible. However, because bone marrow produces the blood cells that the body needs to survive, destroying the bone marrow would be fatal without replacement. This is why stem cell transplantation is necessary. After the high-dose chemotherapy, healthy stem cells are given to the patient to replace those destroyed in the bone marrow. These new stem cells can rebuild the bone marrow and restore its ability to produce blood cells.^[7]

There are two main types of stem cell transplants. In an autologous transplant, stem cells are collected from the patient’s own bone marrow or blood before the high-dose chemotherapy begins. These cells are frozen and stored, then returned to the patient after the intensive chemotherapy is complete. Because the cells come from the patient’s own body, there is no risk of rejection, though there is a possibility that some cancer cells might be present among the collected stem cells.^[8]

In an allogeneic transplant, stem cells are collected from another person, called a donor. The donor is usually a close genetic match to the patient, often a sibling or other family member, though unrelated donors can also be used. Allogeneic transplantation carries different risks than autologous transplantation, including the possibility that the donor’s immune cells will attack the patient’s tissues in a condition called graft-versus-host disease. However, this approach may be considered if disease remains after an autologous stem cell transplant, as it may offer additional anti-cancer effects through the donor’s immune system recognizing and attacking any remaining lymphoma cells.^[8]

Radiation Therapy

Radiation therapy may be offered to treat recurrent Hodgkin lymphoma that returns or persists in only one lymph node area, particularly if the patient did not receive radiation therapy as part of their initial treatment. Radiation therapy uses high-energy rays or particles to destroy cancer cells in the targeted area. It may be given alone or combined with chemotherapy, depending on the individual situation. Radiation therapy can also be used as preparation for a stem cell transplant, helping to eliminate cancer cells before the transplant procedure.^[8]

A specific type of radiation therapy called involved site radiation therapy (ISRT) may be used. This approach focuses the radiation beam precisely on the areas where disease is present, minimizing exposure to surrounding healthy tissues. This precision helps reduce the risk of long-term side effects from radiation while still effectively targeting cancer cells.^[1]

Treatments Under Investigation

Although the cure rate for Hodgkin lymphoma is already relatively high compared to many other cancers, research continues actively to find better ways to treat patients who are refractory to standard treatments and those who experience relapse. Many promising new therapies are currently being studied in clinical trials. Clinical trials are carefully controlled research studies that test whether new treatments are safe and effective before they become widely available.^[1]

Among the experimental approaches being investigated are anti-CD30-CAR T cells, which are a form of cellular therapy where a patient’s own immune cells are genetically modified to recognize and attack lymphoma cells. Other drugs being studied include atezolizumab (Tecentriq), bortezomib (Velcade), carfilzomib (Kyprolis), and everolimus (Afinitor). These medications work through various mechanisms to interfere with cancer cell growth and survival.^[1]

Additional investigational agents include ibrutinib, itacitinib, ipilimumab, lenalidomide, magrolimab, mocetinostat, pralatrexate, romidepsin, ruxolitinib, tislelizumab, and umbralisib. Some of these drugs target specific molecular pathways that cancer cells use to grow and survive, while others work by enhancing the immune system’s ability to recognize and eliminate cancer cells. Patients interested in accessing these experimental treatments may wish to discuss clinical trial participation with their healthcare team.^[4]

Prevention of Recurrence

While there is no guaranteed way to prevent Hodgkin lymphoma from returning after treatment, maintaining regular follow-up care is essential for early detection if relapse does occur. Once treatment is finished, doctors typically schedule follow-up appointments every few months, with the frequency gradually decreasing over time if no problems arise. These appointments usually include physical examinations, blood tests, and sometimes imaging studies to check for any signs that the disease may be returning.^[17]

Some healthcare systems now use a model called supported self-management or patient-triggered follow-up for monitoring Hodgkin lymphoma survivors. Instead of having regularly scheduled appointments, patients are educated about symptoms to watch for and can contact their medical team if concerns arise. Regular blood tests may still be performed at the patient’s general practitioner’s office to monitor overall health. Whichever follow-up approach is used, it is important that patients understand how it works and know how to reach their healthcare team if needed.^[17]

After about two to three years of monitoring without any signs of relapse, some hospitals transfer ongoing care back to the patient’s regular doctor. This timing is based on the fact that most relapses occur within the first three years after treatment, though it is important to remember that late relapses can occasionally happen. Even after formal cancer follow-up ends, people who have been treated for Hodgkin lymphoma should continue seeing their primary care provider regularly and report any concerning symptoms promptly.^[17]

How the Body Changes with Recurrent Disease

Understanding what happens in the body when Hodgkin lymphoma returns helps explain why certain symptoms occur and why specific treatments are chosen. Hodgkin lymphoma originates in germ-fighting white blood cells called B lymphocytes, which are part of the lymphatic system. The lymphatic system is a complex network that includes lymph fluid, lymph vessels, lymph nodes, and organs such as the spleen, thymus, tonsils, and bone marrow. All of these components work together as part of the body’s immune defense system.^[2]

When Hodgkin lymphoma develops or returns, abnormal lymphocytes begin multiplying uncontrollably. These cancerous cells can accumulate in lymph nodes, causing them to swell. The lymph nodes most commonly affected by Hodgkin lymphoma are those in the neck, chest area (particularly in a region called the mediastinum, which is the space between the lungs), underarms, abdomen, pelvis, and groin. However, because the lymphatic system extends throughout the entire body, Hodgkin lymphoma can potentially affect lymph nodes and organs in many different locations.^[6]

Under a microscope, tissue from Hodgkin lymphoma contains characteristic abnormal cells called Reed-Sternberg cells. These are very large cells that have a distinctive appearance and are key to diagnosing Hodgkin lymphoma. Most cases of Hodgkin lymphoma are classified as classical Hodgkin lymphoma, which includes several subtypes: nodular sclerosing Hodgkin lymphoma, mixed cellularity Hodgkin lymphoma, lymphocyte-depleted classical Hodgkin lymphoma, and lymphocyte-rich classical Hodgkin lymphoma. Each subtype has slightly different characteristics when examined under a microscope, but all are treated similarly.^[2]

As the disease progresses, cancer cells can spread beyond lymph nodes to other organs and tissues in the body. This extranodal spread can affect organs such as the lungs, liver, bone marrow, or bones. When lymphoma cells infiltrate these areas, they can interfere with normal organ function. For example, lymphoma in the bone marrow can disrupt normal blood cell production, leading to low blood counts. Disease in the lungs may cause breathing difficulties, while involvement of the liver can affect how the body processes nutrients and medications.^[6]

The systemic symptoms that many people with recurrent Hodgkin lymphoma experience—such as fever, night sweats, and weight loss—occur because of the body’s response to the cancer. Lymphoma cells release various chemical messengers called cytokines that can affect the body’s temperature regulation, metabolism, and overall function. The fatigue that many patients experience is multifactorial, resulting from the body’s energy being consumed by rapidly growing cancer cells, the effects of cytokines on normal body functions, and sometimes from low blood counts if the bone marrow is affected.^[2]