Lymphomas (Non-Hodgkin's)

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Lymphomas (Non-Hodgkin's)

WHAT ARE NON-HODGKIN'S LYMPHOMAS?

Lymphomas

Lymphomas are malignancies of the lymph system that are generally subdivided into two groups, Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). [ See Box The Lymphatic System.]

Hodgkin's disease accounts for about 15% of all lymphomas and is discussed in another report. [ See Report # 83, Hodgkin's Disease. ]

THE LYMPHATIC SYSTEM

Lymphomas, such as non-Hodgkin's lymphomas and Hodgkin's disease, represent tumors of the lymphatic system. This system is a network of organs, ducts, and nodes that interacts with the blood's circulatory system to transport a watery clear fluid called lymph throughout the body. The lymphatic system produces lymphocytes, important immune factors, and so is a major line of defense against infectious organisms. This system also restores 60% of the fluid that leaks out from blood capillaries back into circulation, and its ducts provide transportation for fats, proteins, and other substances that it collects from the body's tissues.

Lymphocytes

The lymphatic system is involved in the production and transport of lymphocytes, white blood cells that are a primary component of the immune system. Among other vital functions, certain lymphocytes are responsible for producing antibodies, factors that can target and attack specific foreign agents (antigens). To understand the lymphatic system, it is helpful to track part of the life cycle of these lymphocytes:

Lymphocytes develop in the thymus gland or bone marrow and are therefore categorized as either B-cells (bone marrow-derived cells) or T-cells (thymus gland-derived cells).
B-cells complete their structural growth and definition (known as differentiation) and mature in the bone marrow.
T-cells also start out in the bone marrow but differentiate and mature in the thymus gland , located beneath the breastbone. This small gland is active mostly in the fetal stage through the first ten years of life, after which it atrophies (shrinks).
B-cell and T-cell lymphocytes leave these organs through the blood stream, which eventually branches out into the tiny blood vessels called capillaries.
Some lymphocytes, along with fluid, proteins, and other substances, migrate out of the capillaries into the surrounding tissues. A proportion of these lymphocytes and other substances, along with fluid, then enter the lymphatic vessels .
Lymphatic vessels begin as tiny, blind-ended tubes and lead to larger lymphatic ducts and branches until they drain into two ducts in the neck, where the fluid re-enters the blood stream.
Along the way, the fluid passes through lymph nodes , which are oval structures composed of lymph vessels, connective tissue, and white blood cells. Here, the lymphocytes either are filtered out or are added to the contents of the node.

Lymph Nodes

The lymph node provides an environment where lymphocytes can receive their initial exposure to foreign agents (antigens) such as bacteria or other microorganisms, which then activates the lymphocytes to perform their immune functions. The size of a lymph node varies generally from that of a pinhead to a bean. Most nodes are in clusters located throughout the system; important node clusters are found in the neck, lower arm, armpit, and groin.

Other Structures in the Lymphatic System

The tonsils and adenoids are secondary organs that are composed of masses of lymph tissue, which also play a role in the lymphatic system. The spleen is another important organ that processes lymphocytes from incoming blood.

Locations of Non-Hodgkin's Lymphomas

Non-Hodgkin's lymphomas occur most often in lymph nodes in the chest, neck, abdomen (called the mesenteric nodes), tonsils, and the skin. NHLs may also develop in sites other than lymph nodes. In Americans this occurs most commonly in the digestive tract, although primary lymphomas of the central nervous system are on the rise. In Europeans, lymphomas outside the lymph nodes are more likely to develop around the tonsils.

Cells Affected in NHL

About 85% of non-Hodgkin's lymphomas arise in B-cells; the rest occur in T-cells. Activation of a gene called BCL-2 is believed to be partly responsible for many B-cell lymphomas. This defect prevents apoptosis in the lymphoma cells (a natural process whereby cells self-destruct).

Non-Hodgkin's Lymphomas Categories

There are more than 20 distinct types of non-Hodgkin's lymphomas, and even experts disagree about the exact groupings. Lymphomas are categorized in a number of ways.

Classification by Cell Type, Appearance, and Genetic Make-up: The REAL System. Different classification systems for lymphoma have been proposed. The current classification system used in this report is called REAL (Revised European-American Lymphoma Classification). It classifies all lymphomas by appearance, cell type, and genetic make-up:

Non-Hodgkin's lymphomas are first grouped into B-cell or T-cell categories.
They are then further categorized by whether the B- and T-cell lymphomas malignancies derived from immature ( precursor) cells or mature ( peripheral) cells.
The peripheral B- and T-cells are then further classified by their appearance, genetic make-up, and specific chemical "markers" that further identify them.

It should be noted that T-cell lymphomas, Hodgkin's disease, and certain leukemias and aggressive lymphomas are covered in the REAL classification but require discussions beyond the scope of this report are not referred to in the table below.

Groups by Slow or Fast Growth. Each non-Hodgkin's lymphoma is further defined by how aggressive it is:

Indolent (slow-growing).
Aggressive (fast-growing).

Groups by Properties. Lymphomas are also grouped by certain properties:

Size (large versus small).
Shape (round versus irregular).
Whether they are or resemble blood plasma cells.
Whether they are follicular (organized in round clusters) or diffuse (spread evenly throughout the lymph node).

Staging. Staging the disease is the next important step in classifying lymphomas. The stage (I through IV) of an NHL is determined by the number of tumors and whether they are still localized or have spread beyond the lymph node. In general, the higher the stage, the poorer the outcome, but, again, other factors are important for a precise prognosis.

Classifications of B-cell Lymphomas

Indolent (Slow-Growing) Lymphomas (also referred to as Low-Grade):

Follicular lymphomas. Follicular small cleaved cell lymphoma (grade 1) and follicular mixed small and large cell lymphoma (grade II). FLs account for 70% of indolent tumors and 30% of all NHLs in industrialized countries.

Lymphoplasmacytoid/Waldenstrom's macroglobulinemia. Often found in bone marrow, lymph nodes, and spleen. Can cause blood to become viscous and "sticky."

Marginal zone lymphomas (MZL). MZLs often occur as a result of a preexisting disorder, such as hepatitis C, infection in the stomach ( H. pylori ), or autoimmune disorder (eg, Sjögren's disease in the salivary glands or Hashimoto's thyroiditis in the thyroid gland). They may be classified s follows:

Monocytoid B-cell lymphoma (involves only lymph nodes).
Splenic marginal zone lymphoma (affects the spleen, which becomes greatly enlarged, and also blood and bone marrow).
Mucosa-associated lymphoid tissue lymphoma (MALT) (involves other sites, usually the gastrointestinal tract, thyroid, lung, breast, or skin). There is some controversy over whether MALT is a variation of MZL or a distinct entity, which is more suitably classified as a separate low-grade lymphoma. At this time, it is classified as an MZL.

Aggressive Lymphomas (also referred to as Intermediate- and High-Grade)

Diffuse large-cell lymphomas (DL). DLs are the most common NHLs, comprising about 30% of all cases. Subtypes include the following:

Primary mediastinal large B-cell lymphoma.
Follicular large cell lymphoma.
Anaplastic large cell lymphoma.
Others include some T-cell lymphomas. (T-cell lymphomas are not covered in this report.)

In about 40% of cases, these lymphomas appear in areas outside lymph nodes, including digestive tract, skin, bone, thyroid, and testes.

Burkitt's lymphoma/diffuse, small noncleaved cell lymphoma . This is the most common childhood NHL. In African children, it often involves facial bones and is associated with Epstein-Barr infection.

Mantle cell lymphoma. Mantle cell lymphomas are found in lymph nodes, the spleen, bone marrow, blood, and sometimes the gastrointestinal system (lymphomatous polyposis). It is similar to indolent lymphomas at the time of diagnosis but it is more aggressive.

Lymphoblastic lymphoma. This lymphoma often occurs in young people. Associated with large mediastinal mass (occurring in chest cavity between the lungs) and carries a high risk for spreading to bone marrow and central nervous system.

WHAT ARE THE RISK FACTORS FOR NON-HODGKIN'S LYMPHOMAS?

Non-Hodgkin's lymphoma (NHL) is now the sixth most common malignancy in America. According to estimates, 53,900 cases of non-Hodgkin's lymphomas will develop in 2002. Between 1973 and 1997, the incidence rose by 80%. An annual increase of 4.2% has been reported in Europe, nearly all in middle- to older-aged individuals. The reason for these dramatic increases is unknown. Experts are looking at many factors that may contribute to this increase. A 2001 European study reported that the increase in incidence appeared to be mainly in high-grade lymphomas and tended to occur in different locations depending on gender (more in the respiratory tract in men and in the abdominal region in women). Researchers in the study suggest that the initial locations of the lymphomas may be due to different risk factors.

Gender and Age

In general, NHL is more prevalent in men than women and can develop in people at all ages, including children, although the peak onset is between ages 45 and 60.

Ethnic Differences

Overall, the risk is slightly higher in Caucasians than in African Americans, although among young adults there appears to be no ethnic difference. However, risk factors among men and women and African Americans and Caucasians may vary by lymphoma subtype, according to a major 2000 study. For example, follicular lymphomas were significantly higher in Caucasians than in African Americans and there was little gender difference. High-grade lymphomas were the most rapidly increasing type, particularly among men, with follicular lymphomas increasing most rapidly in African American men. Other studies have also reported ethnic differences by specific lymphoma subtypes.

Family History

Risk in a sibling of a person with the disease is more than two times higher than in the general population. Studies suggest, however, that such family clusters are more likely to be due to environmental factors than genetic factors.

Dietary Factors

A number of studies have observed an association between an increased risk for non-Hodgkin's lymphomas and high consumption of red meat (beef, pork, and lamb) and possibly with transfatty-acids (hydrogenated polyunsaturated fats, which are contained in hard margarines and commercial baked goods and fast foods). There appears to be no higher risk with natural polyunsaturated fats (found in most vegetable and fish oils), and, in fact, fish may be protective. (Interestingly, in one major study, milk, which, except for skim, contains animal fat, appeared to confer protection.)

One major study observed a reduction in risk with high intake of vegetables; another found no protection from vegetables but did with diets rich in fruit. Vitamin supplements have no effect on NHL.

Despite these kinds of reports, the influence of diet on the development of non-Hodgkin's lymphomas remains speculative.

Infections

Viruses or other microorganisms also play a role in some lymphomas. A number are being investigated:

Burkitt's disease occurs most often in African children living in the lowlands and is associated with Epstein-Barr viral infections (the cause of mononucleosis and also a risk factor Hodgkin's disease).
Adult T-cell leukemia-lymphoma, which appears to be caused by a virus known as HTLV-I, has been found in southwestern Japan, the Caribbean, and southeastern United States.
Studies are reporting a higher prevalence of hepatitis C and B in some patients with lymphomas, although hepatitis does not appear to play a major role in triggering lymphoma.
People who have gastritis (stomach inflammation) due to Helicobacter pylori or Helicobacter heilmannii bacterial infections) are at increased risk for mucosa-associated lymphoid tissue lymphomas (MALT). (In some patients who have this lymphoma in an early stage and have evidence of either infection, the use of antibiotics that eliminate the bacteria may result in complete remission of the lymphoma.)
Borrelia burgdorferi , the spirochete (corkscrew-shaped bacterium) that causes Lyme disease has been associated with primary B-cell lymphoma (which mostly occurs on legs and only infrequently spreads to areas outside the skin.)

Disorders of the Immune System

Patients with diseases that affect the immune system may be at higher risk for lymphomas.

Patients with a history of autoimmune diseases, including rheumatoid arthritis, Hashimoto's thyroiditis, Crohn's disease, and Sjögren's syndrome are at a slightly increased risk for certain NHLs, such as marginal zone lymphomas.
AIDS and HIV-positive patients are at higher risk for NHL, and the disease is more likely to be widespread than in patients without the disease. Non-Burkitt's lymphoma is seen most often in AIDS patients. Although these patients have had a very poor prognosis, advances in anti-viral therapy for HIV now allow better management of NHL with some success in achieving favorable outcomes.
People who have organ transplants are at higher risk, probably due to multiple factors, including the drugs used to suppress the immune system and the transplanted organ itself.
at higher risk are those born with certain immunodeficiency syndromes, such as Chediak-Higashi syndrome, ataxia-telangiectasia, B-cell lymphoproliferative syndrome, Bruton agammaglobulinemia, common variable immunodeficiency, and Wiskott-Aldrich syndrome.

Industrial Chemicals and other Environmental Risk Factors

Overexposure to a number of industrial and agricultural chemicals have sometimes been linked to an increased risk for lymphomas. Studies report the following:

Dioxin is a possible suspect as a chemical risk factor for NHL. A 2000 study, for example, found an increased incidence in people who worked around solid waste incinerators and were exposed to dioxin. And, a population study in Italy reported the highest risk with exposure to dioxin after 15 years.
Another study suggested that white spirits, thinners, phenoxy herbicides, wood preservative, aviation gasoline, plastic, and rubber chemicals were associated with a higher risk for lymphomas. Specifically, painters and lumberjacks had a higher risk for NHL, while office and house workers had a lower risk, as did farmers.
In a 2001 study, typesetters had a higher risk for NHL, which warrants further research.
Some studies have found a higher risk for farmers, perhaps because of exposure to dioxins or other chemicals in pesticides. In spite of previous concerns, there is no consistent evidence that hair dye increases the risk for lymphomas. (Some have found an association with long duration and early use of dark hair dyes.)

Risk Factors during and after Pregnancy for the Child

One study observed a higher risk for lymphomas in children with a low weight at birth or with mothers who were heavy smokers during pregnancy. (Breast feeding for more than six months, on the other hand, may offer some protection.)

WHAT ARE THE SYMPTOMS OF LYMPHOMAS?

Symptoms in or around the Nodes

The most common first sign of lymphomas is painless enlargement of one or more lymph node, usually in the neck, armpits, or groin. Patients should see their doctors if these symptoms do not go away within two to three weeks.

Systemic and B Symptoms

Lymphomas sometimes cause systemic symptoms, which are those that affect the whole body, rather than just the specific location of the disease. Some systemic symptoms are referred to as B symptoms. Patients who have B symptoms have a more severe condition than asymptomatic patients with the same cancer stage or tumor location or size.

B systemic symptoms include the following:

Drenching night sweats and weight loss (B symptoms).
Fever is often present, which may occur only at night in episodes that last several days followed by periods of no fever (B symptoms).

Other systemic symptoms include:

Itching all over the body; it is caused by the release of histamines, substances ordinarily triggered by an allergic response. In the case of NHL, this is due to abnormalities in the immune system. Although this is a systemic symptom, it is not usually considered a "B" symptom if other systemic symptoms are not also present.
In late stages, some patients develop a skin rash.
Tumor masses in the chest can cause coughing or breathlessness.
Lymphomas in the stomach can cause nausea and vomiting.

HOW ARE NON-HODGKIN'S LYMPHOMAS DIAGNOSED?

The physician will take a medical history and perform a physical examination to detect any node enlargements. If these simple procedures point to lymphomas, additional tests will be needed either to rule out other diseases or to confirm the diagnosis of lymphomas and determine the extent of the disease. It is sometimes reasonable to wait a period of time for the swelling and symptoms to recede before deciding that additional testing is necessary, since the swelling may be due to a temporary infection. However, it should be noted that in some cases, particularly in follicular, small cleaved cell lymphoma (the most common NHL), that the lymphoma waxes and wanes, so lymph nodes should still be checked periodically to be sure there is no recurrence of swelling.

Ruling Out Other Conditions

Many patients seek medical help for abnormally swollen lymph nodes, but very few turn out to be malignant.

Infections. In the great majority of cases, the cause is an infection:

For example, although Hodgkin's often first appears in the neck, enlarged lymph nodes in that location are much more likely to be a sign of a strep or other throat infections.
In young people, infectious mononucleosis (caused by the Epstein Barr virus) is a common cause of swollen nodes.
The patient should report any recent travel, particularly to countries with a high incidence of tropical diseases, which can trigger similar symptoms.
Other infections that cause similar symptoms include cat scratch fever, Lyme or other tick-borne disease, HIV, tularemia, tuberculosis, syphilis, herpes simplex virus, cytomegalovirus, and hepatitis.
Hodgkin's Disease. Although both Hodgkin's disease and non-Hodgkin's lymphomas are malignancies of the lymph nodes, they can usually be distinguished by certain characteristics. [ See Table Comparison Between Hodgkin's Disease and Non-Hodgkin's Lymphomas.] It is extremely important to differentiate between Hodgkin's lymphomas and non-Hodgkin's lymphomas, since the treatments for these two conditions differ. In particular, a subtype of lymphoma called anaplastic large-cell lymphoma (ALCL) might be confused with Hodgkin's disease under some circumstances. [For more information, see Report #84 Non-Hodgkin's Lymphomas.]

Comparison Between Hodgkin's Disease and Non-Hodgkin's Lymphomas
	Hodgkin's Disease	Non-Hodgkin's Lymphomas
Age and Preelance	Average age is 27.7 with two age peaks, the major one between 15 and 24 with a lesser peak after age 55. It is less common than NHL.	Average age is about 67. It is more common than HD.
Location	In both malignancies, the disease occurs most of in lymph nodes above the collar bone. However, in HD it is more likely to also appear in the chest cavity between the lungs (the mediastinum), particularly in younger patients. Only about 15% to 20% of cases are found in areas below the diaphragm. Disease occurs outside the nodes in about 4% of cases.	In both malignancies, the disease occurs most often in lymph nodes above the collar bone. In NHL, however, it is also more likely to appear in the nodes in the abdomen (called the mesenteric nodes). The disease occurs in the chest cavitiy in less than 40% of patients. (An exception, lymphoblastic lymphoma, which is seen most often in young people, is likely to first appear in the chest.) Disease occurs outside the nodes in about 23% of patients. Slow-growing lymphomas are common in the liver and bone marrow.
Symptoms	More likely than NHL (40%) to have systemic symptoms (such as fever and night sweats.) at the time of diagnosis.	Less like to have systemic symptoms (27%) at the time of diagnosis.
Progression	Less like likely than NHL to be diagnosed in stage IV (10%). Hodgkin's disease usually progresses in an orderly way from one lymph node region to the next. This process may be slow, particularly in younger people, or very aggressive. The disease typically spreads downward from the initial site. If it spreads below the diaphragm, it usually reaches the spleen first; the disease then may spread to the liver and bone marrow. If the disease starts in the nodes in the middle of the chest, it may spread outward to the chest wall and areas around the heart and lungs.	More likely than HD to be diagnosed in stage IV (36%). The lymphomas are less predictable in their course than Hodgkin's disease and they are more apt to spread.

Other Cancers or Serious Conditions in the Lymphatic System. Other cancers that can travel to lymph nodes include breast cancer and leukemia. Very serious causes of enlarged lymph nodes include disorders of the lymph system that include Castleman's disease, lymphomatoid granulomatosis, and angioimmunoblastic lymphadenopathy. These lymph system disorders, although noncancerous, involve abnormal lymph cells. They are often fatal and can be very difficult to distinguish from lymphomas. [ See Report #83, Hodgkin's Disease or Report #86, Acute Lymphocytic Leukemia. ]

Exposure to Chemicals. Exposure to industrial chemicals or certain medications, such as phenytoin (Dilantin), may cause enlarged nodes. In addition, other drugs, such as cephalosporins, penicillins, or sulfonamides can cause enlarged nodes and other symptoms, including fever and rash, that may resemble lymphoma.

Physical Examination

The physician will examine not only the affected lymph nodes but also the surrounding tissues and other lymph node areas for signs of infection, skin injuries, or tumors. The consistency of the node is sometimes indicative of certain conditions: a stony hard node is often a sign of cancer, usually one that has metastasized; a firm rubbery node may indicate lymphoma; soft nodes suggest infection or inflammatory conditions.

Blood Tests

Blood tests help rule out infection and other disease. In a patient already diagnosed with lymphomas, blood tests that measure the enzyme lactate dehydrogenase are important in determining the prognosis; elevated levels indicate bulkier tumors. The presence of anemia may indicate specific NHLs, such as diffuse, small lymphocytic lymphoma.

Biopsy

A biopsy is the most important test for diagnosing lymphomas and can be used to tell the difference between non-Hodgkin's versus Hodgkin's disease. A biopsy has risks, some serious, and should only be performed by a qualified and experienced physician. Sometimes a physician may choose to wait and observe the involved lymph nodes, which will usually regress on their own if a temporary infection is causing the enlargement. (It should be noted, however, that some lymphomas may regress and appear to be benign, only to reappear at a later time.)

The Procedure. The physician removes the node and checks the surrounding areas. The tissue in the node is then examined under a microscope for signs of infection and abnormalities indicating cancer or other conditions.

Results. Even if biopsies do not turn up cellular abnormalities, disease may still be present in some cases. The physician should continue to observe the patient until swelling or other signs of disease are gone. Biopsied tissue samples should be frozen in case special tests are later required. Such tests may include detection of particular antibodies, genetic and immune factors, and certain markers (substances that are indicative of disease) located on the surface of the cells. If lymphoma has been diagnosed, the tissue will be examined for its histology, the cellular structures that will determine the lymphoma type. Biopsies of bone marrow may be performed to find out if the disease has spread.

Imaging Techniques

Chest X-Ray. A chest x-ray allows a view of the lymph nodes in the chest and neck area. It is particularly useful in detecting Hodgkin's disease, which usually starts and is a useful step for detection of enlarged lymph nodes.

Computer Tomography. Computed tomography (CT) scans are more accurate and can detect abnormalities in the chest and neck area, as well as revealing the extent of the cancer and whether it has spread outside the nodes. In one study, CT scans provided evidence of disease in 15% of sites that were considered normal on chest x-ray. A CT scan also is important in detecting lymphomas in the abdominal and pelvic areas if a chest x-ray is normal and lymphomas are still suspected.

Lymphangiography. Lymphangiography is an x-ray of the lymph glands and vessels after an injection of a dye. It provides additional information on lower parts of the body and is a good complement to CT scans if the latter does not reveal abnormal lymph nodes but they are still suspected. On its own, however, lymphangiography misses cancer in 20% of cases. There is a slight risk that the dye will affect the lungs, so this test should not be used in patients with severe lung disease. Lymphangiography is not commonly used for staging non-Hodgkin's lymphomas.

Other Advanced Imaging Techniques. A number of advanced imaging techniques, including gallium scintigraphy and positron emission tomography (PET) are proving to be very helpful. Special PET imaging techniques known as FDG/PET scans may be more accurate than CT scans for staging lymphomas and more accurate than gallium scintigraphy in identifying the disease in the bone. They are also very accurate for evaluating the success of chemotherapy in patients who have been treated for lymphomas and for detecting relapsing lymphoma. Gallium scans are also useful for evaluating the success of chemotherapy. Magnetic resonance imaging (MRI) may be used to detect the spread of the disease to the brain, spine, chest, pelvic, and abdomen. How additional tests such as MRI and PET scanning will impact the management of patients with lymphomas, however, is still unknown.

DNA Tests

Tests of the lymphoma's DNA are in use or being developed to detect particular genetic abnormalities that help determine outlook and may eventually lead to new treatments. Examples of such abnormal genetic arrangements are those that affect normal cell death, resist chemotherapy, or trigger aggressive cancer growth.

Biologic Markers

Biologic markers, called biomarkers for short, are high levels of substances that are released by tumors and indicate the level of cancer activity. Biomarkers can be found in sputum, blood, and tissue samples. Biomarkers can be enzymes, hormones, amino-acid compounds, antigens (identified by antibodies that specifically target them), growth factors, and other chemicals. Some under investigation include the following:

CD44 is a molecule that binds to the surface of cells and may be involved in metastasis. High levels of this molecule may suggest a more aggressive disease.

BCL-6 is a cancer gene implicated in diffuse large B-cell lymphoma. High levels of this gene in these patients indicate a better outlook after treatment.

HOW SERIOUS ARE NON-HODGKIN'S LYMPHOMAS?

General Indicators for Prognosis

Five-year survival rates for NHL range from 20% to 95% depending on the lymphoma type, stage, and other variables. Because the outlook varies so widely, making a definite prognosis is very difficult. For example, indolent lymphomas are difficult to cure but are very slow growing, so patients can live many years. Aggressive lymphomas can cause death rapidly but they are also often curable. It should be noted that the therapies for NHL carry some serious risks, which are discussed under specific treatments.

Outlook for Indolent (Low-Grade) Lymphomas

Follicular lymphomas, the most common indolent NHLs, are potentially curable in early stages I and II. Typically, however, they are diagnosed at advanced stages, often occurring in the lymph nodes, spleen, and bone marrow. In such cases, they are hard to cure. Even if treatment achieves a response, the tumors almost always recur. Even after relapse, however, the tumors are retreatable if they are still indolent (very slow-growing). In general, the average survival rate for indolent lymphomas is 10 years. In many older patients (the most common age group), treatment may not even be necessary for indolent lymphomas diagnosed in advanced stages. Predicting outcome for indolent follicular lymphomas with assurance is more difficult than for aggressive lymphomas.

Factors for Predicting Outlook in Indolent Lymphomas. Six risk factors are proving to be useful for predicting outlook:

Being male.
Being older.
Having stage III or IV disease.
Elevated levels of the enzyme lactate dehydrogenase (LDH).
The presence of "B" symptoms. [ See What Are the Symptoms of Non-Hodgkin's Lymphomas?]
Erythrocyte sedimentation rate over 30.

Patients with a good chance for a positive outcome (10-year survival of 65%) have one or none of these factors; those with intermediate risk (23%) have two factors, and those likely to have a poor outcome (11%) have three to five factors. MALT lymphomas generally have a good prognosis. Primary gastric lymphomas have a three year survival rate of 89%.

Outlook for Aggressive (Intermediate- to High-Grade) Lymphomas

Diffuse large-cell lymphomas, the most common aggressive non-Hodgkin's lymphomas, while fatal if not treated, are often curable with intensive chemotherapy combinations. Five year survival averages 50% to 60%. If relapse occurs after chemotherapy, it usually does so within two years.

Most other aggressive lymphomas respond to aggressive chemotherapy. Mantle cell lymphoma is less responsive to chemotherapy, and average survival time is three to five years.

Factors for Predicting Outlook in Aggressive Lymphomas: A scoring system called the International Prognostic Index has proved to be fairly accurate for predicting outcome in patients with most aggressive B-cell lymphomas. It uses five risk factors to help predict whether the disease will be aggressive:

Being older (over 60 years old).
Having a disseminated tumor (stage III or IV).
Disease that has spread to more than one site beyond the lymph nodes.
A poor performance status.
Having elevated levels of LDH.

Having one or none of these risk factors indicates the best outlook; two factors indicate a low to intermediate likelihood of a poor outlook; three factors predict an intermediate to high likelihood of poor outlooks; and four or five factors pose the highest likelihood of poor survival.

Relapsed Lymphomas

Although relapsed low-grade lymphomas can be treated, even repeatedly, they become more aggressive over time. Patients who relapse from intermediate- and high-grade lymphomas rarely respond to standard treatments, but experimental approaches are showing promise for even these serious situations.

Risk Factors for Central Nervous System Involvement

Lymphoma can spread to the central nervous system or it can appear there first, which is referred to as primary CNS lymphomas (PCNSL). It is a very serious event, particularly if it occurs at relapse. Certain patients with Burkitt's lymphoma are at high risk for CNS relapse. A subset of patients with large-cell lymphomas is also at risk for CNS involvement. Previously, it was believed that this subset consisted of those with disease in the bone marrow, testicles, or facial sinuses. Newer evidence suggests, however, disease in one or more sites outside the lymph nodes along with increased levels of LDH are also risk factors for possible spread of lymphoma to the CNS.

WHAT ARE THE GENERAL GUIDELINES FOR STAGING, CLASSIFYING, AND TREATING LYMPHOMAS?

General Approach for Treating Non-Hodgkin's Lymphoma

Treatment for non-Hodgkin's lymphoma is highly specific for each patient and is determined by the classification and includes following factors:

Stage.
Grade.
Histologic type (its cellular structure).
Location.
Other factors, such as blood levels of lactate dehydrogenase.

Treatment for lymphomas has been primarily dependent on chemotherapy (particularly intensive regimens using several drugs) or a combination of chemotherapy and radiation. For advanced or refractory lymphomas and for relapse, patients may undergo bone marrow or stem-cell transplantation. New treatments, especially those known as biological response modifier (BRM) therapies, are showing promise. [As a reference for particular B-cell lymphomas, see box Classifications of B-cell Lymphomas.]

Assessing Treatment Success

In assessing the success of a clinical trial, experts often refer to the tumor response. A complete response, for example, means that there is no longer any evidence at all of the disease by examination, blood tests, or x-ray studies. It does not necessarily, however, mean that the disease is cured. It may still recur later on.

In judging the success of a treatment for NHL, the most important criteria are overall survival and the duration of time until the disease progresses or the patients dies.

Early Stage Lymphomas (Stage I and Stage II)

In Stage I, lymphoma is found in only one lymph node area or in only one area or organ outside the lymph nodes. Either of the following indicates stage II: lymphoma is found in two or more lymph node areas on the same side of the diaphragm; or lymphoma is found in only one area or organ outside the lymph nodes and in the lymph nodes around it. Other lymph node areas on the same side of the diaphragm may also have lymphoma.

Early Stage Indolent (Low-Grade) Lymphoma. General treatment options. 1. Radiation therapy to local areas can achieve a cure in 40% to 50% of patients. 2. Chemotherapy or watchful waiting in some circumstances. (Patients who choose watchful waiting must be aware of signs and conditions indicating the need for treatment. These include B symptoms, endangered organs, massive bulky tumors, or a steady progression that lasts at least six months.) 3. Radiation plus chemotherapy is under investigation.

The following are treatment options for some specific low-grade lymphomas:

Mucosa-associated lymphoid tissue lymphoma (MALT). When disease is in the stomach (gastric MALT) and the patient is infected with H. pylori bacteria, antibiotics can cause regression in a significant number of stage 1 patients. In patients where antibiotics fail, (or are not felt to be appropriate), radiation alone can achieve significant cure rates in certain patients. Surgery with or without radiation, or chemotherapy with or without radiation are possible options. Treatments options for patients with MALT localized in other sites depend on the location of the specific disease, ranging from radiation to chemotherapy to biologic therapies, such as interferon.
Primary gastric lymphoma (indolent). (Located only in the stomach, small intestine, or other nearby regions.) Radiation. Surgery being reconsidered since it seems to offer no advantage.

Early Stage Aggressive (Intermediate- to High-Grade) Lymphomas. Treatment options: 1. Chemotherapy alone. 2. Combinations of chemotherapy (usually CHOP) plus radiation therapy (combined modality). 3. Radiation alone (rarely). 4. Chemotherapy alone or with surgery for lymphoma in the gastrointestinal region. 5. A clinical trial of high dose chemotherapy and bone marrow or stem cell transplantation. (It is not yet clear if there is an advantage to these treatments over high-dose chemotherapy.) 6. Clinical trial of biologic therapies (eg, rituximab) with or without chemotherapy (eg, CHOP).

Advanced Stage Lymphomas (Stage III and IV)

In stage III, lymphoma is found in lymph node areas on both sides of the diaphragm (for instance, in both the chest and the abdomen). The lymphoma may also have spread to the spleen. In Stage IV, lymphoma has spread via the bloodstream to organs outside the lymph system, such as the bone marrow or brain. Lymphoma cells may or may not be in the lymph nodes near these organs.

Advanced Stage Indolent (Low-Grade Lymphomas). Treatment options: Treatment options are controversial because of the low-cure rate and yet slow-growing nature of these lymphomas. Patients without symptoms are often managed by watchful waiting, in which the disease is monitored closely for development of symptoms or bulky tumor masses, particularly if they threaten major organs. At such times, treatment is started. 1. Chemotherapy combinations (CHOP, CVP, C[M]OPP). 2. Nucleoside analogs (eg, fludarabine) alone or with chemotherapy. 3. Oral alkylating chemotherapy agents (eg, cyclophosphamide, chlorambucil) with or without steroids. 4. Chemotherapy (CHOP) with interferon. 5. Monoclonal antibodies alone or in combinations with CHOP or nucleoside analogs. 6. Clinical trials: Intensive chemotherapy and radiation followed by bone marrow or stem cell transplantation; antisense RNA.

Advanced Stage Aggressive (Intermediate- to High-Grade) Lymphomas. Treatment options. 1. Doxorubicin-based combination chemotherapy (CHOP preferred at this time). 2. Chemotherapy plus radiation therapy. 3. Clinical trials for patients at high risk for relapse: high dose chemotherapy and bone marrow or stem cell transplantation; biologic therapies (eg, monoclonal antibodies) with or without chemotherapy (eg, CHOP). 4. Treatments to prevent disease from spreading to central nervous system in high-risk patients (those with more than one diseased site outside the lymph nodes and elevated levels of the enzyme lactate dehydrogenase are sometimes considered for this approach).

Relapsed or Refractory (Nonresponsive to Treatment) Non-Hodgkin's Lymphoma

Between 40% and 60% of patients either fail to respond to initial therapy or relapse afterward.

Indolent-Lymphomas Relapses. Treatment options: Successful treatment is often possible. Older patients may choose watchful waiting. 1. Radiation alone or with chemotherapy. 2. Chemotherapy (single agents of combinations). 3. High-dose chemotherapy with autologous stem-cell transplant. 4. Clinical trials: monoclonal antibodies, nucleoside analogues alone or in combination with other agents, stem-cell transplantation followed by biologic therapies.

Aggressive Lymphomas Relapse. Treatment options: 1. Bone marrow or peripheral stem cell transplantation. 2. Clinical trials: continuous infusion chemotherapy, biologic therapies (monoclonal antibodies) alone or in combination with transplantation; bone marrow transplantation with radiation.

Lymphoma Restricted to the Central Nervous System

Treatment options: 1. High-dose methotrexate alone or in combination with radiation. 2. Corticosteroids and radiation. 3. Clinical trials: biologic therapies, eg, rituximab or interferon alpha administered directly into the spinal fluid (intrathecal administration) for meningitis related to central nervous system lymphoma.

WHAT ARE THE CHEMOTHERAPY DRUG TREATMENTS FOR LYMPHOMAS?

Chemotherapy plays a role in the treatment of nearly all lymphoma patients and has achieved remarkable results, even some in late stages. It employs cell-killing (cytotoxic) drugs to destroy cancer cells throughout the body, so it is referred to as systemic therapy . Studies are now showing that chemotherapy as sole treatment is adequate for most children and young adults in early and perhaps in many advanced stages. (Radiation has been commonly used for these patients but carries particular dangers for children.) It should be pointed out that when a study on a drug reports a complete response rate this does not mean a cure, only that the drug has caused the tumor to completely recede.

Chemotherapy Administration

A chemotherapy cycle is usually 21 to 28 days and consists of several doses of drug administration followed by a period of rest. Cytotoxic agents may be given orally or as injections. For cancer that has spread to the brain, chemotherapy is injected into the spinal fluid (intrathecal chemotherapy). Intrathecal chemotherapy is also used as a preventive measure in patients at high risk for central nervous system involvement. Treatment may be administered at a medical center or a physician's office. Some patients receiving chemotherapy need to remain in the hospital for several days so the effects of the drug can be monitored. Treatment of some lymphomas, such as lymphoblastic lymphoma, may need long-term maintenance chemotherapy. For others (eg, small-noncleaved-cell and large-cell lymphomas), maintenance therapy does not seem to add any benefit.

Effective Regimens

The standard chemotherapy regimen is called CHOP (cyclophosphamide, doxorubicin hydrocholoride [Adriamycin], vincristine [Oncovin], prednisone). A combination with rituximab is proving to be particularly beneficial for diffuse large-B-cell lymphomas.

Others used are PACEBOM, COP-BLAM, MACOP-B, m-BACOD, and Pro-MACE-CytaBOM. The intensity of chemotherapy varies widely depending on the grade, stage, and other factors. CHOP or other powerful multi-drug regimens may be needed in some cases; in others, a single oral low-dose drug (such as etoposide in elderly patients) may be beneficial. Newer regimens have been designed with the hope they will be more effective than CHOP for many lymphomas. In most cases they have tended to be more toxic but no more effective than CHOP. Other studies are also finding better results with chemotherapy combinations and some of the biological response modifiers.

Studies are showing that a combination of chemotherapy and radiation (combined modality) is more effective than chemotherapy alone for improving progression-free survival in certain patients with stage I or stage II low-grade lymphoma and in patients with intermediate- and high-grade NHL.

Side Effects and Complications

Side effects and complications of any chemotherapeutic regimen are common, are more severe with higher doses, and increase over the course of treatment, though some trials suggest that toxicities can be reduced by administering the drugs for shorter durations without loss of cancer-killing effects.

Common Side Effects . Common side effects include the following:

Nausea and vomiting. Drugs known as serotonin antagonists, such as ondansetron (Zofran) or granisetron (Kyril), can relieve these side effects in nearly all patients given moderate drugs and most patients who take more powerful drugs. In one study, nearly all patients who took a combination of dexamathasone (a steroid) in combination with ondansetron within 24 hours of chemotherapy experienced either a significant reduction or complete control of nausea and vomiting.
Diarrhea.
Hair loss.
Weight loss.
Anemia. Studies are investigating the use of epoetin (Procrit), which increases production of red blood cells, to reduce this effect and improve quality of life.
Depression.

These side effects are nearly always temporary. Most patients are able to continue with normal activities for all but perhaps one or two days a month.

Anemia is common.

Serious Side Effects. Serious side effects can also occur and may vary depending on the specific agents used. They include the following:

Increased chance for infection from suppression of the immune system or from severe drops in white blood cells ( lymphopenia).
Liver and kidney damage.
Abnormal blood clotting ( thrombocytopenia).
Allergic reaction.
Complications.
Fatigue is very common after chemotherapy and can be significant and long-lasting (more than six months).
The most serious long-term complications from chemotherapy are secondary cancers, particularly in people over 40.
Infertility is also a danger, particularly with the use of cyclophosphamide. One study suggested that taking reproductive agents called GnRH analogs before and during chemotherapy may enhance the function of the ovary and so help preserve fertility in young women.
Some patients report osteoporosis and damage in bone cells, possibly related to corticosteroid treatments.
Regimens containing certain drugs, particularly doxorubicin or mitoxantrone, increase the risk for future heart failure.

In general, these serious late side effects are dependent on the cumulative drug dose and rate of administration. There is a 1% to 5% mortality rate from complications of chemotherapy and certain people may be at greater risk. A 2001 study suggested that the risk was highest in those had low performance scores (ie, are more debilitated than others) or have tests that show low levels of white blood cells.

Supportive Agents

Granulocyte Colony-Stimulating Factor. A hormonal treatment called granulocyte colony-stimulating factor or G-CSF (lenograstim, filgrastim, sargramostim, nartograstim) regulate blood-cell growth. It is being used to allow higher doses of chemotherapy and it may allow standard chemotherapies treatments in elderly people, who otherwise could not withstand toxicities. G-CSF may help reduce the rate of infection and speed up recovery after treatment. G-CSF is expensive, however, and does not produce higher survival or remission rate. Studies are mixed on the question of whether its high cost is justified by the benefits it provides. Toxicities and infections are still common, even with the use of G-CSF.

Combinations of Chemotherapy and Radiation (Combined Modality)

Physicians are particularly concerned about the effects of combinations of chemotherapy with radiation. Interestingly, in one study on patients with intermediate- and high-grade NHL, those on chemotherapy alone had more toxic effects than those on combined modality, most likely because it employed fewer cycles of chemotherapy. Better radiation techniques are also reducing the risks of combined modality treatments. Combination treatments may increase the long-term danger for heart disease, however.

Other Agents

Antibiotics for MALT. Antibiotics may cure or put into complete remission about half of mucosa-associated lymphoid tissue (MALT) cases that are caused by H. pylori infection. Those most likely to respond positively to antibiotics are those in early stages.

WHAT ARE THE IMMUNOTHERAPIES FOR NON-HODGKIN'S LYMPHOMAS?

Biological response modifier therapy, also called immunotherapy, uses the body's own immune system to fight cancer using natural or laboratory-developed factors. Drugs designed for such purposes used in combination with other treatments are showing promise in trials. (Of some recent concern were reports of invasive fungal infections in patients who had had immunotherapy plus bone marrow transplantation. More research is needed.)

Monoclonal Antibodies.

Monoclonal antibodies (MAbs) are designed in the laboratory to produce the same effects as natural antibodies and are exciting new weapons in the anti-cancer armament. They bind to specific proteins called antigens and make them vulnerable to attack by other factors in the immune system. Lymphomas carry antigens that provoke strong immune responses and so are believed to be particularly good candidates for MAb therapy.

MAbs are called either conjugated or unconjugated, depending on how they are designed to destroy the cancer cell.

Conjugated monoclonal antibodies are linked to a plant or bacterial toxin or radioisotope. The antibody specifically attacks the antigen on the lymphoma cell and the toxin or radioactive material from the isotope kills it. Problems with this type involve an allergic response to the substance linked to the antibody.
Unconjugated monoclonal antibodies rely on a strong natural immune system. The antibody builds up at the tumor site until it is able to trigger an immune response against the cancer. A possible downside to this form is the potential development of tolerance to the antibody so that it loses its effectiveness. Rituximab is an unconjugated form and the first MAb to be approved for any cancer.

Unconjugated MAbs (Rituximab). Rituximab (Rituxan) is the first monoclonal antibody to be approved for any cancer. It is an unconjugated MAb that targets the CD-20 antigen, which is found on most B-cell lymphomas and normal mature B-cells (although not stem cells).

Combinations with CHOP are particularly promising, achieving in one 2002 study complete remission in 76% of patients with diffuse large-B-cell lymphomas. Response rates of over 50% have been reported in patients with relapsed or treatment-resistant low-grade or follicular B-cell lymphomas, with the time until the tumor progresses again being about a year. A 2000 study suggested that patients can be safely and effectively retreated with rituximab. It is also being studied for lymphomas in the central nervous system.

The treatment has mild to moderate short-term side effects, including nausea, fever, chills, hives, dizziness, and headache. Uncommon and more serious side effects are severe allergic reactions, very low blood pressure, blood abnormalities, wheezing, infections, and sudden heart events. Fatalities associated with a first infusion of the drug occur in four to seven out of 10,000 people. Early studies are also investigating combinations of rituximab with conjugated MAbs, or other biologic modifiers.

Conjugated Monoclonal Antibodies with Radio Isotopes. Conjugated MAbs include ibritumomab tiuxetan (Zevalin), tositumomab (Bexxar), and epratuzumab are showing significant promise. These monoclonal antibodies attach to tiny amounts of radioactive isotopes, which are used to destroy the lymphomas. These agents are showing slightly better response rates than previous chemotherapy and are effective in combination with chemotherapy as first line treatments for low-grade and transformed NHLs. Studies on ibritumomab have reported an 82% response rate in patients with low-grade NHL and this agent is the first to be approved. In general, studies are reporting average response rates of 67% with these agents. Researchers are excited about the possibilities of using combinations of conjugated and unconjugated MAbs (eg, epratuzumab and rituximab) along with chemotherapy.

Conjugated Monoclonal Antibodies with Toxin. Studies are also underway on MAB used with toxins to destroy the cells. In an early 2001 study, the important result was their high toxicity in patients who had previously had radiation treatments.

Nucleoside Analogues

Anti-virus agents called nucleoside analogues include fludarabine (Fludara), gemcitabine, and cladribine. Fludarabine is one of the most active drugs for treating low-grade lymphomas and may be effective for other NHLs, including mantle cell lymphomas. Studies using this agent alone or in combinations with chemotherapy agents have reported overall response rates of up to 50% in previously treated patients and between 70% and 90% in untreated patients. Toxicities and infection rates from high dose nucleoside analogues have been high, however. Promising regimens under investigation that may eventually prove to be effective without posing a high risk for complications include the following:

Low-dose fludarabine.
Fludarabine combined with chemotherapy agents, such as cyclophosphamide, idarubicin, or mitoxantrone.
Combinations of fludarabine and monoclonal antibodies.

Interferon Alpha

Interferon alpha (Intron A) is used as an anti-viral drug but it also has properties that are effective against some common forms of NHL, particularly low grade, follicular non-Hodgkin's lymphoma in advanced stages. It is usually combined with chemotherapy regimens, such as CHOP, that contain an anthracycline drug (usually doxorubicin). In one study this combination produced a better outcome than fludarabine in elderly patients with follicular lymphoma, although a 2000 study reported no early benefits compared to CHOP alone. Interferon is also being studied for lymphomas in the central nervous system.

Side Effects. Side effects of interferon include flu-like symptoms, severe depression, irritability, weight loss, vomiting, general weakness and loss of strength, and fever. About a third of patients have a severe drop in white blood cells. About 10% of patients cannot tolerate the drug's side effects.

Vaccines

Vaccines against lymphomas are showing promise. In a 1999 study, patients were vaccinated after an initial diagnosis of low-grade disease after successfully completing a first chemotherapy treatment. After an average of four years, 18 out of 20 of these patients remained in remission without evidence of microscopic disease.

Lymphoma vaccines use the same principles as those that fight other diseases. A protein taken from a lymphoma surface cell is bound to a carrier and administered to the patient. The body's immune system perceives this substance as a foreign antigen and boosts its response not only against the vaccinated agent but also against the look-alike lymphoma.

Antisense RNA

BCL-2 antisense RNA is a genetic therapy that blocks a protein called BCL-2, which is genetically overexpressed in some lymphomas and prevents apoptosis (a natural process by which all cells, including cancer cells, self-destruct). Agents are in early trials.

WHAT ARE RADIATION TREATMENTS FOR LYMPHOMAS?

Radiation is commonly used for indolent lymphomas. The dose administered ranges from 3,500 to 5,000 cGy and depends on a number of factors: the type of lymphoma, the age of the patient, whether the intent is to cure or relieve symptoms, how close sensitive organs are to the diseased area, and whether radiation is being combined with chemotherapy.

Radiation is tailored to the individual and usually limited to the diseased areas and possibly nearby regions:

If the lymphoma is confined to tissues above the diaphragm, radiation is delivered to the neck, chest, and under arms (called the mantle-field) and sometimes to lymph nodes in the upper abdomen or spleen or both.
If the lymphoma is below the diaphragm, subtotal nodal radiation may be used, which is directed to other regions, including lymph nodes in the upper abdomen, spleen, and pelvis, in addition to the mantle-field.
Radiation to the brain is called cranial radiation .
Total body irradiatio n is sometimes performed, although it is not clear whether its high toxicity outweighs any advantages.

Devices called planning simulators allow physicians to plan x-ray treatments that accurately conform to the patient's anatomy so that protective shields can be created to precisely protect the regions outside the treatment areas.

Side Effects and Complications

Side effects and complications of radiation generally depend on the target site in the body. They include the following:

Dental problems.
Inflammation in the lungs. With carefully conducted therapy, the risks for lung complications are small. Lung impairment may not even be evident, and the lungs usually recover after two or three years.
Hypothyroidism.
Infections.
Long-term risk for heart disease.
Long-term risk for certain cancers. Of particular concern is a possible increased risk for breast cancer. Studies indicate that young women and adolescent girls are at highest risk, with the incidence increasing significantly 15 years after treatment. The risk is greater in those who had higher radiation doses. Radiation may also increase the risk over time for other cancers, including lymphoma and thyroid, lung, and colon cancers, although the risk is still low. Smoking, of course, increases the risk for lung cancer. Radiation of bone marrow increases the risk for leukemia.
Children and adolescents are at special risk for impaired bone growth. Experts are finding, in fact, that radiation for many children and young adults in early stages or NHL is no more effective and has more serious long-term effects than chemotherapy. Some believe that radiation should play no role in the treatment of young people, except in special cases, such as lymphomas that require radiation to the brain.
Infertility. The negative effects on fertility may be worse in women than in men; sperm usually recover within five years. To protect the ovaries, a technique called ovarian transposition is sometimes used. Transposition may sometimes be performed through a laparoscope, a thin tube containing tiny instruments and cameras, which is introduced through a small incision. The physician uses the laparoscope to move the ovaries out of the range of areas being treated with radiation.

WHAT ARE THE TRANSPLANTATION PROCEDURES FOR NON-HODGKIN'S LYMPHOMAS?

In order to administer high-dose chemotherapy for advanced cancer cases, stem cell transplantation procedures may be used. Stem cell procedures have proven to produce long-term survival and even cures in patients with aggressive (intermediate and high-grade) non-Hodgkin's lymphomas. These procedures are based on removal and replacement of stem cells , which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments harm growing cells as well as cancer cells, and so the healthy stem cells must be replaced by transplanting them from the donor into the patient.

Collecting the Stem Cells

Sources of Cells. Stem cells must first be collected in one of the following ways:

Directly from blood (peripheral blood stem cell transplantation).
From bone marrow (bone marrow transplantation).
From fetal umbilical cord or placentas. This procedure uses donor cells but has a lower risk for immune system rejection of the cells than with a standard donor transplant. It takes longer to restore blood cells with this process, however, so at this time its use is limited to children and sometimes adults with low weight. (A small 2001 study on adults suggested it might also be useful for adults with normal weights. )

Current evidence suggests that the stem cell and bone marrow procedures produce similar benefits in terms of survival. However, because stem-cell transplantation seems to be superior in terms of cost, quality of life, and the need for less supportive care, it is discussed here.

Donor or Patient Cells. The marrow or blood stem cells can be taken from the patient or from a matched donor:

An allogeneic transplant is one in which bone marrow or stem cells are taken from a donor. The donor and recipient must be matched as closely as possible to avoid rejection by the immune system. Siblings are the best possibility. This report discusses the allogeneic transplant procedure.
An autologous transplant is one in which marrow or blood cells used are the patient's own. The advantage to this procedure is that the patient is not at risk for rejection by the immune system. There is some danger, however, that the cells used may contain tumor cells and the cancer can regrow. (This risk is lower in peripheral stem cells transplants than in bone marrow transplants.) A number of studies, however, are reporting good success with this transplant. It may be a good choice in selected HD patients with a relapse or with disease that does not respond to other treatments.
Blood Stem Cell Collection Procedure.
The donor is usually given a drug called granulocyte colony-stimulating factor, or G-CSF (filgrastim, lenograstim) to stimulate stem cell growth.
The donor (or patient in an autologous procedure) then undergoes apheresis. With this process the blood is withdrawn from one of the patient's veins, then passes through a machine that filters out the white cells and platelets, which contain the stem cells. The blood is returned through another vein. The entire procedure takes three to four hours but needs to be repeated several times.
The stem cells are then frozen.

The Transplant Procedure.

Allogeneic transplants are preceded by chemotherapy treatment known as conditioning. The point of this treatment is to inactivate the immune system and to kill any residual malignant cells. Researchers are also testing other variations. One trial of transplantation preceded and followed by monoclonal antibodies showed promise for mantle cell lymphoma, a disease with a poor outlook that is particularly difficult to treat. Another used high-dose sequential chemotherapy preceding the transplant procedure following by high-dose regimens with autologous stem cell transplantation. Three-year survival rates were 47%.
The thawed donated stem cells are administered through a vein. This may take several hours. Patients may experience fever, chills, hives, shortness of breath, or a fall in blood pressure during the procedure.
The patient may be treated with granulocyte colony-stimulating factor after chemotherapy. The goal is to stimulate the growth of infection-fighting white blood cells. Because this increases immune factors, there is some concern that it might also heighten the immune attack against the donor cells, but to date, studies have been encouraging and are reporting a low risk. (Adding another substance, thrombopoietin may prove to enhance stem cell production.)
The patient is kept in a protected environment to minimize infection and he or she usually needs blood cell replacement and nutritional support.

Candidates and Success Rates

Candidates. The procedures are typically used for patients with relapsed aggressive lymphoma who are still sensitive to the effects of chemotherapy. The procedures are not effective for patients whose tumors are not responsive to drugs. (One study did suggest that certain primary (non-relapsed) lymphomas initially unresponsive to a first round of chemotherapy but who respond to a second round may benefit from combination of high-dose chemotherapy and radiation followed by transplantation.) It is also being investigated as first-line therapy for patients with aggressive lymphomas, although at this time evidence does not support its use.

Success Rates. Success rates vary depending on many factors. The following are survival rates reported by a few 2000 and 2001 studies of patients with different lymphomas:

In patients with refractory or relapsed intermediate grade NHL who received autologous transplantation, five-year survival rates averaged 34%.
In a study of allogenic bone marrow transplantation, 58% of patients with late-stage low-grade lymphoma had survived after an average of 29 months.
Patients with anaplastic large-cell lymphoma were treated with autologous stem cell transplantation with intensified chemotherapy as first line-therapy. Survival rates were 87% at five and more years afterward. (Survival was much lower with other lymphomas.)
Patients with diffuse aggressive NHL who did not achieve a first remission but who are still sensitive to chemotherapy achieved a five-year survival rate of up to 37% after autologous stem cell transplantation.
In one study, 35% of patients with an initial poor prognosis were still alive five years after an allogeneic stem cell transplantation, although mortality probability from the treatment itself was very high (48%).

Side Effects and Complications

Common side effects include nausea, vomiting, fatigue, mouth sores, and loss of appetite. The procedures themselves are fairly dangerous and carry a small risk for death. Potentially serious complications are the following:

Infection resulting from a weakened immune system. This is the most common side effect and can persist for several months after the transplant. Because the stem cell procedure is done more swiftly, the risk period is shorter than with bone marrow transplantation. Many patients develop severe herpes zoster virus infections (shingles) or have a recurrence of herpes simplex virus infections (cold sores and genital herpes). Pneumonia, cytomegalovirus, aspergillus (a type of fungus), and Pneumocystis carinii (a protozoan) are among the most important life-threatening infections.
Graft-versus-host-disease (GVHD) is a serious attack by the patient's immune system triggered by the donated new marrow. It occurs in over half of allogeneic transplants. GVHD can results in weight loss, bacterial infections, and skin and organ problems that may persist for up to three years after the procedure. In some cases it is fatal. Careful matching of the donor and preventive immunosuppressive drugs, such as corticosteroids, methotrexate, and cyclosporine (Sandimmune), may reduce the risk for this potentially life-threatening side effect. (Interestingly, however, patients who develop mild GVHD are less likely to have a relapse than are patients who never have the reaction.)
Bleeding because of reduced platelets. This risk is highest within the first four weeks after BMT.
Infertility.
Organ complications to the liver, heart, kidney, or lungs.
Failure. The marrow graft may fail or new marrow cells may now grow.
Secondary Cancers. Transplant procedures poses a long-term risk of 2% to 10% for developing secondary cancers in the brain, oral cavity, thyroid, melanoma, or bone. One study reported that aggressive high-dose chemotherapy after bone marrow transplantation was associated with a 10% rate of leukemia or myelodysplasia within five years. The risk varies considerably depending on the patient's age, general health, menopausal status (for women), and previous history of radiation. Highest risks have been identified in patients receiving BMT before 10 years of age, probably because these patients are more likely to have received cranial irradiation. Patients, particularly men, who developed GVHD were at high risk for oral and skin cancers.

HOW IS SURGERY USED IN NON-HODGKIN'S LYMPHOMA?

Surgery is sometimes used to remove as much malignant tissue as possible, particularly bulky tumors that occur in the stomach, before administering chemotherapy. Surgery is sometimes performed for primary gastric lymphoma, but its advantages are uncertain. Some studies indicate that chemotherapy alone or with radiation may be sufficient and could spare many patients from surgery.

WHERE ELSE CAN INFORMATION ABOUT LYMPHOMAS BE OBTAINED?

National Cancer Institute, Call (800-4-CANCER) (800-422-6237) during working hours
Deaf and hard of hearing callers with TTY equipment may call (800-332-8615). Call CancerFax at 800-624-2511 or 301-402-5874 from your touch-tone phone or from the telephone on a fax machine (the machine must be set to touch-tone dialing). or on the Internet (http://www.nci.nih.gov/)

American Cancer Society, 1599 Clifton Road, NE, Atlanta, GA 30329 Call (800-ACS-2345) or (404-320-3333) or on the Internet (http://www.cancer.org) and (http://www.ca-journal.org)

American Society of Clinical Oncology, 1900 Duke Street, Suite 200, Alexandria, VA 22314 Call (703)-299-0150 or on the Internet (http://www.asco.org/)

The Lymphoma Research Foundation of America, 8800 Venice Blvd. Suite, 207 Los Angeles, CA 90034. Call (310-204-7040) or on the Internet (http://www.lymphoma.org) and (http://www.lymphomafocus.org)

Cure for Lymphoma Foundation, 215 Lexington Ave., York, NY 10016-6023. Call (212-213-9595) or on the Internet (http://www.cfl.org/)

The Leukemia and Lymphoma Society, 1311 Mamaroneck Ave., White Plains, N.Y., 10605. Phone: (914) 949-5213 or on the Internet (http://www.leukemia.org/)

The National Coalition for Cancer Survivorship (NCCS), 1010 Wayne Avenue, Suite 770, Silver Spring, MD 20910-5600 Call: (301) 650-9127 or (877) NCCS-YES (877-622-7937) or on the Internet (http://www.cansearch.org/)

The National Association of Hospital Hospitality Houses, Inc., P.O. Box 18087, Asheville, N.C. 28814-0087 Call (800-542-9730), (828-253-1188) or on the Internet (http://www.nahhh.org/)
This non-profit organization has locations through the US that provide lodging and support services to families and their loved ones who are receiving medical treatment away from their home communities. Costs generally range from about $5 to $40 per day, and services vary.

For Internet Users

Oncolink (http://www.oncolink.com/) HODGKIN'S SITE at Univ. of Pennsylvania

Listing of clinical trials (http://www.centerwatch.com/studies/listing.htm)

Journal of Clinical Oncology (http://www.jco.org/)

Lymphoma Information Network (http://www.lymphomainfo.net/)