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Being Alive

A Perspective on AIDS Lymphoma




 

Being Alive 1994 Mar 5: 7

(Since the incidence of AIDS lymphomas continues to increase and since we have not presented an overview in these pages since 1990, we are presenting a fuller version of Dr. Levine's talk which was briefly summarized in the February 1994 issue. Dr. Levine, Chief of the Division of Hematology at the USC Medical School, is an international leader in the study and treatment of lymphoma. Her early and continuing work with AIDS-related lymphomas has been instrumental in characterizing this condition, in improving treatment and in urging more attention to its unsolved problems.

Readers are referred to our most comprehensive previous article, an interview with another leading AIDS hematologist/oncologist, Dr. Ron Mitsuyasu of UCLA (October 1990 issue). In particular, his description of the types, diagnosis and stages of lymphoma amplifies Dr. Levine's remarks and remains accurate. His discussion of treatments is also still very useful, but should be updated by combining the information presented below. For a copy of this interview, call or write the Being Alive office.) Background The pattern of occurrence of malignancies in AIDS Kaposi's sarcoma, the lymphomas, and certain other cancers of the reproductive and genito-urinary system in men and women closely resembles that in other forms of profound immune suppression, particularly that deliberately induced by drugs to prevent rejection of transplanted organs. These diseases are 30 to 100 times more likely to happen in the context of immune system diseases than among the population as a whole.

While KS incidence has declined sharply overall, lymphoma incidence continues to increase. This change is found both in a gradual increase in the number of lymphomas reported as the initial major AIDS symptom and more sharply in terms of secondary diagnoses among PWAs. Whereas lymphoma can present anywhere in roughly the last third of HIV disease progression, the risk of developing is greatest in late stage infection. We see proportionately more cases as more people live longer. We don't know precisely how likely it is; estimates from different studies range from 10 to 40% or more over three years after the development of other symptoms.

Why Is the Risk So High? As usual, we don't know exactly. However, several aspects of AIDS are probably important in the origin of the most common lymphomas. Lymphoma literally means a tumor ("oma") originating from cells of the lymph system meaning lymphocytes (one kind of white blood cell) in the blood stream, particular lymph organs like nodes and/or lymph tissue that resides in most other body organs including the skin and mucous membranes.

There are more than 15 different kinds of lymphoma, but more than 90% of AIDS lymphomas are of three kinds that can be grouped as "intermediate to high grade B-cell lymphomas." The grading refers to the rate of growth and aggressiveness of the tumors. AIDS lymphomas tend to be quite aggressive. The "B-cell" part means they originate from the B lymphocytes which make the antibodies in one's body and thus constitute the "humoral" part of the immune system. T-cells or T lymphocytes are the basis of the "cellular" immune system.

The "deficiency" in AIDS is of T-cells, not B-cells. Indeed, one thing that happens in the syndrome is that B-cells are "turned on" to an abnormally activated state and reproduce much more rapidly than in healthy immune systems. And, though our understanding is incomplete, this high level of B-cell activity is a good thing, in that it helps contain HIV for several years. However, this constant rapid reproduction means that more errors are made in copying the genetic material.

One of these "genetic mistakes" becomes the basis for a lymphoma. For instance, genes from one chromosome split off and fuse with genes from another, leading to a cell which has lost its connection to the systems regulating growth. This one cell then reproduces independently and out of control and gives rise to the tumor. Even if the lymphoma spreads throughout the body, all of its cells are identical clones of this original "immortalized" cell which survived a genetic accident.

Epstein Barr virus (EBV), a ubiquitous virus which can replicate extensively in the context of AIDS, also turns on B-cells and is associated with B-cell lymphomas and is also probably a contributing cause, though recent data show that it is not so commonly found in AIDS lymphomas as once believed.

Another likely reason is the abnormal production of cytokines (hormone-like chemicals secreted by immune system cells) in HIV infection and AIDS. HIV stimulates the overproduction of interleukin 6 (IL-6), which is a growth factor for both normal B-cells and for B-cell lymphomas. B-cell lymphomas can also make IL-6 themselves, sort of like a car (or a fire!) which can make its own gasoline. IL-10 is also produced in increased quantities by HIV-infected lymphocytes and in turn stimulates B-cells and related lymphomas.

Characteristics and CNS Lymphomas There is no such thing as a localized lymphoma it spreads wherever there is lymphoid tissue. One can find the "lumps and bumps" of lymphoma everywhere from the earlobe to the mouth to the limbs to the gallbladder to the heart to the bone marrow to the brain. Like most cancers, it exists and spreads long before it becomes obvious on the surface. And, aside from lumps, it may manifest itself in symptoms very similar to those of certain OIs (fevers, night sweats or weight loss, for instance) or in changes in the functioning of the nervous system.

Lymphoma of the central nervous system (CNS) is distinguished into two very different forms a spread from systemic lymphoma vs. primary CNS lymphoma. The metastatic form does not cause substantial masses (tumors) in the brain itself, but is more like lymphoma cells floating in the spinal fluid and can cause meningitis-like symptoms, problems in facial muscles, jaw pain or even no symptoms at all. Because it may be asymptomatic but later get more serious, it is important to do a spinal tap as part of any lymphoma diagnostic workup. So long as one knows it is present in the CNS, and plans treatment accordingly, this kind of lymphoma is treatable with the same success as lymphomas elsewhere in the body.

Unfortunately, the same is not yet the case with primary CNS lymphomas, ones which start and grow primarily in the brain and represent according to one study 25% of the lymphomas that affect the CNS. This form does cause what's called a "space-occupying lesion" or mass which causes dramatic symptoms, though in some cases the symptoms may begin gradually, such as personality changes. Typical presentations include seizures, sudden weakness or paralysis on one side, confusion or severe headaches.

Evolution of Treatment Initially, we started with what was considered the best therapy for very aggressive non-AIDS-related lymphomas, a kind of atomic bomb approach. The idea was that if you threw a variety of high-dose chemotherapies at the lymphoma before it could get any more established, you would have the best chance of knocking it out for good. We found early on in our first protocol that this was the wrong idea. It knocked out the bone marrow and thus what was left of the immune system so thoroughly that 78% of those treated developed severe OIs and died.

Then we tried, after a big struggle for permission from the FDA who thought it was too little to work, a much reduced course of the standard chemotherapy regimens (mBACOD or CHOP, for example, the acronyms representing the drug combinations). We gave (in ACTG protocol 008, results published in JAMA in 1990) half the dose of each component drug and for only four rather than the usual 10 monthly treatments. This worked much better. We found a complete remission rate of 50%, and nearly 90% of these remissions were "durable," i.e., no relapse. Moreover, the incidence of OIs was only 20%, many of them treatable.

This or similar regimens have become the standard for now, which we are working to improve. One improvement came from adding an antiretroviral drug, in our study ddC (since AZT is too toxic to the bone marrow which chemotherapy also hits hard). The results showed complete remission of 56% with only 10% incidence of treatment-associated OIs. Furthermore, the improvement came by improving the odds for those who started with a "poorer risk profile," meaning those with very low CD4 counts, a previous AIDS-defining condition, severely impaired physical functioning and/or lymphoma involvement of the bone marrow. Those with these characteristics are less likely to respond to lymphoma treatment.

We are awaiting the results from another trial which explored whether using blood cell growth factors (EPO, G-CSF, GM-CSF) would allow the safe use of higher doses of chemo and whether this in turn will yield more remissions.

New Treatments and Research Directions This evolution illustrates what I believe will be the course of finding a cure for lymphoma: it will not come with a single dramatic development or "magic bullet" that works in all cases. Rather, as with most cancers, progress comes in small but, one hopes, continuous steps.

I see at least two main needs: accelerated study of primary CNS lymphoma so that we can find treatments that work for this form too, and therapies that reach the 40-50% of systemic lymphoma patients who currently do not achieve remission or who relapse. It is very frustrating to me that we have no effective treatment and thus cannot achieve remission in the primary CNS lymphomas. We can and do use radiation therapy, which does not prolong life much if at all but can make a big difference in quality of that life. Patients wake up from comas or regain use of their muscles. Progress has been slowed by the reluctance of physicians to study and treat primary CNS aggressively, believing such effort to be futile. However, a similar pessimism once stymied treatment of systemic lymphomas where we have made substantial progress, so I continually challenge my medical colleagues to rise above it here as well.

Promising new therapies for those who don't respond to other chemo are in development, two being tested at USC. One is B-4 blocked ricin, which is a genetically engineered substance based on a potent poison found naturally in some beans. Natural ricin contains an attachment site on its molecular surface which is capable of hooking up to any cell in the body after which the poison kills the cell. Here, the developers genetically removed this "universal adaptor" and replaced it with a genetically engineered adaptor (the B-4 monoclonal antibody) that will only permit attachment to B-cell lymphoma cells.

Preliminary results testing this compound in those for whom regular chemo failed, or resulted in relapse, have been very encouraging. We have now started to test it in combination with a still-more-abbreviated form of chemo as frontline treatment after initial lymphoma diagnosis. B-4 blocked ricin treatment requires continuous IV infusion through a central catheter. However, after an initial two days in hospital it can be administered through a small beeper-sized pump worn on one's belt.

The other promising new treatment uses MGBG, which was a lymphoma treatment discarded years ago as ineffective. However, a Texas scientist promoted a new attempt, believing that it had not been used correctly before. Preliminary results show a 50% response to treatment among people who have previously totally failed to respond to standard chemotherapy. It has the advantage of not causing bone marrow suppression or nausea and vomiting, and of crossing the blood/brain barrier (the "invisible shield" designed to protect the brain but which also keeps out many drugs that might be helpful for conditions inside the brain).

For information regarding these and other AIDS lymphoma protocols at USC, call J.J. Anderson at 213.226.7622.



 




Information in this article was accurate in March 5, 1994. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.