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Curable But Not Conquered: Hodgkin’s Lymphoma Todayby Sunni Hosemann
The impact of cancer is often brought home to us by numbers: how many people it strikes, how many will die from it, and how short or long will be the time between. Hodgkin’s lymphoma is not the most prevalent or the most deadly type of cancer. The coming year will see perhaps 7,800 new cases in the United States, and of those, more than 80% will be cured. To appreciate the real impact of Hodgkin’s lymphoma, one must view it in terms of productive life years either lost altogether or marked by lingering morbidity, explained Anas Younes, M.D., professor of medicine and director of Clinical and Translational Research at The University of Texas M. D. Anderson Cancer Center’s Department of Lymphoma. The main target of Hodgkin’s lymphoma is the young: for a 20-something patient who dies of the disease, perhaps a half-century of productive years are lost; those cured remain at increased risk for related illnesses or long-term complications that will potentially shorten their lives. Although in the field of oncology, an 80% cure rate is an unqualified success, Dr. Younes thinks it would be short-sighted to assume that because there is a good standard treatment, there is no need to continue searching for something better. Finding something better is the focus of Dr. Younes and his colleague Michelle Fanale, M.D., an assistant professor in the Department of Lymphoma, who together oversee clinical trials for Hodgkin’s lymphoma at M. D. Anderson. They want “cure” to mean more than freedom from Hodgkin’s. They want it to mean a long, healthy life. Where we are today Hodgkin’s lymphoma has been considered curable in most patients for over three decades, with the use of various combinations of chemotherapy and radiation. The current standard treatment for early-stage disease is combination chemotherapy ABVD (Adriamycin, bleomycin, vincristine, and dacarbazine) with or without radiation therapy. More potent (and therefore more grueling) treatments are used in advanced, refractory, or recurrent disease, including more powerful drugs and drug combinations and high-dose regimens with bone marrow or stem cell transplants. Despite the high cure rate, many of these patients—many of whom are in the prime of their lives—will experience long-term effects related to these treatments: they may develop leukemias, non-Hodgkin’s lymphomas, sarcomas, melanomas, cancers of the breast, thyroid, and lung, or cardiac and pulmonary diseases. The high cure rate of Hodgkin’s lymphoma and the relatively young age of most patients makes complications more likely to arise in their lifetimes. Paralleling general trends in oncology, the quest for better treatments for this disease is focused on two goals: to improve efficacy and to reduce side effects and long-term morbidities. In medical oncology today, those goals are pinned on new molecular agents that can more specifically target tumor cells without harming healthy ones. Novel therapies
According to Dr. Younes, there are two fundamental targets for new agents in clinical trials for Hodgkin’s lymphoma: the well-known Reed-Sternberg (RS) tumor cells that are the hallmark of this disease and the benign reactive cells that surround them (B and T cells, monocytes, and eosinophils). “These cells have been shown to be contributors, rather than the benign bystanders they were once thought to be,” said Dr. Fanale. “They support the survival and growth of the tumor cells by providing key cell signaling processes.” In fact, researchers have found that tumor cells are difficult to culture in their absence. Dr. Younes noted the irony of host immune cells providing survival factors to malignant cells, a sort of “immune betrayal.” But now that their role has been clarified, he said, “The use of novel agents to eliminate these reactive cells from the microenvironment may deprive the tumor cells of critical survival factors, causing their death.” Most of the novel agents are either monoclonal antibodies or small molecules. Monoclonal antibodies are engineered to bind to a specific protein on a cell surface, causing an immune response to those cells. For specificity, the key is to find a protein that is unique to—or expressed in abundance by—the target cells. Rituximab is an example of a drug that targets the CD20 protein that has been used successfully in non-Hodgkin’s lymphomas and, more recently, by Dr. Younes for Hodgkin’s lymphoma. This was considered a novel use: because CD20 is not frequently expressed by the RS tumor cells in Hodgkin’s lymphoma, it hadn’t been formally investigated for that disease. But the B cells in the microenvironment do express CD20, and Dr. Younes got encouraging results from an ongoing clinical trial combining anti-CD20 antibody (rituximab) with ABVD chemotherapy. Anti-CD30 agents, on the other hand, are targeted to the RS cells themselves, where CD30 is abundantly expressed. According to Dr. Fanale, when given as a single agent in a recent phase I-II clinical trial, anti-CD30 produced remissions in some patients. “Now we’re building on that,” she said. “In a new trial, for example, we will use an anti-CD30 antibody in combination with gemcitabine chemotherapy in combination with a dexamethasone, and we will compare these results with gemcitabine chemotherapy alone.” Small molecules are agents that act by disrupting signaling pathways critical to the life of the cell, often by interfering with receptors or regulatory enzymes such as histone deacetylase (HDAC) used by the cell to maintain its biologic life functions. One of the current phase II studies uses an HDAC inhibitor for patients with relapsed Hodgkin’s lymphoma. 17-AAG (17-allylamino-17- demethoxy-geldanamycin) is another small molecule that affects cell proliferation and cell death functions. Furthermore, other agents such as AMG-531, a thrombopoietin-like agent, are being evaluated to potentially decrease the incidence of thrombocytopoiesis during chemotherapy. Current trials: the patient experience The advantages of new agents are that they have fewer side effects, and some of them can be taken orally. According to Amanda Wedgwood, an advanced practice nurse who coordinates the Hodgkin’s lymphoma trials, the oral formulation and ease of protocols is a source of relief and even delight for patients accustomed to the more grueling standard treatments.
In one current study, patients with relapsed disease take an oral HDAC inhibitor three times a week and come to M. D. Anderson for checkups once a month. “The fact that they can do this at home and still see their own physicians is important to our patients, especially since most of them don’t live in Houston,” said Ms. Wedgwood, who nevertheless keeps in touch with her patients and encourages them and their physicians to contact her with any questions or concerns. “Staying in contact is an important factor,” she said. “It just makes people feel secure. But the best part of this trial is how easy and gentle these treatments are compared with what many of them have been through before.” The side effects are minimal—fatigue is the major one. Drs. Younes and Fanale, along with Ms. Wedgwood, are buoyed by the success they have seen so far and optimistic that it may lead to new standard treatments. For that to happen, though, they need more patients in trials. “Things are moving in Hodgkin’s lymphoma research—moving fast,” said Dr. Younes. “But not fast enough. Enrollment numbers in our trials are lower than we’d like. We want to change that by getting the word out that we can achieve not just better short-term survival and remission rates, but also hopefully have a long-term impact in the form of longer remission and lower toxicity rates.” Clinical trials are available for patients of all ages with any stage of Hodgkin’s lymphoma, including those newly diagnosed who have had no previous treatment, those in first relapse, and those who have had extensive treatment. For more information, visit www.mdanderson.org/departments/lymphmyeloma.For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789. Other articles in OncoLog, December 2006 issue:
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