Lymphoma, Non-Hodgkin

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    Non-Hodgkin lymphoma refers to any of a large group of cancers of the immune system that can occur at any age and are often marked by enlarged lymph nodes, fever, and weight loss. Learn about non-Hodgkin lymphoma and find information on how we support and care for children and teens with non-Hodgkin before, during, and after treatment.

The Hematologic Malignancy Center at Dana-Farber Boston Children's Cancer and Blood Disorders Center is one of the top pediatric leukemia and lymphoma treatment centers in the world. In addition to treating lymphomas and leukemias, our center treats the primary types of histiocytosis.

All members of our treatment team — including oncologists, radiation oncologists, surgeons, stem cell transplant physicians and oncology nurses — have specific expertise in pediatric hematologic malignancies. Many of our specialists are recognized as national leaders in their field.

Our clinical research program enables us to offer innovative clinical trials for children of all ages and with many forms of hematologic malignancies. Our clinical team works closely with researchers to develop new treatments based on the latest scientific discoveries.

Our services include:

  • expert hematopathologic evaluation using advanced diagnostic techniques
  • an individualized treatment plan tailored to your child's needs
  • an internationally recognized pediatric stem cell transplant program
  • innovative treatment options for all types of pediatric hematologic malignancies

Additional support services for our patients include:

  • psychologists and social workers for all patients, siblings and parents
  • complementary therapies consultation and treatment integrated into the comprehensive care plan
  • the services of other specialists as needed, including experts in cardiology, pulmonary, endocrinology, reproductive and gynecologic services, neurology, anesthesia, dermatology, nutrition, and physical therapy
  • a survivorship clinic that offers clinical and support resources to address the medical and psychosocial challenges of being a cancer survivor.

Learn more about our Hematologic Malignancy Center.

Information for: Patients | Healthcare Professionals

General Information About Childhood Non-Hodgkin Lymphoma

Childhood non-Hodgkin lymphoma is a disease in which malignant (cancer) cells form in the lymph system.

The lymph system is part of the immune system and is made up of the following:

  • Lymph: Colorless, watery fluid that travels through the lymph system and carries white blood cells called lymphocytes. Lymphocytes protect the body against infections and the growth of tumors.
  • Lymph vessels: A network of thin tubes that collect lymph from different parts of the body and return it to the bloodstream.
  • Lymph nodes: Small, bean-shaped structures that filter lymph and store white blood cells that help fight infection and disease. Lymph nodes grow along the network of lymph vessels found throughout the body. Clusters of lymph nodes are found in the underarm, pelvis, neck, abdomen, and groin.
  • Spleen: An organ that makes lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. The spleen is on the left side of the abdomen near the stomach.
  • Thymus: An organ in which lymphocytes grow and multiply. The thymus is in the chest behind the breastbone.
  • Tonsils: Two small masses of lymph tissue at the back of the throat. The tonsils make lymphocytes.
  • Bone marrow: The soft, spongy tissue in the center of large bones. Bone marrow makes white blood cells, red blood cells, and platelets.
Lymph system; drawing shows the lymph vessels and lymph organs including the lymph nodes, tonsils, thymus, spleen, and bone marrow.  One inset shows the inside structure of a lymph node and the attached lymph vessels with arrows showing how the lymph (clear fluid) moves into and out of the lymph node. Another inset shows a close up of bone marrow with blood cells. 
Anatomy of the lymph system, showing the lymph vessels and lymph organs including lymph nodes, tonsils, thymus, spleen, and bone marrow. Lymph (clear fluid) and lymphocytes travel through the lymph vessels and into the lymph nodes where the lymphocytes destroy harmful substances. The lymph enters the blood through a large vein near the heart.

Because lymph tissue is found throughout the body, childhood non-Hodgkin lymphoma can begin in almost any part of the body. Cancer can spread to the liver and many other organs and tissues.

Non-Hodgkin lymphoma can occur in both adults and children. Treatment for children is different than treatment for adults. (See the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information on treatment in adults.)

There are four major types of childhood non-Hodgkin lymphoma.

The specific type of lymphoma is determined by how the cells look under a microscope. The 4 major types of childhood non-Hodgkin lymphoma are:

  • B-cell non-Hodgkin lymphoma (Burkitt and Burkitt-like lymphoma) and Burkitt leukemia.
  • Diffuse large B-cell lymphoma.
  • Lymphoblastic lymphoma.
  • Anaplastic large cell lymphoma.

There are other types of lymphoma that occur in children. These include the following:

  • Lymphoproliferative disease associated with a weakened immune system.
  • Rare non-Hodgkin lymphomas that are more common in adults than in children.

Possible signs of childhood non-Hodgkin lymphoma include breathing problems and swollen lymph nodes.

These and other symptoms may be caused by childhood non-Hodgkin lymphoma. Other conditions may cause the same symptoms. Check with a doctor if your child has any of the following problems:

  • Trouble breathing.
  • Wheezing.
  • Coughing.
  • High-pitched breathing sounds.
  • Swelling of the head, neck, upper body or arms.
  • Trouble swallowing.
  • Painless swelling of the lymph nodes in the neck, underarm, stomach, or groin.
  • Painless lump or swelling in a testicle.
  • Fever for no known reason.
  • Weight loss for no known reason.
  • Night sweats.

Tests that examine the body and lymph system are used to detect (find) and diagnose childhood non-Hodgkin lymphoma.

The following tests and procedures may be used:

  • Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
  • Biopsy: The removal of cells or tissues so they can be viewed under a microscope by a pathologist to check for signs of cancer. One of the following types of biopsies may be done:
    • Excisional biopsy: The removal of an entire lymph node or lump of tissue.
    • Incisional biopsy: The removal of part of a lump, lymph node, or sample of tissue.
    • Core biopsy: The removal of tissue or part of a lymph node using a wide needle.
    • Fine-needle aspiration (FNA) biopsy: The removal of tissue or part of a lymph node using a thin needle.
    • Bone marrow aspiration and biopsy: The removal of bone marrow, blood, and a small piece of bone by inserting a hollow needle into the hipbone or breastbone.
      Bone marrow aspiration and biopsy; drawing shows a patient lying face down on a table and a Jamshidi needle (a long, hollow needle) being inserted into the hip bone. Inset shows the Jamshidi needle being inserted through the skin into the bone marrow of the hip bone. 
      Bone marrow aspiration and biopsy. After a small area of skin is numbed, a Jamshidi needle (a long, hollow needle) is inserted into the patient’s hip bone. Samples of blood, bone, and bone marrow are removed for examination under a microscope.
     
  • Immunohistochemistry study: A laboratory test in which a substance such as an antibody, dye, or radioisotope is added to a sample of cancer tissue to test for certain antigens. This type of study is used to tell the difference between different types of cancer.
  • Cytogeneticanalysis: A laboratory test in which cells in a sample of tissue are viewed under a microscope to look for certain changes in the chromosomes.
  • Endoscopy: A procedure to look at organs and tissues inside the body to check for abnormal areas. An endoscope is inserted through an incision (cut) in the skin or opening in the body, such as the mouth. An endoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue or lymph node samples, which are checked under a microscope for signs of disease.
  • Mediastinoscopy: A surgical procedure to look at the organs, tissues, and lymph nodes between the lungs for abnormal areas. An incision (cut) is made at the top of the breastbone and a mediastinoscope is inserted into the chest. A mediastinoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue or lymph node samples, which are checked under a microscope for signs of cancer.
  • Anterior mediastinotomy: A surgical procedure to look at the organs and tissues between the lungs and between the breastbone and heart for abnormal areas. An incision (cut) is made next to the breastbone and a mediastinoscope is inserted into the chest. A mediastinoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue or lymph node samples, which are checked under a microscope for signs of cancer. This is also called the Chamberlain procedure.
  • Thoracoscopy: A surgical procedure to look at the organs inside the chest to check for abnormal areas. An incision (cut) is made between two ribs and a thoracoscope is inserted into the chest. A thoracoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue or lymph node samples, which are checked under a microscope for signs of cancer. In some cases, this procedure is used to remove part of the esophagus or lung.
  • Thoracentesis: The removal of fluid from the space between the lining of the chest and the lung, using a needle. A pathologist views the fluid under a microscope to look for cancer cells.
  • Ultrasound exam: A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram. The picture can be printed to be looked at later.
  • PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radioactiveglucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.
  • Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis (chance of recovery) and treatment options depend on:

  • The age of the child.
  • The type of lymphoma.
  • The stage of the cancer.
  • The number of places outside of the lymph nodes to which the cancer has spread.
  • Whether the lymphoma has spread to the bone marrow or central nervous system (brain and spinal cord).
  • Whether there are certain changes in the chromosomes.
  • The type of initial treatment.
  • Whether the lymphoma responds to initial treatment.
  • The patient’s general health.

Stages of Childhood Non-Hodgkin Lymphoma

After childhood non-Hodgkin lymphoma has been diagnosed, tests are done to find out if cancer cells have spread within the lymph system or to other parts of the body.

The process used to find out if cancer has spread within the lymph system or to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment. Some of the tests that are used to diagnose childhood non-Hodgkin lymphoma are also used to stage the disease. The following tests and procedures may be used in the staging process:

  • Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
  • Complete blood count (CBC): A procedure in which a sample of blood is drawn and checked for the following:
    • The number of red blood cells, white blood cells, and platelets.
    • The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
    • The portion of the sample made up of red blood cells.
    Complete blood count (CBC); left panel shows blood being drawn from a vein on the inside of the elbow using a tube attached to a syringe; right panel shows a laboratory test tube with blood cells separated into layers: plasma, white blood cells, platelets, and red blood cells.  
    Complete blood count (CBC). Blood is collected by inserting a needle into a vein and allowing the blood to flow into a tube. The blood sample is sent to the laboratory and the red blood cells, white blood cells, and platelets are counted. The CBC is used to test for, diagnose, and monitor many different conditions.
  • Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it.
  • Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • Bone marrow aspiration and biopsy: The removal of bone marrow, blood, and a small piece of bone by inserting a hollow needle into the hipbone or breastbone. A pathologist views the bone marrow, blood, and bone under a microscope to look for signs of cancer.
  • Lumbar puncture: A procedure used to collect cerebrospinal fluid from the spinal column. This is done by placing a needle into the spinal column. This procedure is also called an LP or spinal tap.
    Lumbar puncture; drawing shows a patient lying in a curled position on a table and a spinal needle (a long, thin needle) being inserted into the lower back. Inset shows a close-up of the spinal needle inserted into the cerebrospinal fluid (CSF) in the lower part of the spinal column. 
    Lumbar puncture. A patient lies in a curled position on a table. After a small area on the lower back is numbed, a spinal needle (a long, thin needle) is inserted into the lower part of the spinal column to remove cerebrospinal fluid (CSF, shown in blue). The fluid may be sent to a laboratory for testing.
  • Bone scan: A procedure to check if there are rapidly dividing cells, such as cancer cells, in the bone. A very small amount of radioactive material is injected into a vein and travels through the bloodstream. The radioactive material collects in the bones and is detected by a scanner.
  • MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).
  • Endoscopy: A procedure to look at organs and tissues inside the body to check for abnormal areas. An endoscope is inserted through an incision (cut) in the skin or opening in the body, such as the mouth. An endoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue or lymph node samples, which are checked under a microscope for signs of disease.

There are three ways that cancer spreads in the body.

The three ways that cancer spreads in the body are:

  • Through tissue. Cancer invades the surrounding normal tissue.
  • Through the lymph system. Cancer invades the lymph system and travels through the lymph vessels to other places in the body.
  • Through the blood. Cancer invades the veins and capillaries and travels through the blood to other places in the body.

When cancer cells break away from the primary (original) tumor and travel through the lymph or blood to other places in the body, another (secondary) tumor may form. This process is called metastasis. The secondary (metastatic) tumor is the same type of cancer as the primary tumor. For example, if breast cancer spreads to the bones, the cancer cells in the bones are actually breast cancer cells. The disease is metastatic breast cancer, not bone cancer.

The following stages are used for childhood non-Hodgkin lymphoma:

Stage I

Stage I childhood non-Hodgkin lymphoma; drawing shows cancer in one group of lymph nodes. An inset shows a lymph node with a lymph vessel, an artery, and a vein. Lymphoma cells containing cancer are shown in the lymph node. 
Stage I childhood non-Hodgkin lymphoma. Cancer is found in one group of lymph nodes or one area outside the lymph nodes, but no cancer is found in the abdomen or mediastinum (area between the lungs).

In stage I childhood non-Hodgkin lymphoma, cancer is found:

  • in one group of lymph nodes; or
  • in one area outside the lymph nodes.

No cancer is found in the abdomen or mediastinum (area between the lungs).

Stage II

Stage II childhood non-Hodgkin lymphoma; drawing shows cancer in lymph node groups above and below the diaphragm, in the liver, and in the appendix. The colon and small intestine are also shown.  An inset shows a lymph node with a lymph vessel, an artery, and a vein. Lymphoma cells containing cancer are shown in the lymph node. 
Stage II childhood non-Hodgkin lymphoma. Cancer is found in one area outside the lymph nodes and in nearby lymph nodes (a); or in two or more areas above (b) or below (c) the diaphragm; or cancer started in the stomach, appendix, or intestines (d) and can be removed by surgery.

In stage II childhood non-Hodgkin lymphoma, cancer is found:

  • in one area outside the lymph nodes and in nearby lymph nodes; or
  • in two or more areas above or below the diaphragm, and may or may not have spread to nearby lymph nodes; or
  • to have started in the stomach or intestines and can be completely removed by surgery. Cancer may or may not have spread to certain nearby lymph nodes.

Stage III

Stage III childhood non-Hodgkin lymphoma; drawing shows cancer in lymph node groups above and below the diaphragm, in the chest, and throughout the abdomen in the liver, spleen, small intestines, and appendix. The colon is also shown. An inset shows a lymph node with a lymph vessel, an artery, and a vein. Lymphoma cells containing cancer are shown in the lymph node. 
Stage III childhood non-Hodgkin lymphoma. Cancer is found in at least one area above and below the diaphragm (a); or cancer started in the chest (b); or cancer started in the abdomen and spread throughout the abdomen (c); or in the area around the spine (not shown).

In stage III childhood non-Hodgkin lymphoma, cancer is found:

  • in at least one area above the diaphragm and in at least one area below the diaphragm; or
  • to have started in the chest; or
  • to have started in the abdomen and spread throughout the abdomen, and cannot be completely removed by surgery; or
  • in the area around the spine.

Stage IV

Stage IV childhood non-Hodgkin lymphoma; drawing shows the brain, spinal cord, and cerebrospinal fluid in and around the brain and spinal cord. An inset shows cancer in the bone marrow. 
Stage IV childhood non-Hodgkin lymphoma. Cancer is found in the bone marrow, brain, or cerebrospinal fluid (CSF). Cancer may also be found in other parts of the body.

In stage IV childhood non-Hodgkin lymphoma, cancer is found in the bone marrow, brain, or cerebrospinal fluid. Cancer may also be found in other parts of the body.

Childhood non-Hodgkin lymphoma is also described as low-stage or high-stage.

Treatment for childhood non-Hodgkin lymphoma is based on whether the cancer is low-stage or high-stage. Low-stage lymphoma has not spread beyond the area in which it began. High-stage lymphoma has spread beyond the area in which it began. Stage I and stage II are usually considered low-stage. Stage III and stage IV are usually considered high-stage.

Recurrent Childhood Non-Hodgkin Lymphoma

Recurrent childhood non-Hodgkin lymphoma is cancer that has recurred (come back) after it has been treated. Childhood non-Hodgkin lymphoma may come back in the lymph system or in other parts of the body.

Treatment Option Overview

There are different types of treatment for children with non-Hodgkin lymphoma.

Different types of treatment are available for children with non-Hodgkin lymphoma. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment.

Because cancer in children is rare, taking part in a clinical trial should be considered. Some clinical trials are open only to patients who have not started treatment.

Children with non-Hodgkin lymphoma should have their treatment planned by a team of doctors with expertise in treating childhood cancer.

Treatment will be overseen by a pediatric oncologist, a doctor who specializes in treating children with cancer. The pediatric oncologist works with other health care providers who are experts in treating children with non-Hodgkin lymphoma and who specialize in certain areas of medicine. These may include the following specialists:

  • Radiation oncologist.
  • Pediatric hematologist.
  • Pediatric surgeon.
  • Pediatric nurse specialist.
  • Rehabilitation specialist.
  • Psychologist.
  • Social worker.

Some cancer treatments cause side effects months or years after treatment has ended.

Side effects from cancer treatment that begin during or after treatment and continue for months or years are called late effects. Late effects of cancer treatment may include the following:

  • Physical problems.
  • Changes in mood, feelings, thinking, learning, or memory.
  • Second cancers (new types of cancer).

Some late effects may be treated or controlled. It is important to talk with your child's doctors about the effects cancer treatment can have on your child. (See the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

Four types of standard treatment are used:

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid (intrathecal chemotherapy), an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas. Intrathecal chemotherapy may be used to treat childhood non-Hodgkin lymphoma that has spread, or may spread, to the brain. When used to prevent cancer from spreading to the brain, it is called central nervous system (CNS) sanctuary therapy or CNS prophylaxis. Intrathecal chemotherapy is given in addition to chemotherapy by mouth or vein. The way the chemotherapy is given depends on the type and stage of the cancer being treated.

Intrathecal chemotherapy; drawing shows the cerebrospinal fluid (CSF) in the brain and spinal cord, and an Ommaya reservoir (a dome-shaped container that is placed under the scalp during surgery; it holds the drugs as they flow through a small tube into the brain). Top section shows a syringe and needle injecting anticancer drugs into the Ommaya reservoir. Bottom section shows a syringe and needle injecting anticancer drugs directly into the cerebrospinal fluid in the lower part of the spinal column. 
Intrathecal chemotherapy. Anticancer drugs are injected into the intrathecal space, which is the space that holds the cerebrospinal fluid (CSF, shown in blue). There are two different ways to do this. One way, shown in the top part of the figure, is to inject the drugs into an Ommaya reservoir (a dome-shaped container that is placed under the scalp during surgery; it holds the drugs as they flow through a small tube into the brain). The other way, shown in the bottom part of the figure, is to inject the drugs directly into the CSF in the lower part of the spinal column, after a small area on the lower back is numbed.

 

Combination chemotherapy is treatment using 2 or more anticancer drugs.

See Drugs Approved for Non-Hodgkin Lymphoma for more information.

Radiation therapy (in certain patients)

Radiation therapy is a cancer treatment that uses high energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated.

High-dose chemotherapy with stem cell transplant

This treatment is a way of giving high doses of chemotherapy and then replacing blood-forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the bone marrow or blood of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.

See Drugs Approved for Non-Hodgkin Lymphoma for more information.


Stem Cell Transplant

 

Drawing of stem cells being removed from a patient or donor. Blood is collected from a vein in the arm and flows through a machine that removes the stem cells; the remaining blood is returned to a vein in the other arm. 
Stem cell transplant (Step 1). Blood is taken from a vein in the arm of the donor. The patient or another person may be the donor. The blood flows through a machine that removes the stem cells. Then the blood is returned to the donor through a vein in the other arm.

 

 

Drawing of a health care provider giving a patient treatment to kill blood-forming cells. Chemotherapy is given to the patient through a catheter in the chest. 
Stem cell transplant (Step 2). The patient receives chemotherapy to kill blood-forming cells. The patient may receive radiation therapy (not shown).

 

 

Drawing of stem cells being given to the patient through a catheter in the chest. 
Stem cell transplant (Step 3). The patient receives stem cells through a catheter placed into a blood vessel in the chest.

 

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Monoclonal antibodies and tyrosine kinase inhibitors are two types of targeted therapy being studied in the treatment of childhood non-Hodgkin lymphoma.

Monoclonal antibody therapy is a cancer treatment that uses antibodies made in the laboratory from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal substances that may help cancer cells grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells. Rituximab is used to treat recurrent childhood non-Hodgkin lymphoma.

Tyrosine kinase inhibitors (TKIs) block signals that tumors need to grow. Some TKIs also keep tumors from growing by preventing the growth of new blood vessels to the tumors. Other types of kinase inhibitors, such as crizotinib and temsirolimus, are being studied for childhood non-Hodgkin lymphoma.

See Drugs Approved for Non-Hodgkin Lymphoma for more information.

New types of treatment are being tested in clinical trials.

Information about clinical trials is available from the NCI Web site.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. See the Treatment Options section that follows for links to current treatment clinical trials. These have been retrieved from NCI's listing of clinical trials.

Follow-up tests may be needed.

Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests. This is sometimes called re-staging.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your child's condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups.

Treatment Options for Childhood Non-Hodgkin Lymphoma

A link to a list of current clinical trials is included for each treatment section. For some types or stages of cancer, there may not be any trials listed. Check with your child's doctor for clinical trials that are not listed here but may be right for your child.

Low-stage Childhood Non-Hodgkin Lymphoma

Treatment of low-stage (stage I or II) non-Hodgkin lymphoma in children and adolescents may include the following:

  • Surgery followed by combination chemotherapy.
  • Surgery and/or radiation therapy for anaplastic large cell lymphoma that affects the skin.
  • A clinical trial of a new treatment.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I childhood large cell lymphoma, stage I childhood small noncleaved cell lymphoma, stage I childhood lymphoblastic lymphoma, stage I childhood anaplastic large cell lymphoma, stage II childhood large cell lymphoma, stage II childhood small noncleaved cell lymphoma, stage II childhood lymphoblastic lymphoma and stage II childhood anaplastic large cell lymphoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.

High-stage Childhood B-cell Non-Hodgkin Lymphoma

Treatment for high-stage (stage III or IV) B-cell (Burkitt and Burkitt-like) non-Hodgkin lymphoma in children and adolescents may include the following:

  • Combination chemotherapy.
  • Intrathecal or systemic chemotherapy for cancer in the brain or spinal cord.
  • A clinical trial of combination chemotherapy with or without a monoclonal antibody.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III childhood large cell lymphoma, stage III childhood small noncleaved cell lymphoma, stage IV childhood large cell lymphoma and stage IV childhood small noncleaved cell lymphoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.

High-stage Childhood Lymphoblastic Lymphoma

Treatment of high-stage (stage III or IV) lymphoblastic lymphoma in children and adolescents may include the following:

  • Combination chemotherapy with or without radiation therapy to the brain.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III childhood lymphoblastic lymphoma and stage IV childhood lymphoblastic lymphoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.

High-stage Childhood Anaplastic Large-cell Lymphoma

Treatment of high-stage (stage III or IV) anaplastic large-cell lymphoma in children and adolescents may include the following:

  • Combination chemotherapy.
  • Intrathecal or systemic chemotherapy for cancer in the brain or spinal cord.
  • A clinical trial of new combination chemotherapy.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III childhood anaplastic large cell lymphoma and stage IV childhood anaplastic large cell lymphoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.

Recurrent Childhood Non-Hodgkin Lymphoma

There is no standard treatment for patients with recurrent childhood non-Hodgkin lymphoma.

All patients with recurrent childhood non-Hodgkin lymphoma should be considered for clinical trials of new treatments.

Burkitt lymphoma and diffuse large B-cell lymphoma  

Treatment options for recurrent Burkitt lymphoma and diffuse large B-cell lymphoma include:

  • Combination chemotherapy.
  • Combination chemotherapy and targeted therapy with a monoclonal antibody.
  • High-dose chemotherapy with stem cell transplant.

Lymphoblastic lymphoma  

Treatment options for recurrent lymphoblastic lymphoma include:

  • Combination chemotherapy.
  • High-dose chemotherapy with stem cell transplant.
  • A clinical trial of targeted therapy (kinase inhibitor) with combination chemotherapy.

Anaplastic large-cell lymphoma  

Treatment options for recurrent anaplastic large cell lymphoma include:

  • Chemotherapy with one or more drugs.
  • High-dose chemotherapy with stem cell transplant.
  • A clinical trial of targeted therapy with a tyrosine kinase inhibitor.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood non-Hodgkin lymphoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.

Lymphoproliferative Disease Associated with a Weakened Immune System

Treatment of lymphoproliferative disease in children and adolescents with weakened immune systems may include the following:

  • Surgery with or without radiation therapy.
  • Combination chemotherapy.
  • Low-dose chemotherapy.
  • A clinical trial of stem cell transplant followed by donor lymphocyte infusion or an infusion of T-celllymphocytes that have been treated in the laboratory.

To Learn More About Childhood Non-Hodgkin Lymphoma

For more information from the National Cancer Institute about childhood non-Hodgkin lymphoma, see the following:

For more childhood cancer information and other general cancer resources, see the following:

About PDQ

PDQ is a comprehensive cancer database available on NCI's Web site.  

PDQ is the National Cancer Institute's (NCI's) comprehensive cancer information database. Most of the information contained in PDQ is available online at NCI's Web site. PDQ is provided as a service of the NCI. The NCI is part of the National Institutes of Health, the federal government's focal point for biomedical research.

PDQ contains cancer information summaries.  

The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries are available in two versions. The health professional versions provide detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions provide current and accurate cancer information.

Images in the PDQ summaries are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in the PDQ summaries, along with many other cancer-related images, are available in Visuals Online, a collection of over 2,000 scientific images.

The PDQ cancer information summaries are developed by cancer experts and reviewed regularly.  

Editorial Boards made up of experts in oncology and related specialties are responsible for writing and maintaining the cancer information summaries. The summaries are reviewed regularly and changes are made as new information becomes available. The date on each summary ("Date Last Modified") indicates the time of the most recent change.

PDQ also contains information on clinical trials.  

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become "standard." In the United States, about two-thirds of children with cancer are treated in a clinical trial at some point in their illness.

Listings of clinical trials are included in PDQ and are available online at NCI's Web site. Descriptions of the trials are available in health professional and patient versions. For additional help in locating a childhood cancer clinical trial, call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

The PDQ database contains listings of groups specializing in clinical trials.  

The Children's Oncology Group (COG) is the major group that organizes clinical trials for childhood cancers in the United States. Information about contacting COG is available on the NCI Web site or from the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).


This information is provided by the National Cancer Institute.

This information was last updated on March 6, 2013.


General Information About Childhood Non-Hodgkin Lymphoma (NHL)

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of children with cancer have been outlined by the American Academy of Pediatrics.[2] At these pediatric cancer centers, clinical trials are available for most of the types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For non-Hodgkin lymphoma (NHL), the 5-year survival rate has increased over the same time period from 45% to 88% in children younger than 15 years and from 47% to 77% for adolescents aged 15 to 19 years.[1] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on the Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Epidemiology

Lymphoma (Hodgkin lymphoma and NHL) is the third most common childhood malignancy, and NHL accounts for approximately 7% of cancers in children younger than 20 years.[3][4] In the United States, about 800 new cases of NHL are diagnosed each year. The incidence is approximately ten cases per million people per year. The incidence of NHL observed in children and adolescents varies depending on age, histology, gender, and race.[3] Although there is no sharp age peak, childhood NHL occurs most commonly in the second decade of life, and occurs infrequently in children younger than 3 years.[3] NHL in infants is very rare (1% in Berlin-Frankfurt-Munster [BFM] trials from 1986 to 2002).[5] The incidence of NHL is increasing overall, which is accounted for because of a slight increase in the incidence for those aged 15 to 19 years; however, the incidence of NHL in children younger than 15 years has remained constant over the past several decades.[3]

Childhood NHL is more common in males than in females, with the exception of primary mediastinal B-cell lymphoma, in which the incidence is almost the same in males and females.[3][6] A review of Surveillance, Epidemiology, and End Results (SEER) data on Burkitt lymphoma diagnosed in the United States between 1992 and 2008 revealed 2.5 cases/million person-years with more cases in males than in females (3.9:1.1). The incidence of diffuse large B-cell lymphoma increases with age in both males and females. The incidence of lymphoblastic lymphoma remains relatively constant across ages for both males and females.

The incidence and age distribution of specific types of NHL according to gender is described in Table 1.

Table 1. Incidence and Age Distribution of Specific Types of NHLa

 

Incidence of NHL per million person-years

 

Males  

Females  

Age (y)  

<5

5–9

10–14

15–19

<5

5–9

10–14

15–19

Burkitt

3.2

6

6.1

2.8

0.8

1.1

0.8

1.2

Lymphoblastic

1.6

2.2

2.8

2.2

0.9

1.0

0.7

0.9

DLBCL

0.5

1.2

2.5

6.1

0.6

0.7

1.4

4.9

Other (mostly ALCL)

2.3

3.3

4.3

7.8b 

1.5

1.6

2.8

3.4b 

ALCL = anaplastic large cell lymphoma; DLBCL = diffuse large B-cell lymphoma; NHL = non-Hodgkin lymphoma.

aAdapted from Percy et al.[3]

bIn older adolescents, indolent and aggressive histologies (more commonly seen in adult patients) are beginning to be found.

The incidence of NHL is higher in whites than in African Americans, and Burkitt lymphoma is more frequent in non-Hispanic whites (3.2 cases/million person-years) than in Hispanic whites (2.0 cases/million person-years).[7]

Relatively little is known of the epidemiology of childhood NHL. However, immunodeficiency, both congenital and acquired (human immunodeficiency virus infection [HIV] or posttransplant immunodeficiency), increases the risk of NHL. Epstein-Barr virus (EBV) is associated with most cases of NHL seen in the immunodeficient population.[3] Although 85% or more of Burkitt lymphoma is associated with the EBV in endemic Africa, approximately 15% of cases in Europe or the United States will have EBV detectable in the tumor tissue.[8]

NHL presenting as a secondary malignancy is rare in pediatrics. A retrospective review of the German Childhood Cancer Registry identified 11 (0.3%) of 2,968 newly diagnosed children older than 20 years with NHL as having a secondary malignancy.[9] In this small cohort, outcome was similar to patients with de novo NHL when treated with standard therapy.[9]

Prognostic Factors for Childhood NHL

With current treatments, more than 80% of children and adolescents with NHL will survive at least 5 years, though outcome is variable depending on a number of factors, including clinical stage and histology.[10]

Prognostic factors for childhood NHL include the following:

  • Age: NHL in infants is rare (1% in Berlin-Frankfurt-Munster [BFM] trials from 1986 to 2002).[5] In this retrospective review, the outcome for infants was inferior compared with the outcome for older patients with NHL.[5]

    Adolescents have been reported to have inferior outcome compared with younger children.[10][11][12][13] A review of survival for various subtypes of NHL in children and adolescents between 1986 and 2007 has been reported by the BFM group.[13] Event-free survival (EFS) was 79% for adolescents and 85% for children. This adverse affect of age appears to be most pronounced for adolescents with T-cell lymphoblastic lymphoma and diffuse large B-cell lymphoma compared with children with these diagnoses.[13] The poorer outcome of patients older than 15 years appears to be attributable primarily to patients with diffuse large B-cell lymphoma.[10] On the other hand, for patients with Burkitt and Burkitt-like lymphoma on the FAB LMB 96 (COG-C5961) clinical trial, adolescent age (≥ 15 years) was not an independent risk factor for inferior outcome, with 3-year EFS of 89% ± 1.0% for children younger than 15 years and 84% ± 3.4% for patients aged 15 years and older.[14]

  • Site of disease: In general, patients with low-stage disease (i.e., single extra-abdominal/extrathoracic tumor or totally resected intra-abdominal tumor) have an excellent prognosis (a 5-year survival rate of approximately 90%), regardless of histology.[15][16][17][18][19][20] Patients with NHL arising in bone have an excellent prognosis, regardless of histology.[21][22] Testicular involvement does not affect prognosis.[16][17][23] As opposed to adults, mediastinal involvement in children and adolescents with nonlymphoblastic NHL results in an inferior outcome.[10][14][15][18] For patients with primary mediastinal B-cell lymphoma, 3-year EFS is 50% to 70%,[15][18][24] and for patients with central nervous system (CNS) disease at presentation, the 3-year EFS is 70%.[18][25]

    In anaplastic large cell lymphoma, a retrospective study by the European Intergroup for Childhood NHL (EICNHL) found a high-risk group of patients defined by involvement of mediastinum, skin, or viscera.[26] An immune response against the ALK protein (i.e., anti-ALK antibody titer) appears to correlate with lower clinical stage and absence of these clinical risk features (mediastinal and visceral organ involvement) and predicts relapse risk but not overall survival.[27] However, in the CCG-5941 study for anaplastic large cell lymphoma patients, only bone marrow involvement predicted inferior progression-free survival.[28][Level of evidence: 2A] Patients with leukemic involvement (>25% blasts in marrow) or CNS involvement at diagnosis require intensive therapy.[17][25][29] Although these intensive therapies have improved the outcome for patients with high-stage (stage III or IV) or advanced-stage disease, patients who present with CNS disease have the worst outcome.[17][25][29] The combination of CNS involvement and marrow disease appears to impact outcome the most for Burkitt lymphoma/leukemia.[25] Patients with leukemic disease only, and no CNS disease, had a 3-year EFS of 90%, while patients with CNS disease at presentation had a 70% 3-year EFS.[25]

  • Chromosomal abnormalities: Though data for cytogenetics is less robust than for childhood leukemia, some chromosomal abnormalities have been reported to have prognostic value.
    • For pediatric Burkitt lymphoma patients, secondary cytogenetic abnormalities, other than c-myc rearrangement, are associated with an inferior outcome,[30][31] and cytogenetic abnormalities involving gain of 7q or deletion of 13q appear to have an inferior outcome on current chemotherapy protocols.[31][32]
    • For pediatric patients with diffuse large B-cell lymphoma and chromosomal rearrangement at MYC (8q24), outcome appears to be lower.[31]
    • For pediatric patients with T-cell lymphoblastic lymphoma, loss of heterozygosity on chromosome 6q was associated with an increased risk of relapse.[33]
     
  • Tumor burden: A surrogate for tumor burden (i.e., elevated levels of lactate dehydrogenase) has been shown to be prognostic in many studies.[15][18][24]

    More recently, detection of minimal disease at diagnosis or minimal residual disease (MRD) appears to be prognostic in most subtypes of childhood NHL. In a retrospective subset analysis, there was evidence that submicroscopic bone marrow and peripheral blood involvement, detected by reverse transcription-polymerase chain reaction (RT-PCR) from NPM-ALK, was found in approximately 50% of patients and correlated with clinical stage;[34] marrow involvement detected by PCR was associated with a 50% cumulative incidence of relapse. The prognostic role of MRD in the treatment of Burkitt leukemia remains unclear.[35][36][37]

  • Response to therapy: One of the most important predictive factors for Burkitt lymphoma/leukemia is response to the initial prophase treatment; poor responders (i.e., <20% resolution of disease) had an EFS of 30%.[15] Results from two studies suggest inferior outcome for patients with Burkitt leukemia that had detectable MRD after induction chemotherapy.[35][36]

References:

  1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.

  2. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.

  3. Percy CL, Smith MA, Linet M, et al.: Lymphomas and reticuloendothelial neoplasms. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649., pp 35-50. Also available online. Last accessed February 01, 2013.

  4. Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334 (19): 1238-48, 1996.

  5. Mann G, Attarbaschi A, Burkhardt B, et al.: Clinical characteristics and treatment outcome of infants with non-Hodgkin lymphoma. Br J Haematol 139 (3): 443-9, 2007.

  6. Jaffe ES, Harris NL, Stein H, et al.: Introduction and overview of the classification of the lymphoid neoplasms. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 157-66.

  7. Mbulaiteye SM, Biggar RJ, Bhatia K, et al.: Sporadic childhood Burkitt lymphoma incidence in the United States during 1992-2005. Pediatr Blood Cancer 53 (3): 366-70, 2009.

  8. Gutiérrez MI, Bhatia K, Barriga F, et al.: Molecular epidemiology of Burkitt's lymphoma from South America: differences in breakpoint location and Epstein-Barr virus association from tumors in other world regions. Blood 79 (12): 3261-6, 1992.

  9. Landmann E, Oschlies I, Zimmermann M, et al.: Secondary non-Hodgkin lymphoma (NHL) in children and adolescents after childhood cancer other than NHL. Br J Haematol 143 (3): 387-94, 2008.

  10. Burkhardt B, Zimmermann M, Oschlies I, et al.: The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol 131 (1): 39-49, 2005.

  11. Cairo MS, Sposto R, Perkins SL, et al.: Burkitt's and Burkitt-like lymphoma in children and adolescents: a review of the Children's Cancer Group experience. Br J Haematol 120 (4): 660-70, 2003.

  12. Patte C, Auperin A, Michon J, et al.: The Société Française d'Oncologie Pédiatrique LMB89 protocol: highly effective multiagent chemotherapy tailored to the tumor burden and initial response in 561 unselected children with B-cell lymphomas and L3 leukemia. Blood 97 (11): 3370-9, 2001.

  13. Burkhardt B, Oschlies I, Klapper W, et al.: Non-Hodgkin's lymphoma in adolescents: experiences in 378 adolescent NHL patients treated according to pediatric NHL-BFM protocols. Leukemia 25 (1): 153-60, 2011.

  14. Cairo MS, Sposto R, Gerrard M, et al.: Advanced stage, increased lactate dehydrogenase, and primary site, but not adolescent age (≥ 15 years), are associated with an increased risk of treatment failure in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB LMB 96 study. J Clin Oncol 30 (4): 387-93, 2012.

  15. Patte C, Auperin A, Gerrard M, et al.: Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109 (7): 2773-80, 2007.

  16. Link MP, Shuster JJ, Donaldson SS, et al.: Treatment of children and young adults with early-stage non-Hodgkin's lymphoma. N Engl J Med 337 (18): 1259-66, 1997.

  17. Reiter A, Schrappe M, Ludwig WD, et al.: Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report. Blood 95 (2): 416-21, 2000.

  18. Woessmann W, Seidemann K, Mann G, et al.: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105 (3): 948-58, 2005.

  19. Gerrard M, Cairo MS, Weston C, et al.: Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Br J Haematol 141 (6): 840-7, 2008.

  20. Seidemann K, Tiemann M, Schrappe M, et al.: Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 97 (12): 3699-706, 2001.

  21. Lones MA, Perkins SL, Sposto R, et al.: Non-Hodgkin's lymphoma arising in bone in children and adolescents is associated with an excellent outcome: a Children's Cancer Group report. J Clin Oncol 20 (9): 2293-301, 2002.

  22. Zhao XF, Young KH, Frank D, et al.: Pediatric primary bone lymphoma-diffuse large B-cell lymphoma: morphologic and immunohistochemical characteristics of 10 cases. Am J Clin Pathol 127 (1): 47-54, 2007.

  23. Dalle JH, Mechinaud F, Michon J, et al.: Testicular disease in childhood B-cell non-Hodgkin's lymphoma: the French Society of Pediatric Oncology experience. J Clin Oncol 19 (9): 2397-403, 2001.

  24. Reiter A, Schrappe M, Tiemann M, et al.: Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 94 (10): 3294-306, 1999.

  25. Cairo MS, Gerrard M, Sposto R, et al.: Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109 (7): 2736-43, 2007.

  26. Le Deley MC, Reiter A, Williams D, et al.: Prognostic factors in childhood anaplastic large cell lymphoma: results of a large European intergroup study. Blood 111 (3): 1560-6, 2008.

  27. Ait-Tahar K, Damm-Welk C, Burkhardt B, et al.: Correlation of the autoantibody response to the ALK oncoantigen in pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with tumor dissemination and relapse risk. Blood 115 (16): 3314-9, 2010.

  28. Lowe EJ, Sposto R, Perkins SL, et al.: Intensive chemotherapy for systemic anaplastic large cell lymphoma in children and adolescents: final results of Children's Cancer Group Study 5941. Pediatr Blood Cancer 52 (3): 335-9, 2009.

  29. Salzburg J, Burkhardt B, Zimmermann M, et al.: Prevalence, clinical pattern, and outcome of CNS involvement in childhood and adolescent non-Hodgkin's lymphoma differ by non-Hodgkin's lymphoma subtype: a Berlin-Frankfurt-Munster Group Report. J Clin Oncol 25 (25): 3915-22, 2007.

  30. Onciu M, Schlette E, Zhou Y, et al.: Secondary chromosomal abnormalities predict outcome in pediatric and adult high-stage Burkitt lymphoma. Cancer 107 (5): 1084-92, 2006.

  31. Poirel HA, Cairo MS, Heerema NA, et al.: Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Leukemia 23 (2): 323-31, 2009.

  32. Nelson M, Perkins SL, Dave BJ, et al.: An increased frequency of 13q deletions detected by fluorescence in situ hybridization and its impact on survival in children and adolescents with Burkitt lymphoma: results from the Children's Oncology Group study CCG-5961. Br J Haematol 148 (4): 600-10, 2010.

  33. Burkhardt B, Moericke A, Klapper W, et al.: Pediatric precursor T lymphoblastic leukemia and lymphoblastic lymphoma: Differences in the common regions with loss of heterozygosity at chromosome 6q and their prognostic impact. Leuk Lymphoma 49 (3): 451-61, 2008.

  34. Damm-Welk C, Busch K, Burkhardt B, et al.: Prognostic significance of circulating tumor cells in bone marrow or peripheral blood as detected by qualitative and quantitative PCR in pediatric NPM-ALK-positive anaplastic large-cell lymphoma. Blood 110 (2): 670-7, 2007.

  35. Mussolin L, Pillon M, Conter V, et al.: Prognostic role of minimal residual disease in mature B-cell acute lymphoblastic leukemia of childhood. J Clin Oncol 25 (33): 5254-61, 2007.

  36. Mussolin L, Pillon M, d'Amore ES, et al.: Minimal disseminated disease in high-risk Burkitt's lymphoma identifies patients with different prognosis. J Clin Oncol 29 (13): 1779-84, 2011.

  37. Shiramizu B, Goldman S, Kusao I, et al.: Minimal disease assessment in the treatment of children and adolescents with intermediate-risk (Stage III/IV) B-cell non-Hodgkin lymphoma: a children's oncology group report. Br J Haematol 153 (6): 758-63, 2011.

Cellular Classification of Childhood NHL

Cellular Classification and Clinical Presentation

In children, non-Hodgkin lymphoma (NHL) is distinct from the more common forms of lymphoma observed in adults. While lymphomas in adults are more commonly low or intermediate grade, almost all NHL that occurs in children is high grade.[1][2][3] The World Health Organization (WHO) has classified NHL on the basis of the following: (1) phenotype (i.e., B-lineage and T-lineage or natural killer [NK] cell lineage) and (2) differentiation (i.e., precursor vs. mature).[4]

On the basis of clinical response to treatment, NHL of childhood and adolescence currently falls into the following three therapeutically relevant categories:

  1. Mature B-cell NHL (Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma).
  2. Lymphoblastic lymphoma (primarily precursor T-cell lymphoma and, less frequently, precursor B-cell lymphoma).
  3. Anaplastic large cell lymphoma (mature T-cell or null-cell lymphomas).

NHL associated with immunodeficiency generally has a mature B-cell phenotype and is more often of large cell than Burkitt histology.[5] Posttransplant lymphoproliferative diseases are classified according to WHO nomenclature as (1) early lesions, (2) polymorphic, and (3) monomorphic.[6] While the majority of posttransplant lymphoproliferative diseases are of B-cell phenotype, approximately 10% are mature (peripheral) T-cell lymphomas.[6]

Other types of lymphoma, such as peripheral T-cell lymphoma, T/NK lymphomas, cutaneous lymphomas, and indolent B-cell lymphomas (e.g., follicular lymphoma), are more commonly seen in adults and occur rarely in children. Refer to the following PDQ summaries for more information:

  • Adult Non-Hodgkin Lymphoma.
  • Primary CNS Lymphoma.
  • Mycosis Fungoides and the Sézary Syndrome.

Each type of childhood NHL is associated with distinctive molecular biological characteristics, which are outlined in the following table. The Revised European-American Lymphoma (REAL) classification and the WHO classification are the most current NHL classifications utilized and are shown below.[2] The Working Formulation is also listed for reference. The WHO classification applies the principles of the REAL classification and focuses on the specific type of lymphoma for therapy purposes. For the most part, the remaining categories do not pertain to pediatric NHL and are not shown.

Table 2. Major Histopathological Categories of Non-Hodgkin Lymphoma in Children and Adolescentsa

Category (WHO Classification/ Updated REAL)

Category (Working Formulation)

Immuno-phenotype

Clinical Presentation

Chromosome Translocation

Genes Affected

Burkitt and Burkitt-like lymphomas

ML small noncleaved cell

Mature B cell

Intra-abdominal (sporadic), head and neck (non-jaw, sporadic), jaw (endemic), bone marrow, CNS

t(8;14)(q24;q32), t(2;8)(p11;q24), t(8;22)(q24;q11)

C-MYC, IGH, IGK, IGL 

Diffuse large B-cell lymphoma

ML large cell

Mature B cell; maybe CD30+

Nodal, abdominal, bone, primary CNS (when associated with immunodeficiency), mediastinal

No consistent cytogenetic abnormality identified

 

Lymphoblastic lymphoma, precursor T-cell leukemia, or precursor B-cell lymphoma

Lymphoblastic convoluted and non-convoluted

Pre-T cell

Mediastinal, bone marrow

MTS1/p16ink4a; Deletion TAL1 t(1;14)(p34;q11), t(11;14)(p13;q11)

TAL1, TCRAO, RHOMB1, HOX11  

Pre-B cell

Skin, bone, mediastinal

Anaplastic large cell lymphoma, systemic

ML immunoblastic or ML large

CD30+ (Ki-1+)

Variable, but systemic symptoms often prominent

t(2;5)(p23;q35); less common variant translocations involving ALK 

ALK, NPM 

T cell or null cell

Anaplastic large cell lymphoma, cutaneous

 

CD30+ (Ki-usually)

Skin only; single or multiple lesions

Lacks t(2;5)

 

T cell

CNS = central nervous system; ML = malignant lymphoma; REAL = Revised European-American Lymphoma; WHO = World Health Organization.

aAdapted from Percy et al.[2]

Burkitt and Burkitt-like lymphoma/leukemia

Burkitt and Burkitt-like lymphoma/leukemia in the United States accounts for about 30% of childhood NHL and exhibits consistent, aggressive clinical behavior.[2][3][7] The overall incidence of Burkitt lymphoma is 2.5 cases per million person-years and is higher among boys than girls (3.9 vs. 1.1).[2][8] The most common primary sites of disease are the abdomen and the lymph nodes, especially of the head and neck region.[3][8] Other sites of involvement include testes, bone, skin, bone marrow, and central nervous system (CNS).

The malignant cells show a mature B-cell phenotype and are negative for the enzyme terminal deoxynucleotidyl transferase (TdT). These malignant cells usually express surface immunoglobulin, most bearing surface immunoglobulin M with either kappa or lambda light chains. A variety of additional B-cell markers (e.g., CD20, CD22) are usually present, and almost all childhood Burkitt/Burkitt-like lymphoma/leukemia express CALLA (CD10). Burkitt lymphoma/leukemia expresses a characteristic chromosomal translocation, usually t(8;14) and more rarely t(8;22) or t(2;8). Each of these translocations juxtaposes the c-myc oncogene and immunoglobulin locus regulatory elements, resulting in the inappropriate expression of c-myc, a gene involved in cellular proliferation.[3]

The distinction between Burkitt and Burkitt-like lymphoma/leukemia is controversial. Burkitt lymphoma consists of uniform, small, noncleaved cells, whereas Burkitt-like lymphoma is a highly disputed diagnosis among pathologists because of features that are consistent with diffuse large B-cell lymphoma.[9] Cytogenetic evidence of c-myc rearrangement is the gold standard for diagnosis of Burkitt lymphoma. For cases in which cytogenetic analysis is not available, the WHO has recommended that the Burkitt-like diagnosis be reserved for lymphoma resembling Burkitt lymphoma or with more pleomorphism, large cells, and a proliferation fraction (i.e., Ki-67[+] of ≥99%).[7] Studies have demonstrated that the vast majority of Burkitt-like or “atypical Burkitt” lymphomas have a gene expression signature similar to Burkitt lymphoma.[10] Additionally, as many as 30% of pediatric diffuse large B-cell lymphoma cases will have a gene signature similar to Burkitt lymphoma.[10][11] Despite the histologic differences, Burkitt and Burkitt-like lymphoma/leukemia are clinically very aggressive and are treated with very aggressive regimens.[12][13][14][15]

Diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma is a mature B-cell neoplasm that represents 10% to 20% of pediatric NHL.[2][3][16] Diffuse large B-cell lymphoma occurs more frequently during the second decade of life than during the first decade.[2][17][18] The WHO classification system does not recommend morphologic subclassification based on morphologic variants (e.g., immunoblastic, centroblastic) of diffuse large B-cell lymphoma.[19] Pediatric diffuse large B-cell lymphoma may present clinically similar to Burkitt or Burkitt-like lymphoma, though it is more often localized and less often involves the bone marrow or CNS.[16][17][20]

About 20% of pediatric diffuse large B-cell lymphoma presents as primary mediastinal disease (primary mediastinal B-cell lymphoma). This presentation is more common in older children and adolescents and has been associated with an inferior outcome compared with other pediatric diffuse large B-cell lymphoma.[13][14][17][21][22][23] Primary mediastinal B-cell lymphoma is associated with distinctive chromosomal aberrations (gains in chromosome 9p and 2p in regions that involve JAK2 and c-rel, respectively) [22][23] and commonly shows inactivation of SOCS1 by either mutation or gene deletion.[24][25] Primary mediastinal B-cell lymphoma also has a distinctive gene expression profile in comparison with other diffuse large B-cell lymphoma, suggesting a close relationship of primary mediastinal B-cell lymphoma with Hodgkin lymphoma.[26][27]

With the exception of primary mediastinal B-cell lymphoma, diffuse large B-cell lymphoma in children and adolescents differs biologically from diffuse large B-cell lymphoma in adults. The vast majority of pediatric diffuse large B-cell lymphoma cases have a germinal center B-cell phenotype, as assessed by immunohistochemical analysis of selected proteins found in normal germinal center B cells, such as the BCL6 gene product and CD10.[18][28][29] Unlike adult diffuse large B-cell lymphoma of the germinal center B-cell type, in which the t(14;18) translocation involving the immunoglobulin heavy-chain gene and the BCL2 gene is commonly observed, pediatric diffuse large B-cell lymphoma rarely demonstrates the t(14;18) translocation.[18] As many as 30% of patients younger than 14 years with diffuse large B-cell lymphoma will have a gene signature similar to Burkitt lymphoma.[10] A subset of pediatric diffuse large B-cell lymphoma cases were found to have a translocation that juxtaposes the IRF4 oncogene next to one of the immunoglobulin loci. diffuse large B-cell lymphoma cases with an IRF4 translocation were significantly more frequent in children than adults (15% vs. 2%), were germinal center–derived B-cell lymphomas, and were associated with favorable prognosis compared with diffuse large B-cell lymphoma cases lacking this abnormality.[30]

Lymphoblastic lymphoma

Lymphoblastic lymphoma comprises approximately 20% of childhood NHL.[2][3][17] Lymphoblastic lymphomas are usually positive for TdT, with more than 75% having a T-cell immunophenotype and the remainder having a precursor B-cell phenotype.[3][31] Chromosomal abnormalities are not well characterized in patients with lymphoblastic lymphoma.

As many as 75% of patients with lymphoblastic lymphoma will present with an anterior mediastinal mass, which may manifest as dyspnea, wheezing, stridor, dysphagia, or swelling of the head and neck. Pleural effusions may be present, and the involvement of lymph nodes, usually above the diaphragm, may be a prominent feature. There may also be involvement of bone, skin, bone marrow, CNS, abdominal organs (but rarely bowel), and occasionally other sites such as lymphoid tissue of Waldeyer ring and testes. Abdominal involvement is less than observed in Burkitt lymphoma. Low-stage lymphoblastic lymphoma may occur in lymph nodes, bone, testes, or subcutaneous tissue. Lymphoblastic lymphoma within the mediastinum is not considered low-stage disease.

Involvement of the bone marrow may lead to confusion as to whether the patient has lymphoma with bone marrow involvement or leukemia with extramedullary disease. Traditionally, patients with more than 25% marrow blasts are considered to have leukemia, and those with fewer than 25% marrow blasts are considered to have lymphoma. It is not yet clear whether these arbitrary definitions are biologically distinct or relevant for treatment design.

Anaplastic large cell lymphoma

Anaplastic large cell lymphoma accounts for approximately 10% of childhood NHL.[17] While the predominant immunophenotype of anaplastic large cell lymphoma is mature T-cell, null-cell disease (i.e., no T-cell, B-cell, or NK-cell surface antigen expression) does occur. The WHO classification system classifies anaplastic large cell lymphoma as a peripheral T-cell lymphoma.[4] Many view ALK-positive anaplastic large cell lymphoma differently than other peripheral T-cell lymphoma because prognosis tends to be superior to other forms of peripheral T-cell lymphoma.[32] All anaplastic large cell lymphoma cases are CD30-positive and more than 90% of pediatric anaplastic large cell lymphoma cases have a chromosomal rearrangement involving the ALK gene. About 85% of these chromosomal rearrangements will be t(2;5)(p23;q35), leading to the expression of the fusion protein NPM-ALK; the other 15% of cases are comprised of variant ALK translocations.[33] Anti-ALK immunohistochemical staining pattern is quite specific for the type of ALK translocation. Cytoplasm and nuclear ALK staining is associated with NPM-ALK fusion protein, whereas cytoplasmic staining only of ALK is associated with the variant ALK translocations.[33] There is no correlation between outcome and ALK translocation type.[34] In a series of 375 children and adolescents with systemic ALK-positive anaplastic large cell lymphoma, the presence of a small cell or lymphohistiocytic component was observed in 32% of patients and was significantly associated with a high risk of failure in the multivariate analysis, controlling for clinical characteristics (hazard ratio, 2.0; P = .002).[35]

Clinically, systemic anaplastic large cell lymphoma has a broad range of presentations, including involvement of lymph nodes and a variety of extranodal sites, particularly skin and bone and, less often, gastrointestinal tract, lung, pleura, and muscle. Involvement of the CNS and bone marrow is uncommon. anaplastic large cell lymphoma is often associated with systemic symptoms (e.g., fever, weight loss) and a prolonged waxing and waning course, making diagnosis difficult and often delayed. Patients with anaplastic large cell lymphoma may present with signs and symptoms consistent with hemophagocytic lymphohistiocytosis.[36] There is a subgroup of anaplastic large cell lymphoma with leukemic peripheral blood involvement. These patients usually exhibit significant respiratory distress with diffuse lung infiltrates or pleural effusions and have hepatosplenomegaly. Most of these patients have an aberrant T-cell immunophenotype with frequent expression of myeloid antigens. Patients in this anaplastic large cell lymphoma subgroup may require more aggressive therapy.[37][38]

Lymphoproliferative disease associated with immunodeficiency in children

The incidence of lymphoproliferative disease or lymphoma is 100-fold higher in immunocompromised children than in the general population. The cause of such immune deficiencies may be a genetically inherited defect, secondary to human immunodeficiency virus (HIV) infection, or iatrogenic following transplantation (solid organ transplantation or allogeneic hematopoietic stem cell transplantation [HSCT]). Epstein-Barr virus (EBV) is associated with most of these tumors, but some tumors are not associated with any infectious agent.

NHL associated with HIV is usually aggressive, with most cases occurring in extralymphatic sites.[39] HIV-associated NHL can be broadly grouped into three subcategories: (1) systemic (nodal and extranodal), (2) primary CNS lymphoma, and (3) body cavity–based lymphoma, also referred to as primary effusion lymphoma. Approximately 80% of all NHL in HIV patients is considered to be systemic.[39] Primary effusion lymphoma, a unique lymphomatous effusion associated with the human herpesvirus-8 (HHV8) gene or Kaposi sarcoma herpesvirus, is primarily observed in adults infected with HIV but has been reported in HIV-infected children.[40] Highly active antiretroviral therapy has decreased the incidence of NHL in HIV-positive individuals, particularly for primary CNS lymphoma cases.[41] Most childhood HIV-related NHL is of mature B-cell phenotype but with a spectrum, including primary effusion lymphoma, primary CNS lymphoma, mucosa-associated lymphoid tissue (MALT),[42] Burkitt lymphoma,[43] and diffuse large B-cell lymphoma. NHL in children with HIV often presents with fever, weight loss, and symptoms related to extranodal disease, such as abdominal pain or CNS symptoms.[39]

NHL observed in primary immunodeficiency usually shows a mature B-cell phenotype and large cell histology.[5] Mature T-cell lymphoma and anaplastic large cell lymphoma have been observed.[5] Children with primary immunodeficiency and NHL are more likely to have high-stage disease and present with symptoms related to extranodal disease, particularly the gastrointestinal tract and CNS.[5]

PTLD represents a spectrum of clinically and morphologically heterogeneous lymphoid proliferations. Essentially all PTLD following HSCT is associated with EBV, but EBV-negative PTLD can be seen following solid organ transplant.[44] The WHO has classified PTLD into the following three subtypes:[6]

  • Early lesions – Early lesions show germinal center expansion, but tissue architecture remains normal.
  • Polymorphic PTLD – Presence of infiltrating T cells, disruption of nodal architecture, and necrosis distinguish polymorphic PTLD from early lesions.
  • Monomorphic PTLD – Histologies observed in the monomorphic subtype are similar to those observed in NHL, with diffuse large B-cell lymphoma being the most common histology, followed by Burkitt lymphoma, with myeloma or plasmacytoma occurring rarely.

The B-cell stimulation by EBV may result in multiple clones of proliferating B cells, and both polymorphous and monomorphous histologies may be present in a patient, even within the same lesion of PTLD.[45] Thus, histology of a single biopsied site may not be representative of the entire disease process. Not all PTLD is B-cell phenotype.[6] EBV lymphoproliferative disease posttransplant may manifest as isolated hepatitis, lymphoid interstitial pneumonitis, meningoencephalitis, or an infectious mononucleosis-like syndrome. The definition of PTLD is frequently limited to lymphomatous lesions (low stage or high stage), which are often extranodal (frequently in the allograft).[44] Although less common, PTLD may present as a rapidly progressive, high-stage disease that clinically resembles septic shock, which almost always results in death despite therapy.[46]

Rare NHL occurring in children

Low- or intermediate-grade mature B-cell lymphomas, such as small lymphocytic lymphoma, MALT lymphoma, mantle cell lymphoma, myeloma, or follicular cell lymphoma, are rarely seen in children. The most recent WHO classification has identified pediatric follicular lymphoma and pediatric nodal marginal zone lymphoma as unique entities.[1]

Pediatric follicular lymphoma is a disease that differs from the adult counterpart genetically and clinically. The genetic hallmark of adult follicular lymphoma, the translocation of t(14;18)(q32;q21), is typically not detectable in pediatric follicular lymphoma. Pediatric follicular lymphoma is more likely to be localized disease, in contrast to adult follicular lymphoma, which usually presents as disseminated disease. Cervical lymph nodes and tonsils are common sites, but disease has also occurred in extranodal sites such as the testis, kidney, gastrointestinal tract, and parotid.[47][48][49][50] The outcome of pediatric follicular lymphoma is excellent, and in contrast to adult follicular lymphoma, the clinical course is not dominated by relapses, if the BFM protocols for diffuse large B-cell lymphoma and BL are used. In pediatric follicular lymphoma, a simultaneous diffuse large B-cell lymphoma can frequently be detected at initial diagnosis but does not indicate a more aggressive clinical course in children.[48][49]

Other diseases appear to reflect the disease observed in adult patients. For example, MALT lymphomas observed in pediatric patients usually present as low-stage (stage I or II) disease and are associated with H. pylori and require no more than local therapy involving curative surgery and/or radiation therapy.[51] Intralesional interferon-alpha for conjunctival MALT lymphoma has been described.[52]

Other types of NHL may be rare in adults and are exceedingly rare in pediatric patients, such as primary CNS lymphoma. Due to small numbers, it is difficult to ascertain if the disease observed in children is the same as in adults and, therefore, it is difficult to determine optimal therapy. Reports suggest that the outcome of pediatric patients with primary CNS lymphoma (overall survival 70%–80%) may be superior to that of adults with primary CNS lymphoma. These reports suggest that long-term survival can be achieved without cranial irradiation.[53][54][55][56] Most children have diffuse large B-cell lymphoma or anaplastic large cell lymphoma. Therapy with high-dose intravenous methotrexate and cytosine arabinoside is most successful and intrathecal chemotherapy may be needed only when malignant cells are present in the cerebral spinal fluid.[54][56] There is a case report of repeated doses of rituximab, both intravenous and intraventricular, being administered to a 14-year-old boy with refractory primary CNS lymphoma, with an excellent result.[57] This apparently good outcome needs to be confirmed, especially since similar results have not been observed in adults. (Refer to the PDQ summary on Primary CNS Lymphoma Treatment for more information on treatment options for nonacquired immunodeficiency syndrome–related primary CNS lymphoma.)

Peripheral T-cell lymphoma, excluding anaplastic large cell lymphoma, is rare in children. Mature T-cell/NK-cell lymphoma or peripheral T-cell lymphoma has a postthymic phenotype (e.g., TdT negative), usually expresses CD4 or CD8, and has rearrangement of T-cell receptor (TCR) genes, either alpha/beta and/or gamma/delta chains. The most common phenotype observed in children is peripheral T-cell lymphoma-not otherwise specified, although angioimmunoblastic lymphoma, enteropathy-associated lymphoma (associated with celiac disease), subcutaneous panniculitis-like lymphoma, angiocentric lymphoma, and extranodal NK/T-cell peripheral T-cell lymphoma have been reported.[58][59][60] Mycosis fungoides has rarely been reported in children and adolescents.[61] A Japanese study described extranodal NK/T-cell lymphoma, nasal type as the most common peripheral T-cell lymphoma subtype among Japanese children (10 of 21 peripheral T-cell lymphoma cases). In adults, extranodal NK/T-cell lymphoma, nasal type is generally EBV-positive, and 60% of the cases observed in Japanese children were EBV-positive.[62] Though very rare, hepatosplenic T-cell lymphoma is associated with children and adolescents who have Crohn disease and have been on immunosuppressive therapy; this lymphoma has been fatal in all cases.[63]

Optimal therapy for peripheral T-cell lymphoma is unclear, even for adult patients. There have been three retrospective analyses of treatment and outcome for pediatric patients with peripheral T-cell lymphoma. The United Kingdom Children's Cancer Study Group (UKCCSG) reported on 25 children diagnosed over a 20-year period with peripheral T-cell lymphoma, with an approximate 50% 5-year survival rate.[58] The UKCCSG also observed that the use of acute lymphoblastic leukemia (ALL)–like therapy, instead of NHL therapy, produced a superior outcome. The Children's Oncology Group (COG) reported 20 patients older than 8 years treated on Pediatric Oncology Group NHL trials.[59] Eight of ten patients with low-stage disease achieved long-term disease-free survival compared to only four of ten patients with high-stage disease. A study of Japanese children with peripheral T-cell lymphoma (N = 21) reported a 5-year overall survival rate of 85.2%. Treatment for peripheral T-cell lymphoma was not consistent in this study and included chemotherapy (n = 18), radiation (n = 2), and autologous (n = 2) and allogeneic (n = 9) stem cell transplantation.[62]

In an attempt to learn more about the clinical and pathologic features of these types of NHL seen rarely in children, the COG has opened a registry study (COG-ANHL04B1). This study banks tissue for pathobiology studies and collects limited data on clinical presentation and outcome of therapy.

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Stage Information for Childhood NHL

The most widely used staging scheme for childhood non-Hodgkin lymphoma (NHL) is that of the St. Jude Children’s Research Hospital (Murphy Staging).[1]

Stage I Childhood NHL

In stage I childhood NHL, a single tumor or nodal area is involved, excluding the abdomen and mediastinum.

Stage II Childhood NHL

In stage II childhood NHL, disease extent is limited to a single tumor with regional node involvement, two or more tumors or nodal areas involved on one side of the diaphragm, or a primary gastrointestinal tract tumor (completely resected) with or without regional node involvement.

Stage III Childhood NHL

In stage III childhood NHL, tumors or involved lymph node areas occur on both sides of the diaphragm. Stage III NHL also includes any primary intrathoracic (mediastinal, pleural, or thymic) disease, extensive primary intra-abdominal disease, or any paraspinal or epidural tumors.

Stage IV Childhood NHL

In stage IV childhood NHL, tumors involve bone marrow and/or central nervous system (CNS), regardless of other sites of involvement.

Bone marrow involvement has been defined as 5% malignant cells in an otherwise normal bone marrow with normal peripheral blood counts and smears. Patients with lymphoblastic lymphoma with more than 25% malignant cells in the bone marrow are usually considered to have leukemia and may be appropriately treated on leukemia clinical trials.

CNS disease in lymphoblastic lymphoma is defined by criteria similar to that used for acute lymphocytic leukemia (i.e., white blood cell count of at least 5/μL and malignant cells in the cerebrospinal fluid [CSF]). For any other NHL, the definition of CNS disease is any malignant cell present in the CSF regardless of cell count. The Berlin-Frankfurt-Munster (BFM) group analyzed the prevalence of CNS involvement in NHL in over 2,500 patients.[2] Overall, CNS involvement was diagnosed in 6% of patients. Involvement by cell type was as follows:

  • Burkitt lymphoma/leukemia: 8.8%
  • Precursor B-cell lymphoblastic lymphoma: 5.4%
  • T-cell lymphoblastic lymphoma: 3.7%
  • Anaplastic large cell lymphoma: 3.3%
  • Diffuse large B-cell lymphoma: 2.6%
  • Primary mediastinal large B-cell lymphoma: 0%

Mature B-cell NHL (Burkitt lymphoma and diffuse large B-cell lymphoma) patients have been treated based on features of the disease, other than stage.

Table 3. FAB/LMB and BFM Staging Schemas for B-cell NHL

 

Stratum

Disease Manifestation

FAB/LMB International Study[3][4][5]

A

Completely resected stage I and abdominal stage II

B

Multiple extra-abdominal sites

Nonresected stage I and II, III, IV (marrow <25% blasts, no CNS disease)

C

Mature B-cell ALL (>25% blasts in marrow) and/or CNS disease

 

BFM Group[6]

R1

Completely resected stage I and abdominal stage II

R2

Nonresected stage I/II and stage III with LDH <500 IU/L

R3

Stage III with LDH 500–999 IU/L

Stage IV, B-ALL (>25% blasts), no CNS disease, and LDH <1,000 IU/L

R4

Stage III, IV, B-cell ALL with LDH >1,000 IU/L

Any CNS disease

ALL = acute lymphoblastic leukemia; BFM = Berlin-Frankfurt-Munster; CNS= central nervous system; FAB = French-American-British; LDH = lactate dehydrogenase; NHL = non-Hodgkin lymphoma.

References:

  1. Murphy SB, Fairclough DL, Hutchison RE, et al.: Non-Hodgkin's lymphomas of childhood: an analysis of the histology, staging, and response to treatment of 338 cases at a single institution. J Clin Oncol 7 (2): 186-93, 1989.

  2. Salzburg J, Burkhardt B, Zimmermann M, et al.: Prevalence, clinical pattern, and outcome of CNS involvement in childhood and adolescent non-Hodgkin's lymphoma differ by non-Hodgkin's lymphoma subtype: a Berlin-Frankfurt-Munster Group Report. J Clin Oncol 25 (25): 3915-22, 2007.

  3. Patte C, Auperin A, Gerrard M, et al.: Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109 (7): 2773-80, 2007.

  4. Cairo MS, Gerrard M, Sposto R, et al.: Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109 (7): 2736-43, 2007.

  5. Gerrard M, Cairo MS, Weston C, et al.: Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Br J Haematol 141 (6): 840-7, 2008.

  6. Reiter A, Schrappe M, Tiemann M, et al.: Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 94 (10): 3294-306, 1999.

Treatment Option Overview

Many of the improvements in childhood cancer survival have been made using combinations of known and/or new agents that have attempted to improve the best available, accepted therapy. Clinical trials in pediatrics are designed to compare potentially better therapy with therapy that is currently accepted as standard. This comparison may be done in a randomized study of two treatment arms or by evaluating a single new treatment and comparing the results with those previously obtained with standard therapy.

All children with non-Hodgkin lymphoma (NHL) should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists with experience treating tumors of childhood is strongly recommended to determine, coordinate, and implement treatment to achieve optimal survival. Children with NHL should be referred for treatment by a multidisciplinary team of pediatric oncologists at an institution with experience in treating pediatric cancers. Information about ongoing clinical trials is available from the NCI Web site.

NHL in children is generally considered to be widely disseminated from the outset, even when apparently localized; as a result, combination chemotherapy is recommended for most patients.[1]

In contrast to the treatment of adults with NHL, the use of radiation therapy is limited in children with NHL. Early studies demonstrated that the routine use of radiation had no benefit for low-stage (I or II) NHL.[2] It has been demonstrated that prophylactic central nervous system (CNS) radiation can be omitted in lymphoblastic lymphoma.[3][4] It has also been demonstrated that CNS radiation can be eliminated for patients with anaplastic large cell lymphoma and B-cell NHL, even for patients who present with CNS disease.[5][6] Further data to support the limited use of radiation in pediatric NHL comes from the Childhood Cancer Survivor Study.[7] This analysis demonstrated that radiation was a significant risk factor for secondary malignancy and death in long-term survivors.

Treatment of NHL in childhood and adolescence has historically been based on clinical behavior and response to treatment. A study by the Children’s Cancer Group demonstrated that the outcome for lymphoblastic NHL was superior with longer acute lymphoblastic leukemia–like therapy, while nonlymphoblastic NHL (Burkitt lymphoma) had superior outcome with short, intensive, pulsed therapy.[8]

Medical Emergencies

There are two potentially life-threatening clinical situations that are often seen in children with NHL: (1) mediastinal masses and (2) tumor lysis syndrome, most often seen in lymphoblastic and Burkitt or Burkitt-like NHL. These emergent situations should be anticipated in children with NHL and addressed immediately.

Mediastinal masses

Patients with large mediastinal masses are at risk of cardiac or respiratory arrest during general anesthesia or heavy sedation.[9] Due to the risks of general anesthesia or heavy sedation, a careful physiologic and radiographic evaluation of the patient should be carried out and the least invasive procedure should be used to establish the diagnosis of lymphoma.[10][11] Bone marrow aspirate and biopsy should always be performed early in the workup of these patients. If a pleural effusion is present, a cytologic diagnosis is frequently possible using thoracentesis. In those children who present with peripheral adenopathy, a lymph node biopsy under local anesthesia and in an upright position may be possible.[12] In situations in which the above diagnostic procedures are not fruitful, consideration of a computed tomography (CT)–guided core needle biopsy should be contemplated. This procedure can frequently be carried out using light sedation and local anesthesia before proceeding to more invasive procedures. Care should be taken to keep patients out of a supine position. Most procedures, including CT scans, can be done with the patient on their side or prone. Mediastinoscopy, anterior mediastinotomy, or thoracoscopy are the procedures of choice when other diagnostic modalities fail to establish the diagnosis. A formal thoracotomy is rarely, if ever, indicated for the diagnosis or treatment of childhood lymphoma. Occasionally, it will not be possible to perform a diagnostic operative procedure because of the risk of general anesthesia or heavy sedation. In these situations, preoperative treatment with steroids or localized radiation therapy should be considered. Since preoperative treatment may affect the ability to obtain an accurate tissue diagnosis, a diagnostic biopsy should be obtained as soon as the risk of general anesthesia or heavy sedation is thought to be alleviated.

Tumor lysis syndrome

Tumor lysis syndrome results from rapid breakdown of malignant cells, resulting in a number of metabolic abnormalities, most notably hyperuricemia, hyperkalemia, and hyperphosphatemia. Hyperhydration and allopurinol or rasburicase (urate oxidase) are essential components of therapy in all patients except those with the most limited disease.[13][14][15][16] An initial prephase consisting of low-dose cyclophosphamide and vincristine does not obviate the need for allopurinol or rasburicase and hydration. Gastrointestinal bleeding, obstruction, and (rarely) perforation may occur. Hyperuricemia and tumor lysis syndrome, particularly when associated with ureteral obstruction, frequently result in life-threatening complications. Patients with NHL should be managed only in institutions having pediatric tertiary care facilities.

Role of Radiographic Imaging in Childhood NHL

Radiographic imaging is essential in the staging of patients with NHL. Ultrasound may be the preferred method for assessment of an abdominal mass, but CT scan and, more recently, magnetic resonance imaging (MRI) have been used for staging. Radionucleotide bone scans should be considered for patients where bone involvement is suspected.

The role of functional imaging in pediatric NHL is controversial. Gallium scans have been replaced by fluorodeoxyglucose positron emission tomography (PET) scanning, which is now routinely performed at many centers.[17] A review of the revised International Workshop Criteria comparing CT imaging alone or CT together with PET imaging demonstrated that the combination of CT and PET imaging was more accurate than CT imaging alone.[18][19] While the International Harmonization for PET had been attempted in adults, it has yet to be evaluated in pediatric populations.[17][20]

The value of PET scanning for staging pediatric NHL is under investigation, but there are no data that support the use of PET to upstage a patient.

The use of PET to assess rapidity of response to therapy appears to have prognostic value in Hodgkin lymphoma and some types of NHL observed in adult patients, and this is also under investigation in pediatric NHL. However, there are no data in pediatric NHL to support the hypothesis that early response to therapy assessed by PET has prognostic value.

Caution should be used in making the diagnosis of relapsed disease based solely on imaging because false-positive results are common.[21][22][23][24] There are also data demonstrating that PET scanning can produce false-negative results.[25] Before undertaking changes in therapy based on residual masses noted by imaging, a biopsy to prove residual disease is warranted.

References:

  1. Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334 (19): 1238-48, 1996.

  2. Link MP, Shuster JJ, Donaldson SS, et al.: Treatment of children and young adults with early-stage non-Hodgkin's lymphoma. N Engl J Med 337 (18): 1259-66, 1997.

  3. Burkhardt B, Woessmann W, Zimmermann M, et al.: Impact of cranial radiotherapy on central nervous system prophylaxis in children and adolescents with central nervous system-negative stage III or IV lymphoblastic lymphoma. J Clin Oncol 24 (3): 491-9, 2006.

  4. Sandlund JT, Pui CH, Zhou Y, et al.: Effective treatment of advanced-stage childhood lymphoblastic lymphoma without prophylactic cranial irradiation: results of St Jude NHL13 study. Leukemia 23 (6): 1127-30, 2009.

  5. Seidemann K, Tiemann M, Schrappe M, et al.: Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 97 (12): 3699-706, 2001.

  6. Cairo MS, Gerrard M, Sposto R, et al.: Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109 (7): 2736-43, 2007.

  7. Bluhm EC, Ronckers C, Hayashi RJ, et al.: Cause-specific mortality and second cancer incidence after non-Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. Blood 111 (8): 4014-21, 2008.

  8. Anderson JR, Jenkin RD, Wilson JF, et al.: Long-term follow-up of patients treated with COMP or LSA2L2 therapy for childhood non-Hodgkin's lymphoma: a report of CCG-551 from the Childrens Cancer Group. J Clin Oncol 11 (6): 1024-32, 1993.

  9. Azizkhan RG, Dudgeon DL, Buck JR, et al.: Life-threatening airway obstruction as a complication to the management of mediastinal masses in children. J Pediatr Surg 20 (6): 816-22, 1985.

  10. King DR, Patrick LE, Ginn-Pease ME, et al.: Pulmonary function is compromised in children with mediastinal lymphoma. J Pediatr Surg 32 (2): 294-9; discussion 299-300, 1997.

  11. Shamberger RC, Holzman RS, Griscom NT, et al.: Prospective evaluation by computed tomography and pulmonary function tests of children with mediastinal masses. Surgery 118 (3): 468-71, 1995.

  12. Prakash UB, Abel MD, Hubmayr RD: Mediastinal mass and tracheal obstruction during general anesthesia. Mayo Clin Proc 63 (10): 1004-11, 1988.

  13. Pui CH, Mahmoud HH, Wiley JM, et al.: Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients With leukemia or lymphoma. J Clin Oncol 19 (3): 697-704, 2001.

  14. Goldman SC, Holcenberg JS, Finklestein JZ, et al.: A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood 97 (10): 2998-3003, 2001.

  15. Cairo MS, Bishop M: Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 127 (1): 3-11, 2004.

  16. Cairo MS, Coiffier B, Reiter A, et al.: Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol 149 (4): 578-86, 2010.

  17. Juweid ME, Stroobants S, Hoekstra OS, et al.: Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 25 (5): 571-8, 2007.

  18. Brepoels L, Stroobants S, De Wever W, et al.: Hodgkin lymphoma: Response assessment by revised International Workshop Criteria. Leuk Lymphoma 48 (8): 1539-47, 2007.

  19. Cheson BD, Pfistner B, Juweid ME, et al.: Revised response criteria for malignant lymphoma. J Clin Oncol 25 (5): 579-86, 2007.

  20. Cheson BD: The International Harmonization Project for response criteria in lymphoma clinical trials. Hematol Oncol Clin North Am 21 (5): 841-54, 2007.

  21. Nasr A, Stulberg J, Weitzman S, et al.: Assessment of residual posttreatment masses in Hodgkin's disease and the need for biopsy in children. J Pediatr Surg 41 (5): 972-4, 2006.

  22. Levine JM, Weiner M, Kelly KM: Routine use of PET scans after completion of therapy in pediatric Hodgkin disease results in a high false positive rate. J Pediatr Hematol Oncol 28 (11): 711-4, 2006.

  23. Rhodes MM, Delbeke D, Whitlock JA, et al.: Utility of FDG-PET/CT in follow-up of children treated for Hodgkin and non-Hodgkin lymphoma. J Pediatr Hematol Oncol 28 (5): 300-6, 2006.

  24. Meany HJ, Gidvani VK, Minniti CP: Utility of PET scans to predict disease relapse in pediatric patients with Hodgkin lymphoma. Pediatr Blood Cancer 48 (4): 399-402, 2007.

  25. Picardi M, De Renzo A, Pane F, et al.: Randomized comparison of consolidation radiation versus observation in bulky Hodgkin's lymphoma with post-chemotherapy negative positron emission tomography scans. Leuk Lymphoma 48 (9): 1721-7, 2007.

Low-Stage Childhood NHL Treatment

Patients with stage I and II disease have an excellent prognosis, regardless of histology. A Children’s Cancer Group study demonstrated that pulsed chemotherapy with cyclophosphamide, vincristine, methotrexate, and prednisone (COMP) administered for 6 months for low-stage (stage I or II) nonlymphoblastic non-Hodgkin lymphoma (NHL) was equivalent to 18 months of therapy with radiation to sites of disease, resulting in more than 85% disease-free survival (DFS) and more than 90% overall survival (OS). However, patients with lymphoblastic lymphoma had a much inferior outcome.[1][2] A Pediatric Oncology Group (POG) study tested 9 weeks of short, pulsed chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), with or without radiation to involved sites and with or without 24 weeks of maintenance chemotherapy.[3] The results showed no benefit of radiation or maintenance chemotherapy, but the DFS for nonlymphoblastic lymphoma was superior to that of lymphoblastic lymphoma (90% vs. 60%).

For low-stage mature B-cell NHL (Burkitt lymphoma or diffuse large B-cell lymphoma), DFS is about 95%. The Berlin-Frankfurt-Munster (BFM) group has treated risk group R1 (completely resected disease) with two cycles of multiagent chemotherapy (GER-GPOH-NHL-BFM-90 and GER-GPOH-NHL-BFM-95).[4][5] For unresected stage I/II disease (R2), patients received a cytoreductive phase followed by five cycles of chemotherapy.[4][5] In the NHL-BFM-90 study, it was shown that reducing the dose of methotrexate did not affect the results for low-stage disease.[4] In NHL-BFM-95, it was demonstrated for low-stage disease that prolonging the duration of methotrexate infusion did not improve outcome.[5] The French Society of Pediatric Oncology (SFOP) and French-American-British (FAB) studies have treated all completely resected stage I and abdominal stage II (group A) with two cycles of multiagent chemotherapy, without intrathecal chemotherapy (COG-C5961 [FAB/LMB-96]).[6][Level of evidence: 2A] For unresected stage I/II disease (group B), the above-mentioned FAB study demonstrated that reducing the duration of therapy to four cycles of chemotherapy following a cytoreduction phase and reducing the cumulative doses of cyclophosphamide and doxorubicin did not affect outcome.[7]

For low-stage lymphoblastic lymphoma (stage I/II disease), about 60% of patients can achieve long-term DFS with short, pulsed chemotherapy.[2][3] However, using an acute lymphoblastic leukemia approach with induction, consolidation, and maintenance for a total of 24 months, the BFM group (NHL-BFM-90/95) has shown more than 90% DFS for low-stage lymphoblastic lymphoma.[8][9]

For low-stage anaplastic large cell lymphoma, the best results have come from using pulsed chemotherapy similar to mature B-cell NHL therapy. In the POG study for low-stage lymphoma using three cycles of CHOP, a 5-year event-free survival (EFS) of 88% for large cell lymphoma (anaplastic large cell lymphoma and diffuse large B-cell lymphoma) patients was reported.[3] The BFM group has used three cycles of chemotherapy following a cytoreductive prophase for completely resected stage I/II disease.[10] The FRE-IGR-ALCL99 trial used three cycles of chemotherapy following cytoreductive prophase for patients with stage I completely resected disease. The minority of stage I patients had complete resections (6 out of 36) but there were no treatment failures for these six patients. The therapy for patients without complete resection was the same as the therapy for patients with disseminated disease and the 3-year EFS (81%) and OS (97%) were not statistically different from the outcomes for patients with higher stage disease.[11][Level of evidence: 2A]

Primary cutaneous anaplastic large cell lymphoma presents a particular problem. The diagnosis can be difficult to distinguish from more benign diseases such as lymphoid papulosis.[12] Primary cutaneous anaplastic large cell lymphoma usually does not express ALK and may be treated successfully with surgical resection and/or local radiation therapy without systemic chemotherapy.[13] There are reports of surgery alone being curative for ALK-positive cutaneous anaplastic large cell lymphoma, but extensive staging and vigilant follow-up is required.

Follicular lymphoma is rare in children, with only case reports and case series to guide therapy. Case series reporting a variety of chemotherapy approaches have resulted in good outcomes.[14]

Standard treatment options are based on histology; however, current data do not suggest superiority between regimens listed below for a specific histology.

Standard Treatment Options

Table 4. Standard Treatment Options for Low-Stage Non-Hodgkin Lymphoma

Disease

Treatment Options

Burkitt lymphoma or diffuse large B-cell lymphoma (DLBCL) (completely resected)  

GER-GPOH-NHL-BFM-95 (R1): Two cycles of chemotherapy.[5]

COG-C5961 (FAB/LMB-96) (Group A): Two cycles of chemotherapy.[6]

 

Burkitt lymphoma or DLBCL (nonresected stage I/II)  

GER-GPOH-NHL-BFM-95 (R2): Prephase + four cycles of chemotherapy (4-hour methotrexate infusion).[5]

COG-C5961 (FAB/LMB-96) (Group B): Prephase + four cycles of chemotherapy (reduced-intensity arm).[7]

POG-8314/POG-8719: Three cycles of chemotherapy (no radiation or maintenance therapy).[3]

 

Lymphoblastic lymphoma  

GER-GPOH-NHL-BFM-95: Induction, consolidation, intensification, and maintenance therapy (2 years of total therapy); ALL-type induction and consolidation, high-dose methotrexate courses × 4, and ALL-type maintenance therapy (2 years of total therapy).[8][9]

 

Anaplastic large cell lymphoma  

POG-8314/POG-8719: Three cycles of chemotherapy (no radiation or maintenance therapy).[3]

GER-GPOH-NHL-BFM-90: Prephase + three cycles of chemotherapy (only for completely resected disease).[10]

FRE-IGR-ALCL99: Prephase + six cycles of chemotherapy (for disease not completely resected).[11]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I childhood large cell lymphoma, stage I childhood small noncleaved cell lymphoma, stage I childhood lymphoblastic lymphoma, stage I childhood anaplastic large cell lymphoma, stage II childhood large cell lymphoma, stage II childhood small noncleaved cell lymphoma, stage II childhood lymphoblastic lymphoma and stage II childhood anaplastic large cell lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Meadows AT, Sposto R, Jenkin RD, et al.: Similar efficacy of 6 and 18 months of therapy with four drugs (COMP) for localized non-Hodgkin's lymphoma of children: a report from the Childrens Cancer Study Group. J Clin Oncol 7 (1): 92-9, 1989.

  2. Anderson JR, Jenkin RD, Wilson JF, et al.: Long-term follow-up of patients treated with COMP or LSA2L2 therapy for childhood non-Hodgkin's lymphoma: a report of CCG-551 from the Childrens Cancer Group. J Clin Oncol 11 (6): 1024-32, 1993.

  3. Link MP, Shuster JJ, Donaldson SS, et al.: Treatment of children and young adults with early-stage non-Hodgkin's lymphoma. N Engl J Med 337 (18): 1259-66, 1997.

  4. Reiter A, Schrappe M, Tiemann M, et al.: Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 94 (10): 3294-306, 1999.

  5. Woessmann W, Seidemann K, Mann G, et al.: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105 (3): 948-58, 2005.

  6. Gerrard M, Cairo MS, Weston C, et al.: Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Br J Haematol 141 (6): 840-7, 2008.

  7. Patte C, Auperin A, Gerrard M, et al.: Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109 (7): 2773-80, 2007.

  8. Reiter A, Schrappe M, Ludwig WD, et al.: Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report. Blood 95 (2): 416-21, 2000.

  9. Burkhardt B, Woessmann W, Zimmermann M, et al.: Impact of cranial radiotherapy on central nervous system prophylaxis in children and adolescents with central nervous system-negative stage III or IV lymphoblastic lymphoma. J Clin Oncol 24 (3): 491-9, 2006.

  10. Seidemann K, Tiemann M, Schrappe M, et al.: Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 97 (12): 3699-706, 2001.

  11. Attarbaschi A, Mann G, Rosolen A, et al.: Limited stage I disease is not necessarily indicative of an excellent prognosis in childhood anaplastic large cell lymphoma. Blood 117 (21): 5616-9, 2011.

  12. Kumar S, Pittaluga S, Raffeld M, et al.: Primary cutaneous CD30-positive anaplastic large cell lymphoma in childhood: report of 4 cases and review of the literature. Pediatr Dev Pathol 8 (1): 52-60, 2005 Jan-Feb.

  13. Hinshaw M, Trowers AB, Kodish E, et al.: Three children with CD30 cutaneous anaplastic large cell lymphomas bearing the t(2;5)(p23;q35) translocation. Pediatr Dermatol 21 (3): 212-7, 2004 May-Jun.

  14. Kumar R, Galardy PJ, Dogan A, et al.: Rituximab in combination with multiagent chemotherapy for pediatric follicular lymphoma. Pediatr Blood Cancer 57 (2): 317-20, 2011.

High-Stage Childhood B-cell NHL Treatment

Patients with high-stage (stage III or stage IV) mature B-lineage non-Hodgkin lymphoma (NHL) (Burkitt or Burkitt-like lymphoma and diffuse large B-cell lymphoma) have an 80% to 90% long-term survival.[1][2][3] Unlike mature B-lineage NHL seen in adults, there is no difference in outcome based on histology (Burkitt or Burkitt-like lymphoma or diffuse large B-cell lymphoma) with current therapy in pediatric trials.[1][2][3]

Involvement of the bone marrow may lead to confusion as to whether the patient has lymphoma or leukemia. Traditionally, patients with more than 25% marrow blasts are classified as having mature B-cell leukemia, and those with fewer than 25% marrow blasts are classified as having lymphoma. It is not clear whether these arbitrary definitions are biologically distinct, but there is no question that patients with Burkitt leukemia should be treated with protocols designed for Burkitt lymphoma.[1][3]

Tumor lysis syndrome is often present at diagnosis or after initiation of treatment. This emergent clinical situation should be anticipated and addressed before treatment is started. (Refer to the Tumor lysis syndrome subsection in the Treatment Option Overview section of this summary for more information.) For reduction of the complications of tumor lysis syndrome, current treatment regimens use a prophase of reduced intensity to cytoreduce patients;[1][2][3] however, this does not obviate the use of hyperhydration and allopurinol or rasburicase (urate oxidase). Hyperuricemia and tumor lysis syndrome, particularly when associated with ureteral obstruction, frequently result in life-threatening complications. Gastrointestinal bleeding, obstruction, and (rarely) perforation may occur. Patients with NHL should be managed only in institutions having pediatric tertiary care facilities.[4]

In the NHL-BFM-95 trial, it was shown that when the dose of methotrexate was reduced for R1 and R2 patients, outcome was not inferior; however, reducing the infusion time of methotrexate from 24 hours to 4 hours for R3 and R4 group patients resulted in less mucositis, but inferior outcome.[1] Event-free survival (EFS) with best therapy in NHL-BFM-95 was more than 95% for R1 and R2 group patients and was 93% for R3 and R4 group patients. Inferior outcome was observed for patients with primary mediastinal B-cell lymphoma (50% 3-year EFS) and CNS disease at presentation (70% 3-year EFS).[5] In the COG-C5961 (FAB/LMB-96) study, the outcome of group B patients, who had a greater than 20% response to cytoreductive prophase, was not affected by a reduction of the total dose of cyclophosphamide by 50% and elimination of one cycle of maintenance therapy.[2] The 3-year EFS was 98% for stage I/II, 90% for stage III, and 86% for stage IV (CNS-negative) patients, while patients with primary mediastinal B-cell lymphoma had a 3-year EFS of 70%.[2] In group C patients, reduction in cumulative dose of therapy and number of maintenance cycles resulted in inferior outcome.[3] Patients with leukemic disease only, and no CNS disease, had a 3-year EFS of 90%, while patients with CNS disease at presentation had a 70% 3-year EFS.[3] This study identified response to prophase reduction as the most significant prognostic factor, with poor responders (i.e., <20% resolution of disease) having an EFS of 30%.[3] Both the Berlin-Frankfurt-Munster (BFM) and FAB/LMB studies demonstrated that omission of craniospinal irradiation, even in patients presenting with CNS disease, does not affect outcome (COG-C5961 [FAB/LMB-96] and NHL-BFM-90 [GER-GPOH-NHL-BFM-90]).[1][2][3][5]

Rituximab is a mouse/human chimeric monoclonal antibody targeting the CD20 antigen. Among the lymphomas that occur in children, diffuse large B-cell lymphoma and Burkitt lymphoma both express high levels of CD20.[6] Rituximab has been safely combined with standard doxorubicin, cyclophosphamide, vincristine, and prednisone (CHOP) chemotherapy and has been shown to improve outcome in a randomized trial of adults with diffuse large B-cell lymphoma (CAN-NCIC-LY9).[7][8] In an adult study, rituximab has also been safely combined with an intensive chemotherapy regimen used to treat patients with Burkitt lymphoma.[9] In children, a single-agent phase II study of rituximab performed by the BFM group showed activity in Burkitt leukemia and lymphoma.[10][Level of evidence: 2Div] A Children's Oncology Group (COG) pilot study (COG-ANHL01P1) to test the toxicity of adding rituximab to FAB/LMB-96 (COG-C5961) has completed accrual and results are pending.

Standard Treatment Options

Current data do not suggest superiority for either of the following standard treatment options.

Table 5. Standard Treatment Options for High-Stage B-cell NHL

 

Stratum

Disease Manifestations

Treatment

FAB/LMB-96 International StudyCOG-C5961 (FAB/LMB-96)[2][3]

B

Multiple extra-abdominal sites

Prephase + four cycles of chemotherapy (reduced intensity arm) [2]

Nonresected stage I and II, III, IV

Marrow <25% blasts

No CNS disease

C

Mature B-cell ALL (>25% blasts in marrow) and/or CNS disease

Prephase + eight cycles of chemotherapy (full intensity arm) [3]

 

BFM Group[1][5]

R2

Nonresected stage I/II and stage III with LDH <500 IU/L

Prephase + four cycles of chemotherapy (4 h methotrexate infusion) [1]

R3

Stage III with LDH 500–999 IU/L

Prephase + five cycles of chemotherapy (24 h methotrexate infusion) [1]

Stage IV, B-cell ALL (>25% blasts) and LDH <1,000 IU/L

No CNS disease

R4

Stage III, IV, B-cell ALL with LDH >1,000 IU/L

Prephase + six cycles of chemotherapy (24 h methotrexate infusion) [1]

Any CNS disease

ALL = acute lymphoblastic leukemia; BFM = Berlin-Frankfurt-Munster; CNS = central nervous system; LDH = lactate dehydrogenase; NHL= non-Hodgkin lymphoma.

Treatment Options Under Clinical Evaluation

The following is an example of a national or international clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

  • COG-ANHL1131 (Combination Chemotherapy With or Without Rituximab in Treating Younger Patients With Stage III–IV Non-Hodgkin Lymphoma or B-Cell Acute Leukemia): This randomized study of patients with high-risk disease (defined as Group B with high lactate dehydrogenase and Group C) examines the addition of rituximab to the standard FAB LMB 96 (COG-C5961) chemotherapy regimen. Additionally, the dose-adjusted EPOCH-R regimen (etoposide, prednisone, vincristine, doxorubicin, and rituximab) will be tested in a single-arm, phase II trial for pediatric patients with primary mediastinal B-cell lymphoma.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III childhood large cell lymphoma, stage III childhood small noncleaved cell lymphoma, stage IV childhood large cell lymphoma and stage IV childhood small noncleaved cell lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Woessmann W, Seidemann K, Mann G, et al.: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105 (3): 948-58, 2005.

  2. Patte C, Auperin A, Gerrard M, et al.: Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109 (7): 2773-80, 2007.

  3. Cairo MS, Gerrard M, Sposto R, et al.: Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109 (7): 2736-43, 2007.

  4. Cairo MS, Bishop M: Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 127 (1): 3-11, 2004.

  5. Reiter A, Schrappe M, Tiemann M, et al.: Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 94 (10): 3294-306, 1999.

  6. Perkins SL, Lones MA, Davenport V, et al.: B-Cell non-Hodgkin's lymphoma in children and adolescents: surface antigen expression and clinical implications for future targeted bioimmune therapy: a children's cancer group report. Clin Adv Hematol Oncol 1 (5): 314-7, 2003.

  7. Coiffier B, Lepage E, Briere J, et al.: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346 (4): 235-42, 2002.

  8. Pfreundschuh M, Trümper L, Osterborg A, et al.: CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7 (5): 379-91, 2006.

  9. Thomas DA, Faderl S, O'Brien S, et al.: Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer 106 (7): 1569-80, 2006.

  10. Meinhardt A, Burkhardt B, Zimmermann M, et al.: Phase II window study on rituximab in newly diagnosed pediatric mature B-cell non-Hodgkin's lymphoma and Burkitt leukemia. J Clin Oncol 28 (19): 3115-21, 2010.

High-Stage Childhood Lymphoblastic Lymphoma Treatment

Patients with high-stage (stage III or IV) lymphoblastic lymphoma have long-term survival rates higher than 80%.[1] Unlike other pediatric non-Hodgkin lymphoma (NHL), it has been shown that lymphoblastic lymphoma responds much better to leukemia therapy with 2 years of therapy than with shorter, intensive, pulsed chemotherapy regimens.[1][2][3]

Involvement of the bone marrow may lead to confusion as to whether the patient has lymphoma or leukemia. Traditionally, patients with more than 25% marrow blasts are classified as having leukemia, and those with fewer than 25% marrow blasts are classified as having lymphoma. It is not yet clear whether these arbitrary definitions are biologically distinct or relevant for treatment design. All current therapies for advanced-stage lymphoblastic lymphoma have been derived from regimens designed for the treatment of acute lymphoblastic leukemia (ALL).

Mediastinal radiation is not necessary for patients with mediastinal masses, except in the emergency treatment of symptomatic superior vena caval obstruction or airway obstruction, where either corticosteroid therapy or low-dose radiation is usually employed. (Refer to the Treatment Option Overview section of this summary for more information on such complications.) Because of the complexities of optimal therapeutic regimens and the possibility of toxic side effects, patients should be offered the opportunity to enter into a clinical trial. Information about ongoing clinical trials is available from the NCI Web site.

The best results to date come from the Berlin-Frankfurt-Munster (BFM) group. In the GER-GPOH-NHL-BFM-90 study, the 5-year disease-free survival was 90%, and there was no difference in outcome between stage III and stage IV patients.[1] Precursor B-cell lymphoblastic lymphoma appears to have similar results using the same therapy.[4] In the GER-GPOH-NHL-BFM-95 study, the prophylactic cranial radiation was omitted, and the intensity of induction therapy was decreased slightly. There were no significant increases in central nervous system (CNS) relapses, suggesting cranial radiation may be reserved for patients with CNS disease at diagnosis.[3] Of interest, the probability of 5-year event-free survival (EFS) rates was worse in NHL-BFM-95 than in NHL-BFM-90 (82% vs. 90%, respectively). Although this difference was not statistically different, NHL-BFM-95 had a reduction of asparaginase and doxorubicin in induction, which may have affected outcome. It was proposed that the major difference in EFS between NHL-BFM-90 and NHL-BFM-95 resulted from the increased number of secondary malignancies observed in NHL-BFM-95.[3] A single-center study suggests that patients treated for lymphoblastic lymphoma have a higher incidence of secondary malignancy than do patients treated for other pediatric NHL; however, studies from the Children's Oncology Group and the Childhood Cancer Survivor Study Group do not support this finding.[5][6][7]

The Pediatric Oncology Group conducted a trial to test the effectiveness of the addition of high-dose methotrexate in T-cell ALL and T-cell lymphoblastic lymphoma. In the lymphoma patients, high-dose methotrexate did not demonstrate benefit. However, in the small cohort (n = 66) of lymphoma patients who did not receive high-dose methotrexate, the 5-year EFS was 88%.[8][Level of evidence: 1iiA] Of note, all of these patients received prophylactic craniospinal radiation therapy, which has been demonstrated not to be required in T-cell lymphoblastic lymphoma patients.[3]

Standard Treatment Options

Current data do not suggest superiority for the following standard treatment options.

  • GER-GPOH-NHL-BFM-95: prednisone, dexamethasone, vincristine, daunorubicin, doxorubicin, L-asparaginase, cyclophosphamide, cytarabine, methotrexate, 6-mercaptopurine, 6-thioguanine, and CNS radiation therapy for CNS-positive patients only.[1]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III childhood lymphoblastic lymphoma and stage IV childhood lymphoblastic lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Reiter A, Schrappe M, Ludwig WD, et al.: Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report. Blood 95 (2): 416-21, 2000.

  2. Anderson JR, Jenkin RD, Wilson JF, et al.: Long-term follow-up of patients treated with COMP or LSA2L2 therapy for childhood non-Hodgkin's lymphoma: a report of CCG-551 from the Childrens Cancer Group. J Clin Oncol 11 (6): 1024-32, 1993.

  3. Burkhardt B, Woessmann W, Zimmermann M, et al.: Impact of cranial radiotherapy on central nervous system prophylaxis in children and adolescents with central nervous system-negative stage III or IV lymphoblastic lymphoma. J Clin Oncol 24 (3): 491-9, 2006.

  4. Burkhardt B, Zimmermann M, Oschlies I, et al.: The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol 131 (1): 39-49, 2005.

  5. Leung W, Sandlund JT, Hudson MM, et al.: Second malignancy after treatment of childhood non-Hodgkin lymphoma. Cancer 92 (7): 1959-66, 2001.

  6. Abromowitch M, Sposto R, Perkins S, et al.: Shortened intensified multi-agent chemotherapy and non-cross resistant maintenance therapy for advanced lymphoblastic lymphoma in children and adolescents: report from the Children's Oncology Group. Br J Haematol 143 (2): 261-7, 2008.

  7. Bluhm EC, Ronckers C, Hayashi RJ, et al.: Cause-specific mortality and second cancer incidence after non-Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. Blood 111 (8): 4014-21, 2008.

  8. Asselin BL, Devidas M, Wang C, et al.: Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children's Oncology Group (POG 9404). Blood 118 (4): 874-83, 2011.

High-Stage Childhood Anaplastic Large Cell Lymphoma Treatment

Children and adolescents with high-stage (stage III or IV) anaplastic large cell lymphoma have a disease-free survival of approximately 60% to 75%.[1][2][3][4][5] It is unclear which strategy is best for the treatment of high-stage anaplastic large cell lymphoma. The German Berlin-Frankfurt-Munster (BFM) group used six cycles of intensive pulsed therapy, similar to their B-cell non-Hodgkin lymphoma (NHL) therapy (GER-GPOH-NHL-BFM-90 [NHL-BFM-90]).[2]; [6][Level of evidence: 1iiA] Building on these results, the European Intergroup for Childhood NHL (EICNHL) group conducted the FRE-IGR-ALCL99 study (based on the GER-GPOH-NHL-BFM-90 regimen). First, this randomized study demonstrated that methotrexate 1 g/m2 infused over 24 hours plus intrathecal methotrexate and methotrexate 3 g/m2 infused over 3 hours without intrathecal methotrexate yielded similar outcomes.[7][Level of evidence: 1iiC] However, methotrexate 3 g/m2 over 3 hours had less toxicity than methotrexate 1 g/m2 over 24 hours.[7]; [6][Level of evidence: 1iiDi] Secondly, FRE-IGR-ALCL99 randomly assigned patients to limited vinblastine versus prolonged (1 year) vinblastine exposure. Patients receiving the vinblastine plus chemotherapy regimen had a better event-free survival (EFS) in the first year after therapy (91%) than those not receiving vinblastine (74%); however, after 2 years of follow-up, the EFS was 73% for both groups.[8][Level of evidence: 1iiDi] Of note, the Pediatric Oncology Group (POG) trial (POG-9317) demonstrated no benefit of adding methotrexate and high-dose cytarabine to 52 weeks of the APO (doxorubicin, prednisone, and vincristine) regimen.[3] The Italian Association of Pediatric Hematology/Oncology group has used a leukemia-like regimen for 24 months in LNH-92, with similar results as other regimens.[4] The CCG-5941 study tested an approach similar to LNH-92, with more intensive induction and consolidation with maintenance for 1 year total duration of therapy, with similar outcome, but significant hematologic toxicity was observed.[5][Level of evidence: 2A]

Standard Treatment Options

Current data do not suggest superiority for the following standard treatment options.

  • APO: doxorubicin, prednisone, and vincristine.[3] This regimen can be administered in the outpatient setting. The duration of therapy is 52 weeks and the cumulative dose of doxorubicin in 300 mg/m2.
  • FRE-IGR-ALCL99: dexamethasone, cyclophosphamide, ifosfamide, etoposide, doxorubicin, IV methotrexate (3 g/m2 arm), cytarabine, prednisolone, and vinblastine.[6] This regimen usually requires hospitalization for administration. The total duration of therapy is 5 months and the cumulative dose of doxorubicin is 150 mg/m2.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III childhood anaplastic large cell lymphoma and stage IV childhood anaplastic large cell lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Brugières L, Deley MC, Pacquement H, et al.: CD30(+) anaplastic large-cell lymphoma in children: analysis of 82 patients enrolled in two consecutive studies of the French Society of Pediatric Oncology. Blood 92 (10): 3591-8, 1998.

  2. Seidemann K, Tiemann M, Schrappe M, et al.: Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 97 (12): 3699-706, 2001.

  3. Laver JH, Kraveka JM, Hutchison RE, et al.: Advanced-stage large-cell lymphoma in children and adolescents: results of a randomized trial incorporating intermediate-dose methotrexate and high-dose cytarabine in the maintenance phase of the APO regimen: a Pediatric Oncology Group phase III trial. J Clin Oncol 23 (3): 541-7, 2005.

  4. Rosolen A, Pillon M, Garaventa A, et al.: Anaplastic large cell lymphoma treated with a leukemia-like therapy: report of the Italian Association of Pediatric Hematology and Oncology (AIEOP) LNH-92 protocol. Cancer 104 (10): 2133-40, 2005.

  5. Lowe EJ, Sposto R, Perkins SL, et al.: Intensive chemotherapy for systemic anaplastic large cell lymphoma in children and adolescents: final results of Children's Cancer Group Study 5941. Pediatr Blood Cancer 52 (3): 335-9, 2009.

  6. Brugières L, Le Deley MC, Rosolen A, et al.: Impact of the methotrexate administration dose on the need for intrathecal treatment in children and adolescents with anaplastic large-cell lymphoma: results of a randomized trial of the EICNHL Group. J Clin Oncol 27 (6): 897-903, 2009.

  7. Wrobel G, Mauguen A, Rosolen A, et al.: Safety assessment of intensive induction therapy in childhood anaplastic large cell lymphoma: report of the ALCL99 randomised trial. Pediatr Blood Cancer 56 (7): 1071-7, 2011.

  8. Le Deley MC, Rosolen A, Williams DM, et al.: Vinblastine in children and adolescents with high-risk anaplastic large-cell lymphoma: results of the randomized ALCL99-vinblastine trial. J Clin Oncol 28 (25): 3987-93, 2010.

Recurrent Childhood NHL Treatment

Outcome for recurrent non-Hodgkin lymphoma (NHL) in children and adolescents depends on histologic subtype. A Children's Cancer Group study (CCG-5912) was able to achieve complete remission (CR) in 40% of NHL patients.[1] A Pediatric Oncology Group study showed a 70% response rate and 40% CR rate.[2] Radiation therapy may have a role in treating patients who have not had a complete response to chemotherapy. All patients with primary refractory or relapsed NHL should be considered for clinical trials.

For recurrent or refractory B-lineage NHL, survival is generally 10% to 20%.[3][4][5][6][7] Chemoresistance is a major problem, making remission difficult to achieve. There is no standard treatment option for patients with recurrent or progressive disease. The use of single-agent rituximab, as well as rituximab combined with standard cytotoxic chemotherapy, has shown activity in the treatment of B-cell lymphoma patients.[8][Level of evidence: 3iiiDii] A Children's Oncology Group (COG) study using rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) to treat relapsed/refractory B-cell NHL (diffuse large B-cell lymphoma and Burkitt lymphoma) showed a CR/partial remission (PR) rate of 60%.[9][Level of evidence: 3iiA] If remission can be achieved, high-dose therapy and stem cell transplantation (SCT) may be pursued. The benefit of autologous versus allogeneic SCT is unclear.[5][10][11][12]; [13][Level of evidence: 2A]; [14][Level of evidence: 3iiiDii] An analysis of the Center for International Blood and Marrow Transplant Research (CIBMTR) data demonstrated no difference using either autologous or allogeneic donor stem cell sources, with 2-year event-free survival (EFS) to be 30% for diffuse large B-cell lymphoma and 50% for Burkitt lymphoma. This analysis also showed patients not in remission at time of transplant do significantly worse.[12][13] For patients who have a second relapse after initial autologous SCT, an allogeneic SCT was found to be a promising treatment in a study of adults with diffuse large B-cell lymphoma.[15]

For recurrent or refractory lymphoblastic lymphoma, survival in the literature ranges from 10% to 40%.[5][16]; [17][18][Level of evidence: 3iiiA] As with Burkitt lymphoma, chemoresistant disease is common. There is no standard treatment option for patients with recurrent or progressive disease. A COG phase II study of nelarabine (compound 506U78) as a single agent demonstrated a response rate of 40%.[19] The CIBMTR analysis demonstrated that EFS was significantly worse using autologous (4%) versus allogeneic (40%) donor stem cell source, with all failures resulting from progressive disease.[12]

For recurrent or refractory anaplastic large cell lymphoma, 40% to 60% of patients can achieve long-term survival.[5][20][21] There is no standard approach for recurrent/refractory anaplastic large cell lymphoma; standard chemotherapy, followed by autologous SCT or allogeneic SCT, if remission can be achieved, have all been employed in this setting.[5][12][20][21]; [13][Level of evidence: 2A] In a retrospective study of relapsed or refractory anaplastic large cell lymphoma in patients who received Berlin-Frankfurt-Muenster–type first-line therapy, reinduction chemotherapy followed by autologous stem cell transplant resulted in 59% 5-year EFS and 77% overall survival.[21][Level of evidence: 2A] However, outcome of patients with bone marrow or central nervous system involvement, relapse during first-line therapy, or CD3-positive anaplastic large cell lymphoma was poor. These patients may benefit from allogeneic transplantation.[21] Several additional studies suggest that allogeneic SCT may result in better outcome for refractory/relapsed anaplastic large cell lymphoma.[12][22] Vinblastine is active as a single agent in recurrent/refractory anaplastic large cell lymphoma, inducing CR in 25 (83%) of 30 evaluable patients in one study.[23] Nine of 25 patients treated with vinblastine alone remained in CR with median follow-up of 7 years since the end of treatment.[23][Level of evidence: 3iiiA]

Crizotinib, a kinase inhibitor that blocks the activity of the NPM-ALK fusion protein, has been evaluated in children and adults with relapsed/refractory anaplastic large cell lymphoma.[24][25] There are two case reports of adults with anaplastic large cell lymphoma who achieved complete responses to crizotinib, and seven of eight children with anaplastic large cell lymphoma treated on the pediatric phase I study of crizotinib achieved complete responses.[24][25]

Brentuximab vedotin has been evaluated in adults with anaplastic large cell lymphoma. A phase I study in adults with CD30-positive cancers identified a recommended phase II dose of 1.8 mg/kg, administered every 3 weeks; two of two patients with anaplastic large cell lymphoma achieved CR.[26] A phase II trial in adults with relapsed anaplastic large cell lymphoma has shown CR rates of approximately 55% to 60% and PR rates of 29%.[27] The number of pediatric patients treated with brentuximab vedotin is not sufficient to determine whether they respond differently than adult patients.

Treatment Options

Burkitt lymphoma and diffuse large B-cell lymphoma

  • DECAL: dexamethasone, etoposide, cisplatin, cytarabine, and L-asparaginase.[1]
  • ICE (ifosfamide, carboplatin, and etoposide) plus rituximab (for B-cell lymphoma).[9]
  • Allogeneic or autologous bone marrow transplantation (BMT).[12]

Lymphoblastic lymphoma

  • DECAL: dexamethasone, etoposide, cisplatin, cytarabine, and L-asparaginase.[1]
  • ICE: ifosfamide, carboplatin, and etoposide.[2]
  • Allogeneic BMT.[12]

Anaplastic large cell lymphoma

  • DECAL: dexamethasone, etoposide, cisplatin, cytarabine, and L-asparaginase.[1]
  • ICE: ifosfamide, carboplatin, and etoposide.[2]
  • Vinblastine (for anaplastic large cell lymphoma).[23]
  • Allogeneic or autologous BMT.[12]

Treatment Options Under Clinical Evaluation

The following is an example of a national or international clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

  • COG-ADVL0912 (Crizotinib in Treating Young Patients With Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma): The ALK inhibitor, crizotinib, is under phase I evaluation in children. The study has a stratum for children with ALK and anaplastic large cell lymphoma.
  • COG-ADVL1114 (Temsirolimus, Dexamethasone, Mitoxantrone Hydrochloride, Vincristine Sulfate, and Pegaspargase in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia [ALL] or NHL): This is a phase I trial to determine the feasibility and safety of adding three doses of temsirolimus (intravenously) to the United Kingdom ALLR3 induction regimen for patients with relapsed ALL and NHL.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Kobrinsky NL, Sposto R, Shah NR, et al.: Outcomes of treatment of children and adolescents with recurrent non-Hodgkin's lymphoma and Hodgkin's disease with dexamethasone, etoposide, cisplatin, cytarabine, and l-asparaginase, maintenance chemotherapy, and transplantation: Children's Cancer Group Study CCG-5912. J Clin Oncol 19 (9): 2390-6, 2001.

  2. Kung FH, Harris MB, Krischer JP: Ifosfamide/carboplatin/etoposide (ICE), an effective salvaging therapy for recurrent malignant non-Hodgkin lymphoma of childhood: a Pediatric Oncology Group phase II study. Med Pediatr Oncol 32 (3): 225-6, 1999.

  3. Cairo MS, Sposto R, Perkins SL, et al.: Burkitt's and Burkitt-like lymphoma in children and adolescents: a review of the Children's Cancer Group experience. Br J Haematol 120 (4): 660-70, 2003.

  4. Atra A, Gerrard M, Hobson R, et al.: Outcome of relapsed or refractory childhood B-cell acute lymphoblastic leukaemia and B-cell non-Hodgkin's lymphoma treated with the UKCCSG 9003/9002 protocols. Br J Haematol 112 (4): 965-8, 2001.

  5. Attarbaschi A, Dworzak M, Steiner M, et al.: Outcome of children with primary resistant or relapsed non-Hodgkin lymphoma and mature B-cell leukemia after intensive first-line treatment: a population-based analysis of the Austrian Cooperative Study Group. Pediatr Blood Cancer 44 (1): 70-6, 2005.

  6. Cairo MS, Sposto R, Hoover-Regan M, et al.: Childhood and adolescent large-cell lymphoma (LCL): a review of the Children's Cancer Group experience. Am J Hematol 72 (1): 53-63, 2003.

  7. Cairo MS, Gerrard M, Sposto R, et al.: Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109 (7): 2736-43, 2007.

  8. Attias D, Weitzman S: The efficacy of rituximab in high-grade pediatric B-cell lymphoma/leukemia: a review of available evidence. Curr Opin Pediatr 20 (1): 17-22, 2008.

  9. Griffin TC, Weitzman S, Weinstein H, et al.: A study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent/refractory B-cell (CD20+) non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 52 (2): 177-81, 2009.

  10. Ladenstein R, Pearce R, Hartmann O, et al.: High-dose chemotherapy with autologous bone marrow rescue in children with poor-risk Burkitt's lymphoma: a report from the European Lymphoma Bone Marrow Transplantation Registry. Blood 90 (8): 2921-30, 1997.

  11. Sandlund JT, Bowman L, Heslop HE, et al.: Intensive chemotherapy with hematopoietic stem-cell support for children with recurrent or refractory NHL. Cytotherapy 4 (3): 253-8, 2002.

  12. Gross TG, Hale GA, He W, et al.: Hematopoietic stem cell transplantation for refractory or recurrent non-Hodgkin lymphoma in children and adolescents. Biol Blood Marrow Transplant 16 (2): 223-30, 2010.

  13. Harris RE, Termuhlen AM, Smith LM, et al.: Autologous peripheral blood stem cell transplantation in children with refractory or relapsed lymphoma: results of Children's Oncology Group study A5962. Biol Blood Marrow Transplant 17 (2): 249-58, 2011.

  14. Andion M, Molina B, Gonzalez-Vicent M, et al.: High-dose busulfan and cyclophosphamide as a conditioning regimen for autologous peripheral blood stem cell transplantation in childhood non-Hodgkin lymphoma patients: a long-term follow-up study. J Pediatr Hematol Oncol 33 (3): e89-91, 2011.

  15. van Kampen RJ, Canals C, Schouten HC, et al.: Allogeneic stem-cell transplantation as salvage therapy for patients with diffuse large B-cell non-Hodgkin's lymphoma relapsing after an autologous stem-cell transplantation: an analysis of the European Group for Blood and Marrow Transplantation Registry. J Clin Oncol 29 (10): 1342-8, 2011.

  16. Abromowitch M, Sposto R, Perkins S, et al.: Shortened intensified multi-agent chemotherapy and non-cross resistant maintenance therapy for advanced lymphoblastic lymphoma in children and adolescents: report from the Children's Oncology Group. Br J Haematol 143 (2): 261-7, 2008.

  17. Mitsui T, Mori T, Fujita N, et al.: Retrospective analysis of relapsed or primary refractory childhood lymphoblastic lymphoma in Japan. Pediatr Blood Cancer 52 (5): 591-5, 2009.

  18. Burkhardt B, Reiter A, Landmann E, et al.: Poor outcome for children and adolescents with progressive disease or relapse of lymphoblastic lymphoma: a report from the berlin-frankfurt-muenster group. J Clin Oncol 27 (20): 3363-9, 2009.

  19. Berg SL, Blaney SM, Devidas M, et al.: Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group. J Clin Oncol 23 (15): 3376-82, 2005.

  20. Mori T, Takimoto T, Katano N, et al.: Recurrent childhood anaplastic large cell lymphoma: a retrospective analysis of registered cases in Japan. Br J Haematol 132 (5): 594-7, 2006.

  21. Woessmann W, Zimmermann M, Lenhard M, et al.: Relapsed or refractory anaplastic large-cell lymphoma in children and adolescents after Berlin-Frankfurt-Muenster (BFM)-type first-line therapy: a BFM-group study. J Clin Oncol 29 (22): 3065-71, 2011.

  22. Woessmann W, Peters C, Lenhard M, et al.: Allogeneic haematopoietic stem cell transplantation in relapsed or refractory anaplastic large cell lymphoma of children and adolescents--a Berlin-Frankfurt-Münster group report. Br J Haematol 133 (2): 176-82, 2006.

  23. Brugières L, Pacquement H, Le Deley MC, et al.: Single-drug vinblastine as salvage treatment for refractory or relapsed anaplastic large-cell lymphoma: a report from the French Society of Pediatric Oncology. J Clin Oncol 27 (30): 5056-61, 2009.

  24. Gambacorti-Passerini C, Messa C, Pogliani EM: Crizotinib in anaplastic large-cell lymphoma. N Engl J Med 364 (8): 775-6, 2011.

  25. Mosse YP, Balis FM, Lim MS, et al.: Efficacy of crizotinib in children with relapsed/refractory ALK-driven tumors including anaplastic large cell lymphoma and neuroblastoma: a Children's Oncology Group phase I consortium study. [Abstract] J Clin Oncol 30 (Suppl 15): A-9500, 2012.

  26. Younes A, Bartlett NL, Leonard JP, et al.: Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363 (19): 1812-21, 2010.

  27. Pro B, Advani R, Brice P, et al.: Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol 30 (18): 2190-6, 2012.

Lymphoproliferative Disease Associated With Immunodeficiency in Children

Regardless of the etiology of the immune defect, immunodeficient children with lymphoma have a worse prognosis than does the general population with non-Hodgkin lymphoma (NHL).[1][2][3][4] One potential exception is the more indolent low-grade lymphomas (e.g., mucosa-associated lymphoid tissue [MALT] lymphomas), which have developed in patients with common variable immunodeficiency or other immunodeficient states.[5][6] If the disease is localized and amenable to complete surgical resection and/or radiation therapy, the outcome is quite favorable; however, most NHL in this population is high-stage (stage III or IV) and requires systemic cytotoxic therapy. These patients usually tolerate cytotoxic therapy poorly, with increased morbidity and mortality due to increased infectious complications and often increased end-organ toxicities. (Refer to the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information about MALT lymphomas.)

In the era of highly active antiretroviral therapy, children with human immunodeficiency virus and NHL should be treated with standard chemotherapy regimens for NHL, but careful attention to prophylaxis against and early detection of infection is warranted.[1][7] Patients with primary immunodeficiency can achieve complete and durable remissions with standard chemotherapy regimens for NHL, though again, toxicity is increased.[2] Recurrences in these patients are common and may not represent the same clonal disease.[8] Immunologic correction through allogeneic stem cell transplantation is often required to prevent recurrences. Patients with DNA repair defects (e.g., ataxia-telangiectasia) are particularly difficult to treat.[4][9] Cytotoxic agents produce much more toxicity and greatly increase the risk of secondary malignancies in these patients. Survival is rare at 5 years postdiagnosis.

In posttransplant lymphoproliferative disease (PTLD), first-line therapy is the reduction of immunosuppression as can be tolerated.[3][10] Rituximab, an anti-CD20 antibody, has been used with some success, but data for its use in children are sparse. Rituximab plus low-intensity chemotherapy may also be effective, even in posttransplant lymphoproliferative diseases with the t(8;14) Burkitt lymphoma marker.[11][Level of evidence: 3iiDiii] Another larger study suggested that more conventional lymphoma therapy is effective for PTLD with c-myc translocations and Burkitt histology.[12][Level of evidence: 3iiDiii] Patients with T-cell or Hodgkin-like PTLD are usually treated with standard lymphoma-specific chemotherapy regimens.[13][14][15][16]

Standard Treatment Options

  • Standard chemotherapy regimens for specific histology.[1][2][8][12][17]
  • Low-dose chemotherapy.[3][11][Level of evidence: 3iiDiii]

Treatment Options Under Clinical Evaluation

The following is an example of a national or international clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

  • Adoptive immunotherapy with either donor lymphocytes or ex vivo–generated Epstein-Barr virus–specific cytotoxic T-cells have been effective in treating PTLD following blood or bone marrow transplant.[18][19] Though this approach has been demonstrated to be feasible in patients with PTLD following solid organ transplant, it has not been demonstrated to be as effective or practical.

References:

  1. McClain KL, Joshi VV, Murphy SB: Cancers in children with HIV infection. Hematol Oncol Clin North Am 10 (5): 1189-201, 1996.

  2. Seidemann K, Tiemann M, Henze G, et al.: Therapy for non-Hodgkin lymphoma in children with primary immunodeficiency: analysis of 19 patients from the BFM trials. Med Pediatr Oncol 33 (6): 536-44, 1999.

  3. Gross TG, Bucuvalas JC, Park JR, et al.: Low-dose chemotherapy for Epstein-Barr virus-positive post-transplantation lymphoproliferative disease in children after solid organ transplantation. J Clin Oncol 23 (27): 6481-8, 2005.

  4. Dembowska-Baginska B, Perek D, Brozyna A, et al.: Non-Hodgkin lymphoma (NHL) in children with Nijmegen Breakage syndrome (NBS). Pediatr Blood Cancer 52 (2): 186-90, 2009.

  5. Aghamohammadi A, Parvaneh N, Tirgari F, et al.: Lymphoma of mucosa-associated lymphoid tissue in common variable immunodeficiency. Leuk Lymphoma 47 (2): 343-6, 2006.

  6. Ohno Y, Kosaka T, Muraoka I, et al.: Remission of primary low-grade gastric lymphomas of the mucosa-associated lymphoid tissue type in immunocompromised pediatric patients. World J Gastroenterol 12 (16): 2625-8, 2006.

  7. Kirk O, Pedersen C, Cozzi-Lepri A, et al.: Non-Hodgkin lymphoma in HIV-infected patients in the era of highly active antiretroviral therapy. Blood 98 (12): 3406-12, 2001.

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  19. Rooney CM, Smith CA, Ng CY, et al.: Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood 92 (5): 1549-55, 1998.


This information is provided by the National Cancer Institute.

This information was last updated on November 26, 2012.

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