Overview of DLBCL

Diffuse large B-cell lymphoma (DLBCL), a type of aggressive B-cell lymphoma, accounts for about 30% of all cases of non-Hodgkin’s lymphomas (NHLs).

If you have been diagnosed with diffuse large B-cell lymphoma (DLBCL), you probably have many questions and concerns about your disease and its treatment. This patient treatment summary, which is based on the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for non-Hodgkin’s lymphoma, will help you understand the best available treatments for DLBCL. Talk with your doctor about these therapies so that together you can decide on a treatment plan that is right for you.

Background

NHL is a group of blood cancers that affect the lymphatic system, which is part of the immune system. The immune system defends the body against infections and other diseases. The lymph system is made up of blood, lymph, lymph vessels, lymph nodes, spleen, thymus, tonsils, and bone marrow. DLBCL, a subtype of non-Hodgkin’s lymphoma, is a B-cell lymphoma that starts in B-lymphocytes, a type of white blood cell that makes antibodies.

DLBCL is a type of fast-growing, aggressive B-cell lymphoma. DLBCL often starts in the lymph nodes and spreads to other parts of the body. Lymph nodes are found in the neck, underarms, chest, abdomen, and groin. The lymph nodes trap and remove harmful bacteria and other substances in the lymph. Lymph nodes often become enlarged when the body is fighting infections, such as when you have a cold or sore throat. Most of the times enlarged lymph nodes are not a problem. However, if they stay swollen for more than 2 weeks, a doctor should be consulted, because swollen lymph nodes are one of the common symptoms of DLBCL.

Diagnosis of DLBCL

The most common symptom of NHL is an enlarged lymph node. You may also experience other symptoms, which may include fever, night sweats, feeling tired, loss of appetite, weight loss, and rash. The initial diagnosis of NHL will involve an incisional or excisional lymph node biopsy, during which your doctor will remove part or all of the enlarged lymph node for examination by a hematopathologist. It is recommended that your biopsy sample be reviewed by an expert hematopathologist, because diagnosing lymphoma can be difficult. Once it is confirmed to be lymphoma, more tests will need to be performed on the sample to determine if it is DLBCL or another subtype of NHL.

The hematopathologist will perform a procedure known as immunophenotypic analysis (IPA) on the biopsy sample to help identify what type of lymphoma you have. IPA enables your doctor to determine whether you have a B-cell or T-cell lymphoma. IPA also helps to differentiate DLBCL from other subtypes of NHL.

Staging of DLBCL

A formal system called staging is used to identify how localized or widespread your cancer is. Staging is an important part of developing the best treatment plan for you.

DLBCL is broken down into five stages:

• Stage I: Involvement of a single lymph node group
• Stage II: Involvement of multiple lymph node groups on the same side of the diaphragm (thin muscle that separates the chest from the abdomen)
• Stage III: Involvement of multiple lymph node groups on both sides of the diaphragm
• Stage IV: Involvement of multiple lymph nodes groups and spread to other organs besides the lymph nodes

Some doctors will also divide patients into “A” or “B” categories, depending on their symptoms, if any. If you are experiencing B symptoms, you have unexplained high fever, weight loss of more than 10% of your original body weight, heavy sweating during the day, and drenching night sweats. If you are not experiencing these symptoms, you are in the “A” category.

In order to stage your cancer, your doctors will perform several tests, including:

• A thorough physical exam, which will include several questions about any symptoms you might have had, your general health, and your medical history
• Blood tests, including CBC, metabolic profile, and LDH levels (lactate dehydrogenase)
• Computerized tomography (CT) scan of chest, abdomen, and pelvic region
• Positron emission tomography (PET) scan; usually used together with a CT scan

In some circumstances, the following tests may be needed:

• Bone marrow biopsy and aspirate
• Brain imaging such as magnetic resonance imaging (MRI)
• Lumbar puncture to analyze fluid in your spine

The doctors also use a special scale called the International Prognostic Index (IPI) to categorize patients into four risk groups: low, low-intermediate, high-intermediate, and high-risk, based on five factors: your age; performance status (which specifies how the disease is impacting your daily activities); the level of an enzyme called lactate dehydrogenase (LDH) in your blood; the number of disease sites outside of lymph nodes; and the stage of your disease. These prognostic scores help predict if the treatment will be successful in a particular patient. Patients with normal LDH levels in the blood, early-stage disease, and age younger than 60 years with good performance status have a good prognosis.

Although DLBCL is an aggressive type of lymphoma, it is potentially curable. It is very important for your doctor to perform all tests needed to ensure that you receive the correct diagnosis and stage so that the appropriate treatment can be started.

Treatment of DLBCL

Treatment of DLBCL involves a number of specialists who plan and work as a team to coordinate a patient’s care, and most often uses a combination of several approaches. Therefore, it is very important that you receive your medical care at a hospital or cancer center where doctors are experienced in treating patients with lymphoma. If the doctors at your hospital do not have a lot of experience treating these illnesses, ask your physician for a referral to a large cancer center where the staff have seen and treated many cases of these diseases. Treatment of DLBCL aims to relieve symptoms, slow progression, improve quality of life, and provide a cure.

Before you begin treatment your doctor may perform the following tests:

• MUGA scan or echocardiograms to monitor heart function. One of your treatment options, chemotherapy, may involve a class of drugs called anthracyclines, which can damage your heart. It is important to know the health of your heart before beginning treatment.
• Hepatitis B testing. Your doctor will also need to know if you are a carrier of hepatitis B or if you have recovered from hepatitis B infection. Treatment with chemotherapy and immunotherapy may reactivate hepatitis B, but your doctor can give you antiviral drugs to prevent this from happening.
• Pregnancy testing for women with childbearing potential.
• Some treatment options may affect fertility. Depending on your age and future plans, you may wish to discuss with your doctor how treatment may impact your fertility, and options for preservation.

In general, treatments rely on the following approaches, often in combination:

• Chemotherapy: Drugs are used to kill or slow the growth of cancer cells, including any that have broken away from the original tumor.
• Immunotherapy: Antibodies are used to identify cancerous cells and destroy them. Rituximab is a monoclonal antibody used to treat NHL.
• Chemoimmunotherapy: The combination of chemotherapy and immunotherapy agents is used to treat NHL. This is the most common form of treatment for DLBCL.
• Radiation therapy (or radiotherapy): High-energy beams are used to kill tumor cells.
• High-dose chemotherapy with autologous stem cell rescue (HDT/ASCR): High-dose chemotherapy is used to destroy any residual lymphoma cells in your bone marrow. However, because this form of treatment will also destroy your own developing blood cells, the bone marrow cells that were destroyed by chemotherapy are then replaced with an infusion of your own healthy blood and marrow (see later section on Stem Cell Rescues and Transplants Overview).
• High-dose chemotherapy with allogeneic stem cell transplant (HDT/ASCT): High-dose chemotherapy is used to destroy any residual lymphoma cells in your bone marrow. However, because this form of treatment will also destroy your own developing blood cells, the bone marrow cells that were destroyed by chemotherapy are then replaced with an infusion of stem cells from a matched donor (see later section on Stem Cell Rescues and Transplants Overview).
• Clinical trials: Investigational drugs and protocols will be tried. Despite improvements in outcomes, there is still need for better treatment options. Clinical trials may test novel drugs or alternative ways of giving established drugs that may lead to improved outcomes for all patients.

In many cases, some of the tests that were performed to diagnosis and stage your DLBCL will be repeated during your treatment. This interim restaging will help your doctor determine how well your lymphoma is responding to the treatment, and make decisions about your future treatments.

Below you will find more detailed treatment information based on the stage of your DLBCL. Treatment plans are divided between stage I/II and stage III/IV.

Treatment for Stage I/II DLBCL

If you are diagnosed with stage I or II DLBCL, your initial treatment will be chemotherapy combined with immunotherapy. The most common regimen is known as RCHOP, which is a combination of rituximab and 4 chemotherapy drugs (cyclophosphamide, doxorubicin, vincristine, and prednisone). You will receive 3 or 6 cycles of RCHOP if you have non-bulky disease (tumor < 10 cm). If your disease is bulky (tumor > 10 cm), then your treatment will start with 6 cycles.  After you have completed the required number of cycles of chemoimmunotherapy, your disease will be restaged before you receive further treatment.

If you experience a complete response (disappearance of all evidence of disease) to chemoimmunotherapy, you will then complete the recommended radiation therapy protocol.

If you experience a partial response (shrinkage of the lymph nodes and no new disease spots), then you can be treated in several ways. Your treatment may be radiation therapy at a higher dose than initially planned, high-dose chemotherapy with autologous stem cell rescue, or enrollment in a clinical trial. For more detailed information on stem cell rescues, please see below

If you experience no response or your disease progresses, your treatment options are detailed below under Treatment for Recurrent or Refractory DLBCL.

If you are not a candidate for chemotherapy, radiation therapy may be given.

If you experience a complete or partial response to initial chemoimmunotherapy, you will again be restaged after you finish radiation therapy so that the effectiveness of your treatment can be evaluated. If you maintain a complete response or now experience a complete response, you will be followed up every 3 months for 2 years, and every 6 months for 3 years after that, to check for recurrence of disease.

If after radiation therapy you do not experience a complete response, your DLBCL may be considered refractory. Response will be determined through both a physical exam and imaging tests (CT and PET scans). If there is a suggestion of residual or persistent disease, you should undergo a biopsy. If the biopsy shows active disease, your lymphoma can be called refractory. Your treatment options are detailed below under Treatment for Recurrent or Refractory DLBCL.

Treatment for Stage III/IV DLBCL

The treatment for stage III/IV DLBCL is similar to the treatment for stage I/II DLCBL except for the use of radiation therapy; radiation therapy is used sparingly in stage III/IV DLBCL.

If you have stage II/IV DLCBL, your treatment will include six to eight cycles of chemoimmunotherapy with the previously mentioned RCHOP regimen. RCHOP is the most common chemoimmunotherapy, but many options are available in clinical trials. After three to four cycles of treatment, your cancer will be restaged to determine how well your lymphoma is responding to the treatment. If you show a complete or partial response to the treatment, the remaining cycles of treatment will be given. If you do not show a response or your disease progresses after these initial cycles of treatment, your DLBCL is considered refractory. Your treatment options are detailed below under Treatment for Recurrent or Refractory DLBCL.

After finishing all six to eight cycles of RCHOP, your disease will once again be restaged. If you show a complete response, you can consider undergoing radiation therapy to the areas where you initially had bulky disease. Otherwise, you will be followed up every 3 months for 2 years, and every 6 months for 3 years after that, to check for disease recurrence.

If you do not show a complete response after completing chemoimmunotherapy, your treatment options are detailed below under Treatment for Recurrent or Refractory DLBCL.

Treatment for Recurrent or Refractory DLBCL

If your DLBCL comes back after treatment (recurrence) or does not respond to initial treatment (refractory), you will be given second-line therapy. Your second-line therapy choices will depend on whether you are a candidate for high-dose therapy.

Response will be determined through both physical examinations and imaging tests (CT scans and PET scans). If there is a suggestion of residual or persistent disease, you should undergo a biopsy. If the biopsy shows active disease, your lymphoma can be called refractory.

If you are a candidate for high-dose therapy, you will receive a high-dose chemotherapy regimen (with or without rituximab) that is different from your initial chemotherapy. If your disease responds to therapy, you may undergo autologous stem cell rescue or allogeneic stem cell transplant to further control your disease. These procedures are described in more detail in the later section on Stem Cell Rescues and Transplants Overview).

If your disease does not respond to the high-dose therapy, you should consider entering a clinical trial to receive an investigational treatment. Your doctor may also recommend radiation therapy or other treatment options to relieve your lymphoma-related complications.

If you are not a candidate for high-dose therapy, you can enroll in a clinical trial. Alternatively, your doctor may also recommend less-intensive chemotherapy regimens that you have not received before or radiation therapy.

If you experience disease relapse two or more times, the recommended treatment is enrollment in a clinical trial. Most patients whose disease progresses after three successive chemotherapy regimens are unlikely to benefit from currently used chemotherapy regimens.

Stem Cell Rescues and Transplants Overview

Stem cell rescues and transplants are demanding treatments. Both treatments use chemotherapy at a higher dose than the regular chemotherapy regimens. High-dose chemotherapy is used to destroy the rapidly dividing cancer cells in the bone marrow, but the dose is also high enough to destroy other rapidly dividing normal blood cells in the bone marrow. Therefore, these blood cells are replaced with an infusion of either your own blood and marrow (autologous) or blood and marrow from a matched donor (allogeneic). These cells then seed your own bone marrow and your body starts making new blood cells.

Autologous stem cell rescue is the much more common treatment in patients with DLBCL. Randomized clinical trials have shown that consolidation therapy with high-dose chemotherapy and autologous stem cell rescue has a higher likelihood of long-term cure in patients whose disease responds to second-line therapy.

However, if your DLBCL has spread to your bone marrow, you may be a candidate for an allogeneic stem cell transplant, although this procedure is generally considered investigational for the treatment of DLBCL.

High-Dose Chemotherapy With Autologous Stem Cell Rescue (HDT/ASCR)

HDT/ASCR is the standard of care for treating recurrent or refractory DLBCL in patients whose disease responds to second-line chemotherapy. Before undergoing an autologous stem cell rescue, your own stem cells will be harvested from your body when you are free of disease (after second-line chemotherapy). This can be done in two ways: the stem cells can be removed from your bone marrow in a procedure called a bone marrow aspiration, or the stem cells can be removed from your blood through filtration. Most patients will need to be treated with a growth factor (granulocyte colony–stimulating factor [G-CSF]) to encourage the body to make and release more stem cells into the bloodstream before harvesting.

Once your stems cells have been harvested, you will receive high-dose chemotherapy that wipes out your own developing blood cells in the bone marrow along with any residual lymphoma cells that remain after prior treatment. This high-dose chemotherapy is called conditioning. You may also receive radiation therapy in addition to chemotherapy.

There are two different conditioning regimens: myeloablative and non-myeloablative. Myeloablative conditioning destroys all bone marrow cells along with any residual lymphoma cells and is harder on the patient, and therefore is often used in younger patients. Non-myeloablative (or reduced-intensity) conditioning uses lower-intensity chemotherapy that suppresses your immune system and allows the transplant to take, but is not strong enough to destroy all bone marrow cells, and is an option for patients who are not considered candidates for myeloablative conditioning, such as those who are older than 55 years.

Once conditioning is complete, your own new stem cells are infused into your bone marrow. These cells will begin to grow and divide in your bone marrow, and grow new blood cells.

Because of the risks associated with stem cell transplants, the decision to pursue this option must be made after careful discussion with your doctor.

High-Dose Chemotherapy With Allogeneic Stem Cell Transplant (HDT/ASCT)

Allogeneic stem cell transplants are generally considered investigational for the treatment of DLBCL. An allogeneic stem cell transplant may be considered if you have bone marrow involvement.

In order to have an allogeneic stem cell transplant, you must have a donor who is a close match to you. Most often the donated stem cells will come from a close relative such as a sibling or from a matched unrelated donor (MUD) or cord blood. These donated stem cells provide a powerful form of immunotherapy.

Prior to allogeneic stem cell transplantation, you will undergo high-dose chemotherapy (conditioning) that wipes out your own developing blood cells in the bone marrow along with any residual lymphoma cells that remain after prior treatment.

There are two different conditioning regimens: myeloablative, and non-myeloablative. Myeloablative conditioning destroys all bone marrow cells along with any residual lymphoma cells and is harder on the patient, and therefore is often used in younger patients. Non-myeloablative (or reduced-intensity) conditioning uses lower-intensity chemotherapy that suppresses your immune system and allows the transplant to take, but is not strong enough to destroy all bone marrow cells, and is an option for patients who are not considered candidates for myeloablative conditioning, such as those who are older than 55 years.

Once conditioning is complete, new stem cells are infused into your bone marrow. These cells begin to grow and divide in your bone marrow, and grow new blood cells.

Graft-versus-host disease (GVHD) is a potentially life-threatening long-term side effect of allogeneic stem cell transplant. In GVHD, transplanted donor blood cells attack the patient’s immune system. Acute GVHD occurs immediately after transplant, and chronic GVHD may occur from 3 months to 1 year after transplant.

You will receive immunosuppressive drugs (1 or 2 days prior to transplant) to prevent GVHD and related complications. You may need to take immunosuppressive drugs regularly for many months after transplantation to prevent GVHD.

Because of the risks associated with stem cell transplants and the possibility of rejection of the new stem cells by your immune system, the decision to pursue this option must be made after careful discussion with your doctor.

Side Effects of Treatment

DLBCL treatments may result in uncomfortable side effects. Talk to your doctor about what to expect from each treatment and how to manage the possible effects. For example:

• A common side effect of treatment is low blood counts. Many patients experience febrile neutropenia (low white blood cell counts), which can lead to increased risk of infection. Your doctor may prescribe growth factors to encourage your body to make more white blood cells. Your doctor may also prescribe antibiotics to decrease your chance of infection and treat any infections you develop.
• After radiation therapy, people are often fatigued; some may have shortness of breath. Your health care provider can use the NCCN Clinical Practice Guidelines in Oncology™ on cancer-related fatigue to help you reduce fatigue caused by cancer treatments. Also, see Fighting Cancer Fatigue.
• After chemotherapy, people may experience mouth sores, hair loss, fatigue, and/or loss of appetite.
• Your doctor may give you antiemetic (anti-vomiting/anti-nausea) drugs to decrease or prevent nausea and/or vomiting. The NCCN Clinical Practice Guidelines in Oncology™ on antiemesis can help your doctor determine the most appropriate antiemetic regimen for your situation.
• After chemotherapy, many patients experience constipation. Be sure to report this problem to your doctor so that proper medication and diet changes can be prescribed. Constipation can become life-threatening when accompanied by low blood counts, and it is also associated with a higher risk of infection.
• Damage to the heart muscle by chemotherapy drugs is called cardiac toxicity. As a result of this damage, the heart is not able to pump enough blood to supply the body with essential oxygen and nutrients. The most common cause of cardiac toxicity is treatment with chemotherapy drugs called anthracyclines. Doxorubicin is a frequently used anthracycline in chemotherapy. If you have impaired cardiac function, your doctor will monitor your condition and adjust the dose of chemotherapy accordingly. You may also be treated with regimens containing other anthracyclines that cause considerably lower cardiac toxicity.
• Hepatitis B virus reactivation can occur mainly in patients who received chemotherapy and rituximab and who are carriers of hepatitis B or have recovered from hepatitis B infection. Your doctor will give you antiviral drugs, such as lamivudine, to prevent the viral reactivation. Hepatitis B–positive patients may be asked to consult a hepatologist.

Talk to your doctor or oncology nurse about the best ways to manage side effects. It is important for you to discuss any possible side effects as soon as they appear.

Prognosis

In determining a prognosis—the likely course or outcome of a disease and its treatment—a doctor may look at survival statistics taken from studies of large groups of patients with DLBCL. However, such statistics:

• Are estimates only
• Can vary widely with each cancer stage
• Are sometimes based on older data that do not reflect recent advances in treatment options
• Cannot be used to precisely predict your survival

Your individual prognosis, although difficult to predict, will be affected by many factors, including:

• Your age
• Your overall health, including other diseases you may have
• The risk category of your cancer
• Your response to the treatment(s) being used

Newer therapies and combinations of therapies are enabling people with cancer to live longer, better quality lives than ever before. You may want to find out whether you are eligible to participate in a clinical trial, which may test novel drugs or alternative ways of giving established drugs that may lead to improved outcomes for patients.

Life After Treatment

Once your treatment is completed, you will need to see your doctor for follow-up visits at regular intervals to make sure that you remain healthy and that any long-term effects of cancer or its treatment can be attended to.