Lymphoma Therapy Improves with New Targeted Agents
by
Gary I. Cohen, MD,
Director of the Cancer Center at GBMC

Lymphoma is a malignancy of lymphoid cells. Approximately 24,000 people will be diagnosed nationally with Non-Hodgkins Lymphoma in 2003. It has long been considered one of the “curable” types of cancer, primarily because of the sensitivity of lymphoma cells to chemotherapy agents. However, despite excellent remissions with chemotherapy, some lymphomas continually recur and eventually lead to death.

The classification of lymphoma has been revised numerous times over the past two decades. The lymphocyte is the cell of origin for lymphomas, but that cell is ubiquitous in the human body, present in many different organs, and has many varied cell subtypes which interact to effect the complex system of immunity which we depend upon. More than 20 different histologic subtypes of lymphoma have therefore been described. A “Working Formulation” attempted to classify lymphomas primarily on the basis of prognosis. Subsequent revisions included the Revised European-American Lymphoma  (REAL) classification, and most recently, the World Health Organization (WHO) classification. In these advanced classification schemes, new information about cellular functions, pathologic/ immunologic characteristics of cells and prognosis were incorporated to more effectively guide clinicians to predict outcome and devise appropriate treatment strategies.

A renewed effort to develop treatments specifically targeted to malignant cells has resulted in several interesting approaches to management for lymphoma patients. Ideally, “targeted” therapies should be highly specific in destroying the abnormal cells, and have little or no cross-reaction with surrounding normal cells, resulting in minimal toxicity. Many lymphomas derive from the “B-cell” which has a characteristic CD20 antigen on its surface. Thus, an antibody that specifically binds to CD20 would initiate a cascade of immunologic events leading to death of the lymphoma cell. Such antibodies (rituximab) are now readily available and highly effective for treatment of lymphoma. The best results for remission and cure appear to be achieved when rituximab is combined with appropriate chemotherapy agents. However, improved results are also now described in low-grade lymphomas when rituximab is used alone. The usual course of treatment is 4-8 weekly injections, and treatment is very well tolerated in most patients, although infusion reactions, such as fever and chills, are occasionally observed. More recent data suggests that the duration of remission may be prolonged with “Maintenance” therapy, giving additional injections of rituximab every 3-6 months after the initial induction program.

Despite the promise of monoclonal antibodies to CD20, some patients fail to respond to treatment or relapse after an initial response, and further therapy with rituximab is no longer effective. Antibodies to other surface antigens on lymphoma cells (CD19, CD22) are currently in development and look promising. Researchers have also explored the reasons for failure of antibody therapy in lymphoma patients and several explanations have been proposed, including inability to mount an effective immune response to destroy the CD20 positive cells, and loss of the CD20 antigen as the malignancy progresses.

These mechanisms of resistance can be overcome in part by combining a radioactive chemical with a monoclonal antibody (producing a “radio” pharmaceutical). The radioactivity selectively destroys the lymphoma cell to which the antibody is attached, without requiring an intact effective immune mediated cytotoxic response mechanism from the patient. Furthermore, the radioactive chemical may actually kill not only the target cell, but several nearby cells as well (the “bystander effect”), thereby resulting in death of other cells which may have already lost, or decreased, their surface CD20 antigen. Two different radiopharmaceuticals have recently been approved by the FDA for use in lymphoma patients (Zevulin and Bexxar). GBMC oncologists were fortunate to have offered one of these agents to patients with lymphoma even prior to FDA approval as part of the clinical trials program. The early experience with radiopharmaceuticals at GBMC has led to an organized multidisciplinary effort involving medical oncologists, radiation oncologists, physicists, pharmacists and nuclear medicine physicists to optimize patient care.

Although various surface antigens have been identified which are present primarily on lymphoma cells, these antigens are not entirely unique but also exist on normal early progenitor lymphoid cells. The surface of the malignant cell in low-grade lymphomas contains “light chain” protein antigens as well. In contrast to the CD antigens, rearrangements in these light chains are absolutely unique for an individual with lymphoma. Therefore, patients can be “vaccinated” against their lymphoma by making a specific antibody against these rearrangements
(anti-idiotypes) that is highly specific for their lymphoma, and has no cross reactivity with any other normal cells. GBMC is currently a participant in an experimental program investigating the value of adding these highly specific antibodies to the standard rituximab for patients with low-grade lymphomas.

Notwithstanding advances in targeted therapies, the mainstay of effective treatment for many lymphoma subtypes is still chemotherapy, with or without monoclonal antibodies. Most lymphomas are highly sensitive to chemotherapy, with response rates approaching 90% in some cases, and with “cure” in 50% or more. Advances in chemotherapy have paralleled the newer targeted treatments, and many new regimens are now available for patients who fail the initial interventions or for those who relapse. Chemotherapy does have some added toxicities compared to the specific targeted therapies, but new growth factors, antiemetics, and other supportive measures have resulted in far more tolerable regimens with equal or better efficacy compared to the older treatment programs. For example, a new anthracene dione compound is currently in testing at GBMC for patients with relapsed or refractory low-grade lymphomas. The experimental drug has been inserted into the standard “FND-R” chemotherapy regimen, with the hope of improved response rates and decreased risk of cardiac toxicity, which was a common concern with additional cycles of the standard regimen.

These and other advances bring continued hope that we can expect a cure, or at least prolonged disease control, for most newly diagnosed lymphoma patients, and every day brings new improvements.