For years now, the incidence of some types of lymphoma – the cancer that killed former US Sen. Paul Tsongas, Jackie Onassis and Jordan’s King Hussein – has been among the fastest rising of all cancers, and no one is quite sure why.
The death rate has been increasing, too. This year, 64,000 Americans will get lymphoma and 27,000 will die from it.Yet lymphoma, which springs up in the core of the immune system – in B and T cells in the blood, lymph nodes, and lymph vessels – may be the cancer with the brightest hopes for treatment, and even cure.
There’s good reason for this. In solid tumors such as breast cancer, cancer cells are packed together with normal cells; in the liquid cancers – leukemia and lymphoma – some cancerous cells float freely in the blood.
This makes them “easier to capture,” says Dr. David Rosenthal, head of the Harvard University Health Services and immediate past president of the American Cancer Society.
Over the years, the ability to study these cells has yielded a detailed knowledge of markers on the cell surface, against which promising new drugs called monoclonal antibodies are being targeted.
Lymphoma comes in two basic types – Hodgkin’s disease, which has four subtypes, and non-Hodgkin’s, which has 30 subtypes “and more as we get smarter,” says Dr. Morton Coleman, director of the center for lymphoma and myeloma at New York Presbyterian Hospital-Cornell Medical Center.
Chemotherapy and radiation work well for Hodgkin’s, which unlike non-Hodgkin’s, has been declining in incidence. Ten years after diagnosis, 77 percent of Hodgkin’s patients are alive, according to the American Cancer Society.
With the most common form of the aggressive non-Hodgkin’s lymphoma, chemotherapy can cure about 50 percent of patients. Of those who aren’t cured initially, 50 percent can be cured with high dose chemotherapy and bone marrow transplants.
“These data are really quite convincing,” says Dr. Lawrence Shulman, vice-chairman for clinical services for adult oncology at the Dana-Farber Cancer Institute.
Paradoxically, it’s the less aggressive forms of non-Hodgkin’s lymphoma that have been incurable. However, some of these do respond to monoclonal antibodies and to relatively new chemotherapy drugs like Fludara, Leustatin and Nipent.
The work that led to the development of monoclonal antibodies against lymphoma began years ago, when researchers discovered that all B cells carry a marker called CD20 on their surface, notes Dr. Andrew Zelenetz, chief of the lymphoma service at Memorial Sloan-Kettering Cancer Center in New York.
A year and a half ago, Rituxan, made by Genentech, Inc. and IDEC Pharmaceuticals, was approved by the Food and Drug Administration for a cancer called follicular lymphoma.
Rituxan works by finding and destroying all cells, normal and malignant, that carry the CD20 marker. Afterwards, stem cells in the bone marrow create a new crop of B cells. In some patients, the new crop is cancer-free. In others, it contains both healthy and malignant cells. But because Rituxan has few side effects, treatment can be repeated.
Rituxan has now been used in 15,000 patients, many of whom had relapsed after other therapy. So far, half have responded favorably, and six percent of those get a complete remission, meaning that cancer is undetectable. The benefits last about a year.
Just behind Rituxan in the pipeline is Bexxar, made by the Coulter Pharmaceutical Co. and expected to be approved later this year. It’s like Rituxan, but has a radioactive compound (I-131) attached. In trials with patients who have relapsed after other treatment, it produces a favorable response in 70 percent; of those, 30 percent had a complete remission for three years.
In patients who have not had prior treatment, Bexxar seems to produce a whopping 100 percent response rate – with 70 percent in complete remission. But Dr. Bruce Cheson, head of the medicine section in the division of cancer treatment and diagnosis at the National Cancer Institute, is cautious: “Patients relapse – no one is cured.”
Because it makes a patient’s body radioactive for a few days, Bexxar will probably have to be given in a hospital in some states, says Dr. James Levine, a lymphoma specialist at Beth Israel Deaconess.
But other states, including Massachusetts, have recently redrafted their regulations to comply with new requirements of the federal Nuclear Regulatory Commission. The NRC has concluded that at the doses suggested, such drugs drugs do not present a danger to people in close proximity to patients and therefore can be given on an outpatient basis.
Also in the pipeline is another radioactive monoclonal antibody called Y2B8, which contains yttirum and has some of the advantages of both Rituxan and Bexxar. The manufacturer, IDEC, says it will probably seek FDA approval in mid-2000.
Yet another drug, Oncolym, is aimed at a different cellular marker, HLAdr. It’s being developed by Techniclone Corp. and will be marketed by Schering AG of Germany; it could be on the market within a year and a half. Still another, LymphoCide, by Immunomedics Inc., is aimed at a different marker, CD22.
Beyond the new antibodies, scientists are trying to find other ways to treat lymphoma, including so-called antisense RNA compounds to block a gene called Bcl2 that often goes awry in lymphoma, customized vaccines to prevent relapse, and new variations on bone marrow transplants.
The bottom line is that lymphoma “is the area where there has been the most progress” in basic science, much of which is already being translated to new therapies says Dr. Jerome Groopman, chief of experimental medicine at Beth Israel Deaconess Medical Center.
Indeed, there are “more exciting treatments currently being explored for patients with lymphoma than probably for any other tumor,” says Cheson of NCI.
“Given the rapid pace of development,” adds Coleman of New York, “I fully anticipate that the overwhelming majority of patients will be cured within the next decade.”
Concern over rare tumor
A year and a half ago, Zenar Ambrozik thought he’d had a stroke – he became incontinent and began stumbling badly.
Ambrozik, now 81, was rushed from his Wakefield home to Melrose-Wakefield Hospital, where he had a brain scan. “They said, ‘Oh, boy. There’s something in your brain,’ ” he says.
There certainly was. At Massachusetts General Hospital, where he was later seen, doctors found a kind of brain tumor that is rare – it strikes 3,000 Americans a year – but it is increasing so fast some experts fear it could become the most common brain tumor.
It’s called brain lymphoma, or primary central nervous system lymphoma, and it’s a strange cancer indeed. It also appears highly sensitive to a therapy pioneered at MGH.
Between 1973 and 1991, brain lymphoma increased 10-fold nationwide; researchers initially thought it might be linked to better diagnosis or perhaps to AIDS.
But neither of those would completely explain the increase, says Dr. Tracy Batchelor, director of neuro-oncology at MGH.
Brain lymphoma appears to be a subtype of non-Hodgkin’s lymphoma, a systemic cancer that affects B cells of the immune system. But brain lymphoma is confined to the nervous system and the tumors are “biologically very distinct,” says Dr. Michael Grossbard, an MGH lymphoma specialist. They “don’t get out into the rest of the body.”
In other words, people with brain lymphomas don’t usually have systemic lymphoma, even though the latter can spread to the brain. “Even when systemic lymphomas do spread to the brain, they look very different from primary brain lymphomas,” says Dr. John W. Henson, executive director of the MGH brain tumor center.
Nobody knows where brain lymphomas arise, but it’s probably some “cryptic location elsewhere,” says Dr. Fred Hochberg, an MGH neuro-oncologist. What is clear is that brain lymphomas are highly lethal. “This kills people within four months if it’s not treated,” he says.
Historically, doctors used whole-brain radiation, which temporarily eradicated tumors, but caused memory loss and did not have a long-term survival benefit. The new treatment – high dose methotrexate – does seem to work, MGH doctors say. In fact, Zenar Ambrozik is back to playing golf and says his progress has been “fantastic.”
Over the last three years, MGH has treated 30 patients and 80 percent went into remission. Half relapse after two years, but half of those can achieve remission again with re-treatment.
“This is very unusual for brain tumors,” says Batchelor. “This is a uniquely sensitive tumor.” The team is now working with nine other medical centers to broaden their research.
More information
For more information, you may contact:
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Cure for Lymphoma Foundation, 212-213-9595 begin_of_the_skype_highlighting 212-213-9595 end_of_the_skype_highlighting; on the Web it’s www.clf.org.
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Lymphoma Foundation of America, 800-500-9976 begin_of_the_skype_highlighting 800-500-9976 end_of_the_skype_highlighting or 310-204-7040 begin_of_the_skype_highlighting 310-204-7040 end_of_the_skype_highlighting; on the Web, it’s www.lymphoma.org.