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  • Large B-cell Lymphoma

    Non-Hodgkin’s lymphomas (NHLs) are a very heterogeneous group of cancers that develop in the lymph nodes present throughout the body. There are over 25 subtypes of NHL, although most are diagnosed infrequently.

    Diffuse large B-cell lymphoma (DLBCL) is by far the most common, accounting for 31% of cases. Although some NHLs are very indolent in nature, DLBCL is considered an aggressive lymphoma.

    This means that although the disease tends to progress rapidly, it is very sensitive to treatment with chemotherapy, and a large proportion of patients can be cured.

    Approximately 20,000 patients are diagnosed with DLBCL in the United States each year. Although some cancers tend to occur more often in one gender or the other, cases and deaths due to DLBCL are evenly split between men and women.

    Risk Factors

    The exact cause of DLBCL is most often unknown. Unlike lung cancer, in which smoking is a clear contributor in the majority of patients diagnosed, there has been no single carcinogen or risk identified that is present in the majority of DLBCL cases. As with most cancers, a family history increases a patient’s risk to some extent.

    In addition, suppression of the immune system may lead to the development of DLBCL. This includes immune suppression associated with organ transplant (from the drugs taken to prevent organ rejection) and with HIV/AIDS infection. Occupational exposures, notably pesticides, also increase the risk of DLBCL.

    In fact, the Midwest, where farming is prevalent, has the highest incidence of NHL in the United States. Finally, infection with viruses, such as hepatitis C and the Epstein-Barr virus, may increase the risk of developing DLBCL.

    Signs and Symptoms

    Enlarged (swollen) lymph nodes are the most common presenting sign in patients with DLBCL. The swollen lymph nodes are usually hard, fixed in place, and painless to the touch. In addition, some patients also have non-specific symptoms, such as fevers, drenching night sweats, and unexplained weight loss greater than 10% of body weight. These are termed ìBî symptoms and indicate the presence of more advanced disease.

    Diagnosis and Staging

    The most important diagnostic procedure in patients suspected of having lymphoma is the lymph node biopsy. Many cancers can be diagnosed by inserting a small needle into the tumor mass and withdrawing cells for examination under a microscope. This is called a ìfine needle aspirationî or FNA.

    For lymphoma diagnosis, however, the preferred technique is removal of the entire affected lymph node for examination by a pathologist. It is of the utmost importance that these biopsies are examined by a pathologist who is experienced in diagnosing lymphomas. Knowing the subtype of NHL is crucial for determining long-term prognosis and treatment options.

    Once the diagnosis of DLBCL is established, patients should undergo tests to determine the extent of disease. This should include CT scans of the chest, abdomen, and pelvis, a bone marrow biopsy, a complete blood count, serum chemistries (including lactate dehydrogenase (LDH) and uric acid), and an HIV test.

    Hepatitis B testing is also recommended due to reports of hepatitis reactivation during chemotherapy. Finally, a baseline echocardiogram or MUGA scan to evaluate heart function should be done prior to chemotherapy, as some drugs can damage the heart.

    All of the above testing leads physicians to establish a stage of DLBCL for each patient. Stages for DLBCL include the following:

    Stage I: One involved lymph node group
    Stage II: Two or more involved lymph node groups on the same side of the diaphragm
    Stage III: Multiple lymph node groups involved on both sides of the diaphragm
    Stage IV: Disseminated involvement of extra-nodal sites, such as the liver or bone marrow

    An “A” or “B” is added to the stage number to indicate the presence or absence of the “B” symptoms previously described. For example, a person with DLBCL on both sides of the diaphragm with recurrent night sweats and weight loss would be considered to have “stage IIIB” disease.

    Prognostic Factors

    When considering all stages, the overall five-year survival for DLBCL is 50 to 60%. The majority of lymphoma relapses occur within two years; therefore, patients surviving five years or more are generally considered cured.

    Stage at the time of diagnosis is by far the most important prognostic factor in patients with DLBCL: A higher stage indicates more advanced DLBCL, and therefore has a worse prognosis.

    Other poor prognostic factors include presence of “B” symptoms, presence of extra-nodal lymphoma involvement, concurrent HIV/AIDS infection, age greater than 60 years, high LDH level time of diagnosis (indicative of more advanced disease), and poor performance status (inability to care for oneself). Patients with two or more of these risk factors have less than a 50% chance of surviving five years.

    First-Line Treatment of DLBCL

    The benefit of DLBCL being an aggressive lymphoma is that it tends to respond well to combination chemotherapy in a majority of patients, many of whom will be cured. The disadvantage is that if it does not respond well or recurs soon after chemotherapy, DLBCL is often fatal.

    Treatment of localized disease (stages I and II) should consist of “R-CHOP” chemotherapy (3 to 8 cycles) plus radiation to the sites of lymphoma. An alternative to this is “R-CHOP” alone for 4 to 8 cycles. The “R-CHOP” regimen includes the drugs rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.

    Over 90% of patients with localized DLBCL will live at least two years disease-free following this treatment strategy, and most will be cured. Patients with non-bulky disease (less than 10 cm lymphoma masses) should receive three cycles of chemotherapy, whereas those with bulky disease should receive six to eight cycles.

    Treatment of advanced disease (stages III and IV) should consist of “R-CHOP” chemotherapy for six to eight cycles, with the drugs listed above. Many clinical trials have compared this regimen to more complicated regimens with more drugs and higher doses, but none have proved superior to the R-CHOP regimen for advanced DLBCL. Patients with stage III or IV disease with multiple poor prognostic factors may consider participation in a clinical trial of new agents or new combinations of agents.

    Note that in both localized and advanced DLBCL, the addition of “R”, or rituximab, is critical to improving survival in all patients. This medication is a monoclonal antibody that specifically kills B-cell lymphomas. It is synergistic with chemotherapy, meaning that the two types of medications work better together. There are clinical trials ongoing comparing various doses of the “R-CHOP” drugs, giving the drugs more frequently (every 14 days rather than every 21 days), and adding new drugs with different mechanisms of action.

    Injection of chemotherapy into the spinal fluid (called “intrathecal” therapy) is often administered to patients who have a high risk of the lymphoma spreading to this area. This includes patients with involvement in the testes, facial sinuses, or vertebrae. The drug most often given intrathecally is methotrexate.

    If a complete response is obtained after first-line therapy (disappearance of all detectable lymphoma), patients are monitored with labs and CT scans every three months for two years, then every six months for three years. Recurrence of DLBCL after five years is uncommon. Patients who achieve only a partial response to first-line therapy, those who do not respond at all to treatment, as well as those whose lymphoma recurs, should be treated as described below.

    Treatment of Recurrent/Refractory DLBCL

    Many salvage chemotherapy regimens have been studied for recurrent DLBCL. None has proven superior to another, and patients are rarely cured with these standard-dose regimens. Participation in a clinical trial is always a good choice for patients with relapsed DLBCL.

    Examples of commonly employed salvage chemotherapy regimens include:

    • DHAP: dexamethasone, high-dose cytarabine, cisplatin
    • ESHAP: etoposide, methylprednisolone, high-dose cytarabine, cisplatin
    • MINE: mesna, ifosfamide, mitoxantrone, etoposide
    • ICE: ifosfamide, mesna, carboplatin, etoposide

    Hematopoietic stem cell transplant (so-called ìbone marrow transplantî) is the standard of care in patients with a good performance status who have recurrent or refractory DLBCL.

    The most common procedure is an ìautologousî transplant, in which the patientís own blood stem cells are harvested, then re-infused following very-high-dose chemotherapy.

    Allogeneic bone marrow transplants (blood stem cells from another person, usually a sibling) are also used as treatment for relapsed DLBCL. 20 to 40% of patients who undergo a bone marrow transplant for DLBCL will have long-term survival, and many will be cured. Bone marrow transplantation is associated with a high degree of toxicity and should only be performed at cancer centers with staff experienced and skilled in this procedure.

    Supportive Care Issues

    Tumor lysis syndrome leading to kidney failure and heart arrhythmias is a risk in DLBCL patients with advanced disease. These patients can be identified by a high LDH level, high uric acid level, and/or bulky disease (greater than 10 cm). Patients at high risk for tumor lysis syndrome usually receive their cycle or two of chemotherapy in the hospital.

    Infections due to bone marrow involvement with lymphoma and/or chemotherapy immune suppression are common in DLBCL patients. Prophylaxis with antibiotics may be appropriate in some, and patients should always contact their oncologist if they develop a fever.

    Although it is a drug critical to the cure of DLBCL, doxorubicin has the potential to cause congestive heart failure. Patients at highest risk are those receiving cumulative doses greater than 450 mg/m2, age greater than 70 years, and those with a history of heart disease.

    All patients receiving doxorubicin should have their heart function monitored regularly, and if there is evidence of heart failure, doxorubicin therapy should be stopped. Once damage to the heart occurs, it is generally not reversible.