AIDS TREATMENT NEWS No. 093; December 15, 1989
Denny Smith

Like KS, lymphoma occurring as a consequence of HIV infection is considered an opportunistic neoplasm, or cancer, rather than an infection caused by organisms. In spite of that distinction, however, the development of some lymphomas has been linked to infections of a herpes-family virus, Epstein-Barr (EBV). This virus can cause infectious nucleosis, and implicated in the development of lymphomas in people who must take immuno-suppressing transplant medications. For similar reasons, an HIV-impaired immune response may allow a latent EBV infection to reactivate, and theoretically provoke lymphoproliferations. EBV is already known to be implicated in hairy leukoplakia, and has been much discussed as a possible cofactor in HIV immune deterioration -- each virus has been observed in vitro to activate the other. However, EBV is not always present in people with HIV, nor uniformly evident in AIDS-associated lymphoma tissue. In data collected at San Francisco General Hospital, EBV was identified in only about a third of lymphoma biopsies, suggesting that EBV could be a passenger virus which coincides with but is not the cause of AIDS lymphoma.

Diagnosing lymphoma can involve several complications. The symptoms of CNS lymphoma in adults might resemble other, more common AIDS-related neurological problems such as toxoplasmic encephalitis. By contrast, CNS lesions in children with AIDS will much more likely prove to be lymphoma than otherwise. The non-invasive tests for diagnostic purposes, CT or MRI scans, are not usually dependable for distinguishing infections from lymphoma in the brain. A conclusive diagnosis can be made by biopsy, but antibiotic therapy may be tried first in adults to rule out infections, and if the symptoms fail to respond then presumptive treatment can begin for lymphoma. For children that approach could represent a dangerous delay in appropriate treatment, given the probability of finding lymphoma behind these symptoms.

Symptoms of lymphoma in the rest of the body may resemble lymphadenopathy but are easily verified with a biopsy. Obtaining a sample of tissue through a fine-needle aspiration is less invasive than a surgical biopsy, although needle aspirations produce a somewhat higher rate of false-negative results.

Standard treatments for lymphoma have involved radiation or chemotherapy, or both. These and a few experimental therapies are briefly discussed below. The occurrence of AIDS-related lymphoma, like any consequence of HIV, warrants the start or continuation of an anti-HIV agent such as AZT to address the underlying problem. A review of patients treated for CNS lymphoma at three Los Angeles medical centers pointed to concurrent opportunistic infections as a factor diminishing the rate of survival following otherwise successful lymphoma treatments. The report suggests that an HIV therapy would affect positively a course of treating lymphoma. Ironically, the underlying problem can be exacerbated by treatments for secondary infections. Radiation and chemotherapy, for example, each suppress bone marrow production of blood cells (myelosuppression) independently of HIV or AZT. We spoke to several AIDS- experienced physicians about refinements in lymphoma therapy which, like new approaches to KS, attempt to minimize this danger.

CNS lymphoma usually develops as small, individual lesions on the brain, and can be treated with a series of localized, low- volume doses of radiation over a period of 5 to 7 weeks. If the lymphoma is disseminated, present at multiple sites within the central nervous system, radiation treatment alone is not advised and is augmented with a chemotherapy agent, such as methotrexate, administered intrathecally (injected into the cerebrospinal fluid) since many drugs given intravenously fail to penetrate the blood-brain barrier. William Wara, M. D., of the Department of Radiation Oncology at the University of California in San Francisco, described his modification of the treatment for AIDS- related CNS lymphoma. By irradiating lesions with larger dose volumes and shortening the duration of the total therapy to 3 weeks, Dr. Wara obtains an optimum tumor response while minimizing the trauma of a longer course of therapy. He found this more intensive regimen improved on previous practice without increasing immunosuppression, because the field of radiation remains very small and specific.

Treatments of peripheral lymphomas, those diagnosed at sites outside the CNS, are relieved of the challenge of crossing the blood-brain barrier; therefore the diseases can be addressed with a wider spectrum of treatments. The first line of options consists of various chemotherapy combinations, both with and without radiation.

A list of chemotherapeutic agents tried against lymphoma, in addition to methotrexate already mentioned, includes bleomycin, cyclophosphamide, daunorubicin, dexamethasone, doxorubicin, etoposide, ifosfomide, prednisone, procarbazine, and vincristine. Apparently no consensus regarding the choice of agents or degree of treatment aggressiveness has been established. Physicians at San Francisco General Hospital noted shortened survival rates among patients who were treated with high-dose cyclophosphamide, and they suggest that lymphoma regimens be designed to control toxicity or to include agents for reducing bone marrow and immune suppression. Another report at the Montreal Conference described a decision by clinicians at the Los Angeles Oncologic Institute and Baylor University Medical Center in Dallas to decrease the aggressiveness of lymphoma chemotherapy. They then obtained excellent results in five patients with cautious use of bleomycin, vincristine, and prednisone combined with acyclovir and low-dose AZT (abstract B. 588).

The investigational agent called granulocyte macrophage- colony stimulating factor (GM-CSF) may prove useful for protecting the bone marrow from damage associated with chemotherapy, and permit the addition of other valuable but potentially suppressive therapies, such as AZT and interferon. Researchers at thentro di Riferimento Oncologico in Aviano, Italy, presented a report at the International Conference on AIDS last June finding GM-CSF effective for reversing myelosuppression due to chemotherapy and AZT in some people with KS or lymphoma (abstract M. C. P. 103). GM-CSF is available in the U. S. only through clinical trials.

Refractory lymphomas, those which resist other treatment attempts, have been affected by mitoxantrone with cytarabine. Researchers at the Johns-Hopkins University describe a man successfully treated for AIDS-associated NHL with a bone marrow transplant from his sister (Montreal abstract W. B. P. 319). Anti-idiotype antibody therapy and chlorodeoxyadenosine (CDA) are both currently pursued in clinical trials in the U. S.

We spoke to Lawrence Kaplan, M. D., an oncologist at San Francisco General Hospital and principle investigator for five trials there involving some of the potential treatments mentioned above. These trials are all still in progress, and we hope to report any conclusive results in the future. Dr. Kaplan was willing to share some early positive impressions:

CDA, a novel drug used with success in treating another diagnosis, has been helpful for some patients with NHL which was unresponsive to previous treatments.

Anti-idiotype antibody therapy, also for relapsed lymphoma, is a strategy which borrows functions ordinarily employed by natural immune defenses. This treatment appears useful in about 25 percent of certain lymphomas.

In a randomized study, GM-CSF is being administered to two of every three participants, all of whom receive chemotherapy for NHL. Dr. Kaplan is optimistic for the potential of GM-CSF to reduce the neutropenia following chemotherapy, and shorten associated hospitalizations. For this trial and two others at San Francisco General Hospital which include chemotherapy, the particular agents used are cyclophosphamide, doxorubicin, vincristine, and prednisone. These trials are open for recruitment, and persons interested in participating in any of them should call 415/821-5531.

REFERENCES

Epstein, L G and others,"Primary Lymphoma of the Central Nervous System in Children With Acquired Immunodeficiency Syndrome," Pediatrics volume 82, number 3, September, 1989.

Formenti, S C and others, "Primary Central Nervous System Lymphoma in AIDS-Results of Radiation Therapy," Cancer, volume 63, number 6, pages 1101-1107, March 15, 1989.

Ho, A D and others, "Mitoxantrone and High-Dose Cytarabine as Salvage Therapy for Refractory Non-Hodgkin's Lymphoma," Cancer, volume 64, number 7, pages 1388-1392, October 1, 1989.

Kaplan, L D and others, "AIDS-Associated Non-Hodgkin's Lymphoma in San Francisco," Journal of the American Medical Association, volume 261, number 5, pages 719-724, February 3, 1989.

Lang, D J and others, "Seroepidemiologic Studies of Cytomegalovirus and Epstein-Barr Virus Infection in Relation to Human Immunodeficiency Virus Type 1 Infection in Selected Recipient Populations," Journal of Acquired Immune Deficiency Syndromes, volume 2, number 6, pages 540-549, 1989.

Rahman, M A and others, "Enhanced Antibody Responses to Epstein-Barr Virus in HIV-Infected Homosexual Men," The Journal of Infectious Diseases, volume 159, number 3, pages 472-479, March 1989.

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