Treatment of Mature B-Cell Lymphomas

This content has been reviewed and approved by

James O. Armitage, MD
The Joe Shapiro Professor of Internal Medicine
Section of Oncology/Hematology
University of Nebraska Medical Center

Diffuse Large B-Cell Lymphoma 

Diffuse large B-cell lymphoma is a curable disease. Cure rates are higher for patients who have a localized (confined) disease without any other risk factors, but all patients have some chance for a cure. In almost every patient, the best initial treatment for diffuse large B-cell lymphoma is a combination of drugs, with some patients receiving radiation and/or bone marrow transplant after the chemotherapy.

For patients with localized diffuse large B-cell lymphoma, the most common treatment used in the United States is a combination of Cytoxan® (cyclophosphamide), Adriamycin® (doxorubicin), Oncovin® (vincristine), and prednisone plus the antibody Rituxan® (rituximab).

This regimen is usually called R-CHOP. A common approach is to administer these medicines at 3 weekly intervals for three or four treatments followed by irradiation to the site of localized (confined to one area) lymphoma.

Recently, there has been some evidence that patients might do as well with a complete course of drugs (six to eight cycles) without radiation. Most physicians will withhold the radiation if there are some special problems regarding the site. For example, irradiating the salivary glands can lead to dry mouth and loss of teeth, and irradiating the breast in a young woman increases the risk for breast cancer.

However, as is always true in medicine, this decision is a trade off of risks and benefits. Although a brief course of CHOP alone plus radiation was not as effective as a complicated chemotherapy regimen widely used in France -- ACVBP -- there is no study of the relative merits of CHOP plus rituximab for a full treatment course versus CHOP plus rituximab for a brief course followed by radiation. Either approach is still reasonable.

For patients with wide spread diffuse large B-cell lymphoma, almost all patients in the United States are treated with CHOP plus rituximab. Several studies have demonstrated an approximately 20 percent higher survival rate when rituximab is combined with CHOP or other similar regimens versus CHOP alone.

Many physicians will repeat the laboratory and imaging studies that were abnormal at the outset of treatment after approximately four cycles. Patients who are in complete remission at that point might receive a total of six cycles of therapy, although some physicians would favor a total of eight cycles. Patients who are in complete remission at the completion of therapy, that is, no abnormalities on exam, laboratory tests, imaging studies, or a repeat bone marrow biopsy, have a good chance to be cured.

Patients who have a very bulky mass, including masses in the mediastinum, often receive radiotherapy at the site of bulky disease after the completion of the chemotherapy treatment. This is to eliminate that site for any subsequent relapse.
Patients with very high risk of disease will sometimes undergo an autologous bone marrow transplant in first remission to try to reduce the possibility of relapse.

Patients with particular problems, such as heart failure, might have their treatment modified to address their specific problem. For example, the patient with heart failure might not receive Adriamycin because that drug often has cardiac toxicity.

Patients with diffuse large B-cell lymphoma who don't go into initial remission or in whom the cancer recurs after remission have a serious situation, but there is still the possibility of a cure. Patients who respond to subsequent chemotherapy regimens of a different type, such as drugs containing platinum compounds, ifosfamide, etoposide, cytarabine, or other agents are candidates for autologous bone marrow transplantation. Patients who have had a good response to the salvage chemotherapy regimen have a 30 percent to 50 percent chance for a cure with the transplant, with a higher proportion of patients benefiting for some time.

Allogeneic bone marrow transplantation has not been as widely used in diffuse large B-cell lymphoma and is not as effective as it is in some other lymphomas. However, an occasional patient may have an excellent response. Even if the disease is not able to be cured, further therapy with other drugs or the judicious use of radiation can frequently alleviate symptoms and improve the patient's quality of life.

Diffuse large B-cell lymphoma occurring in certain clinical situations deserves special consideration. For example, very elderly patients sometimes are poor candidates for the treatment regimens described above. In some patients who are very debilitated or seriously ill with other illnesses, cautious treatment aimed at eliminating symptoms might be the best approach. However, patients should not be denied the chance for curative therapy based only upon age. Diffuse large B-cell lymphoma involving the mediastinum sometimes occurs in pregnant young women. In these patients, treatment with CHOP plus rituximab can be administered relatively safely from the second trimester on, and therapeutic abortion is not absolutely necessary. 

Follicular Lymphoma

One of the most complicated topics in oncology is the choice of treatment for patients with follicular lymphoma. Patients who are asymptomatic and don't have disease threatening the function of vital organs can observed without specific treatment. Some patients would much prefer to avoid any toxicity from therapy and favor this approach.

This is often true of older patients. Other patients are very anxious about the presence of lymphoma and would not be comfortable leaving it untreated even if it was not making them ill. This is a personal decision, and neither choice is right or wrong.

When treatment is elected, there are many treatment options that work and could be reasonably used. For patients with localized follicular lymphoma (a very rare situation), radiotherapy applied to the site of lymphoma can yield durable complete remissions--40 percent to 50 percent of patients remaining without signs of recurrence for 10 years.

However, most patients have more wide spread disease. In these patients, treatment options include single chemotherapy drugs, such as Leukeran® (chlorambucil) or Cytoxan (cyclophosphamide); combinations of drugs, including cyclophosphamide, vincristine, prednisone (CVP), cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); and Fludara® (fludarabine) in combination with other drugs, such as Novantrone® (mitoxantrone) or cyclophosphamide.

It is not clear that any one of these regimens is superior to the others, although each has strong advocates. As a general principle, it is better to have your physician using the regimen with which he or she is most comfortable and has the most experience.

At the present time, standard chemotherapy drugs should not be administered alone for patients with follicular lymphoma. A number of studies have shown an improved response rate, and some have shown improved survival time when these combination chemotherapy regimens are used with the antibody rituximab.

However, rituximab can also be administered alone. Although the complete response rate is not the same as CVP, CHOP, or regimens containing fludarabine, the side effects are less. In elderly patients, those who want to prevent hair loss or those whose health makes some of the standard chemotherapy regimens more dangerous (for example, doxorubicin in a patient with heart failure), rituximab can also be used as an individual agent with four weekly infusions.

When rituximab is given alone, and if the patient responds, the drug is often given in an ongoing manner to try to maintain the remission. When used in this way, it is either given in one dose every 2 or 3 months or by repeating the initial four injections at six monthly intervals.

Monoclonal antibodies have also been combined with radioactive atoms to deliver "targeted" radiotherapy. Two drugs are available in the United States: Bexxar® (I131 tositumomab) and Zevalin® (Y90 Ibritumomab tiuxetan). These drugs require only one treatment and they have a very high response rate.

In patients with recurrent disease, more than half will respond and a small proportion will have very long remissions. In one study using radioantibodies as the initial treatment, almost all patients responded and the average time to failure was approximately 7 years, with many patients remaining in remission for long periods. However, most insurance companies would not pay for this very expensive treatment as the initial management for patients with follicular lymphoma.

Many other drugs have been used for patients with follicular lymphoma and show activity, but are generally reserved for treatment after relapse. These include alpha-interferon and Velcade® (bortezomib).

Both autologous and allogeneic bone marrow transplantation have a place in the management of patients with follicular lymphoma. Autologous bone marrow transplantation has been studied as part of the primary therapy, and one European study showed an increased chance of remaining in remission.

However, this approach has been rarely used in the United States. When patients fail their initial treatment, autologous bone marrow transplantation can produce a complete remission in the majority of patients. Two large studies have shown that 40 percent to 50 percent of patients remain in remission for 10 years or longer.

When treatment with autologous bone marrow transplantation fails, the most likely reason is recurrence of lymphoma. In contrast, allogeneic bone marrow transplantation, presumably through a graft-versus-lymphoma effect, has rare relapses of lymphoma. Unfortunately, the graft-versus-host disease, which often accompanies allogeneic bone marrow transplantation, can be a serious problem itself.

Because of this, the overall survival time using the two approaches has not varied greatly. Allogeneic bone marrow transplantation is safer in young patients. The use of so-called miniallogeneic transplants or nonmyeloablative allogeneic transplants has allowed the treatment to be applied to older patients. The exact place for allogeneic bone marrow transplantation in patients with follicular lymphomas is not yet clear.

Patients with follicular lymphoma who relapse and are not transplant candidates often continue to respond to different treatments. The disease can often be controlled for extended periods of time with the careful use of alternative drugs and radiation.

However, the physician must always be alert for the possibility that the follicular lymphoma will change to diffuse large B-cell lymphoma. The onset of rapidly growing lymph nodes in one area and new fevers, sweating, or weight loss should generally call for a biopsy to be certain that the disease has not changed its nature. This would alter the treatment approach.

Mantle Cell Lymphoma

Until recently, mantle cell lymphoma was associated with a very poor treatment outcome, and few patients achieved a complete remission. However, the addition of the antibody rituximab and the use of more intensive regimens, such as hyper-CVAD (an intensive combination of cyclophosphamide, doxorubicin, vincristine, prednisone, methotrexate, and cytarabine) has dramatically improved the chances for a complete remission.

The very intensive regimens, however, can frequently not be tolerated by elderly patients and an alternate approach needs to be identified. Patients who enter remission are sometimes offered autologous bone marrow transplant in remission. Allogeneic bone marrow transplantation is an excellent therapy for mantle cell lymphoma, but few patients are young enough to undergo this treatment. Patients who relapse and cannot undergo transplantation are candidates for a number of new drugs that show activity, including bortezomib and Gemzar® (gemcitabine).

MALT Lymphoma

MALT lymphomas that are localized to the stomach are almost always associated with infection by the microorganism Helicobacter pylori. In these patients, eradication of H. pylori using antibiotics often leads to regression of the lymphoma that can be long lasting. When that treatment fails, radiotherapy will usually cause remission.

Patients who have MALT lymphomas in other sites are generally treated with either surgical removal or radiotherapy. Either treatment is associated with a high chance for a complete remission, and many patients do not relapse. In the minority of patients with MALT lymphoma who have wide spread disease, there is no consensus on the best therapy. Some patients are treated with the antibody rituximab, which seems to be very active. Single chemotherapy agents or combinations of chemotherapy drugs are also active.

Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia

The treatment for this disease is the same as recommended for chronic lymphocytic leukemia. A combination of fludarabine-containing regimens and the antibody rituximab have dramatically changed the outcome for this disease, with many patients now achieving complete remission.

Autologous bone marrow transplantation has rarely been effective for patients with this disease, but allogeneic bone marrow transplantation appears to have the possibility of cure. Unfortunately, most patients are older and the use of allogeneic bone marrow transplantation is problematic and risky.

Other Marginal Zone Lymphomas

Nodal marginal zone lymphoma is generally treated in a manner similar to what is outlined above for follicular lymphoma. Splenic marginal zone lymphoma was once treated with a splenectomy (spleen removal) as the initial treatment. This alleviated many of the low blood counts and symptoms, but tumor cells remained in the blood and bone marrow. It appears that the antibody rituximab may be highly effective as an individual agent and is now generally the first treatment.

Burkitt's Lymphoma

Burkitt's lymphoma is highly curable with very intensive chemotherapy regimens. Today, these regimens are usually combined with the antibody rituximab. When treating Burkitt's lymphoma, great attention must be paid to the risk of rapid cancer cell death and the complication known as tumor lysis syndrome. In this process, rapid death of the cancer cells leads to their contents being dumped into the body with a resultant increase in potassium and uric acid among other chemicals.

This can be prevented with use of allopurinol, good hydration, and careful monitoring and some times the use of Elitek® (rasburicase). For most patients with lymphoma, the initiation of allopurinol will precede the start of treatment. However, in Burkitt's lymphoma, attention to these problems is vital.

This content was last reviewed August 15, 2010 by Dr. Reshma L. Mahtani.
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